ST. JMC JOURNAL OF MEDICINE ISSN 0970-4221 VOL.III NO. 3 SEPTEMBER 1990
Item
- Title
- ST. JMC JOURNAL OF MEDICINE ISSN 0970-4221 VOL.III NO. 3 SEPTEMBER 1990
- extracted text
-
COMMUNITY HEALTH CELL
328. V Main, I Block
Koramangala
Bangalore-660034^/^
India
- -
ISSN 0970-4221
ST. JOHN’S MEDICAL COLLEGE
JOURNAL OF MEDICINE
EMJ
VOL III No 3
September 1990
EDITORIAL
60
ORIGINAL ARTICLES
Cutaneous Manifestations of Diabetes Mellitus
62
How Reliable are Superficial Tonsillar Swabs?
64
MEDICINE SYMPOSIUM - DIABETES MELLITUS
67
The Regulation of Insulin Biosynthesis and Secretion
68
Diabetes in South India
72
Glycosylated Hemoglobin in South Indian Non-lnsulin Dependent Diabetics Role in Predicting Diabetic Control
76
Diet in Diabetes
79
Insulin Therapy - Current Concepts
83
Hemorrheology and Genesis of Diabetic Microangiopathy
87
Diabetic Nephropathy - The Current Thinking
91
INFORMATION FOR CONTRIBUTORS
EDITOR-IN-CHIEF
Ashley. J. D'Cruz
Submitting the Manuscript
EDITORIAL BOARD
The St John’s Medical College Journal of Medicine accepts scientific contributions from all fields of
modem medicine and from all institutions and health care professionals. The journal is a quarterly
publication which will be published in March, June, September and December. It is owned by the
C.B.C.I. Society for Medical Education and published by the Principal. St John’s Medical College. The
journal is a part of it’s commitment to continuing medical education. Articles and all editorial
communications should be addressed to the Editor, Alumni Office, St John’s Medical College,
Bangalore-560 034.
Rajini Macaden
Ravi C. Nayar
Mario Vaz
Original articles, short case reports and review articles are accepted for publication. Review articles .
and editorials are usually on invitation by the Editorial Board. Letters to the Editor will be considered
for publication only if received at least six weeks prior to the next publication.
A.B. Kilpadi
PREPARING THE MANUSCRIPTS
A.S. Arvind
Anil Abraham
All manuscripts should be submitted in 3 copies (including the glossy prints). They should be neatly
typewritten on bond paper, one side of the paper only, with double spacing and margins of at least
2.5 cms. Please be sure to include an accurate address for editorial communications and for reprint
requests.
A brief abstract of the material of the paper should precede the body of the paper, to run no more than
500 words. INDEX WORDS for the purpose of indexing and computer programming, should appear
on the same page.
The format for articles suggested is as follows: INTRODUCTION, MATERIALS AND METHODS,
RESULTS, DISCUSSION, REFERENCES.
Measurements should be in metric system.
OVERSEAS
R.R. Baliga
A.V. Kurpad
ILLUSTRATIONS AND TABLES
Figures and tables should be cited in order in the text; their position should be marked in the margin
of the manuscripts. Arabic numbering should be used for both figures and tables. All line drawings
should be submitted in duplicate as clear, glossy, black and white, 5“ x 7" photographs. Photomicro
graphs should also be submitted in duplicate, with allowance made for the effects of reduction if
necessary. Legends for illustrations should be typewritten, double-spaced, oh a separate sheet, and
included at the end of the manuscripts. A legend must accompany each illustration. Each table should
be typed on a separate sheet and appropriately numbered. Legend should be typed on the same sheet
as the tables. The contributors must bear all the costs connected with printing' colour illustrations.
REFERENCES
PUBLISHER
Prof. A.F.A. Mascarenhas
Principal
References should be compiled at the end of the articles according to the order of citation in the text,
not alphabetically. They should be typewritten, double-spaced under the heading REFERENCES.
Abbreviation for titles of medical periodicals should conform to those used in the latest edition of Index
Medicus. Give inclusive page numbers.
EXAMPLES OF REFERENCES
Journal Articles upto six authors, list all names:
Kurpad AV, Shetty PS: Dietary Fibre and the colon. St.John’s J Med, 1988;1:5-12.
Journal Articles more than six authors, list three authors followed by et al:
Complete book
Gallagher JR: Medical Care of the Adolescent (ed 2). New York, Appleton, 1966; pp 208-215
Subscription
Single Copy
Rs. 30/Annual
; India Rs. 100/Abroad U.S. $ 20/Payable in cash/bank drafts/cheques to the St John's Medical College Journal of Medicine, I Floor,
Robert Koch bhavan, St John's Medical College, Bangalore 560 034.
PUBLICATION COMMITTEE
The advertisement charges:
C. Ramachandra
Cover (back age): Rs. 3000/- Inside Cover (back page): Rs. 2000/-
S.C. Rajendra
All contributions towards the Journal come under 80 (G) exemption.
J. Alapatt
Founded by the Alumni Association of St. John's Medical College In 1988.
St. John’s Medical College Journal of Medicine
EDITORIAL
INTRA UTERINE FETAL CARE-THE LINGERING DILEMMA IN DIABETES
Most diabetic mothers today can hope to achieve as successful an outcome in pregnancy as their non-diabetic sisters. This
optimism is born out of the remarkable strides that have been made in the management of pregnancy complicated by diabetes
mellitus. In the pre-insulin era, pregnancy in a diabetic woman was rare and perinatal mortality, fearsome. As pointed
out by White in 1978, perinatal mortality in diabetes has steadily declined from 600/1000 live births in 1922, to a nadir
of 21/1000 in 1984, a figure, which is no different from non-diabetic pregnancies. (Golde 1985).
Contribution to this remarkable reduction in mortality comes from stratification of care and intervention engendered by the
classification of diabetes by White (1949), avoidance of preterm induction of labour and the resultant, much dreaded
iatrogenic respiratory distress syndrome, intensified and consistently tight metabolic and glucose control, technological
advances in antenatal and intrapartum fetal surveillance and improvement in perinatal intensive care. The objective of this
editorial is to dwell on the advances and obstacles observed in the methods of antepartum testing in diabetes. The evolution
ofthese predictive tests for fetal well-being as well as maturity have a firm foundation in the better understanding of placental
functions, endocrinological dynamics peculiar to pregnancy and the fetal heart rate variations in a variety of situations.
The tests currently employed for fetal surveillance can be broadly divided into two groups; biochemical and biophysical.
Initially, the assay of human placental lactogen (HPL) which is secreted by the placental syncytiotrophoblast appeared
to promise much potential. Since the amount of HPL depends directly upon the placental mass and perfusion, this strict
relationship makes it worthless in the management of pregnancy complicated by diabetes, in which the placenta is usually
large. Hobbins concluded in 1978, that HPL is an inefficient predictor of fetal distress and an inconsistent indicator of fetal death.
Maternal estriol (E3) levels reflectthecombined function of the placenta and fetus and also the clearance of E3 conjugates.
Several workers (Greene 1965, Duenhoelter 1976) have relied upon the serum E3 values and others (Roversi etai 1979)
upon the urinary E3 assays to assess fetal integrity in diabetes. Apart from being expensive and impractical, daily E3 assays
add little to the detection of fetal jeopardy, according to Ray et al (1986).
The observation that the heart rate in a nonhypoxic fetus in metabolic homeostasis tends to accelerate with fetal movement
(Hammacher 1966), yielded dividends in the form of Non Stress Test (NST) devised by Rochard et al ten years later. A
reactive NST predicts fetal well-being for about a week, but a non-reactive NST carries a high false positive rate (Miller
1983).Contraction Stress Tests (CST) are also of limited value. While a negative CST can predict fetal survival upto one
week.it has a false positive rate of almost 60%. The combination of daily E3 assay and biweekly NST appears to be an
appropriate protocol since the specific value of any single test is hard to discern. (Gabbe 1984, Golde 1984).
The biophysical profile incorporates a scoring system (Manning & Platt 1980) based on electronic fetal monitoring and various
ultrasonographic parameters. Apart from being time consuming and tedious, it has other disadvantages: failure to obtain
proper and consistent biological signals, the effect of sleep-wake cycles, the impact of depressant drugs on fetal heart
response and the possibility of spontaneous decelerations caused by maternal supine hypotension. Ultrasonography
however, has contributed immensely to the management of diabetic pregnancy through accurate dating, detection of
malformations, measurement of liquor volume, assessment of placental size as well as maturity and evaluation of fetal weight,
growth rate and well-being.
Macrosomia, a cause of fetal morbidity occurs in 25-40% of diabetic pregnancies. Diagnosis based on ultrasonographic
estimation of fetal weight, and size has not been accurate. Correlating various parameters such as chest diameter
with biparietal diameter (Elliot 1982) and abdominal circumference with femoral length and biparietal diameter (Brassero
et al 1985) have yielded encouraging but not entirely accurate results, especially in cases of IUGR associated with diabetes.
Antenatal fetal surveillance in diabetic mothers is still being dogged by two significant drawbacks: the absence of clear
criteria to predict fetal integrity and the difficulties in interpretation of different tests. The traditional dilemma in balancing
the risk of preterm induction of labour against the risk of sudden fetal demise still persists.
When preterm termination of pregnancy is necessitated by the results of surveillance tests, precise determination of fetal
maturity in diabetes poses additional problems. Radiological identification of closure of bony epiphyses yields erroneous
and contradictory dates in diabetes. Further, X-rays cannot indicate macrosomia or pulmonary development.
----- SEPTEMBER
1990
60 —
St. John’s Medical College Journal of Medicine
Amniotic fluid studies were initially claimed to be more reliable in assessing fetal lung maturity. Differential cytology for fetal
fat cells has more than 25% false negative rate in diabetes (Morrison 1977). In normal pregnancy, amniotic fluid creatinine
correlates well with functional renal development. Advanced diabetes may result in failure of normal progression of
creatinine levels and polyhydramnios can yield false negative results. Conversely, higher values obtained between 36
and 37 weeks of gestation in diabetes may give false positive results (Lofstrand et ai 1976).
The lecithin-sphingomyelin (L/S) ratio in the amniotic fluid has not been of much value in diabetes mellitus. Paired L/S ratio
and foam stability tests showed delayed lung maturity in diabetic pregnancies (Sharf et al 1976). Moreover, hypertension
which frequently accompanies diabetes can accelerate L/S ratio and polyhydramnios can dilute the values (Gabbe et al
1977). Drury et al (1977) analysed the results in more than 600 diabetic pregnancies and concluded that the value of
L/S ratio in diabetes is still controversial. Morrison (1977) suggested that the perplexing problem of false positive L/S
ratio can be assessed through phosphatidyl glycerol (PG), since absent PG in amniotic fluid is a biochemical marker
of respiratory distress syndrome. Phosphatidyl choline (James 1983) and phosphatidyl inositol (Hallman and Teramo
1979) are two other substances which have been tried out. According to some studies, desaturated phosphatidylcholine
(DSPG) and gas liquid chromatography (Torday et al 1979) may offer additional accuracy in pregnancy dating. Similarly,
estimation of heat stable alkaline phosphatase (HSAP) maybe useful in diabetes complicated by hypertension, since an
elevated HSAP indicates failing placental function.
As the perinatal mortality in diabetic pregnancy is directly related to the mean maternal blood glucose level, preponderance
of evidence suggests that the key to better perinatal survival is a tight metabolic control. Even the increase of fetal
malformations which constitutes about 50% of mortality could be reduced by preconception idealisation of diabetic control
(Steel 1982). Implementation of this policy, coupled with an intense antenatal fetal supervision can further bring down the
perinatal mortality figures in diabetes mellitus.
Dr. R. Narayanan,
Professor & Head, Department of
Obstetrics & Gynaecology,
St. John's Medical College Hospital,
Bangalore - 560 034
SELECTED READING:
1. Drury Ml, Greene AT and Stronge JM : Pregnancy complicated by clinical diabetes mellitus - A study of 600 pregnancies. Obstet and Gynecol.
1977;49:5,519-522.
2.
Gabbe SG: Diabetes in pregnancy, din. ob. Gyn Sept 1985;pp516-527.
3.
Jorge CS, Artal R, Paul RH et al.'Antepartum fetal surveillance in diabetic pregnant patients: Am.J.Obstet Gynecol: 1981 ;141,641 -645.
4.
Landon MB and Gabbe SG. Antepartum fetal surveillance in gestational diabetes mellitus: Diabetes 1985;34(2),50-54.
61
VOL III No. 3-----
ORIGINAL ARTICLES
St. John’s Medical College Journal of Medicine
CUTANEOUS MANIFESTATIONS OF DIABETES MELLITUS
ANIL ABRAHAM, SURRINDER KAUR
KEY WORDS
142 of 200 (71 %) diagnosed diabetics screened showed skin
changes either specific or non-specific. Infections were the
frequent of which candidial infection was the most
common.
Diabetic dermopathy, skin tags, acanthosis
nigricans and generalized pruritus were the other frequent
changes noted.
Cutaneous changes were documented on 142 of the 200
diabetics included in the study (71%). There was some
degree of overlap and more than one skin change were
seen in single patients. Infections (bacterial, fungal and
viral) were the most common cutaneous finding and were
seen in 86 patients (43%), with Candida being the most
frequent offender. The other manifestations noted included
diabetic dermopathy, generalized pruritus, granuloma
annulare, transepidermal elimination disorders, skin tags,
acanthosis nigricans, sclerederma adultorum, diabetic foot
and drug rashes. The findings and relative frequency in the
patients studied are summarized in Table 1.
INTRODUCTION
Table 1: Cutaneous Manifestations in Diabetes
. Cutaneous changes either specific or non specific have been
well established as part of the clinical spectrum of manifest
diabetes mellitusl. These changes may be early pointers to
diagnosis, markers of systemic involvement or therapeutic
dilemmas, or even suggest deterioration of disease control.
a)
Infectious
Candida
Bacterial
Erythrasma
Tinea
86 (43%)
49
36
2
2
PATIENTS AND METHODS
b)
c)
d)
e)
f)
g)
h)
i)
j)
k)
Diabetic dermopathy
Acanthosis nigricans
Sclerederma adultorum
Generalized pruritus
Granuloma annulare
Skin tags
Kyrle’s disease
Diabetic foot
Maculopapular drug rash
Necrobiosis lipoidica
diabeticorum
24 (12%)
12
4
4
2
2
2
2
1
Total
142
Cutaneous, Diabetes mellitus
SUMMARY
200 diagnosed diabetics (WHO criteria)2 either being
followed up at a Diabetes Clinic or referred to the Skin OutPatient were included in the study over a 3 year period,
irrespective of age, sex, classification or treatment status.
Patients underwent a thorough screening for cutaneous
changes as per a standard clinical proforma. Control of
diabetes and treatment modalities were also noted, as were
systemic complications of diabetes. Relevant investigations
based on clinical diagnosis were earned out where necessary
for confirmation of diagnosis.
RESULTS
The patients examined ranged in age from 32-60 years
(average 52 years) with a male preponderance (2:1). The
patients included those diagnosed as NIDDM (65%) IDDM
(28%) and others (iatrogenic, gestational).
DR. ANIL ABRAHAM MD,DNB(DERM)
DEPARTMENT OF DERMATOLOGY,
ST.JOHN’S MEDICAL COLLEGE HOSPITAL
BANGALORE - 560 034.
PROF. SURRINDER KAUR MD, FAMS
DEPARTMENT OF DERMATOLOGY
PGI, CHANDIGARH
*62
(Several patients had more than one skin lesion)
DISCUSSION
The cutaneous signs of diabetes are the manifestations
of multiple factors3. Abnormal carbohydrate metabolism,
other altered
metabolic
pathways,
atherosclerosis,
microangiopathy, neurone degeneration and impaired host
defense may all pay a role resulting in diverse clinical
manifestations as evidenced in the present study.
£>iabetics are frequently obese, which leads to the
development of intertrigo and moniliasis in areas of skin
apposition. Additionally, poor diabetic control with elevated
glucose levels favours the growth Candida albicans, resulting
in more frequent and severe monilial infections4,5.
Candidiasis at various sites therefore, is a sign to alert the
clinician to the possibility of diabetes.
VOL III No. 3-----
St. John’s Medical College Journal of Medicine
Diabetic dermopathy or shin spots appeared to be less
common (12%) in the present study, than in comparable
reviews conducted in a western population where 60% of
male diabetics and 30% of female diabetics demonstrated
shin spots. Trauma and chronic folliculitis resulting in postinflammatory scars were excluded in this study which could
partially explain a bias.
CONCLUSION
Skin changes in the present study have spanned the
spectrum from specific to non specific demonstrating
unequivocally that the skin can be the mirror of internal
disease. Cutaneous manifestations can alert the physician
to an early diagnosis or serve as a marker of special disease
groups in the setting of diabetes mellitus.
Pseudo acanthosis nigricans confirmed on histopathology
was seen in 6% of the patient population studied, all of whom
were obese, and were well controlled with insulin. None of the
patients had been suspected to have insulin resistance,
clinically, or on investigation.
REFERENCES
1. Huntley AC: The cutaneous manifestations of diabetes mellitus. J Am
Acad Dermatol, 1982;7:427-55
Sclerederma adultorum in 4 adult diabetics showed
characteristic non-spotting induration that took unusually long
to resolve. This conforms to earlier studies carried out at
a Veterans Administration Hospital diabetes clinic, where
sclerederma was noted in 2.5% of non-insulin dependent
diabetics6. Kyrle’s disease was seen in two patients both
of whom had diabetic nephropathy. The low incidence of
necrobiosis lipodica diabeticorum (0.5%) correlated with the
findings of previous workers?, who, however, stress the need
for careful follow up of this uncommon lesion for latent
diabetes.
2. Little RR, England JR, Wiedmeyer et al: (quoted in) Relationship of
Glycosylated Haemoglobin to Oral Glucose Tolerance. Diabetes, 1988,
37:60-64.
3. Sibbald RG and Schachter RH: The skin and Diabetes Mellitus. Int J
Dermatology, 1984;23:567-582.
4. Sonek CE, Somersalo O. The yeast flora of the anogenital region in
diabetic girls. Arch Dermatol, 1963;88:846-52.
5. Alteras I, Saryt E. Prevalence of pathogenic fungi in the toe-webs and toe
nails of diabetic patients. Myopathologica, 1979;67:157-9.
6. Cole GW, Headley J, Skowsky R Scleredema cutaneous manifestation
of diabetes mellitus. Diabetes Care. 1983;6:189-92
7. Feingoid KR, Elias PM. Endocrine - skin interactions. J.Amer Acad
Dermatol. 1987;921-946.
FORTHCOMING SYMPOSIUM
DECEMBER
-
1990
DERMATOLOGY SYMPOSIUM
ALLERGY
----- SEPTEMBER
1990
63 —
St. John’s Medical College Journal of Medicine
HOW RELIABLE ARE SUPERFICIAL TONSILLAR SWABS ?
R.C. NAYAR, J.XAVIER
ABSTRACT
MATERIALS
33 children who underwent tonsillectomy were studied.
Superficial tonsillar swabs, were compared to tonsillar core
cultures obtained after tonsillectomy.
INTRODUCTION
33 children (18 female/15 male) age ranging from 3 to 9
years with a median age of 6.6 years, who underwent
tonsilllectomy in the ENT service of the St.John’s Medical
College, formed the subject group of this study. All were
diagnosed as having chronic tonsillitis, and had repeated
episodes of acute
tonsillar infection in the past. As
tonsillectomy was performed only during a quiescent period,
none had clinical evidence of acute tonsillar infection at
admission. Prophylactic antibiotics were not used.
The bacteriology of Oropharyngeal infections (Tonsillitis)
has been investigated extensively. Though voluminous
data has accrued, the results have been described as
“somewhat puzzling’’1.
A superficial throat swab was obtained preoperatively by
gently rubbing cotton wool swab over the tonsillar surface,
taking care to avoid oral, dental contamination, (only one
tonsillar surface was studied)
The precise significance of isolating a bacteria from a
conventional throat swab in a patient of tonsillitis, is
controversial. Many studies have shown that the
organisms cultured from throat swabs in children during an
attack of acute tonsillitis, does not differ from those of normal
children2-3-4.
After tonsillectomy (No topical bactericidal agents used), the
same tonsil was sectioned with a sterile knife, and core
samples were obtained on a cotton wool swab, as advised by
Brook et al (1981)8.
4 superficial swabs, and 15 core swabs grew pathogens.
This highlights the inadequacy of the superficial tonsillar
swab in identifying pathogens of the oropharynx.
The accuracy of the office procedure of “Throat swab” in
predicting the complete microbial flora of the tonsil has been
shown to be only about 54%5. This may be due to a sampling
error as the procedure is a surface sampling technique6, or
routine laboratory isolation techniques may be inadequate7.
The present study attempts to define the accuracy of the
throat swab technique in identifying the complete tonsillar
flora in our hospital setting.
DR. R.C. NAYAR
J.XAVIER
AND
METHODS
The specimens were transported to the laboratory where
inoculation, aerobic culture and antibiotic sensitivity studies
were done as per routine procedures.
RESULTS
Of the 33 superficial swabs examined, only 4 showed
evidence of pathogenic bacteria, of which B Haemolytic
streptococcus was found in 2 cases. (Table 1)
Of the 33 core samples obtained, however 15 showed
pathogenic bacteria, of which Staphyloccocus Aureus, was
the commonest isolate. (Table 2). It was noted however that
the pathogenic bacteria isolated in cultures from superficial
swabs, were the same as that from the respective core
swabs, in those 4 patients whose superfical swabs showed
presence of pathogenic bacteria.
ASSISTANT PROFESSOR
RESIDENT
DEPARTMENT OF ENT
ST.JOHNS MEDICAL COLLEGE HOSPITAL
BANGALORE
The antibiotic sensitivity patterns showed a variable
sensitivity pattern, with all organisms being sensitive to
gentamycin, and many showing resistance to pencillin.
(Table 3)
ADDRESS FOR CORRESPONDENCE:
DISCUSSION
DR. RAVI C. NAYAR
ASSISTANT PROFESSOR
DEPARTMENT OF ENT
ST.JOHNS MEDICAL COLLEGE HOSPITAL
BANGALORE
The tonsillar crypts are deep, narrow and blind recessess
which penetrate nearly the whole thickness of the tonsil.
These crypts contain desquamated epithelial debris and
cells and have a potential for harbouring infection9. During
an attack of acute tonsillitis, minute abscesses form in the
lymphoid follicles which if not adequately treated, continue
64
vol ni No. y—
St. John’s Medical College Journal of Medicine
to exist within a fibrous capsule, inaccessible to superficial
swabs5,8.
Therefore, it would appear logical to assume that a culture
from a superficial throat swab would not be representative
of the complete bacterial flora of the tonsil. This conclusion
has been supported by studies which show that the efficiency
of the throat swab in predicting bacteriology of the tonsil varies
from 344% to 71 %, aver aging 54%5. Others however report
a 90% efficiency using a superficial swab8.
In the present study, 11/33 (33%) of cultures would have
been presumed negative if only superficial cultures were
studied.
There is need for caution in attributing etiologic significance
to bacterial isolates from the oropharynx. Studies on the
bacterial flora of the upper respiratory tract in general and
oropharynx in particular have shown that pathogenic isolated
were obtained with equal frequecy irrespective of the
presence or absence of infection 2A4. Consequently, it has
been suggested that the usefulness of such cultures, lies in
its-capability to exclude potentially pathogenic organisms
from etiologic consideration2.
As the superficial throat swab itself identifies only some of
the pathogens present in a tonsil (36% in our study) its
usefulness is further restricted.
When superficial cultures were positive, they were identical
to the deep swabs in 4/15 (27%) cases in the present study.
This is at variance with the results of another study, wherein
it was reported that in 9/65 (14%) of cases superficial and
deep swabs grew different pathogens, on culture8.
The role of proper microbiological techniques of isolation
transport and culture, has been highlighted by studies
reporting that upto 80% of chronically inflammed tonsils,
TABLE 1 : SUPERFICIAL TONSIL SWABS, TOTAL NO OF CASES 33
ORGANISM
nos
B-HEMOLYTIC STREP
STAP.AUREUS
KLEBSIELLA
NO OF PATHOGENIC STRAINS
NO OF COMMENSALS
2
1
1
4 (12%)
29 (88%)
TABLE 2 : INTRATONSILLAR SWAB, TOTAL NO OF CASES 33
ORGANISAM
Nos
STAP AUREUS
KLEBSIELLA
B-HEMOLYTIC
PSEUDOMONAS
STREPT VIRIDANS
6
4
2
2
1
NO OF PATHOGENS
NO OF COMMENSALS
15(45%)
18 (55%)
TABLE 3: CULTURE SENSITIVITY INTRA TONSILLAR SWAB, TOTAL NO OF CASES 33
SEPT
TETR
ERYT
CHLOR
PENIC
GENTA
AMPIC
----- SEPTEMBER
1990
Stap
bStrep
+
+
+
+
+
-
+
+
+
+
+
+
StrepV
Kleb
Pseud
+
+
+
+
+
+
+
+
+
-
+
-
+
65 —
St. John’s Medical College Journal of Medicine
may harbour anaerobic organisms.3 0.
2. Box QT, Clevel RT and Willard Ct. Bacterial Flora of the Upper
Respiratory Tract Am. J. of dis of Chil: 1961 ;102:293-301.
CONCLUSION
The superficial throat swab was found to identify only 36% of
the complete tonsillar flora, identified by taking core samples
after tonsillectomy.
In the present study when the superficial cultures were
positive they were identical with cultures taken from the
tonsillar core.
The reliabbility of the superfical tonsillar swab has been
discussed in the light of these and other studies.
REFERENCES
1. Hibbert J: Scott Browns Otolaryngology Vol 6 (ed 5),
Butterworths 1987,368.
66
London,
3. Reilly S, timmes P, Beevan AG et al : Possible role of Anaerobes in
Tonsillitis J of Clin Path 1981 ;34:542-547.
4 Toner JG, Stewart TJ, Campbell JB et al Tonsil Flor in the very young
Tonsillectomy patient Clin Otol 1986;11:171-174.
5. Peter G and Smith AD : Group A Streptococcal infections of Skin &
Pharynx N.eng. J. of Med 1977;297:6:310-317.
6. Rosen G, Samuel J, and Vered J : Surface tonsillar microflora versus
deep tonsillar microflora in recurrent tonsillited J.LaryngolOtol 1977;91:911913.
7.
Everre tt MT: The cause of tonsillitis Practitioner 1979;223:19-21.
8. Brook I, Yocum P & Friedman EM .'Aerobic and aanaerobic bacteria
in tonsils of children with recurrent tonsillitis Ann. OtoI.Rhinol. Laryngol
1981;90:261-263.
9. Beasley P:Scott Browns Otolaryngology vol 1 (ed
Butterworths 1987;268.
5)
London,
VOL III No. 3-----
St. John’s Medical College Journal or Medicine
MEDICINE SYMPOSIUM - DIABETES MELLITUS
Theme Editorial
Diabetes mellitus is the subject forthe symposium in this issue of the St. John’s Medical College Journal
of Medicine. It is an apt subject, for diabetes invades the whole gamut of medicine from primary care
tothe specialities. Yet, when Banting and Best announced the isolation ofinsulinand its use in diabetic
patients, they would hardly have visualised that 70 years later mankind would still be under the scourge
ofthisdisease.lt was universally expected in the 1920s that but forthe inconvenience of a few injections
the diabetic would be no different from the non-diabetic. We are now wiser, if sadder. Diabetes is the
largest cause of chronic renal failure and a major cause of blindness, loss of limbs, myocardial
ischaemia and infarction and strokes. Physicians and scientists have had to go back to basic sciences,
to genetics and molecular biology to try and find the answers to the riddle of diabetic pathology. The
answers have yet to be found but they seem tantalizingly close. Therapy of diabetes has followed
new strategies. The wheel has turned a full circle and we are back to reccomending multiple injections
of insulin daily or even continuous infusions in an attempt to maintain near normal 24 hours blood
glucose control. The hope is that complications may thus be prevented. There is some evidence that
they may but only time will tell - physicians have become cynical of such claims.
The articles in this issue highlight certain aspects of diabetes mellitus. The first, by Dr. Jayarajan and
Shetty takes us to basic physiology, reviewing current knowledge of the physiology of insulin secretion.
Indians as a race are particularly prone to diabetes and the pattern of the disease in India has its own
characteristics. The Diabetes Research Centre, Madras, has done pioneering and original work in
diabetes in South India. Dr. Mohan’s article discusses some of the epidemiological data which the centre
has collected. Two articles by Drs. Sridhar andSekhar discuss the use of glycosylated haemoglobin
and the importance of diet in the management of diabetes together with some of their own data. As
mentioned above much has changed in insulin therapy. Dr. Chandramouli describes the state of the art
in this field. Micro and Macro vascular complications of diabetes remain a nightmare for diabetics. Dr.
Ross reviews its pathogenesis and the article by Drs. Vincent and Ramkumar describes one of
these complications - diabetic nephropathy.
Dr. Prem Pais MD
Professor of Medicine
St.John’s Medical College & Hospital
---- SEPTEMBER 1990
67 —
St. John’s Medical College Journal of Medicine
MEDICINE - SYMPOSIUM
THE REGULATION OF INSULIN BIOSYNTHESIS
AND SECRETION
M.PREM JAYARAJAN, P.S. SHETTY
Since
a German medical student, Paul Langerhans,
discovered in 1869 that there were small, isolated islands of
endocrine tissue, scattered in the exocrine pancreatic tissue,
there have been tremendous strides in our knowledge of
pancreatic endocrine function. Insulin has been studied in
microscopic detail - we know how and where it is
synthesized and secreted, its physiologic functions and the
regulation and control of its production. The primary
structure of bovine insulin was determined for the first time
in 1955 by Sanger and his group in Cambridge. Since then,
the amino acid sequences of many insulins from hag fish to
that of man have been established.
Compared to other proteins, insulin has been highly
conserved in evolution. It is now believed that the regions of
the insulin molecule which are highly conserved, may be
essential for its biological activity. Human insulin (Molecular
weight about 6000 daltons) has 51 amino acids arranged as
2 polypeptide chains (an A chain of 21 amino acids and a B
chain of 30 amino acids) which are linked by 2 disulphide
bridges. In addition there is an interchain disulphide bridge
in the A chain. The B chain is a U-shaped structure with a
single - helical region towards the amino-terminal, while the
A chain has 2 - helical regions and lies in the hydrophobic
cleft of the B-chain.
BIOSYNTHHESIS OF INSULIN AND ITS REGULATION
Insulin is synthesized in the B cells by a complex pathway
involving two intermediates, pre-proinsulin and proinsulin.
This seems to be necessary to ensure that the insulin
molecule is synthesized with the correct orientation of the
disulphide bridges and that it is packaged and stored within
the B-granules for future secretion. Several organelles are
involved in the synthesis of insulin. The genetic information
for insulin biosynthesis is initially encoded on to a specific
mRNA of 600 nucleotides, the transcription of which results
in the production of pre-proinsulin.
Pre-proinsulin has a hydrophobic pre-region of 23 amino
acids which possibly promote the association of ribosomes
with the membrane of the endoplasmic reticulum. This
ensures the discharge of the precursor into the cisternal
M.PREM JAYARAJAN AND PS. SHETTY
DEPARTMENT OF PHYSIOLOGY,
ST JOHNS MEDICAL COLLEGE
BANGALORE - 560 034.
68
space of the rough endoplasmic reticulum. In the
endoplasmic reticulum rapid proteolytic cleavage occurring
within 30 seconds, transforms pre-proinsulin into proinsulin
and a 23 amino acid leader’ sequence is cleaved by a
membrane bound enzyme.
Proinsulin with 86 amino acids contains both the A and B
chains of insulin plus a 'connecting peptide’ (C-peptide) of 3035 amino acids connecting the two chains. The purpose of the
C-peptide is to facilitate the correct folding of A and B chains
and for the alignment of the disulphide bridges prior to
cleavage. Proinsulin is then transported by microvesicles to
the golgi complex by an energy dependent process.
From the golgi complex proinsulin is packaged in trans golgi
vesicles and surrounded by a membrane containing an ATPdependent proton pump. The conversion of proinsulin to
insulin continues within the maturing secretory granule by
proteases which are active at a low pH. In the maturing
vesicle, H+ ions are actively transported inwards and the pH
decreases, thus activating the proteases. This ensures that
insulin is produced only within the maturing secretary
granules. The proteases split the proinsulin molecule
liberating the connecting C-peptide from between the A and
B chains and also two pairs of basic amino acids from either
end of the C-peptide. With the removal of the C-peptide the
solubility of insulin is decreased and it precipitates along with
Zinc contained within the granule. Rhombohedral zinc insulin hexameric microcrystals are now formed with a ratio
of 2 zinc to 6 insulin molecules. The crystals of insulin and
C-peptide are stored together in the granule sac and are
secreted in equimolar amounts. Normally 95% of the
hormone is secreted as Insulin and less than 5% as
proinsulin. The sequence of cellular events leading to the
formation of crystalloid insulin ready for secretion, takes
less than 3 hours from the initiation of the biosynthetic
process.
Regulation of insulin biosynthesis in the B-cell is largely
mediated by glucose and other sugars, as well as their
metabolites. Increased extracellular glucose cocentration
causes a rapid increase in proinsulin synthesis and a
sigmoidal relationship exists between glucose concentration
and insulin biosynthetic activity; the threshold value being
2- 4 mM of glucose which is lower than the threshold for
stimulation of insulin
secretion. Glucose-mediated
stimulation of insulin biosynthesis occurs at the translational
level and increases synthesis of proinsulin. Glucose does
not alter the rate of conversion of proinsulin to insulin.
In addition to glucose, many other agents can stimulate
VOL III No. 3-----
St. John’s Medical College Journal of Medicine
insulin biosynthesis, although it is unlikely that they have an
important physiological role to play. Agents that stimulate
insulin biosythesis include mannose, glyceraldehyde,
leucine and glucagon, while adrenaline is known to inhibit
insulin biosynthesis.
REGULATION OF INSULIN SECRETION
Although the major physiological stimulus for insulin
secretion in mammals, is glucose, a large number of
physiological and pharmacological agents also act to
influence the secretion of preformed insulin. Agents that
influence insulin secretion are not necessarily those that
influence insulin biosynthesis since the two processes are
not obligatorily linked (Table 1).
These agents are classified into three broad groups:
1. Initiators or Primary Stimuli : Those that directly
stimulate insluin release eg. glucose, certain amino acids.
2. Potentiators or Secondary Stimuli : Those that
increase insulin release in response to a primary stimulus
such as glucose or amino acids but do not directly affect the
secretory
rate themselves
eg. glucagon or
phosphodiesterase inhibitors such as theophylline and
caffeine.
3. inhibitors : These agents inhibit the responses to both
primary and secondary stimuli.
The process of insulin secretion by the B-cell has a number
of unique features. Since the secretory process is regulated
by a variety of factors, it implies that the B-cell has several
distinct sensory systems for the identification of each of these
regulatory factors. Stimulus recognition follows the insulin
secretory response, which entails the activation of
intracellular signal molecules such as calcium and cyclic
AMP. Insulin is released from the B-cell by a process of
exocytosis which has been confirmed by scanning and freeze
etching electron microscopy. The cytoskeletal elements i.e.
microtubules and microfilaments play a key role in the
Table 1:
intracellular translocation of storage granules of insulin. In the
unstimulated B-cell, the insulin storage granules are
randomly distributed in the cytoplasm. During stimulation
there is a relative increase in the number of granules close to
the cell membrane. The intracellular movement of these
granules may be via transport by the microtubular system
from the general cytoplasmic pool towards the plasma
membrane, while microfilaments are responsible for the final
delivery of the granule to the membrane.
Glucose : In man, following an oral glucose load, blood
insulin levels are increased five-fold and return to basal levels
in 2 hours. The most dramatic effects of glucose on insulin
secretion are observed at glucose concentrations just
above fasting levels.
This is crucial since insulin is responsible for the maintenance
of blood glucose concentration at fasting levels. The
secretory response to glucose is fairly specific and the B-cell
is likely to possess a specific glucose recognition unit,
probably protein; its location whether membrane or
intracellular is not known. The B-cell response to glucose
is rapid and exhibits a biphasic pattern of release, with a
spike-like first phase which is followed by a slowly rising
prolonged second phase. A similar rapid biphasic response
in insulin release is also seen following intravenous infusions
of glucose in man.
The molecular basis of the bi-phasic secretory response
of insulin to glucose is unclear. Several theories have been
proposed to explain the dynamics of the glucose induced
biphasic insulin release. These include a two compartment
hypothesis according to which there are two types of granules
in B-cells-one that is small and labile to glucose and the other
a larger, stable granule, which is released at a slower rate. B
and D-cell interaction in the islets may also explain this
response. Glucose stimulates both insulin and somatostatin
release; somatostatin from D-cells inhibits insulin secretion,
which occurs after the initial rapid phase of insulin output
from the B-cell. the microtubular-microfilamentous system
of the B-cell may also contribute to this dual response.
Granules already aligned on the microtubules of the B-cell are
Differences between the Regulation of Insulin Biosynthesis and Insulin Secretion
Insulin Synthesis
Insulin Secretion
No
Yes
Inhibits
Yes
No
None
Effect of sulphonylureas
Inhibits
None
None1
None
Inhibits
Stimulates
Threshold concentration of
2-4 mM
4-6mM
Calcium dependency
Magnesium dependency
Effect of cycloheximide
Effect of puromycin
Effect of trifluoperazine
glucose sensitivity
----- SEPTEMBER
1990
69 —
St. John’s Medical College Journal of Medicine
released quickly while the slower phase is a result of the
release of free granules in the cytoplasm which attach later
on to the microtubular system.
The electrical activity of the B-cell in response to glucose
stimulation is biphasic. The biphasic changes in membrane
permeability to ions, in particular to calcium, may result in
biphasic changes in concentration of cytosolic calcium
which might explain the biphasic insulin response. It has been
proposed that the activation of a calcium influx induces a
transient increase in insulin release. The slower response
has been attributed in this case to an increase in
phospholipid metabolism. Despite the numerous hypotheses
postulated, the exact mechanism of the biphasic response of
insulin release, to glucose stimulus, remains unclear.
Glucose metabolism appears to be essential for its effect
on Insulin secretion. Thus insulin release occurs in response
to glucose and other sugars that are metabolised, while the
release fails to occur with the addition of mannoheptulose, an
inhibitor of glucose metabolism. Glucose metabolism
increases the ATP content of the B-cells in a dose response
manner. Inhibition of oxidative phosphorylation inhibits
insulin release, implicating a regulatory role for ATP in the
insulin secretory process. The increase in the rates of insulin
secretion that occur with an increase in extracellular glucose
concentration is correlated with an increase in the levels of
reduced pyridine nucleotides. The changes in reduced
pyridine nucleotides parallel the biphasic insulin response
and both events can be inhibited by mannoheptulose.
Further, agents that reduce levels of pyridine nucleotides
inhibit insulin release thus implying that the increase in
reduced pyridine nucleotide levels has a role to play in the
mechanism of glucose induced insulin release, it is
postulated that reduced pyridine nucleotide (NAD(P)H) levels
may act as a trigger for insulin secretion by reducing
permeability to K+ ions, which in turn results in opening of
voltage dependent calcium channels, to calcium influx and
Insulin secretion. This influx of calcium, is also responsible
for the typical electrical activity of the islet cells which is seen
on glucose stimulation.The opening of the voltage gated
calcium channelscan also be initiated by the entry of amino
acids leucine and arginine, which can stimulate insulin
release in the absence of glucose.
Neural Control of Insulin Secretion
The islets are innervated by the autonomic nervous system,
with a sympathetic input from the middle splanchnic nerve
and parasympathetic input from the vagus. Vagal stimulation
results in insulin release which can be mimicked by
acetylcholine administration and blocked by atropine. The
cholinergic release of insulin is dependent on the presence
of glucose and calcium uptake. Sympathatic stimulation,
adrenaline and noradrenaline inhibit insulin release via
activation of A and B adrenergic receptors.
Hormonal control of Insulin secretion
secretion. Glucagon enhances glucose-induced insulin
secretion, probably by raising cyclic AMP levels
by
activatiorn of adenylate cyclase. -Somatostatin decreases
basal insulin release possibly by impaired calcium handing
by the B-cell. Gastric Inhibitory Peptide (GIP) increases
nutrient-stimulated insulin release. Pancreozymin and
Secretin also have similar effects. The relationship between
these gut hormones and the endocrine pancreas is called the
enteroinsular axis. These agents also possibly act via AMP
which in turn exerts its effect by activation of protein kinases.
Coupling of Stimulus with Insulin Secretion
The role of intracellular messengers: The response of the Bcell to specific stimuli resulting in the release of stored insulin
by exocytosis, is mediated by several interactive processes
and intracellular messengers. The process of 'stimulus
secretion coupling’ and the mediation of a specific
intracellular messenger depends upon whether
the
concerned stimulus is a primary stimulus, a potentiator or
whether the secretion is the result of
activation of
neurotransmitters (Table 2). Glucose and other primary
secretogogues of insulin stimulate calcium uptake of islet
cells by activating calcium transport systems on the cell
membrane. The interaction of calcium ions mobilized intra
cellularly, with Calmodulin, the Calcium binding protein,
results in the activation of a Calmodulin-responsive protein
kinase activity. The resulting protein phosphorylation is said
to activate the systems responsible for the translocation of
the stored insulin granules and their subsequent exocytosis.
Secondary stimuli or potentiators mediate their stimulus
secretion coupling via activation of adenylate cyclase, the
consequent production of AMP activating a protein kinase
which then brings about insulin release. Neurotransmitters
such as acetylcholine released from vagal nerve endings,
possibly use a different second messenger mechanism.
They generate intracellular signals such as
inositol
triphosphate and diacylglycerol which activate protein kinase
and lead to insulin release. All three postulated mechanisms
of ‘stimulus-secretion coupling’ interact with each other and
the net effect of activation of protein kinases, is to cause
protein phosphorylation in order to activate the effector
systems for insulin release.
Short-term and long term regulation of insulin secretion: The
major factor for short-term insulin regulation is the
concentration of various circulating nutrients. Glucose is
most important, although amino acids, fatty acids and ketone
bodies also act as stimuli. Hormones modulate the
responsiveness of the B-cell to these nutrients. Glucagon,
pancreozymin and secretin all potentiate the B-cell response
to glucose (mediated by the cyclic AMP system of the B-cell).
Catecholamines inhibit insulin release by activating receptors on the B-cell. Acetylcholine, a parasympathetic
neurotransmitter stimulates insulin secretion.
Glucagon increases while somatostatin decreases insulin
In the B-cell, regulatory mechanisms exist which mediate long
term adaptation of the insulin secretory respose. These
— 70---------------------------------------- —--------------------------
VOL III No. 3—
St. John’s Medical College Journal of Medicine
Table 2 : Schematic representation of stimulus-secretion coupling and the mediation of intra-cellular messengers
in the insulin secretory response
POTENTIATORS
PRIMARY STIMULI
NEUROTRANSMITTERS
I
Cell
membrane
Adenylate
cyclase
Calcium transport
system
' n+
n
Inositollipid
turnover
Calcium
cAMP
Protein Kinase A
calmodulin
Diacylglycerol
Protein Kinase B
Protein Kinase C
PROTEIN PHOSPHORYLATION
INSULIN SECRETION
mechanisms enhance B-cell responsiveness to metabolic
stimuli durinng pregnancy and lower its responsiveness
during starvation.
REFERENCES
1. Ashcroft SJH. Glucoreceptor mechanisms and the control of insulin
release and biosynthesis Diabetologia 1980;18:5-15
2. Campbell IL, Hellquist LN, Taylor KW. Insulin biosynthesis and its
regulation. Clinical Science 1982:62,449-455.
5. Howell SL, Tyhurst M. The pancreatic B-cell cytoskeleton and insulin
secretion. Diabetes/Metabolism Reviews 1986;2:107-123.
6. Howell SL, Bird G.SLJ. Biosynthesis and secretion of insulin. British
Medical Bulletin 1989;45:19-36.
7. Lacy PE. Beta cell secretion. From the standpoint of a pathobiologist.
Diabetes 1970;19:895-905
8. Montague W. Insulin synthesis, storage and secretion. Diabetes and the
endocrine pancreas. A Biochemical approach 1983;p27-60. Groom & Helm,
London.
3. Hedeskov CJ. Mechanism of glucose-induced insulin secretion. Physiol
Rev 1980:60,442-509.
9. Tomlinson S, Walker SW, Brown BL.
secretion.Diabetologia 1982;22:1 -5
4. Howell SL The mechanism of insulin secretion (Review). Diabetologia
1984;26:319-327.
10. Wollheim CB, Sharp GWG. Calcium regulation of insulin release.
Physiol Rev 1981;61:914-973.
----- SEPTEMBER
1990
Calmodulin
and
Insulin
7 1 —
MEDICINE - SYMPOSIUM
St. John’s Medical College Journal of Medicine
DIABETES
IN
SOUTH
INDIA
V. MOHAN
Diabetes mellitus in developing tropical countries shows
considerable differences from that seen in western
countries1. Studies at the Diabetes Research Centre, Madras
during the last 2 decades have highlighted these differences
and these have been recently reviewed2-4. This article deals
with the spectrum of diabetes in South Indians and is based
on studies done at our own centre. It will be considered under
the following headings:
I Non-insulin Dependent Diabetes Mellitus
II Insulin Dependent Diabetes Mellitus
III Malnutrition Related Diabetes Mellitus
1 NON - INSULIN DEPENDENT DIABETES MELLITUS
(NIDDM)
1) EPIDEMIOLOGICAL STUDIES
a)
Studies on migrant Indians
During the last two years, a number of papers have appeared
on diabetes
in migrant Indians. Studies on migrant
populations are significant because they provide valuable
data on genetic-environmental interactions in diabetes
mellitus. The Southall diabetes survey5 showed that the
crude prevalence of ‘known’ diabetes was two fold higher
among Indians in the UK (2.2%) compared to Whites (1.2%)
or Afro-Carribeans (1.2%). In the 40-64 age group, the
prevalence was atleast five fold higher in Indians compared
to Europeans. Further studies showed that Indians have
increased familial aggregation with higher prevalence of
diabetes in parents and that vertical transmission through
two or more generations was more common among
Indians6. Insulin resistance was also found to be more
marked in Indians. Evidence for this comes from our studies
which showed that Indians had higher serum immunoreactive
insulin responses to a glucose load
compared to
Europeans7. Euglycaemic clamp studies done by us also
confirmed the greater degree of insulin resistance in Indians8.
It is not clear whether this insulin resistance has a genetic
basis or is the effect of environmental factors.
b)
Diabetes in Indians
As an extension of the Southall survey, the prevalence of
DR. V. MOHAN, MD., MNAMS, PH.D.,
DEPUTY
DIRECTOR
DIABETES RESEARCH CENTRE,
5, MAIN ROAD, ROYAPURAM
MADRAS - 600 013
INDIA
72
diabetes in Indians in India was assessed in the Darya Ganj
area, a reltively affluent suburb of New Delhi9-10. It was seen
that the prevalence of diabetes was in fact higher in Indians
in Darya Ganj, than in Indians in Southall! This study is
important because it was hitherto assumed that the
prevalence of diabetes was high only among migrant
Indians. It now appears that when similar degrees of
obesity, affluence etc. are present the prevalence of
diabetes in India may not be significantly different from that
seen in migrant Indians. Recent studies from our centre by
Ramachandran et al11 have shown that the prevalence of
diabetes is high even in S.India. The overall prevalence rate
for diabetes was found to be 5%. When age adjusted for
the Southall population the prevalence rate in fact rose up to
10%! This confirms that the prevalence of diabetes in India
has risen sharply compared to the figures of 2.1% for urban
areas and 1.5% for rural areas reported in 1975 by the ICMR
multicentric study12.
2) STUDIES ON GENETICS OF NIDDM PATIENTS
Few studies have been reported on the genetics of NIDDM
patients in tropical countries. Viswanathan et al13 reported
on the prevalence of diabetes in offspring of two diabetic
parents. He found that 62% of the offspring of two diabetic
parents developed diabetes. Using a life table analysis, it was
shown that more than 90% would ultimately develop
diabetes by the age of 60 years. Even when one parent has
diabetes and if the other parent has a positive family history
of diabetes, the offspring have a very high risk for diabetes14.
These prevalence rates are the highest reported for any
population studied, suggesting that the genetic factors are
stronger in Indians compared to Europeans.
II
INSULIN DEPENDENT DIABETES MELLITUS (IDDM)
1) GENETIC FACTORS
a) HLA studies
A study from South India by Kirk et al15 has shown some
interesting findings. The HLA profile in IDDM in South India
is quite different from that reported from North India. In the
south, HLA-B8 is associated with IDDM, which is similar to
the findings in the Caucasian IDDM. However, unlike the
latter findings, there was no asssociation with B15. These
studies appear to provide evidence for genetic differences
in susceptibility to IDDM between Indians and Caucasians
and even between the North-and South-Indian populations.
They also corroborate the earlier studies of Hammond and
Asmal16.
b) Studies on properdin (BF) system
cALTH
properdin (BF) system which is associated with the
----------------------------------------------------------------- VOL HI No. 3 —
St. John’s Medical College Journal of Medicine
alternate complement pathway, is situated close to the HLA
region on Chromosome 6. The BF haplotype associated with
IDDM in Caucasian populations is the BFS. An association
between the properdin system and insulin-dependent
diabetes in South India has been reported by Kirk et al17.
There was a significant increase among IDDM patients in the
BFF phenotype and a corresponding fall in the BFS
phenotype. This increase in the BFF phenotype was
reflected also in a significant difference in the BFF gene
frequency between IDDM patients and controls. There were
no significant differences between controls and NIDDM. The
relative risk for the BFF phenotype in IDDM was 4.1.
In contrast to the previous reported results for North Indian
IDDM patients18 there was no significant association of the
BFS1 haplotype with either IDDM or NIDDM patients in the
South Indian population studied. This suggests that the
susceptibility allele(s) for IDDM in South India arose
independently from the susceptibility allele(s) in North India.
Alternatively, it is possible that a different etiological factor
with a distinctive genetic susceptibility is present in South
Indians.
c)
RFLP studies
More recently we have done extensive genetic studies using
the technique of Restriction Fragment Length Polymorphism
(RFLP) in collaboration with Dr. G Hitman of the London
Hospital, UK. These studies showed that IDDM shows a
strong association with the HLA-DQ beta gene19. Here again,
minor differences were noted between Indians and
Caucasian studies.
In summary, the above studies on HLA and BF system do
seem to indicate that a) differences exist between the
Indian and Caucasian races with respect to susceptibility to
IDDM; and more interestingly, b) there are differences
between North and south Indians.
Ill MALNUTRITION RELATED DIABETES MELLITUS
(MRDM)
One of the types of diabetes peculiar to tropical regions is that
associated with malnutrition. Two subgroups of MR DM have
been proposed:
a) protein-deficient diabetes mellitus
(PDDM) and b) fibrocalculous pancreatic diabetes (FCPD).
a) Protein-deficient diabetes mellitus (PDDM)
The important features of this subtype of MRDM as first
described by Hugh-Jones from Jamaica (and hence J type
diabetes) include: resistance to the development of ketosis,
partial resistance to the action of insulin, extreme degrees of
wasting and emaciation, and onset of symptoms before the
age of 35 yr, commonly between 15 and 25 yr of age20. The
disease has since been reported from several countries in
Asia and Africa. The previous names forthis disease such as
J type diabetes, ‘M’ type diabetes, Ketosis resistant, youth
----- SEPTEMBER
1990
onset diabetes, etc. have been discarded by the WHO Study
Group. One of the problems with the PDDM variety of MRDM
is the lack of a specific diagnostic marker. The commonly
suggested criteria21 such as body mass index <18 (some
authors use BMI < 19), ketosis resistance or requirement of
large doses of insulin are not specific enough. Low BMI was
noted in 70% of classical IDDM patients and a small number
of NIDDM in one report22. Low body weight could result from
delayed diagnosis and consequent weight loss due to
uncontrolled diabetes, ketosis resistance, while a useful
feature, is again not of diagnostic value because very often
IDDM goes through a pre-ketotic phase23. ICA are also not
of much help because one report found ICA in 30% of IDDM
and 37.5% of PDDM 24. The problem of classification of
patients is illustrated by Lester’s study in Ethiopia25 where
patients initially classifedas PDDM eventually turned out to
have IDDM.
The available evidence to date neither dismisses nor
establishes the presence of PDDM. Obviously, more studies
need to be done and specific markers for PDDM have to be
found.
b) Fibrocalculous Pancreatic Diabetes (FCPD)
In contrast to PDDM, the second variety of MRDM, namely
FCPD, is easier to diagnose because of more reliable
markers for the disease. Most features of PDDM are also
present in FCPD but there are 3 additional characteristics:
1) a history of recurrent abdominal pain; 2) radiographic or
other evidence of intraductal pancreatic calculi or dilatation of
the ducts; and 3) malabsorption of nutrients caused by
exocrine pancreatic insufficiency.
Cases of FCPD have been described from several countries
in Asia, Africa and South America, particularly Brazil. Clinical
features of FCPD have been described by us elsewhere2-3
and are also described in the WHO report26. A recent
monograph by Geevarghese, one of the pioneers in this
field, provides a wealth of information about FCPD27.
Diabetic Complications in FCPD
It was formerly believed that being a secondary form of
diabetes, specific diabetic complications were uncommon in
FCPD. It has been recently shown by us that severe
retinopathy,
namely proliferative
retinopathy
and
maculopathy, does occur in FCPD patients28. These findings
have been confirmed by other workers 27-29-30. Nerve
conduction studies showed that neuropathy was as common
in FCPD as in NIDDM patients 31. Systolic time interval
studies showed evidence of subclinical left ventricular
dysfunction in FCPD patients 32. Macrovascular
complications also do occur in FCPD although their
frequency is low 33. Thus, patients with FCPD are prone to
specific diabetic complications just like those with primary
forms of diabetes.
73 —
St. John’s Medical College Journal of Medicine
Ketosis resistance
REFERENCES
One of the characteristics of FCPDisthat, despite requiring
insulin, patients are usually resistant to ketosis when insulin
is withdrawn. Our studies 3435 have show that the mechanism
of ketosis resistance seen in FCPD is perhaps related to the
fact that there is partial preservation of pancreatic beta cell
function in these patients. Recent studies by other groups
have confirmed these observations 36*38.
1. Mohan V, Ekoe JM, Ramachandran A et al: Diabetes in the Tropics:
differences from diabetes in the west. Acta Diabetol. Lat 1986:23:91.
Aetiopathogenesis
The 2 main factors incriminated in the pathogenesis of FCPD
are protein calorie malnutrition and cassava (tapioca)
ingestion. Recent evidence suggests that the roles of both
these factors need to be re-examined. In west Africa,
Teuscher et al39 failed to find evidence of either FCPD or
PDDM in a population which had a high cassava and low
protein intake in their diet. In another study, FCPD was not
seen among cassava consuming tribal groups in Brazil40. A
third study from the Ivory Coast41 has reported that the
chronic pancreatitis seen in that region was not related to
either childhood malnutrition or cassava ingestion. While
other aetiological factors have not been adequately explored,
one study 42 found evidence of raised antibody titres against
mumps and CMV viruses and Mycoplasma pneumoniae.
Immunological changes have also been described 43
Studies from our centre have recently shown that familial
or genetic factors may also play a role in causation of FCPD.
Studiesof families of FCPD patients showed that there was
evidence of familial aggregation of the disease in many
families
In another study we showed45 that FCPD shows
genetic similarities to both IDDM (with respect to its
association with the HLA-DQ beta gene) and NIDDM (with
respect to its association with the insulin gene).
Criteria for diagnosis of FCPD
To date no definite criteria have been laid down for the
diagnosis of FCPD. Based on an extensive review of
lieterature and our own work, we proposed the following
criteria46 for diagnosis of FCPD: 1) Diabetes must be present
according to the Criteria of the National Diabetes Data Group
(NDDG) or WHO Study Group report. 2) The disease must
be present in a person from a tropical country. 3) There must
be evidence of chronic pancreatitis. The single most
important diagnostic criterion is the presence of pancreatic
calculi on plain X-ray of the abdomen. In cases wherecalculi
are absent at least 3 of the following must be present, a)
structural pathology in the pancreas such as fibrosis or
ductal dilatation as demonstrated by CT scan, ultrasound,
ERCP or by histopathology; b) history of recurrent abdominal
pain from childhood; c) steatorrhoea; and d)abnormal
exocrine pancreatic function tests such as the secretin
pancreozymin test or tubeless tests, such as the PABA test.
4) Other causes of chronic pancreatitis such as alcoholism
must be excluded.
2. Mohan V, Ramachandran A, Viswanathan M. : Tropical Diabetes. In:
Alberti KGMM, Krall LP (Eds). Diabetes Annual/I, Elsevier Science
Publishers BV, Amsterdam, 1985;p.82.
3. Mohan V, Ramachandran A, Viswanathan M : Tropical Diabetes. In:
Alberti KGMM, Krall LP (Eds). Diabetes Annual/2, Elsevier Science
Publishers BV, Amsterdam, 1986;p.3O.
4. Mohan V, Ramachandran A, Viswanathan M.: Diabetes in the Tropics.
In: Alberti KGMM, Krall LP (Eds). Diabetes Annual/4, Elsevier Science
Publishers BV, Amsterdam, 1988;p.46
5. Mather HM, Keen H : The Southall diabetes survey: prevalence of known
diabetes in Asians and Europeans. Br.Med.J 1985:291:1081.
6. Mohan V, Sharp PS, Aber VR et al : Family histories of Asian and
European non-insulin dependent diabetic patients. Practical Diabetes.
1986:3-254.
7. Mohan V, Sharp PS, Cloke AR et al : Serum immunoreactive insulin
responses to glucose load in Asian Indian and European Type 2 diabetic
patients. Diabetologia. 1986;29:235.
8. Sharp PS, Mohan V, Levy JC et al: Insulin resistance in patients of
Asian Indian and European origin with non insulin dependent diabetes. Horm.
Metab. Res. 1987;19:84.
9. Verma NPS, Mehta SP, Madhu S et al: Prevalence of known diabetes
in an urban Indian environment: the Darya Ganj diabetes survey. Br. Med. J.
1986;293:423.
10. Mather HM, Verma NPS, Mehta S et al: The prevalence of known diabetes
in Indians in New Delhi and London. J.Med. Assn. Thailand. 1987;70
(suppl. 2 ):54
11. Ramachandran A, Jali MV, Mohan V et al: High prevalence off diabetes
in an urban population in South India. BMJ. 1988:297:587.
12. Ahuja MMS : Epidemiological studies on diabetes mellitus in India. In:
Ahuja MMS (Ed). Epidemiology of diabetes in developing countries, Interprint,
New Delhi, India 1979;p.29.
13. Viswanathan M, Mohan V, Snehaltha C etal: High prevalence of type-2
(non-insulin dependent) diabetes among offspring of conjugal diabetic
parents in India. Diabetologia 1985:28:907
14. Ramachandran a, Mohan V, Snehalatha C et al: Prevalence of non-insulin
dependent diabetes mellitus in Asian Indian families with single diabetic
parent, diab. Res. Clin. Pract.1988;4:241.
15. Kirk RL, Ranford PR, Serjeantson SW et al: HLA, complement C2, C4,
properdin factor B and glyoxalase types in south Indian diabetics. Diab.
Res.Clin. Pract. 1985:1:41
16. Hammond MG, Asmal Ac: HLA and insulin dependent diabetes in South
African Indians. Tissue Antigens 1980;15:244.
17. Kirk RL, Ranford PR, Viswanathan M et al : Another Association
between properdin system (BF) and insulin dependent diabetes in S.india.
Tissue Antigens 1983:22:170.
18. Kirk RL, Ranford PR, Theophilus J et al: The rare factor BFSI of the
properdin system strongly associated with insulin dependent diabetes in
N.India. Tissue Antigens 1982:20:303.
19. Hitman GA, KarirPK,Sachs JAetal: HLA-D region RFLPsindicate that
susceptibility to insulin dependent diabetes in south India fe located in the
-------------------------------------------------------------------------- VOL III No. 3-------
St. John’s Medical College Journal of Medicine
HLA-DQ region. Diabetic Medicine. 1988;5:57.
20.
Hugh-Jones P : Diabetes in Jamaica. Lancet 1955;2:891.
21. Ahuja MMS: Heterogeneity in tropical pancreatic diabetes. Diabetologica
(letter). 1985,28:708
22. Mohan V, Sharp PS, Aber VRetal: Insulin resistance in maturity onset
diabetes of the young. Diabete and Metabolisme 1987,13:193.
23. Krolewski AS, Warram JA, Christlieb AR : Onset, course, complications
and progressions of diabetes mellitus. In: Marble A, Krall LP, Bradley RF,
Christlieb AR, Soeldner JS (Eds). Joslin's Diabetes Mellitus, 12th edition,
Lea & Febiger, Philadelphia, 1985;p.259.
34. Mohan V, Snehalatha C, Jayashree R et al: Pancreatic beta cell function
in tropical pancreatic diabetes. Metabolism 1983;32:1091.
35. Mohan V, Mohan R, Susheela L et al : Tropical pancreatic diabetes in
S.lndia: heterogeneity in clinical & biochemical profile. Diabetologia
1985,28:229.
36. VanasaengS, NitiyanantW, Vachayanrat A etal : c-peptide secretion in
calcific tropical pancreatic diabetes. Metabolism 1986;35:814.
37. Ahuja MMS, Sharma GP: Serum C-peptide content in nutritional diabetes.
Horm. Metab. Res. 1985,17:267
38. Samal KC, Das S, Parija CR et al: C-peptide response to glycaemic
stimuli. J.Assn. Phys. Ind.1987;35:362
24. Hazra DK, Singh R, Singh B et al : Autoantibodies in tropical, ketosis
resistant but insulin dependent diabetes mellitus. In: Bajaj JS (Ed). Diabetes
mellitus in developing countries, Interprint, New Delhi, 1984;p.165.
39. Teuscher T, BaiHod P, Rosman JB et al: Absence of diabetes in a rural
West African with a high carbohydrate cassava diet. Lancet. 1987; 1:765
25. Lester FT : A search for malnutrition related diabetes mellitus in an
Ethiopian diabetes clinic. Bull. Internat. Diab. Fed. 1984;29:14.
40. Franco LJ, Baruzzi RG, Mareovito LF: Glucose tolerance among cultured
Brazilian Indians with high cassava intake diet Bull Health Care Delivery in
Developing Countries. 1985,6:14.
26. Diabetes Mellitus Report of a WHO study group : (Technical Report Series
727) WHO, Geneva. 1985.
27. Geevarghese PJ : Calcific Pancreatitis. Varghese Publishing House,
Bombay.
41. Sarles H, Sauniere JF, Atia F et al: Pancreatic function in children and
chronic calcifying pancreatitis in the Ivory Coast. The tropical form of CCP is
not due to kwashiorkar or cassava. ln:Gyr KE, Singer MV, Sarles H (Eds).
Pancreatitis : Concepts and classification. Elsevier, Amsterdam 1984;p.365.
28. Mohan R, Rajendran B, Mohan V et al: Retinopathy in tropical pancreatic
diabetes. Arch. Opthlmol. 1985;103:1487.
42. Shenoy KJ, Shanmugham J, Balakrishnan V: Viral and mycoplasmsa
pneumoniae antibodies in chronic pancreatitis of tropics. Ind. J. Med. Res.
1986;84:22.
29. Samal KC, Tripathy BB, Nayak GC : Correlation between clinical
appearance of retinal and renal complications of diabetes mellitus. Diab.
Bull. (Res. Soc. Study Diab in India). 1987,1:48.
43. Balakrishnan V,: Chronic calcifying pancreatitis in the tropics. Ind. J.
Gastroenterol. 1984;3:65.
30. Sridhar GR, Satish K, Ahuja MMS : Evaluation of retinopathy in
malnutrition related diabetes mellitus using non-mydriatic retinal colour
photography. Diab. Bull. (Res. Soc. Study Diab, in India). 1987,1:36
31. Ramachandran A, Mohan V, Kumaravel TS et al: Peripheral neuropathy
in tropical pancreatic diabetes. Acta Diabetol. Latina. 1986;23:135.
32. Ramachandran A, Mohan V, Snehalatha C et al: Left ventricular function
in fibrocalculous pancreatic diabetes. Acta Diabetol. Latina. 1987,24:81.
33. Mohan V, Ramachandran A, Viswanathan M : Two case reports of
macrovascular complications in Fibrocalculous Pancreatic Diabetes. Acta
Diabetol. Latina. 1989;26:345.
----- SEPTEMBER 1990
44. Mohan V, Chari ST, Hitman GA et al: Familial aggregation in Tropical
Fibrocalculous Pancreatic Diabetes. Pancreas 1989;4:690.
45. Kambo PK, Hitman GA, Mohan V et al : The genetic predisposition
to fibrocalculous pancreatic diabetes. Diabetologia 1989;32:45.
46. Mohan V, Ramachandran A, Viswanathan M : Diabetes secondary to
pancreatopathy in the tropics. In: Tiengo A, Alberti KG MM, Del Prato S, Vranic
M (Eds). Proceedings of the post EASD International Symposium on
diabetes secondary to pancreatopathy. Excerpta Medica, Amsterdam
1988;p.215.
75 —
MEDICINE - SYMPOSIUM
St. John’s Medical College Journal of Medicine
GLYCOSYLATED HEMOGLOBIN IN SOUTH INDIAN NON
INSULIN DEPENDENT DIABETICS - ROLE IN PREDICTING
DIABETIC CONTROL.
C.B. SRIDHAR, LATHA SEKHAR
A number of proteins are non-enzymatically glycosylated
when exposed to high levels of glucose. These include
hemoglobin, red cell membrane, albumin and other serum
proteins, collagen, the crystalline lens and glomerular
basement membrane1. This chemical reaction - linkage
between a reducing sugar and a receptive aminoacid was
first described in relation to food proteins by Maillard2 in 1913.
In 1958, the three negativley charged minor components of
normal adult hemoglobin, designated HbA1a, HbA1b, and
HbAlc (collectively HbA,) were separated by cation
exchange chromatography. Four years later Huisman and
Dozy were the first to observe that HbA1 fraction was
increased in diabetic patients2. This was confirmed by other
studies. In particular HbA 1c levels were noticed to be 2-3
times higher than normal in diabetics.
In 1975 Fluckiger and Winterhalter showed that HbA1c could
be formed in vitro by incubating whole blood or purified
hemoglobin in the presence of glucose at 37° C2. In 1976
Koeing et al found that glycosylated Hb levels which were
initially elevated fell approximately 4 weeks after attainment
of improved glycaemia2. By early 1980s the usefulness of
HbA1c as an objective and retrospective index of glycaemia
was confirmed.
Formation of glycosylated hemoglobin: In the normal non
diabetic adults, 5% of total hemoglobin is HbA1c, 1% HbAlb
and 1% HbA1a.Addition of glucose or its’derivatives to the beta
chain of HbA change the charge characteristics so that the
molecules travel faster in certain
chromatographic
separation techniques.
The reaction between glucose and the beta chain of
hemoglobin is 1) slow, 2) mostly irreversible 3) non
enzymatic 4) Continuous over the life span of the red blood
cells and 5) proportional to the glucose concentration to which
the red cell is exposed3.
HbAlc
is
the
most abundant minor component
DR. C.B. SRIDHAR, LATHA SEKHAR
DIVISION OF ENDOCRINOLOGY AND *
METABOLISM
DEPARTMENT OF MEDICINE
ST.JOHNS MEDICAL COLLEGE HOSPITAL
BANGALORE
76
of
hemoglobin in normal erytrocytes. It consists of hemoglobin
A, to the beta chain N terminus of which, glucose is attached
by ketoamine
linkages. This nonenzymatic reaction
proceeds as follows:
rapid
HbA + Glucose
♦
preAic
aldimine
Schiff base
slow
------- > HbA,c
ketoamine
The first step is rapid and reversible and the first product
formed - the aldimine is not stable (labile HbA1 or Pre A1c) A
small amount of pre A1c is slowly converted to HbA1c a
ketoamine by a molecular arrangement. This step is
irreversible and Hb 1c accumulates in the red blood cells
throughout their life span.The older the red blood cell the
greater the concentration of HbA lc it will have. Unfortunately
pre A1c is also measured by both ion chromatography and
high performance liquid chromatography methods. This
explains an approximately 1-2% drop in HbA1cwihthin a
day or two of bringing an uncontrolled patient into near
euglycaemia. During this short period pre A1c has mostly
returned to glucose and haemoglobin3. In unstable diabetic
patients Hba1c value may even fluctuate by 1 -4%. Incubation
of the red cells in saline or dialysis of the hemolysate before
application to column will allow Pre-A1c to disappear3. The
resultant HbAlc value does not fluctuate and is a valid
measure of diabetic control.
SIGNIFICANCE OF GLYCOSYLATED HEMOGLOBIN
VALUES IN DIABETIC PATIENTS
A number of studies have demonstrated that levels of either
HbA1 or HbAlc are proportional to fasting plasma glucose
concentrations, postprandial glucose levels, values
obtained during a glucose tolerance test (GTT), the amount
of urinary glucose excreted and clinical estimates of control3.
Being a time-integrated measure of the prevailing glucose
concentrations to which red blood cell is exposed, the levels
of HbA1c correlate closely with glycaemic control over the
previous 6-10 weeks. The best correlation between the
average blood sugar and the amount of glycosylated Hb is at
2 months. Therefore, if a patient starts to control his or her
diabetes mellitus (DM) more carefully,
it will
take
approximately 8 weeks before the improved glucose levels
will be reflected in a lower HbAlc. HbA1c is not affected by
short term fluctuations in blood sugar (hour to hour) and
hence gives a relatively precise reflection of long term blood
VOL III No. 3 —
St. John’s Medical College Journal of Medicine
glucose control In DM4.
The role of HbA1c in routine clinical management of IDDM
patients has been confirmed. Studies have demonstrated
that in IDDM patients there is a positive correlation between
glycosylated hemoglobin and duration of diabetes2.
Continuing
endogenous insulin secretion shown by
measurable levels of G-peptide, was a major influence in the
maintenance of near normal HbA1c levels.
The risk in trying to keep HbA1c ‘near normal’ is of increasingly
frequent or severe hypoglycaemia2. HbA1c levels can be a
useful clinical guide to identify patients who are most likely
to develop serious symptomatic hypoglycaemia5. On the
assumption that the majority of patients will have some
endogenous insulin secretion for at least 2 yrs a HbA1c level
of 8.5% is aimed for during that period2. A level of 9% is
allowed for 2-5 yrs duration, after which less than 10%
seems to be a . realistic target. Maintaining the HbAlc
constantly at less than 10% over the long term in a patient
with long standing IDDM is extremely difficult.
The “normal” value of HbA1c varies from laboratory to
laboratory6. As a general rule, however, the higher the test
level the poorer the degree of control during the previous
month or two.
Table Shows The Ranges and the interpretation of the
HbA1} used at Joslin clinic6.
Glycohemoglobin *
(%)
Average blood
glucose level
(mg%)
Interpretation
5.4 - 7.4
7.4 - 8.5
8.6 -10.5
10.6-13.00
13.00
120
120-150
150-200
200 - 300
300
non diabetic
excellent
good
fair
poor
Other disadvantages of separation by ion chromatography results are influenced by conditions under which blood is
collected, shipped and stored, the columns are very
sensitive to changes in temperature and buffer pH and
falsely high levels may be seen in thalassemia (HbFcoelutes
with HbA1), other hemoglobinopathies (S,C,D,G, etc)
uremia, in patients ingesting large doses of aspirin, lead
poisoning and possibly alcoholics.
Affinity chromatography3 - pre A1c and aldimine linkages are
not bound to phenylboronate resin and consequently
measures of HbA, are a valid index not influenced by
conditions of blood collection, shipping and storage.
The colorimetic method8 is based on the principle that when
HbA1c is subjected to mild acid hydrolysis, 5 hydorxymethyl
furfural (5-HMF) is released and can combine with
thiobarbituric acid (TDA) to form a coloured product. It is
unaffected by HbF, hemoglobin variants and Hb pre A1c.
This is a simple inexpensive method. However, the test may
be~difficult^to standardize. Falsely high values may result
because of 5 HMF formation due to condensation of free
glucose (when present in
high concentration) with
hemoglobin in vitro. Also the precision of this test is limited
by a variable degree background colour absorbance from
non-glycosylated hemoglobin.
Regardless of methodology used, the presence of conditions
that shorten the red cell life (hemolytic anemias, bleeding)
will produce falsely low values. Conversely if the life span of
the red blood cell is extended (e.g. splenectomy) the values
will be falsely high3.
OTHER FEATURES OF INTEREST
* HbA lc values are measures of HbA at the Joshin Clinic. Values may vary
A study by Klein et al provides persuasive evidence that the
level of glycaemic control as assessed by HbAlc is
positively associated with the risk of both development and
progression of retinopathy9. NIDDM patients, although their
risk of retinopathy is by no means negligible, have a lower risk
(for a given level of HbA1c) than IDDM patients.
at other laboratorties and institutions with varying methods of testing.
METHODS OF GLYCOSYLATED HEMOGLOBIN
DETERMINATION
Glycosylated hemoglobin can be measured by the following
methods:
1. Chromatographic technique
2. Electrophoretic technique
3. Calorimetic method
4. Radioimmunoassay
5. Spectrophotometric test
Cation exchange chromatography is the most commonly
used laboratory method7. Pretreatment of the sample to
remove labile HbAlc is required to avoid false high results.
----- SEPTEMBER
1990
Evidence
of seasonal variation in concentration of
glycosylated hemoglobin in children with IDDM was shown
by 3 controlled trials12. Lower levels of HbA1c were seen
during the summer. The authors suggest that exercise,
dietary changes and the frequency of minor illnesses may all
contribute to this fluctuation.
In conclusion, glycosylated hemoglobin assay provides
information about the degree of long term glucose control
that is not otherwise obtainable. It does not however replace
urine and blood glucose monitoring which provide important
information for day to-day decisions.
SOME PRELIMINARY OBSERVATION
The Division of Endocrinology and Metabolism in the
77 —
St. John’s Medical College Journal of Medicine
Department of Medicine, St. John’s Medical College &
Hospital had an opportunity to make a randomized
observation of glycosylated hemoglobin values in NIDDM
patients with less than three years duration of diabetes
among the South Indian population. This observation is
made as part of an on-going I.C.M.R. trial.
CRITERIA FOR INCLUSION INTO THE TRIAL
1. Patients newly diagnosed to have NIDDM or within 3
years of diagnosis
2.
Patients aged 35 - 60 years
CRITERIA FOR EXCLUSION
1.
2.
3.
4.
5.
6.
Presence of nephropathy or retinopathy
CNS disease or CVS complications
Insulin administration essential
BMI less than 19
Pregnancy
Lactation
A HbA1c value of 6.8 +1.35 seems to indicate that there will
be a good control of blood sugars on diabetic diet alone (i.e.
FBS < 120, PPBS < 180), which is statistically significant
(p<0.01).
A randomized observation of HbAlc estimations of NIDDM
patients (of upto 3 yrs duration) in a South Indian population
shows that the mean HbA1c among these patients is 7.7%.
This shows that the patients are in a fairly controlled state
when attending the OPD. This observation supports what is
shown in literature and so holds good among our South
Indian Population too.
REFERENCES
1. Bunn H.F. Evaluation of glycosylated hemoglobin In diabetic patients,
Diabetes 1981 ;30:613-617
2. L.Kennedy, T.J. Lyons: Non*enzymatic glycosylation. British Medical
Bulletin, Diabetes 1989;Vol.45, No.1, pp.174-190
A total of 200 patients were enrolled into the trial. Initial
fasting and 2 hr. postprandid blood sugar estimations were
done using standard analytical techniques. Glycosylated
hemoglobin was estimated using the ion-exchange resin
method.
The patients were put on diabetic diets taking into account
their body mass index, ideal weight, actual weight, age, sex,
physical activity, occupation etc.
3. Mayer B,Davidson : Diabetes Mellitus : Diagnosis and Treatment (ed 2),
New York, John Wiley & Sons, 1986,p.298-303
4. Bunn H.F. Gabbey K.M. Gollop P.M. The glycosylation of hemoglobin
: relevance to Diabetes Mellitus Science 1978200:21
5. Goldstein, D.E. Parker K.M. Clinical application of glycosylated
hemoglobin measurements. Diabetes 1982;31(suppl.3) 70-78.
6.
Krall L.P, Beaser R.S., Joslins Diabetes Manuel 1989
7. Nakashima K. et al. Immediate elimination of labile HbAte with allosteric
effectors of hemoglobin Diabetes 1990;39:17-21.
RESULT
At the end of one month, fasting 2 hr post prandial blood
sugars and glycosylated hemoglobin were estimated.
Glycosylated hemoglobin values before and after diet was
available in 78 patients.
Out of the 78 patients diabetic control was achieved in 15
patients i.e. FBS 120 and PPBS 180. The remaining
patients (63) were still uncontrolled after 1 month of diet and
hence were started on oral hypoglycaemic drugs.
The mean HbA1c values of all the patients and the various
group are as follows.
Total patients
(78)
DISCUSSION
Mean HbAlc%
before diet
Mean HbAlc%
after diet
7.71 + 1.76
7.7 + 2.07
8. A study of effects of chronic opioid administration on insulin receptors in
rats and evaluation of glucose homeostatis in opioid addicts by glycosylated
hemoglobin (Thesis submitted to the Faculty of A.I.I.M.S. Ajay Sood 1987)
9. Klein et al Glycosylated hemoglobin predicts the incidence and
progression of diabetic retinopathy, JAMA 1988;260(19):2864-71
10. Ostiund R.E. Semenkovich CF, Schenchtman K.B. Quantitative
relationship between plasma lipids and glycohemoglobin in Type I Patients,
Diabetes Care, 1989;12:332-336.
11. Lucas, M.J. et al. Early pregnancy glycosylated hemoglobin severity of
diabetes and fetal malformations An J. Obstet Gynecol, 1989;161:426-431.
12. Hinde F.R.J. Standen P.J. Mann N.P., Johnston D.l. Seasonal variation
of hemoglobin A1 in children with insulin -dependent D.M. Eur.J.Pediatr,
1989;148:597-599.
COMMUNITY HEALTH CELL
Patients controlled
on diet (15)
Patients not
controlled on diet
(63)
6.8
+ 1.35
6.61 + 1.34
326. V Main, I Block
Korambngala
/
Bangalore-560034 * Z
India
7.93 + 1.77
7.96 + 2.13
vol in No. 3 —
MEDICINE - SYMPOSIUM
St. John’s Medical College Journal of Medicine
DIET IN DIABETES
C.B. SRIDHAR, LATHA SEKHAR
Diabetes Mellitus (DM) is a clinical syndrome characterised
by hyperglycaemia, due to deficiency or diminished
effectiveness of insulin. Approximately 90% of patients with
diabetes mellitus are non-insulin dependent diabetics (Type
II) occuring mainly in the middle-aged and elderly and
compatible with long survival often not necessitating
treatment other than dietary adjustment1.
There is still a strong feeling among community doctors that
diabetics with blood sugar values above normal have to be
started on oral hypoglycaemic therapy or insulin, without
focusing on diet. Thus, these patients continue on drug
therapy when this may not be needed.
Regulation of the type and quantity of food ingested is the
basis of treatment for all patients with diabetes. This
statement remains fundamentally as correct today as in the
pre-insulin erawhen dietary restriction, often severe was the
only method of treatment available2.
In our experience approximately 21% of Type II diabetic
patients can be controlled on diabetic diet alone, irrespective
of initial blood sugar values.
DEVELOPMENT OF DIABETIC DIETS
Attempts to modify diabetes mellitus by diet were made by
the Egyptians in 3500B.C. Arateusof Cappadocia (Second
Century A.D.) recommended milk with cereals, starch,
autumn fruits and sweet wines. In India, as early as 2500
years ago Sushruta and Charaka realized the importance
of diet restriction in the treatment of diabetes mellitus. They
adopted measures to correct obesity in diabetics. They
recognized that DM could be precipitated by taking rich
foods in large quantities. They also insisted on measuring
the diet for diabetics3. In the early twentieth century prior
to the discovery of insulin, the treatment of diabetes
included
intermittent
fasting, undernutrition and
carbohydrate restriction i.e. the Allen “Starvation diet".
Since the discovery of insulin, physicians specializing in the
care of diabetic patients have proposed a variety of “ideal
diets”. Between the extremes of “free" diets advocated by
the Tolstoi school and the weighed diets favoured by the
DRS. C.B. SRIDHAR, LATHA SEKHAR
DIVISION OF ENDOCRINOLOGY AND
METABOLISM
DEPARTMENT OF MEDICINE
ST.JOHNS MEDICAL COLLEGE HOSPITAL
BANGALORE.
----- SEPTEMBER 1990
Joslin Clinic, lie numerous proposals for high fat, low fat,
high carbohydrate and high polyunsaturated fat diets3.
The objectives of a rational approach to diabetes in addition
to limiting the effects of abnormal carbohydrate metabolism,
the diabetic diet should be designed to prevent or ameliorate
two problems that may be associated with diabetes - obesity
and hyperlipidemia.
The diabetic diet has four goals4
1. to provide good nutrition
Applicable to
2. to achieve normal weight and growth general
3. to decreases abnormal metabolism population
by attention to the total
whether diabetic
energy consumed.
or not
4. to prevent or delay diabetic
complications.
Such a diet requires consideration of the proper balance
of all the constituents of food (carbohydrates, protein,
fat,fibre etc)
CARBOHYDRATE: After the introduction of insulin, diets
were gradually liberalised, but in the early 1970’s most
dietary prescriptions still involved substantial restriction of
carbohydrate intakes. In 1935 Hinsworth had demonstrated
that in healthy volunteers a high carbohydrate intake was
associated with improvement in glucose tolerance.
Subsequently several investigators showed that low fat diets
(of necessity being high carbohydrate) not only reduced
plasma lipid levels but also did not worsen blood glucose
controls.
In the 1980’s the most important change in the dietary
recommendations for diabetes was the advice that
carbohydrates should provide at least 50% of total energy
intake, primarily as complex carbohydrates6. The European
and US guidelines suggest that carbohydrate might be
increased to provide 50-60% of total energy7. The National
Institutes of Health Consensus Conferences and
the
influential Standard group are against
increasing
carbohydrates on the grounds that such diets may induce
or accentuate hyper-triglyceridemia, lower high density
lipoprotein cholesterol concentrates or even result in
deterioration of glycaemic control. All these effects may
occur when high carbohydrate diets are not accompanied by
an increase in dietary fibre. The European and US
recommendations, emphasize that
only certain
carbohydrate containing, foods are acceptable.
In
particular foods high in soluble fibre (e.g. legumes, lentils,
oats and barley) or starchy foods that evoke a low
postprandial glycaemic response7 (e.g. pasta or rye-bread).
79 —
St. John’s Medical College Journal of Medicine
Glycaemic index is defined as the area under the 2 hour
blood glucose response curve for a particular food x 100
divided by the area under the 2 hour blood glucose response
curve for an equivalent amount of glucose. The present
studies emphasising the use of legumes and other “slow
release” or " lente” carbohydrates have demonstrated their
use in the dietary management of diabetes6.
FIBRE : Fibre being unabsorbable and resistant to
degradation in the bowel, slows the absorption of
carbohydrate
and
thereby flattens
post prandial
hyperglycaemia. This slow absorption is produced by slower
gastric emptying and slower small intestinal absorption.
Whatever the mechanisms, the addition of fibre to a meal
decreases postprandial glucose and insulin concentrations.
Trowell (1976) promoted the view that low fibre intake
predisposed to diabetes development and Kiehm et al.
(1976) demonstrated beneficial effects in terms of blood
glucose control of high carbohydrate/high fibre diets. Mann
and his colleagues in Oxford have systematically studied
the effects of high carbohydrate high fibre diets and have
clearly demonstrated that the latter-with much of the
additional fiber coming from legumes - produce an average
improvement in blood glucose levels throughout the day
in both IDDM and NIDDM together with a reduction in LDL
cholesterol levels5. Chronic ingestion of a high carbohydrate
(60%) and high fibre (25 gms of plant fibre/1000 cals.) also
reduces the requirement of oral hypoglycaemic drugs and
the insulin dosage. An equal benefit from a diet with added
cereal fibre and leguminous fibre was observed on a long
term9. Leguminous fibre is however by far most effective in
lowering blood cholesterol while cereal fibres do not lower
cholesterol. The use of foods that are lower in fat and higher
in fibre has found to be a useful adjunct to weight loss
protocols - because it allows patientsto eat similar quantities
of food that arecalorically more dilute10. Possible deleterious
effects of high fiber diets in vitamin and mineral balance
have not been documented in short term studies and must
be investigated further.
FAT : Fat is the most energy dense of all nutrients and so
reducing its intake is important in reducing total energy.
Decreasing the intake of saturated fatty acids to 10% or less
of total energy is also advised as this helps lower total and
low density lipoprotein cholesterol concentration and hence
probably reduces the risk of coronory artery disease7. The
elevation of triglyceride seen with high starch feeding is
mainly the effect of caloric excess11. It is not yet clear
whether serum triglyceride level is an independent risk factor
lor diabetic vascular disease. High caloric regimens tend
to raise serum triglyceride level whether the main source
is sugar, fat or starch. Increasing the intake of
monounsaturated fatty acids avoids hypertriglyceridaemia 7.
In IDDM patients lipid abnormalities secondary to the
diabetic state are most often corrected with achievement
of near normoglycaemia. However, other causes of
dyslipidaemia both secondary or primary should be treated
80
accordingly. The most important dietary modification is a
reduction in the total fat contentto approx. 25-30%of the total
daily caloric intake made up as 10% polyunsaturated, 10%
monounsaturated and 10% saturated fat. The cholesterol ■
content should be below 300 mg/day.
Unlike poly
unsaturated fat, there is no depressive effect on plasma HDL
concentrations by monounsaturated fat.
Persistant
significant hyperlipidaemia in the IDDM patient despite
improved glycaemic control and dietary measures for at least
3 months may indicate possible therapy with hypolipidaemic
drugs13.
In NIDDM patients adverse lipid and lipoprotein levels are
more commonly encountered13. Attention here should be to
improving glycaemic control and reducing obesity. Weight
loss is the most important dietary manipulation that will lower
insulin resistance and improve glucose utilisation in patients
with Type II diabetes. Despite strenuous efforts, a
considerable number of patients remain with moderate to
poor glycaemic control, often associated with obesity. In
these patients there is often a persistantly low plasma HDL
concentration with a raised plasma triglyceride and possible
raised cholesterol. These patients should be treated as
for primary hyperlipidaemia and hypolipidaemic drugs
should be prescribed if modified fat dietary advice has failed.
The drugs of the fibric acid and nicotinic acid group are
particulalry useful in this situation for treating the mixed
hyperlipidemia and these drugs may result in improved
glucose tolerance.
PROTEIN : A protein intake of approx 15% of the total
energy requirment is recommended today. Evidence has
suggested that too much protein may be bad for diabetics9.
For example 30-40% of IDDM patients have a slightly
raised albumin excretion rate (microalbuminuria) which is
thought to be a marker for future diabetic nephropathy.
Restriction of dietary protein does, in some cases reverse
the abnormality (Wiseman et al 1987). Animal protein may be
more harmful than vegetable protein.
For diabetic patients with nephropathy, food intake should
be planned to maintain the patient in a normal nutritional
status as with diabetic diets generally. In the presence of
poor renal function dietary proteins should be reduced to
between 30-50 gms/day but adequate caloric intake must
be assured by carbohydrate and fat supplementation to
prevent malnutrition especially in the presence of severe
proteinuria. The fluid intake should be adjusted to the point
of producing a urine volume of 1200 to 1500 ml daily.
Caloric allowances : The caloric allowances for a given
diabetic are calculated on the basis of age, weight, sex and
physical activity. The aim should be to provide sufficient
calories - to achieve and maintain a reasonable body weight.
In IDDM patients, excessive body weight is infrequent at the
onset of diabetes. Hence a diet to maintain ideal body weight
is prescribed for these patients. NIDDM patients may be
obese or non obese. Caloric restriction and weight reduction
VOL III No. 3 —
St. John’s Medical College Journal of Medicine
Chart showing changes in the diabetic diet (Pre-1958-Now)
Fat 15%
Fat 25 %
Fat 30 %
Fat 50 %
Protein 19 %
Protein 15 %
Protein 10 %
Protein 17 %
Carbohydrate
33%
Carbohydrate
60%
Carbohydrate
restricted diet
Pre 1958
High Carbohydrate
diet 1958-68
represents an optimal initial treatment for obese patients.
The non obese patients need a diet which is approximately
isocaloric with that prior to onset.
Lean and James reported that compliance with diet is
extremely poor*. In fact, in patients on energy restricted diets
only the group with an energy reduction of 500 k cals or less
a day showed acceptable levels of compliance. Hence, the
importance of realistic dietary goals must be emphasized.
In the assessement of obesity, Body Mass Index is used
frequently.
Carbohydrate
67%
High carbohydrate
high fibre diet
1968 onwards
Classification of obesity14
Body Mass Index
Grade 0
Normal
20
- 24.9
Grade 1
Moderately
obese
25
- 29.9
Grade II
Grade III J
Severely
29.9 - 39.9
obese
>40 _
(b) allowing 30 calories/kg of ideal body weight if the patient
needs to maintain weight
(c) 35-40 calories/kg of ideal body weight for patients who
need to gain weight, for adolescent patients or for patients
whose usual physical activity is deemed excessive.
After the age of 50 years for each decade 10% of the total
calories is lowered because of the decreases in physical
activity, lean body mass and resting metabolic rates that are
associated with aging.
Some of the current recommendations of the British
Diabetic Association are listed9:
-
-
The actual total caloric intake is calculated
(a) allowing 20-25 calories/ kg of ideal body weight if the
patient needs to lose weight *
1990
Now
A recent survey of diabetic dietary management in 26
European Diabetes Centres revealed widely differing views9.
Consensus was reached only on 3 points that all diabetic
should have a high fibre intake, overweight diabetics should
restrict total calories and ID diabetics should have regular
meals.
Weight (Kg)
Body Mass Index = ----------------------------height2 (meters)
----- SEPTEMBER
Carbohydrate
60%
-
Total energy content of the diet is most important
Most carbohydrates should be taken as polysacharides
such as bread, potatoes, cereals and beans. Mono and
disacharides should be avoided when possible.
Fat intake should be restricted to 35% of the total energy
value and therefore carbohydrate should be increased to
50% or more.
Saturated fats in particular should be eaten only in small
quantities
8 1 —
St. John’s Medical College Journal of Medicine
-
Timing of meal is important if the patient is taking insulin or
oral hypoglycaemic drugs and some system of carbohy
drate portions of exchange remains essential in these
patients.
In summary the best diet forpatients with NIDDM is one that
optimizes plasma lipid levels, minimises hypperglycaemia
and reduces obesity.
Study at St.John's Medical College and Hospital
The Endocrinology Division of Department of Medicine St.
John’s Medical College and Hospital has conducted a trial to
assess the efficacy of diabetic diet alone in the
management of NIDDM patients.
improve although blood sugar levels normalized.
DISCUSSION
In the treatment of NIDDM all too often, one observes the
typical obese
patient presenting only with moderate
hyperglycaemia who has been committed immediately to
treatment with oral agents or insulin. In the worst examples,
this error is compounded by the use of such agents without
any
attempt
to
prescribe
an appropriate diet
concommitantly.
CONCLUSION
1. Newly diagnosed or untreated cases of DM Type II
(i.e. NIDDM)
2. Patients aged 35-60 years
In conclusion employment of a diabetic diet alone should
be initiated forpatients with NIDDM and tried for a minimum
period of 1 month before starting antidiabetic agents
irrespective of blood sugar values. The patients should be
instructed regarding the symptoms of uncontrolled diabetes
such as excessive thirst, polyuria and weight loss. Further
patients should be taught home monitoring of urine for
sugars and ketone bodies. In our experience all the patients
have accepted the diet without any problems.
Criteria for exclusion were :
REFERENCES
The following were the selection criteria :
1. Davidson's Principles and Practice of Medicine (ed.15) UKLongmann
Group, 1987;pp461-62
1. Presence of nephropathy or retinopathy
2. Neurological or cardiovascular disease
3. Insulin administration essential
4. BMI less than 19
5. Pregnancy
6. Lactation
2. Krall L.P. Beaser R.S.: Joshin's diabetes mellitus (ed. 12) Philadelphia,
Lea & Febiger, 1985.p.357
3. Max Ellenberg Harold Refkin: Diabetes Melitus: Theory and Practice US,
McGraw Hill, 1970;pp.595-96
A total of 169 patients were screened and enrolled for the trial.
BMI was calculated for each patient. Patients were put on
a weight reducing diet (if obese). Initial fasting and 2 hour
postprandial blood sugar estimations were done using
standard analytical techniques. Total caloric intake was
calculated for each patient using ideal weight, actual
weight, age, sex, physical acitivity and occupation. The
patients were put on this diet for one month. At the end of the
one month, fasting and 2 hour, pbstprandial blood sugars
were repeated.
4. Besser G.M. Bodensky M.J. Cudworth A.G. : Clinical
Philadelphia, JB Lippincott Company 1989;p.18.2
5.
Diabetes,
R.J. Jarret: Diabetes Mellitus, Massachusetts, Littleton, 1986, p.80.
6. Lean MEJ, James W.P.T. : Prescription of diabetic diets in the 1980's
Lancet 1986;1:723-5
7.
Mann J: Diabetic dietry prescriptions, Br.Med.J. 1989;298:1535-1536
8. Mayer B Davidson : Diabetes Mellitus : Diagnosis and treatment (ed.2)
New York, John Wiley and Sons, 1986;pp.72-73
9. Simpson H.C. : diet for Diabetes - a critical review Practitioner,
1987;231:1450-1454.
RESULT
36 patients out of 160 were controlled by diet alone :
Patients Controlled on diet (36)
Before diet
Mean Fasting
blood sugar (mgm%)
Mean Post
prandial blood
sugar (mgm%)
163
After diet
103
11. S.Baba, Got Y I.Fukne : Diabetes Mellites in Asia, Ecological Aspects of
Epidemiology, Complications and Treatment, Proceedings of the Second
Symposium, Kyoto, Japan Sept. 9-11, 1975; Amsterdam, Oxford, Exerpta
Medica, 1976;p.27O
12. Podolsky S ‘Clinical Diabetes : Modern Management. New
Appleton, 1980;p.69.
York
13. Betteridge D.J. Diabetes, Lipoprotein Metabolism and atheroscelosis,
British Medical Bulletin, 1989;45:301-302
237
143.
In 83% of the 36 patients the Body Mass Index improved
or remained normal. In some patients, however, BMI did not
82
10. Strain G.W. Zumoft B.: High monounsaturated Fat Diet for NIDDM
(letter) N. Engl. J.Med. 1989,320:535.
14. Jones W.P.T.: Treatment of Obesity : The constraints on Success,
Clinics in Endocrinology and Metabolism 1984;13:636.
15. Gallagher J.R. Medical Care of the Adolescent (ed.2),
appleton, 1966;pp.208-215.
New York,
VOL III No. 3-----
MEDICINE - SYMPOSIUM
St. John’s Medical College Journal of Medicine
INSULIN THERAPY - CURRENT CONCEPTS
K.S. CHANDRA MOULI
INTRODUCTION
The advent of insulin dramatically altered the outlook for
patients with diabetes mellitus, particularly those with the
insulin dependent type. The dramatic reduction in mortality
from the acute metabolic complications, unmasked a
spectrum of longterm micro & macrovascularcomplications
which have become the major causes of moibidity & mortality
in these patients. Studies in animal models showed a definite
cause and effect relationship between
the vascular
complications of diabetes & hyperglycemia. This led to
efforts to achieve euglycemia in diabetics. The advent of self
monitoring of blood glucose and glycosylated hemoglobin
assays made accurate assessment of glycemic control a
possibility and the achievement of euglycemia a reality.
Intensive insulin regimens were introduced, with the hope
that euglycemia would prevent or atleast retard the
progression of long term complications. Controlled trials in
humans having failed to provide a definite answer to the
question of ‘control & complications’1,2 and the risks of
intensive insulin regimens being significant, the question of
how aggressive one should be in the management of
diabetes mellitus remains unanswered, except in a few
situations.
This article reviews the current status of insulin in the
treatment of diabetes mellitus.
INSULIN : THE CHOICE
Standard insulins are preparations that have been purified
by repeated recrystallization. In addition to insulin, these
preparations contain proinsulin, insulin dimers, pancreatic
polypeptide, somatostatin, glucagon and vasoactive
intestinal polypeptide. Single peak insulins are those that
have undergone gel filtration in addition & contain
substantially less proinsulin. Monocomponent or highly
purified insulins are those that have undergone ion exchange
chromatography in addition to the above processes. They
contain much less proinsulin and are almost free of other
contaminants. Purified insulins are much less immunogenic
than the standard preparations and their introduction has
led to a dramatic lowering in the Incidence of immune
mediated side effects of insulin such as lipoatrophy, insulin
allergy & immunologic insulin resistance3. As far as possible
DR. K.S. CHANDRA MOULI, MD
ASSISTANT PROFESSOR
DEPARTMENT OF MEDICINE
ST.JOHNS MEDICAL COLLEGE & HOSPITAL
BANGALORE - 560 034
----- SEPTEMBER
1990
ail patients on insulin should
preparations.
receive
the
purified
Human insulins4 may be semisynthetic or biosynthetic and
are becoming easily available. The clinical significance of
the marginally less immunogenicity of human insulin as
compared to purified porcine insulin remains to be fully
evaluated. Allergic reactions to human insulin have mostly
been reported in patients previously exposed to animal
insulin5. Allergy has also been reported in a patient directly
treated with human insulin6. The definite indications for
human insulin are all newly diagnosed diabetics requiring
insulin, patients requiring insulin temporarily (for eg.at the
time of surgery) as intermittent therapy with insulin
increases it’s antigenicity and patients with any of the
previously mentioned immune mediated reactions to animal
insulins. With the easy availably of human insulin, it seems
logical that animal insulins will be eventually replaced by
human insulin. One possible drawback of human insulin is
that it causes
hypoglycemic unawareness due to
different counterregulatory
hormone responses as
compared to animal insulins. A number of studies done to
resolve the issue have shown conflicting results. Till a
definite answeris obtained, it has been suggested that animal
insulins be continued in patients stable on them, and to revert
back to animal insulins in patients who experience or who are
apprehensive of such a problem.
A dose reduction is warranted while changing from standard
to purified insulins and from purified porcine to human
insulins. Human and purified porcine insulins are of equal
potency and have a
similar action on intravenous
administration.
However, subcutaneously administered
human insulin has an earlier, larger and a shorter
hypoglycemic action, warranting an adjustment of the
dosage schedule when a switch is made from one to another.
A 20% reduction in the dose of human insulin is advocated
on changing over, if the patient is receiving greater than 40
units of purified porcine insulin.
Recombinant DNA technology, by amino acid substitutions
in the human insulin molecule, has made the development
of ‘Designer Insulins’8 with better pharmacokinetic and
pharmacodynamic properties possible. The role of these
insulins in the therapy of diabetes remains to be assessed.
INSULIN : MODE OF ADMINISTRATION
Subcutaneous injection remains the most widely used route
of insulin administration. Intramuscular and intravenous
routes can be used over short periods of time and are most
often employed in the treatment of acute metabolic
complications of diabetes.
83 —
St. John’s Medical College Journal of Medicine
Intranasal administration of insulin is feasible9-10-11 and may
become a viable option for administration of short acting
insulins. Insulin, along with a surfactant to promote it's
absorption is administered in the form of drops or an aerosol.
The major concerns regarding the use of intranasal insulin
are the low potency (one tenth to one fifteenth that of
intravenous insulin), the cost, the long term safety of
surfactants and the influence of rhinitis on the absorption.
Administration
of chymotrypsin inhibitors permit the
absorption of orally administered insulin.12 Absorption of
orally administered insulin, with polyalkylcyanoacrylate
nanocapsules as a drug carrier has been demonstrated in
rats.13 The clinical utility of these findings remain to be
assessed. Continuous intraperitoneal insulin infusion
through a subcutaneous access device has been tried with
success in patients who
were unresponsive to
subcutaneous insulin and in whom an intravenous access
could not be maintained14.
obtaining blood glucose profiles periodically.
INSULIN : REGIMENS
Conventional insulin regimens involve one or two injections
of intermediate acting insulin (NPH or Lente) with or without
the addition of regular insulin. Intensive insulin regimens
employ either multiple daily injections or continuous
subcutaneous insulin infusion21. A brief discussion of the
intensive insulin regimens follows.
MULTIPLE DAILY INJECTIONS (M.D.I.JF^3
The conventional syringe remains the device of choice for
insulin administration. Jet injectors offer no significant
advantage over conventional syringes15 and are less
accurate when used to deliver very small volumes16. Pen
injectors are convenient17
but possible mechanical
breakdown is a disadvantage16. Contamination of insulin
with silicone resulting in clouding and loss of activity has
been reported with the use of disposable syringes17,19.
It is advisable not to reinject into the vial any excess of insulin
drawn into the syringe, to avoid such contamination.
MDI regimens utilize either long acting insulins (PZI or
ultralente) given with supper or intermediate acting insulins
(NPH or lente) given twice daily to provide basal insulin
requirements. Short acting insulin is given before each meal.
Short acting insulin should be given atleast 30-60 minutes
before the meal (provided the preprandial blood sugar is
greater than 60mg/dl) to avoid immediate post prandial
hyperglycemia and late hypoglycemia. While initiating the
regimen, the dosge of intermediate or long acting insulin is
adjusted on the basis of the fasting sugar values and the
regular insulin on the basis of the post prandial values of the
previous day. Once a stable pattern is obtained the daily
regular insulin dose is adjusted on the basis of the preprandial
sugar values obtained before each meal, as shown in the
table below. Changes will also have to be made on the basis
of meal size, composition and anticipated postprandial
exercise.
SELF MONITORING OF BLOOD GLUCOSE (SMBGJ50
Table
The introduction of simple meters for measurement of
blood glucose in the seventies made patient self monitoring of
blood glucose practical. It was found that patients could
obtain capillary blood easily, had few technical difficulties
in performing the test and the determinations were
sufficiently accurate for clinical use. SMBG revolutionized the
monitoring of glycemic control and made the attainment of
euglycemia feasible.
Preprandial
glucose value
mg/dl
<60
60-90
91-120
121-150
151-200
201-250
>250
Change in the
preprandial
insulin dose
- 2
0
+1
+2
+3
+4
+6
SMBG is an integral part of all intensive, insulin regimens
(including pregnancy). A patient being started on an
intensive regimen will require atleast seven measurements
(before and after each meal and in the night) daily till the
desired target sugar is reached and a stable pattern is
achieved. Subsequently, atleast four measurements (before
each meal and at bed time) will have to be taken daily and
a complete profile atleast once a week. Additional
measurements will have to
be
taken
whenever
hypoglycemia is suspected. Periodically, laboratory values
have to be obtained to check the validity of SMBG. SMBG
is also recommended in pateints with 'unstable diabetes’, in
those with abnormal renal thresholds for glucose and in the
documentation of hypoglycemia especially in the presence
of hypoglycemic unawareness. SMBG can also be used
routinely for intermittent assessment of glycemic control by
Insulin is delivered through a 25 gauge scalp vein indwelling
needle positioned subcutaneously in the abdomen, the pump
being worn on a belt. The needle and the site of infusion are
changed every second day. Therapy is initiated with 0.6
to 0.7 units/kg/day, 50% of which is given at a constant basal
rate. The remaining insulin is given as preprandial bolus
S4 ------------------------------------------------------------------ ----------- --------------
VOL HI No. 3 —
----
In patients objecting to multiple injections, insulin can be
adminstered
through
a butterfly
needle
placed
subcutaneously over the abdomen and changed every five
days24.
Continuous subcutaneous insulin infusion (CSII)22,25
St. John’s Medical College Journal of Medicine
doses, 15-30 minutes prior to each meal. SMBG is an
integral part of the regimen. The basal infusion rate is
adjusted on the basis of the 3.00 AM glucose value (the
blood sugar reaches its nadir around this time), upwards
if the value is greater than 120mg/dl and downwards if the
value is less than 80 mg/dl. The preprandial bolus doses
are adjusted on the basis of the postprandial glucose values
of the previous day till
a stable pattern is achieved.
Subsequently the preprandial glucose values are used to
adjust the dose of insulin before each meal. Allowances
will have to be made for the meal size, composition and the
anticipated post prandial exercise.
With CSII it may be difficult to achieve a fasting
normoglycemia without nocturnal hypoglycemia because of
the dawn phenomenon, (the progressive increase in blood
sugar levels following it's nadir around 3.00 AM). Nocturnal
hypoglycemia has to be avoided at all costs. Multiple basal
rate pumps can provide changing infusion rates and avoid
this problem. Subcutaneously implantable glucose sensors
have been developed and when incorporated into closed
loop insulin delivery systems for continuous feed back, will
represent a major advance in CSII and help overcome this
problem.
INTENSIVE REGIMENS : THE RISKS
The most importance disadvantage of intensive insulin
regimens is the three fold increased risk of hypoglycemia as
compared to conventional regimens. The consequences of
prolonged hypoglycemia are only too well known. Nocturnal
hypoglycemia can be particularly dangerous as the patient
may remain unaware of it. Added to this is the problem of
loss of counter regulatory responses to hypoglycemia in
patients with IDDM26,27.
Diminished glucagon
and
catecholamine responses to insulin induced hypoglycemia
have been documented in patients with IDDM. The
importance of monitoring the 3.00 AM glucose value and
ensuring that it remains over 80mg/dl cannot be over
emphasized.
A transient deterioration in retinopathy28, following
introduction of intensive insulin regimens has been
documented and would require appropriate monitoring..
However, a background retinopathy is not considered a
contraindication for intensive therapy. CSII has, in addition
certain unique problems such as mechanical breakdown,
infection at catheter site and a higher incidence of diabetic
ketoacidosis (as compared to MDI). In addition, the cost, the
effort on the part of the patient and the inconvenience of the
regimens (including that of SMBG) are all important
considerations while evaluating a patient for an intensive
regimen.
congenital malformations seen in the infants of diabetic
mothers29,30 and that poor control in the subsequent months
of pregnacy is responsible for most of the perinatal morbidity
and mortality31. Hence, pregnancy is an absolute indication
for SMBG and maintenance of normoglycemia (levels
of 60-120 mg/dl) throughout32. This is rarely possible
without an intensive insulin regimen. It is recommended that
all IDDM patients who wish to concieve should enter a
programme of intensive monitoring and therapy to achieve
euglycemia prior to conception.
Meticulous control is also indicated in all renal tranplant
recipients with the hope that it will prevent the development of
nephropathy in the tranplanted kidney21.
In
patient with IDDM, the question of ‘Control &
Complications’ remains unresolved. The DCCT trial33, the
results of which are expected in 1993 will hopefully provide
a definite answer. Till such time it can not be recommended
that all IDDM patients be routinely treated with intensive
insulin regimens. At present, only highly motivated patients
and those who fail to achieve even minimal treatment goals
(symptomatic relief, relief from ketonuria and normal
development in children) on conventional regimens are
candiates for intensive therapy. With conventional regimens
a HbA1c level of 7.5% to 9.5% (non diabetic range 3.8 to
6.3%), corresponding to a mean plasma glucose level of 160230 mg/dl would be realistic goal. With intensive regimens,
therapy should be directed to achieve preprandial glucose
levels of 70 to 120 mg/dl and HbA1c levels within the normal
range (or atleast less than 7.5%)22.
Treatment goals in patients with NIDDM would be a fasting
plasma glucose value less than 140 mg/dl and a HbA1c value
of less than 8.5%S4. Majority of these patients can be
managed with diet, oral hypoglycemics and conventional
insulin regimens. If these fail, intensive regimens can be
utilized to achieve treatment goals, in well motivated patients.
Other benefits of intensive regimens21 and potential
indications for the same would be a greater feeling of well
being, a greater resistance to infection, improved healing
of foot ulcers, normalization of lipid profiles and improvement
in gastroparesis.
The contraindications for intensive regimens are the loss of
counter-regulatory responses to hypoglycemia and an
inability or unwillingness on the part of the patients to
assume responsibility for implementation of the programme.
Relative contraindications
for
such regimens
are
established
diabetic proliferative
retinopathy
or
nephropathy, cerebrovascular or cardiovascular disease
and a life expectancy of less than 10 years.
INSULIN REGIMENS : SELECTION
CONCLUSION
There is strong evidence that poor glycemic control in the
early weeks of pregnancy is responsible for the
The advent of insulin markedly reduced the mortality due to
acute metabolic complications of diabetes mellilus and made
----- SEPTEMBER
1990
85 —
St. John’s Medical College Journal of Medicine
long term survival possible for patients with IDDM. Intensive
insulin therapy and achievement of euglycemia has vastly
improved the outcome of pregnancy in diabetics and it
remains to be seen whether it will have a similar impact
on the long term complications of diabetes mellitus.
REFERENCES
1. Sounding board : Are continuing studies of metabolic control and
microvascular complications In insulin-dependent diabetes mellitus justified?
The diabetes control and complications trial. N Engl J Med 1988;318:246-250.
2. Zimmerman BR : Influence of the degree of control of diabetes on the
prevention, postponement and amelioration of late complications. Drugs
1989;38:941-956.
3. Reynolds JE (ed): Martindale, The Extra Pharmacopoeia, 29th Edition,
London, The Pharmaceutical Press, 1989,391-397.
4. Brogden RN, Heel RC: Human insulin, a review of it’s biological activity,
pharmacokinetics and therapeutic use. Drugs 1987;34:350-371.
5. Grammer LC, Boyd E: Cutaneous allergy to human (recombinant DNA)
insulin. JAMA 1984;292:933.
6. Krans HMJ : Insulin, glucagon and oral hypoglycemic drugs. In Dukes
MNG, BeeleyL (eds): Side effects of drugs annual 12, Elsevier, Amsterdam,
1988:358.
7.
Gaylarde PM, Sarkany I: Jet injection of insulin. Lancet 1985;1:1513
17. Home PD, Thow JC, Tunbridge FKE: Insulin treatment a decade of
change. Br Med Bull 1989;45:92-110.
18. Krans HMJ : Insulin, glucagon and oral hypoglycemic drugs. In Dukes
MNG, Beeley (eds): Side effects of drugs annual 13, Elsevier, Amsterdam
1989,p:382.
19. Chantelau EA, Berger M: Pollution of insulin with silicone oil, a hazard of
disposable plastic syringes. Lancet 1985;1:1459.
20. Skyler JS : Self monitoring of blood glucose. Med Clin
1982;66:1227-1250
North Am
21. Unger RH, Foster DW: Diabetes mellitus In Jean D Wilson, Daniel W
Foster (eds). Williams Textbook of Endocrinology, Philadelphia, WB
Saunders Company 1985; 1057
22. Nathan DM: Modern management of insulin dependent diabetes mellitus.
Med clin North Am 1988;72:1365-1378
23. Schiffrin A : Treatment of insulin-dependent diabetes mellitus with
multiple subcutaneous insulin injections. Med clin North Am 1982:66:12511267
24. Slama G, Garrel D, Tchobroutsky: Multiple daily insulin injections
through subcutaneously implanted needle. Lancet 1980;1:1078.
25. Raskin P : Treatment of insulin-dependent diabetes mellitus with portable
insulin infusion devices. Med clin North Am 1982;66:1269-1283
MacPherson NJ, Feeley J : Insulin. Br Med J 1990;300:731-736
8. Pickup J: The pursuit of perfect control in diabetes. Better insulin better
delivered Br Med J 1988;297:929-931.
9. Pontiroli AE, Miriam AlberettoM, An toniosecchi, Dossi G.Bosi I, Pozza
G. Insulin given intranasally induces hypoglycemia in normal and diabetic
subjects. Br Med J 1982;284:303-306.
10. Salzman R, Manson JE, Griffing GTetal: Intranasal aerosolized insulin,
mixed meal studies and long term use in Type 1 diabetes. N Engl J Med
1985:312:1978-1084.
11. Lassman-Vague V, Thiers D, Vialettes B, Vague PH: Preprandial
intranasal insulin. Lancet 1988;1:367-368.
12. Masaki Shinomiya, Kohji Shirari, Yasushi Saito, Sho Yoshida, Nobuo
Matsuoka : Effect of new chymotrypsin inhibitor (FK-448) on intestinal
absorption of insulin. Lancet 1985;1:1092-1093.
13. Damge C, Michel C, Aprahamian M, Couvreur P: New approach for oral
administration of insulin with polyalkylcyanoacrylate nanocapsules as drug
carrier Diabetes 1988;37:246-251.
14. Schade DS, Eaton PR, Warhol RM, Gregory JA, Doberneck RC:
Subcutaneous peritoneal access device for Type 1 diabetic patients
nonresponsive to subcutaneous insulin. Diabetes 1982;31:470-473
15.
16.
Editorial: Jet injection of insulin. Lancet 1985;1:1140.
86
26. De Feo P, Bolli G, Perriello G et al: The adrenergic contribution to
glucose counter regulation in Type-I diabetes mellitus. Dependency onA-cell
function and mediation through Beta2 adrenergic receptors Diabetes
1983;32:887 893.
27. Boden G, Reichard Jr GA, Hoeldtke RD , Rejvani I, Owen QE: Severe
insulin induced hypoglycemia associated with deficiencies in the release of
counterregulatory hormones. N Engl J Med 1981;305:1200-1205
28. Jorgensen DK, Brinchmann-Hansen O,'Hansen KF et al: Rapid
tightening of blood glucose control leads to transient deterioration of
retinopathy in insulin-dependent diabetes mellitus: the Oslo study Br Med J
1985:290:811-815.
29. Miller E, Hare JW, Cloherty JPet al: Elevated maternal hemoglobin A1c
in early pregnancy and major congenital anomalies in infants of diabetic
mothers. N Engl J Med 1981;304:1331-1334.
30. Mills JL, Knopp RH, Simpson JL et al: Lack of relation of increased
malformation rates in infants of diabetic mothers to glycemic control during
organogenesis. N EnglJ Med 1988;318:671-676.
31. Jovanovic L, Druzin M, Peterson CM : Effect of euglycemia on the
outcome of pregnancy in insulin dependent diabetic women as compared with
normal control subjects. Am J Med 1981 ;71:921-927. 32. London MB, Gabbe SG : Diabetes and Pregnancy. Med Clin North Am
1988;72:1493-1511.
VOL III No. 3-----
MEDICINE - SYMPOSIUM
St. John’s Medical College Journal of Medicine
HEMORRHEOLOGY AND GENESIS OF DIABETIC
MICROANGIOPATHY
CECIL ROSS
The curse of Diabetes Mellitus has been the microvascular
complications. Ever since Best, Banting & Macleod in 1921
gave us insulin, acute metabolic complications could be
corrected quite rapidly and effectively. The answer to the
micro vascular disease may be in the hemorheological
properties of the blood. Rheology (from the Greek rhein, to
flow) deals with the deformation & flow of matter, and
hemorrheology with the flow properties of blood. The most
important of these properties is viscosity, the reciprocal
of fluidity. Alteration in blood flow and pressure in the micro
circulation is mainly responsible for the microvascular
complications in diabetes. A brief discription of the normal
microcirculation is useful in understanding the genesis of
microangiopathy.
THE NORMAL MICROCIRCULATION
The typical microvascular bed is represented in Fig.1. It
consists of the (a) arteriole (b) the capillaries (c) the post
capillary venule & (d) the distal venule. It has a single layer
of endothelial cells surrounded by their basement
membranes. This splits to enclose an occasional pericyte.
Not only is it best suited fortransport and exchange between
blood and tissue fluids but also for multiple synthetic
functions, anticoagulant activity & contractility.
Fig 1 : Generalised anatomical diagram illustrating component parts of
microvascular networks, including arterioles, capillaries, venules, and
lymhastic. Symbols .* fa, terminal arteriole; c, capillary; I conducting lymphatic;
tb, lymphatic terminal bulb. The arrows show the direction of blood and lymph
flow. The topology is that of a thin, flat tissue (like mesentery).
DR.CECIL ROSS MD,
DEPT. OF MEDICINE,
ST.JOHN'S MEDICAL COLLEGE,
BANGALORE.
----- SEPTEMBER 1990
In between the blood microcirculation, there is the interstitial
network of the lymphatic microcirculation. By this, the excess
of water and extravasated macromolecules are returned to
the blood. Not much is known of its functional detail in health
and of its integrity in Diabetes.
MICROANGIOPATHY - THE PATHOGENESIS
Two theories exist-The Metabolic theory and the Inherited
theory. The Metabolic Theory According to this all forms
of diabetes are characterised by hyperglycaemia and
abnormal insulin secretion. The metabolic changes that
occur are the primary factors for the development of
microangiopathy, the hall mark of which is basement
membrane thickening. The basement membrane producing
cells in diabetics are hypersensitive to Insulin accounting
for some degree of hypertrophy1
Glycosylation of basement membrane (BM) makes it more
resistant to normal process of degradation2. There is an
impaired synthesis of the negatively charged proteoglycans in
the BM, accounting for the reduced charge barrier. Thus, the
capillary wall though thickened, offers a reduced barrier to
macromolecules. It is probable that BM thickening is not
just a consequence of the metabolic derangement. It may
represent a proliferative response of the capillary endothelial
cell to injury or raised capillary pressure.
While hyperglycaemia undoubtedly plays a necessary role in
the pathogenesis and evolution of BM thickening, its
expression may be modified by topographical and
hemodynamic differences in vascular beds. For example the distal capillaries in the lower limbs are exposed to much
higher capillary hydrostatic pressure. Hence the capillary BM
is also thicker in the muscle biopsies taken from distal lower
limb than the thigh3. The data of Williamson Kilo & Co
Workers4 shows that capillary BM thickening increases with
age, and is more in males than in females. This differrence
is aggravated by diabetes mellitus. They also show that on
an average, BM is thicker in diabetics at all ages than
controls. This suggests that it may be related to the diabetic
duration and the duration of undetected asymptomatic
carbohydrate intolerance.
The endothelial function in diabetes : The synthetic
function of the endothelial cells is altered in diabetes5. There
are 4 main pieces of evidence of altered endothelial cell
functions.
1. Increased von Willebrands factor (vWF)
2. Altered fibrinolytic activity
3. Decreased prostacyclin release
4. Decreased lipoprotein lipase activity
87 —
St. John’s Medical College Journal of Medicine
The Sorbitol. Polyol pathway
Aldolase
Glucose----------------------------------------- Sorbitol
Reductase
Sorbitol
-------------------------------------------------------- Fructose
dehydrogenase
Increased Polyol
pathway
Decreased nerve conduction
/b
Decrease in Myoinositol ——■------------------------------------- > Decreased Na+/K* AT Pase activity
There are 15 studies which document increased levels of
plasma vWF in diabetes6.23 studies discuss the fibrinolytic
activity and there is no consistency as to whether activity is
low, normal or elevated6. There are 18 studies in human
subjects showing reduced release of prostacyclin from
vascular endothelium6. Older studies have shown that
lipoprotein lipase may be suppressed. These changes occur
early in diabetes and there is evidence that some of these
changes may be reversed with Insulin therapy. While this
would apply well to kidneys and eyes which have
endothelium, the nerve tissue merits separate consideration
- the sorbitol, accumulation by the polyol pathway. This is
shown above
THE BLOOD CELLULAR BEHAVIOUR IN DIABETES
The work of Siperstein& Co workers suggests that diabetic
vascular disease is an independent lesion of the diabetic
syndrome8-9. There is an inherited abnormality affecting the
capillaries in various tissues that is reflected in the
development of increased capillary basement membrane
thickness. This micro angiopathy though genetically linked to
diabetes is unrelated to hyperglycaemia and/or alteration
in insulin secretion. This forms the pathogenetic basis for
retinopathy and nephropathy. This theory does not explain
the increase incidence of myocardial infarctions and
peripheral arterial occlusions.
Blood is not a simple fluid. Blood vessels are not straight or
rigid and blood flow is pulsatile. For good micro-circulation,
the blood must have minimum viscosity (maximum fluidity).
Blood viscosity is influenced by both the plasma viscosity
and the cellular elementsofblood-theRBCs.theWBCs and
platelets. The viscosity of blood is increased and the red
cell deformability is decreased by poor glycaemic control.
Glycosylation of membrane protein and alteration in the
membrane cholesterol/phospholipid ratios are postualted for
this. Some data suggested that white cells are necessary for
decreasing the red cell deformability and the change in the
rheological properties of the white cells10 may play an active
role in microvascular obstruction and hence ischemia and
infarction11. During poor control, there is increased sensitivity
of platelets to thromboxane and reduced sensitivity to
prostacyclin probably adding to microvascular obstruction.
Despite being an attractive theory, convincing in-vivo proof
is lacking. One study showed that unless ketosis is present
or the arterial pressure head is reduced, there is no
significant change in the blood cellular behaviour12.
However.it is reasonable to conceive that changes in blood
rheology will have maximum impact when the auto
regulatory capacity fails. In the face of rapidly diminishing
vessel diameter, when the endothelial cells are exposed
to hyperaggregable red cells, there is a high shearing force
which is injurious to the microcirculation. This forms the basis
for the recent hemodynamic theory of diabetic micro
angiopathy.13
What is not disputed is that there is widespread alteration in
the ultrastructure of capillaries in long standing diabetes, the
brunt being on the microvascular bed of the kidney and
retina. The dispute is the relationship of these changes to the
diabetic dysmetabolism and its consequences. The
polemics of control versus non-control in pathogenesis of
complications is important. The issue of greater significance
is the understanding and definition of the nature of nonglycemic factors in the pathogenesis of micro angiopathy
and how these factors may modify or condition the putative
beneficial effects of diabetic
control in preventing
microangiopathy.
According to this theory, there is capillary hypertension in the
early stage of diabetes. This is seen in the kidneys by
micropuncture studies14. It is characterised by hyper
Alteration. Due to increased flow and presure, there is
microvascular sclerosis and autoregulatory failure. Such
changes have also been demonstrated in the
cerebrovasculature,15and the eye16. Renal artery stenosis
protects the kidney against glomerulopathy17 and unilateral
carotid artery stenosis protects the ipsilateral retina against
retinopathy18. If areas of an organ are underperfused, the
total organ blood flow being unchanged, it is reasonable
to assume that remaining vascular radicals are over
Hyperglycemia induces increased activation of the polyol
pathway because of aldose reductase found in tissues
subject to diabetic complications.
THE INHERITED THEORY
88
VOL III No. 3-----
St. John’s Medical College Journal of Medicine
perfused. In organs which have intermitted perfusion such
as the heart and the soles of the feet, there is generation of
oxygen free radicals and subsequent reperfusion injury. This
effects the diabetic patient adversly. Prospective clinical
trials are needed to study the effect of pharmacological
amelioration of capillary hypertension.
Against this background of interrelated disturbances working
in concert in the development of microangiopathy, the
following stages can be defined:
I EARLY REVERSIBLE STAGE (functional changes)
II LATE IRREVERSIBLE STAGE (structural changes)
In the early stage capillary hypertension is important. Two
factors determine the risk of development of microangiopathy
1) The level of prevailing blood pressure. 2) The duration
of diabetes post-puberty. At this stage, the disturbances at
the microvascular function may still be reversible.
THE CLINICAL VIEW POINT :
The questions facing the clinican are:
Is there a relationship between the diabetic dysmetabolism
(fig 2) and the incidence of microvascular complications?
Will the restoration of euglycaemia retard or reverse the
microvascular complications? Can this be achieved by
present treatment techniques? Is the timing of intervention
relative to onset of diabetes critical? From the data obtained
in six prospective studies13'24 comparing the effects of strict
diabetic control with conventional standards of control, the
former has beneficial effects
on nephropathy and
neurophysiological abnormalities. It has minimal effects on
retinopathy. Infact, 3 of these studies 20-21-22 showed that it
resulted in retinal infarcts, increased microaneurysms &
retinitis proliferans. Early in diabetes good glycemic control
protects and improves the prognosis of clinical disease.
There is also evidence from animal studies that the initial
period of poor glycemic control can initiate a process that
leads to progressive microvascular disease, even after good
control has been established. There is however general
agreement that when there is already mild nephropathy in
diabetes, tight control is ineffective, in reversing or retarding
the progression of renal failure. Tight control in the early
stage of microalbumenuria has yielded variable results.
In clinical terms an important but unanswered question in
understanding microangiopathy is why is proteinuria a
devastating prognostic sign in IDDM in contrast to its
relatively benign prognosis in NIDDM of similar duration? A
similar dissociation is seen even in retinopathy. Non
proliterative retiopathy occurs to approximately the same
extent (90%) in IDDM and NIDDM of 20 years duration. After
5 more years, in half of the patients with IDDM vision
threatening proliferative retinopathy develops whereas less
than 10% of NIDDM develop this complication20. Neither
nephropathy nor retinopathy is seen before puberty. What
factors hormonal
or
otherwise
initiate
diabetic
microangiopathy at puberty or protect against it before
puberty are not known.
CONCLUSIONS
Microvascular physiology is complex. Much needs to be
Fig 2. Possible mechanisms in diabetic microangiopathy
___ SEPTEMBER 1990
89 —
St. • John’s Medical College Journal of Medicine
learnt about the microvasculature in diabetics which is
subject to the interaction of intermittent pressures and
flows, to the redistribution of pressures and flow despite
normal total organ perfusion. It is like pursuing an unknown
treasure. Nevertheless these are exciting times for those
involved in the care of diabetics. This analysis emphasises
a central
role
for microvascular
hemodynamic
disturbances and has therapeutic implications. Early
optimal diabetic control and alteration of hemodynamic
parameters can alter the course of diabetic complications6.
Altering the regional microvascular hemodynamics without
affecting systemic blood pressure holds therapeutic
promise. Viscosity lowering agents, antiplatelet agents in
diabetic nephropathy, aldolase reductase inhibitors in
neuropathy, glycosylation inhibitors and free radical inhibitors
are other avenues for prospective studies to find a way to
retard or reverse the microvascular complications of diabetes
mellitus.
9. Vermes I, Steinmetz E.T. Zeyan L.J.J.M. Vander Vee E.A. Rheological
properties of WBCs are changed in diabetic patients with microvascular
complications. Diabetologica 1987;30:434-436.
10. Schmid -SchonbeinG.W. Engler R.L Granulocytes as active participants
in acute myocardial ischaemia and infarctions Am. J. Cardiovasc. Pathol.
1983;1:15.
11. Branemark P.l. Lander L. Fagorberg S.E., Briene V. Studies in Rheology
of human diabetes mellitus. Diabetalogia 1971,7:107-112.
12. Zatz R, Brenner B.M. Pathogenesis of diabetic microangiopathy,
The hemodynamic view Am. J.Med. 1986;80:443-453.
13. Zatz Dunn R, Meyer T.W.et al. Prevention of diabetic glomerulopathy
by pharmacological amebiovation of glomerular capillary hypertension.
J.CIin.lnvest 1986;77:1925-1930
14. Kastrup J. Rorsgoard S, Parving H.H, Lassen NA Impaired
autoregulation of cerebral blood flow in long term type I diabetic patients
with(12%) nephropathy & retinopathy. Clin.Physiol. 1986;6:54.
15. SinclairS.H.,GrumwaldsE.,RivaCEetal Retinal vascular autoregulation
in diabetes mellitus Ophthlmology 1982;89:748-750
REFERENCES
1. Ledbetter S.R, Wagner C.W.. Martin G.R., Rorbach DH, Hassel J.R.
Response of diabetic basement membrane producing cell to glucose &
insulin. Diabetes 1987;36:1029-1034.
2. William J.R. Kilo C. Current status of capillary basement membrane
disease in diabetes mellitus. Diabetes 1977;26:65-73
3.
Vracko R. Skeletal muscle capillaries in diabetes
Circulation
1979;41:271-283
4. Kilo C, Volger N. Williamsons J.F. Muscle capillary basement membrane
changes related to aging and to diabetes mellitus. Diabetes 1972,21:881905.
5. Porta M, La Selva M. Molinathi P, Molinathi G.M. Endothelial Cell function
in diabetic microangiopathy Diabetologica 1987;30:601-609
6. Colwell J.A., Lopes Virella M., Winocour PD. Halushka PV. New concepts
of pathogenesis of atherosdersosis in diabetes mellitus In Levin ME. O'Neal
LV. Eds. The Diabetic foot St Louis. Mosby Company 1988;51-70.
16. Berkman J.Rifkin H. Unilateral nodular diabetic gromerulosderosis
(Kimmelstiel-Wilson) Report of a case Metab. Clin. Exp. 1973;22:715-722.
17. Behrendt T. Duane TD. Unilateral complications in Diabetic retinopathy.
Trans. Am. Acad. Ophthalmol. 1979;74:28-32.
18. Holman R.R.,DornanT.LMayon-Whiteetal Prevention of deterioration
of renal and sensory nerve functions by more intensive management of
Insulin Dependent Diabetic patients: a 2 year randomised prospective study.
Lancet 1983;1:204-208.
19. Lauritzen Frost-Larsen K, Larsen HW et al The Stento study group:
Continuous insulin. Lancet 1983;1:1445-1446.
20. Kroc Collaborative Study Group Blood glucose control in evolution of
diabetic retinopathy & albumenuria. N. Enngl. J. Med 1985;311:364-372.
21. Dahl-Jorgensen K.» Brinchmann-Hansen O, Hansen K.F.et al Effect of
near normoglycaemia for 2 years on progression of early diabetic retinopathy,
nephropathy and neuropathy: The Oslo study Br. Med. J. 1986^93:11951199.
diabetic
22. Feldt - Rasmusen B, Mathiesen ER, Deckor T Effect of 2 years of strict
metabolic control on the progression of incipient nephropathy in insulinn
dependent diabetes, Lancet 1986;2:1304-1308.
8. Siperstein MD, Unger RH Madison LL: Studies of muscle capillary
basement membranes in normal subjects, diabetics & prediabetic
patients.J.CIin.lnvest 1968;47:1973.
23. Beck - Mielsen H. Richelsen B, Mogensen Ce et al Effect of Insulin pump
treatment for 1 year on renal function and retinal morphology in patients with
IDDM. Diabetes care 1985;8:585-589.
7. Siperstein MD Capillary basement membranes
microangiopathy - Adv. Intern. Med. 1972;18:325-344.
90
and
VOL III No. 3-----
MEDICINE - SYMPOSIUM
St. John’s Medical College Journal of Medicine
DIABETIC NEPHROPATHY - THE CURRENT THINKING
LLOYD VINCENT, T.S.RAMKUMAR
Kidney disease of diabetes mellitus (KDDM) or diabetic
nephropathy (DN) is a clinical syndrome characterized by
elevated urinary albumin excretion (UAE), hypertension and
progressive renal insufficiency. KDDM is the single most
common cause of end-stage renal disease (ESRD) in the
west and accounts for a continuously increasing number
of the total ESRD population. In addition the 5 year survival
of these patients with KDDM is less than one half of those
patients with ESRD due to other causes. Among the diabetic
ESRD population one half have insulin dependent diabetes
mellitus (IDDM) and the other half consist of non-insulin
dependent diabetes mellitus (NIDDM). The importance of
KDDM lies in the fact that, ESRD due to KDDM can be
expected to account for over one third of all patients with
ESRD by the year 2000 A.D.
MICROALBUMINURIA
Proteinuria has been found to be the laboratory hallmark of
DN and early persistent subclinical increase in urinary
albumin excretion (UAE) is found to be highly predictive of
later occurance of major disease events, especially uremia
and early mortality. The term microalbuminuria was coined in
1982 at Guy's Hospital in London and is defined as an
abnormally elevated UAE, in the absence of clinical
proteinuria. UAE in normal young subjects rarely exceeds
10 g/min, or about 15mg/24h. The albumin/creatinine ratio
rarely exceeds 0.01.
UAE can be estimated from (i) shortterm collections over one
or several hours in the laboratory or clinic (ii) overnight
(approximately 8 hours) urine collection, (iii) a 24 hour
collection, (iv) an early morning urine sample mainly for
screening purposes. Since co-efficient of variance in UAE
is approximately 45%, atleast 3 urine collections are
necesary. In view of a considerable day to day variation in
UAE with time of the day, posture, water loading and
exercise, efforts must be made to collect urine samples
under standardized conditions.
An array of sensitive quantitative techniques are available for
measuring UAE, including radioimmunoassay, enzyme linked immunosorbent assay (ELISA), and turbidometry or
DR. LLOYD VINCENT, MD
DR.T.S.RAMKUMAR, MD, DNB
DEPARTMENT OF NEPHROLOGY,
ST. JOHNS MEDICAL COLLEGE HOSPITAL
BANGALORE - 560 034
----- SEPTEMBER 1990
nephelometry immunoassay. A newly developed screening
procedure, the microalbutest a tablet method, is positive at
a concentration of approximately 40/jg/ml, in contrast to the
albustix test which is positive at a concentration of
approximately 140pg/ml. This can be used as a bedside
examination for microalbuminuria, but quantitative methods
should be employed whenever possible. Before concluding
that a diabetic patient has microalbuminuria associated
with incipient diabetic nephropathy other causes of
microalbuminuria must be excluded. (Table 1).
NATURAL HISTORY OF ALBUMINURIA
The natural history of albuminuria has been well described
in IDDM. Although the majority of patients with IDDM show the
early morphologic changes of DN such as glomerular
basement membrane thickening and mesangial expansion
within a few years of onset of diabetes, for the first five years,
UAE is almost universally within the normal range.
Investigations after this period reveal that some patients with
IDDM demonstrate an elevated UAE. Many of these patients
develop increased UAE with abnormally high glomerular
filteration rate (GFR) and renal hypertrophy. These early
increases in UAE and GFR can be reduced, arrested, or
reversed by early institution of improved glycemic control,
dietary protein restriction and adequate control of any
associated hypertension.
The appearance of microalbuminuria predicts clinical
diabetic nephropathy in IDDM. The discrimination level of
UAE, that isthe level of UAE which, if exceeded, predicts the
development of clinical DN, varies from centre to centre.
However the consensus is that in IDDM, UAE >20pg/min.
(> 30 mg/24h) or an albumin/creatinine ratio >0.02 is known
to predict DN. Clinical DN may be defined as albuminuria >
200 pg/min (>300 mg/24h) or an albumin/creatinine ratio >
0.2 in a patient without clinical or laboratory evidence of other
disease of the kidney or urinary tract and who has had
diabetes for >5 years with evidence of diabetic retinopathy.
While, persistently increased UAE is associated with clinical
DNin 80% of patients in 10 years, patients without
microalbuminuria, whether young or old, have only a small
risk of developing clinical proteinuria over the next decade
and those that do not develop this complication within 30
years of first diagnosis are unlikely to develop it later.
In NIDDM the natural history is not well described as
persistently increased UAE or clinical DN maybe recognized
at diagnosis of diabetes. This may reflect a longer period
of unrecognized hyperglycemia that precedes the diagnosis
of NIDDM. In addition the development of persistantly
9 1 —
St. John’s Medical College Journal of Medicine
increased UAE inNIDDM does not necessarily herald
progressive renal insufficiency. This may reflect a slower
progression of renal disease in NIDDM or a greater
prevalance of other conditions associated with albuminuria
such as age, hypertension, urinary obstruction or urinary
infection. In NIDDM the level of albuminura that predicts
DN is not known. However clinical DN may be defined as
persistent albuminuria > 200 jjg/min (>300g/24h) or an
albumin/creatinine ratio >0.2 in a patient without other
disease of the kidney or urinary tract, who has had diabetes
of any duration associated with diabetic retinopathy.
(Table - 2)
The rate of progression of proteinuria in the early phases of
diabetic renal disease is slow namely a mean rise of
approximately 20% per year. Therefore the microalbuminuria
phase, is likely to last an average of approximately 8-10
years. UAE progresses more rapidly in noncompliant
patients with poor glycaemic control and as fast as 60%
increase in albumin excretion per year in association with
poor blood pressure control. In the case of extraordinarily
rapid progression of proteinuria, non-diabetic renal or
systemic disease should be suspected in addition to the
above.
REDEFINITION OF DIABETIC NEPHROPATHY
With the observation that microalbuminuria is a predictor of
subsequent clinical DN and the recent description of an early
hyperfunction-hypertrophy stage of this disease, a new
scheme that encompasses various developmental stages
of diabetic nephropathy has been proposed. These stages
as well as their main characteristics are outlined in Table 3.
Stage I, present at the time of diagnosis of IDDM is
characterized by glomerular hyperfunction and hyper
trophy. Certain features of this stage can also accompany
Table 1 Causes of microalbuminuria in isulin-dependent diabetes
Approximate level of albumin excretion rate*
(jug/min)
Causes
Newly diagnosed
diabetes
Poor metabolic
regulation
Physical exercise
Essential
hypertension in
diabetes (seldom)
Urinary tract
infection
Non diabetic renal or
systematic disease
Early phases of
diabetic
nephropathy
(incipient
nephropathy)
»5-60
*5-60
*5-60
25 5-20
Moderate increase
variable
20-200
* Baseline values, except for physical exercise
Table 2. Proposed States of Diabetic Nepropathy as Defined by Urinary Albumin Excretion and
Albumin/Creatinine Ratio.
jjg/min
mg/24h
Albumin/Creatinine
<10
20-200
<15
30-300
<0.01
0.02-0.2
>200
>300
>0.2
>200
>300
>0.2
IDDM
Normal range
Increased UAE
Clinical
nephropathy
NIDDM
Clinical
nephropathy
92
VOL in No. 3-----
St. John’s Medical College Journal of Medicine
Table 3. Stages in diabetic nephropathy (DN)
Stage
Designation
Main
Characteristics
Main structural
changes
Stage 1
Hyperfunction
and hypertrophy stage’
Large Kidneys
and glomerular hyperfiltration
Glomerular hy- »150
pertrophy normal basement
membrane and
mesangium
Normal UAE
Increasing
basal membrane (bm)
thickness
and mesangial expansion
No or few
studies
Stage il
In shortterm diabetes (215 yrs)
"Silent" stage
with normal
UAE but stru
ctural lesion
present
In longterm diabetes
Stage III
Early
Incipient DN
Persistently
elevated
UAE
Late
Stage IV
Early
Clinical
proteinuria
or UAE>200
pg/min
Severity
probably in
between II
and IV
Increasing
rate of
glomerular
closure
GFR(mlmin)
Albumin
excretion
(UAE)
Blood
pressure
Suggested
main
pathophysio
logic change
N(May
fall initially
during insulin treatment)
Glomerular
volume expansion and increased intraglomerular pressure
With or without N(Often
hyperfiltrationb increased
in stress
situations)
N
Changes as indicated above
but quite variable (dependent on metabolic control?)
With or without N(Often
hyperfiltrationb increased
in stress
situations
N or slightly In addition inelevated
creased synthesis of bm and
bm-likemateriai
Maybe
increased
Often eleGlomerular
vated comp- closure probaared to heal- bly starts in
thy subjects: this stage
In some patialso blood
pressure el- ents high intraevated dur- tra glomerular
ing exercise pressure
3160
20-70
pg/min
3130
70-200
pg/min
sd 30-70
>20Qpg/min Often frank High rate of
hypertension glomerular
closure and
advancing
mesangial
expansion
Intermediate
Overt DN
Advanced
Stage V
<200pg/min
<200pg/min
Uremia
End-stage
renal failure
Hypertrophy
of remaining
glomeruli (as
in III)
370-30
Generalized
glomerular
closure
30-10
Hypertension
almost
ub-quitous
HypertenHyperfiltration
sion almost in remaining
ubiquitous
glomeruli
(deleterious)
~30-10
Decreasing
High but
often controlled by
dialysis
treatment
Advanced
lesions and
glomerular
closure
■Changes present probably In all stages when control Imperfect.b Marker of future nephropathy (if GFR > 150 ml/min)
----- SEPTEMBER
1990-----------
______ _ --- ———
----------------- '9 3 —
St. John’s Medical College Journal of Medicine
diabetes of longer duration, when metabolic control is
imperfect. Stage II, the “silent” stage is characterized by
the development of renal lesions (predominantly in the
glomerulus), but albumin excretion is normal. Stage III
incipient diabetic nephropathy, is characterized by
microalbuminuria and carries a high risk of development of
overt DN. Stage IV, overt (clinical), diabetic nephropathy,
is characterized by proteinuria, hypertension, and a
subsequent fall in GFR. Stage V, corresponds to end-stage
renal failure with uremia.
in overt DN.
Continuous therapy with an angiotension - coverting enzyme
(ACE) inhibitor has been shown to have a glomerular
vasodepressor effect in the newly diabetic rat and to largely
prevent the subsequent development of a severe, sclerosing
glomerular injury. Preliminary studies in humans with well
established diabetic glomerular injury reveal that ACE
inhibitor therapy has an anti-proteinuric effect and may also
slow the decline in glomerular filtration rate that usually
attends this disorder.
HYPERTENSION AND DIABETIC NEPHROPATHY
Hypertension contributes to the leading causes of morbidity
and mortality in the diabetic population and is approximately
twice as common in persons with diabetes mellitus as it is in
those without. Several types of hypertension can occur in
patients with diabetes mellitus. Essential hypertension is
most prevalent and occurs primarily in patients with NIDDM,
but can also occur in patients with IDDM. Hypertension
associated with diabetic nephropathy is a form of renal
hypertension with sodium and fluid retention, increased
peripheral resistance, and increased cardiac output,
especially if anemia is present. Isolated systolic
hypertension, although most prevalent in older diabetic
persons, may occur at any age. Supine hypertension with
orthostatic hypotension sometimes occurs in patients with
autonomic neuropathy and is the most difficult blood pressure
problem to treat. Today improved management of
hypertension is a major component of any DN control
program, particularly in the young with incipient DN.
CONTROL OF DIABETIC NEPHROPATHY
Optimal conventional insulin treatment and self monitoring
of blood glucose should be employed to achieve best possible
control of diabetes. No significant difference in renal
behaviour is seen between conventional insulin therapy and
continuous insulin infusion. However long term studies over
several years will be required to clarify this point. Since
progression of DN was seen in conventionally treated
patients, it was concluded that years of poor metabolic
control leads to significantly accelerated progression in
incipient diabetic nephropathy and that progression can
be reversed by good control. Poor metabolic control with
elevated HbA1c values, have been identified as a risk factor
Protein restricted diets have been shown to decrease the
UAE, and GFR and thereby show a decline in the progression
of renal disease. To be successful, a low protein diet should
be started early in the course of renal disease, even before
serum creatinine starts to rise above normal. Protein
restriction consists of diets containing approximately 0.6 g/kg
of protein that require no amino acid or keto acid
supplmentation, have no untoward nutritional effects, and are
relatively well accepted by patients. The low protein diet also
induces changes in the low density lipoprotein (LDL)
cholestrol and prevents worsening of large vessel disease,
a major cause of morbidity and mortality. (Table 4)
GENERAL RECOMMENDATIONS FOR PATIENTS WITH
DIABETES
A. For those with diabetes mellitus and normal urinary
albumin excretion.
1. Urine should be tested for microalbuminuria yearly in
patients with IDDM of > 5 years’ duration and in all patients
with NIDDM.
2. Persistently elevated BP levels (> 140/90 mm Hg) should
be treated as recommended by the working group on
hypertension and diabetes in its statement of hypertension
in diabetes mellitus. Among the elderly, a systolic level > 160
mm Hg in the presence of a diastolic level < 90 mm Hg should
be considered for active therapy. Special attention should be
paid to weight reduction for those who are overweight.
3. Blood glucose levels should be well controlled. In IDDM,
this involves the best possible glycemic control without
Table 4 Effect of Different Therapeutic interventions on Microalbuminuria and GFR in Insulin-Dependent Diabetic
Patients
Intervention
Strict blood glucose control
Angiotensin-converting
enzyme inhibitor
Antihypertensive (metoprolol
and thiazide diuretic)
Low-protein diet
94
Albumin Excretion Rate
GFR
Decreases or stops increasing
Decreases
Decreases
Increases
Decreases
Decreases
Decreases
Decreases
VOL III No. 3-----
St. John’s Medical College Journal of Medicine
untoward effects from hypoglycemia. In NIDDM, this
involves dietary modification, increased physical activity,
and if needed, pharmacologic intervention with either an oral
hypoglycemia agent or insulin.
Age above 60 years and severe stenosis of coronary artery
on corononary angiogram are important predictors of
survival.
REFERENCES
4. Dietary protein consumption should be approximately
0.6g/kg body weight for adults.
5. Risk factors for coronary heart disease (including
hypercholesterolemia and cigarette smoking) should be
assessed and treated as needed.
6.
Retinal examinations should be performed at least yearly.
B. For those with diabetes mellitus and increased urinary
albumin excretion or clinical nephropathy.
1. UAE should be measured three times over 6 months and
renal function (serum creatinine and/or creatinine clearance)
should be measured. UAE and renal function should be
measured at least yearly thereafter.
2. Antihypertensive therapy should be instituted if BP has
reached 140/90 mm Hg. Some clinicians recommend
antihypertensive therapy if BP has increased by 20/10 mm
Hg over 2 years. BP levels should be maintained < 140/
90mmHg as long as there are no undue side effects.
3. Efforts to improve the level of glycemic control should be
considered in patients with increased urinary albumin
excretion. Potential benefits of therapy must be weighed
against the increased risks of hypoglycemia. Improved
glycemic control does not appear to affect the course of
clinically overt diabetic nephropathy.
4. Efforts should be made to ensure that dietary protein
consumption does not exceed 0.6g/kg body weight for adults.
1. Bennett PH : ‘Microalbumenuria* and diabetes: A critique - assessment
of urinary albumin excretion and its role in screening for diabetic nephropathy.
Amer J Kidney Dis 1989;13:29-34.
2. Castiglitoni A, Savazzi GM : Pathophysiology and clinical aspects of
diabetic nephropathy. Nephron 1988;50:151-163.
3. Dimario U.et al: New parameters to monitor the progression of diabetic
nephropathy. Amer J Kidney Dis 1989;13:45-58.
4. Fabre J. Balant LP, Dayer PG, Fox HM, and Vernet AR :The kidney in
maturity onset diabetes mellitus: A clinical study of 510 patients. Kidney
International. 1982;21:730-738.
5. Fitzsimmons SC , Agodoa L, Striker L, Conti F and Striker G: Kidney
disease of diabetes mellitus: NIDDK initiative for the comprehensive study
of its natural history, pathogenesis, and prevention. Amer J Kidney Dis
1989;13:7-10
6. Friedman EA : Diabetic nephropathy : Strategies in prevention and
management, nephrology forum, Kidney International 1982;21:780-791.
7. Honey JEA, Browning MCK and Fraser CG: Biologic variation of urinary
albumin: consequences for analysis, specimen collection, interpretation of
results and screening programs.Amer J Kidney Dis 1989;13:35-37.
8. Howthorne VM : Preventing kidney disease of diabetes mellitus: Public
health perspectives, Amer J Kidney Dis 1989;13:1-5.
9. Jarrett R.J: Hypertension in diabetic patients and differences between
insulin dependent diabetes mellitus: Amer J Kidney Dis 1989;13:14-16.
10. Kaplan NM: Critique of recommendations from working group
hypertensions in diabetes. Amer J Kidney Dis 1989;13:38-40.
on
11. Mogensen C.E: Microlbuminuria as a predictor of clinical diabetic
nephropathy. Nephrology forum, Kidney International 1987;13:673-689.
5. Risk factors for coronary heart disease (including hyper
cholesteolemia and cigarette smoking) should be assessed
and treated as needed.
12. Mogensen C.E: Management of diabetic renal involvement and
disease. The Lancet, 1988;1:867-869.
Retinal examinations should be performed atleast yearly.
13. Myers BD, Meyer TW : Angiotension converting enzyme inhibitors in
prevention of experimental diabetic glomerulopathy. Amer J Kidney Dis
1989;13:20-24.
7. Subjects with impending renal failure (serum creatinine
2.0 mg/dL and/or glomerular filtration rate<40 mL/min)
should be referred for renal consultation.
14. Statement on hypertension in diabetic mellitus : The working group on
hypertension in diabetes. Arch Intern Med -1987;147:832-842.
ESRD IN DIABETICS
15. Steffes MW, Chavers BM, Bilous RW, and Mauer MS : The predictive
value of microalbuminuria. Amer J Kidney Dis 1989;13:25-28.
6.
Diabetics with ESRD are today started on dialysis at an
earlier date with a creatinine level averaging less than 10mg/
dL, in view of the better associated survival rate. There
is marked improvement in diabetic patient survival using
continuous ambulatory peritoneal dialysis, hemodialysis,
and transplantation. There is no major survival advantage
of one method over any other, except possibly living related
donor transplantation performed at an experienced and
successful centre. The two most dismaying complications
occuring in diabetics with ESRD, are severe retinopathy and
limb gangrene. The former improves with transplantation.
----- SEPTEMBER 1990
16. Teutsh S, Newman J, and Edgars P. The problem of diabetic renal failure
in the United States: An overview Amer J Kidney dis 1989;13:11-13.
17. Viberti G : Interventions based on microalbuminuria screening and lowprotein diet in the treatment of kidney disease of diabetes mellitus. Amer J
Kidney Dis 1989;13:41-44.
18. Wiseman MJ, Mangili R, Alberetto M, Klen H, and Viberti G; Glomerular
response mechanisms to glycemic changes in insulin - dependent diabetics.
Kidney International 1987I31L1012-1018.
19. Zeller KR and Jacobson H: Reducing dietary intake to retard progression
of diabetic nephropathy, Amer J Kidney Dis 1989;13:17-19.
95 —
Position: 2170 (10 views)