Diabetic Macro- and Microangiopathy 9783110888485, 9783110045338

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Mincu • Diabetic Macroand Microangiopathy

Diabetic Macroand Microangiopathy by Iulian Mincu

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Walter de Gruyter • Berlin • New York 1975

Title of the original romanian edition: Julian Mincu, Angiopathia Diabetica Prof. Dr. Julian Mincu, Chairman of the Department for Nutritional and Metabolic Diseases, Lecturer in Medical Sciences. Bucharest • Romania With 304 illustrations

Translation from the Romanian language made by EDITURA ACADEMIEI REPUBLIC» SOCIALISTE ROMANIA - BUCURE§TI -

© Copyright 1975 by Walter de Gruyter & Co., vormals G. J. Göschen'sche Verlagshandlung, J. Guttentag, Verlagsbuchhandlung Georg Reimer, Karl J. Trübner, Veit & Comp., Berlin 30. All rights reserved including those of translation into foreign languages. No part of this book may be reproduced in any form - by photoprint, microfilm or any other means transmitted or translated into a machine language without written permission of the publisher.

Printed in Germany Printing: Walter de Gruyter & Co., Berlin Binding: Liideritz & Bauer, Berlin ISBN 3 11004533 8 Library of Congress Catalog Card Number 73-82434

Preface

Diabetic angiopathies represent some of the most important complications of diabetes mellitus. The advances in therapeutic approach made within the last 50 years have lead to a complete change in the clinical course and diagnosis of diabetes mellitus. The mortality following diabetic coma which was as high as 80% prior to insulin therapy has now dropped to between 1 and 2% of the cases observed. Although the life expectancy has been considerably increased, macro- and microangiopathies still account for some 70—85% of deaths in diabetics. This problem is considerably worsened by the close involvement of these vessel lesions with, for example, dyslipaemic syndrome, i. e. hyperlipoproteinaemia, arteriosclerosis and obesity. The present report is based on data from the literature as well as observations and experiments carried out at the Clinic of Metabolic Diseases and Nutrition in Bucharest. It is hoped that this represents a modest contribution to this theme without claiming any degree of completeness. 25,000 patients registered as diabetics in our department have been included in these investigations. Furthermore we have carried out epidemiological studies over the last three years using large groups of healthy Rumanians from both town and country districts. I would like to thank all clinicians and research workers of our department, who have given considerable support in the preparation of this book especially: Dr. S. Campeanu, Head Physician; Dr. C. Dumitrescu, Head of the Out-patient Laboratory; Dr. N. Mihalache, Head of the Biochemical Laboratory as well as Dr. P. Niculescu and Dr. Al. Petrovici, Heads of the Laboratories for Electron Microscopy at the Institute Babes and Institute Cantacuzino Bucharest. Moreover I am indebted to Prof. Dr. W. I. H. Butterfield, Vice-Chascellor of the University of Nottingham, whose advise during my visit to Guy's Hospital in 1970 was of profound value to me.

Autumn 1974

I. Mincu

Contents Preface

V

Chapter I Introduction

1

A. B. C. D.

Mortality in Diabetes Mellitus Morbidity of Diabetes Mellitus Angiopathy in Diabetes Mellitus Some General Epidemiological Factors Involved in Diabetic Angiopathy 1. Epidemiology of Dyslipaemia in Random Populations a) Frequency of Global Dyslipaemia (GD) b) Frequency of Differentiated Dyslipaemias (DD) c) Age and Lipaemic Status d) Overweight and Lipaemic Status 2. Epidemiology of Dyslipaemias in Newly Detected Diabetes Mellitus

Chapter II Angiopathy in Diabetics A. Arteriopathy of Diabetic Macroangiopathy B. Diabetic Microangiopathy C. Pathological and Electronmicroscopic Studies - Characteristic Aspects 1. Diabetic Angiopathy of the Eye 2. Diabetic Angiopathy of the Kidney 3. Diabetic Angiopathy in the Muscular System 4. Diabetic Angiopathy in the Digestive Tract 5. Diabetic Angiopathy in the Skin 6. Diabetic Angiopathy in Diabetic Neuropathy D. Investigations on the Functional Stage of Diabetic Angiopathy E. Pathophysiological Problems of Diabetic Angiopathy - Pathogenetical Theories Chapter III Ocular Microangiopathy A. Alterations of the Anterior Ocular Pole 1. Diabetic Alterations of the Conjunctiva 2. Diabetic Alterations of the Cornea 3. Diabetic Alterations of the Iris 4. Diabetic Alterations of the Lens B. Alterations of the Posterior Ocular Pole 1. Diabetic Retinopathy 2. Therapy of Diabetic Retinopathy a) Therapeutic Measures Concerning Metabolic Balance b) Therapy Controlling Capillary Permeability Haemorrhages and Vascular Proliferations c) Hormonal Therapy Chapter IV Renal Diabetic Angiopathy A. Pathomorphology of Renal Diabetic Angiopathy 1. Renal Diabetic Microangiopathy 2. Renal Macroangiopathy in the Diabetic

1 1 5 7 7 8 8 13 14 14 18 20 22 27 27 28 29 33 36 39 41 45 68 71 71 76 77 81 83 83 100 100 102 102 105 105 106 108

Contents

B. C.

D. E.

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3. Ultrastructure of the Renal Diabetic Vascular Lesions 4. Histochemistry of the Renal Alterations in Diabetes Mellitus Prevalence and Incidence Clinical Study of the Renal Diabetic Microangiopathies 1. Clinical Analysis of Kimmelstiel-Wilson Syndrome 2. Pathophysiological Symptomatology 3. Renal Function in Diabetic Renal Angiopathy 4. Additional Investigation Techniques Prognosis in Renal Diabetic Angiopathy Therapy in Renal Diabetic Angiopathy 1. Diet 2. Drug Therapy 3. Surgical Treatment

Chapter V Diabetic Macroangiopathy A. Pathophysiological Problems in Diabetic Macroangiopathy B. Heart Disorders in Diabetic Macroangiopathy 1. Prevalence 2. Classification 3. Late Chronic Angiopathic Disorders of the Heart a) Diabetic Myocardosis b) Disorders in the Coronary Blood Supply C. Clinical Laboratory Picture 1. Determination of the Serum Glycoproteins 2. Determination of the Serum Lipid Fractions 3. Determination of the Serum Fibrinogen D. Treatment of Heart Disorders in Diabetic Macroangiopathy 1. Hygienic and Dietary Prescriptions 2. Medical Treatment 3. Surgical Intervention E. Peripheral Disorders in Diabetic Macroangiopathy 1. Prevalence 2. Clinical Study of Peripheral Diabetic Angiopathy 3. Prognosis in Peripheral Diabetic Macroangiopathy 4. Treatment of Peripheral Diabetic Macroangiopathy a) Conservative Treatment b) Surgical Treatment

Chapter VI Cutaneous and Muscular Angiopathy in Diabetes Mellitus A. Cutaneous Angiopathy in Diabetes Mellitus 1. Necrobiosis Lipoidica Diabeticorum (NLD) B. Muscular Diabetic Angiopathy

Chapter VII Diabetic Neuropathy 1. 2. 3. 4. 5.

Prevalence Problems of Morphology and Ultrastructure in Diabetic Neuropathy Problems of Pathogenesis in Diabetic Neuropathy Clinical Study of Diabetic Neuropathy The Management of Diabetic Neuropathy

References

109 117 122 129 130 130 134 138 139 140 140 140 141

143 142 147 147 148 151 151 153 160 160 161 162 164 165 166 167 167 167 172 176 180 180 183

184 184 184 186

192 192 195 197 200 211

212

Chapter I Introduction Diabetes mellitus is one of the diseases whose seriousness and incidence is becoming ever more manifest as medical scientific research increases and ever larger groups of people can be investigated.

A. Mortality in Diabetes Mellitus Recent research on diabetic mortality has shown that [13, 20, 27, 37, 39]: 1. diabetics' mortality is higher than that of other people, irrespective of the presence of some complications. It was established that over a ten-year period mortality was 2 - 5 times higher in diabetics than in non-diabetics. The average life span of diabetics is shorter than in non-diabetics. 2. the excess mortality is greater in the younger patients because of the severe forms of diabetes mellitus encountered in the age group. 3. the causal factors of the majority of deaths in diabetics under the age of 45 are cardiovascular and renal diseases. 4. finally, in similar pathological conditions, mortality is higher in diabetics. Thus, for instance, obesity investigated over a ten-year period [48] was associated with a mortality 2.8 times higher among diabetics, who apparently had no other complication of the disease, as against non-diabetic obese individuals.

B. Morbidity of Diabetes Mellitus Before tackling the main subject of this work — angiopathy in diabetics — some data is necessary on the incidence of diabetic disease itself. Gorig's thesis (1969) provides a review of the studies on the incidence of diabetes mellitus up to that date. The reported figures are quite varied, ranging from 0.19% in Newcastle to 4.19% in Malta. These differences may to a great extent be due to the detection method employed (Fig. 1) [28]. In the determination of the incidence of diabetes mellitus, two methods have been used predominantly: a) the investigation of postprandial glycosuria, generally followed by a glucose tolerance test in suspect persons. This method usually yields lower values for the incidence of diabetes mellitus. b) investigation of postprandial glycaemia and glycosuria. This device has the advantage of enabling the tracing of forms of diabetes mellitus in the chemical stage of the disease, raising the percentage values of incidence [40]. The International Diabetes Federation recommends that mass investigations for diabetes should be carried out in the following way: 1. the determination of blood sugar and urine levels 2 hours after a meal containing at least 50 g carbohydrate; 2. a complete glucose tolerance test in those cases when initial tests suggest the possibility of diabe-

2

I. Introduction

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Fig. 1. The morbidity (%) attributed to diabetes mellitus in different lands.

tes. This investigation should be carried out in all subjects having glycosuria as well as a blood sugar level of 130 mg/100 ml or more (Fig. 2). Most of the researches carried out with the first method ( 1 9 3 0 - 1 9 5 0 ) showed a relatively low prevalence [2, 8, 20, 21, 46,47],

The following short summary of a research carried out in Rumania in 1968 and 1970, is a good example both of the influence of the applied detection method on the incidence rate of diabetes and the real state of the latter in this country [41]. This investigation of the entire population in rural and urban areas was carried out be tha Antidiabetic Centre in Bucharest (ACB).

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13

D. Some General Epidemiological Factors Involved in Diabetic Angiopathy

The analysis of the association pattern of lipid fractions in PLD shows: — for subjects of normal weight (Fig. 17) decade I : the number of subjects with PLD being too small they were eliminated from this study (Table VII) decade II increases of TG + NEFA + R + p B " III " " R + N E F A + TG + C TG + NEFA + R + p B " IV " " TG + NEFA + C + R — for overweight subjects the most frequent association in decades II, III, IV is TG + NEFA + C + R (Fig. 18) which frequency is the highest in decade IV. This association is followed, as regards the level of frequency, in decades II and III by TG + NEFA + R + pB and C + TG + NEFA + pB for decade II or by C + NEFA + R + pB for decade III. In all PLD the associations which include increased blood pB and C are the most frequent. The high frequency of dyslipaemias and their association pattern may be important in determining PLD

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vascular complications in both normal and diabetic people. There are other factors, such as age and overweight, which definitely favour the appearance of the dyslipaemic patterns.

c) Age and lipaemic status

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Since dyslipaemias represent a risk-factor for arteriosclerosis their early detection is important for a possible prophylaxis. This is also valid for diabetes mellitus.

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Fig. 17.

The diphasic character of the dyslipaemic frequency with age draws the attention to those periods in the life of an individual when the risks become more threatening. The frequency of dyslipaemia is at a minimum between 36 and 45 years and at a maximum between 46—55 and occurs in both GD and in MLD. In the other types of dyslipaemias (DLD, TLD, PLD) a progressive increase in frequency occurs with age. As far as MLD is concerned, the epidemiological research presented above confirms, completes or refutes some previous observations. Thus, for instance, in 1943 Peters and Man [61] denied all

14 influence of age and even sex on lipaemic status, especially for the blood cholesterol level. Numerous investigations made since have generally proved the great variability of the lipaemic status and of blood cholesterol level in particular. It is generally admitted today that they are somehow dependent on age and sex. Many researchers describe increasing values with age [11, 55] especially in women [16,49]. This phenomenon was also noticed during the epidemiological investigation in Bucharest, although we could not confirm the finding that the cholesterol level falls after 55 years, except in overweight cases. Our investigation has further disproved the assumption that any overweight means high blood cholesterol [55]. Regarding pre-beta-lipoproteins, recent research has shown that they occur in a great number of persons [32, 38]. Noble [44] considers that prebeta-lipoproteins can be demonstrated in any adult if the agarose-gel technique is used. Our research indicates a high percentage of prebeta-lipoproteins as a single lipaemic disturbance as well as in association with other lipid fractions (DLD, TLD and PLD). With increasing age, prebeta-lipoproteins are ever more frequently associated with TG or with complex lipoprotein disturbances (R). There is no obvious correlation with sex, while overweight seems to play a certain part in increasing pre-beta-lipoproteins. The correlation between pre-beta-lipoproteins and TG — those of endogenous origin — is confirmed by the TG behaviour in obese people and by the dyslipaemic association patterns within DLD, PLD and TLD. No correlation could be established between sex and abnormally increased NEFA frequencies. NEFA are known to vary considerably from the normal level owing to physical activity, activity of the autonomous nervous system, nutritional state and food supply [36]. A certain variation seems to exist in relation to age and weight. NEFA participate in most associated dyslipaemias so that it might seem that their presence should be correlated with the dyslipaemic state itself, rather than with the respective type of dyslipaemia.

I. Introduction d) Overweight and Lipaemic Status

Overweight seems to be a major factor in determining the frequency of dyslipaemias. In MLD, for example, overweight seems to alter the status of lipid fractions for one sex with the status characteristic of the opposite sex. In TG, overweight determines an increased number of individuals with high blood levels (increased frequency of hypertriglyceridaemia). In DLD, overweight brings about dyslipaemia especially in the last decades, and prevailingly in women. Overweight is also associated with those dyslipaemias where pB lipoproteins are correlated with all blood lipoproteins (R) or hypercholesterolaemia. In both TLD and PLD overweight induces an increased frequency of dyslipaemias in both sexes. We might conclude that obesity or overweight alongside age is an active factor in altering the lipaemic status. Sex, which plays a less important role in determining the character of dyslipaemias, may aggravate the modifications induced by overweight. All these factors, active in normal individuals, are also present in diabetes mellitus which, itself, induces a certain dyslipaemic state.

2. Epidemiology of Dyslipaemias in Newly Detected Diabetes Mellitus

Dyslipaemias in clinical human diabetes mellitus under treatment, as well as in experimental diabetes have been thoroughly investigated [2, 3, 4, 18, 34, 3 5 , 3 6 , 4 2 , 4 7 , 50, 53, 54, 55, 63], No doubt exists about the alterations induced by diabetes in lipid status and it is possible that this effect is present from the earliest stages of the diabetic disease. Chemical diabetes mellitus or newly detected, untreated clinical diabetes has not been amply epidemiologically investigated as yet. But this sort of research seems to be very important. An investigation on a group of 7,113 adults aged between 25—65 was made in 1970 with a view to

15

D. Some General Epidemiological Factors Involved in Diabetic Angiopathy

detecting clinically untreated chemical diabetes mellitus [41]. The group represented 74.52% of the population of a district in Bucharest.

INCIDENCE (f.) OF INCREASED LIPID FRACTIONS IN NORMAL SUBJECTS (AOEO OVfff 50) %'

540 subjects with elevated blood sugar values (above 130 mg % two hours after a glucose meal) were found. These subjects were recalled and a full glucose tolerance test (GTT Duncan) carried out. Within the whole group 332 diabetics were diagnosed in this manner, representing 4.65% of the whole population. After grouping by sex, diabetes mellitus was found in 192 men (5.9%) and 140 women (3.65%). In 328 persons of this group the lipaemic status was investigated. Sex and weight categories of this entire group are presented in Table IX.

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At the end of these introductory considerations, in which some related general problems have been reviewed, one can state that diabetic angiopathy is becoming a major medical priority because of:

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— the great mortality rate among diabetics as compared to the healthy population, especially 50, but the levels attained are different, being higher in diabetics (Fig. 19, 20, 21). Increased NEFA levels are more frequent in men under 50 and women over 50 (Tab. X).

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