Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus.

The risk of premature coronary artery disease (CAD) and its determinants were investigated in a cohort of 292 patients with juvenile-onset, insulin-dependent diabetes mellitus (IDDM) who were followed for 20 to 40 years. Although patients with juvenile-onset IDDM had an extremely high risk of premature CAD, the earliest deaths due to CAD did not occur until late in the third decade of life. After age 30 years, the mortality rate due to CAD increased rapidly, equally in men and women, and particularly among persons with renal complications. By age 55 years the cumulative mortality rate due to CAD was 35 +/- 5%. This was far higher than the corresponding rate for nondiabetic persons in the Framingham Heart Study, 8% for men and 4% for women. Angina and acute nonfatal myocardial infarction followed a similar pattern, as did asymptomatic CAD detected by stress test, so that their combined prevalence rate was 33% among survivors aged 45 to 59 years. Age at onset of IDDM and the presence of eye complications did not contribute to risk of premature CAD. This pattern suggests that juvenile-onset diabetes and its renal complications are modifiers of the natural history of atherosclerosis in that although they profoundly accelerate progression of early atherosclerotic lesions to very severe CAD, they may not contribute to initiation of atherosclerosis.

Islet cell antibodies and other autoantibodies in South African blacks and indians with insulin dependent diabetes mellitus (IDDM).

The presence or absence of islet cell antibodies and other autoantibodies was determined in 47 African and 34 Indian patients with IDDM and 37 controls. Islet cell antibodies (ICA-IgG) were found in over a third of the patients and in only 2 controls. Complement fixing antibodies (ICA-Cf) were found in 10% of patients, but in none of the controls. Persistence of ICA beyond 3 years was more frequent in Black compared to Indian patients. Parietal cell antibodies were found more often in patients (20%) than controls (5%) as were thyroid microsomal antibodies (11% vs. 0%). None of the patients or controls had adrenal antibodies.

HLA antigens and non-insulin-dependent diabetes mellitus in young South African Indians.

HLA, A, B and C antigens were determined in 84 South African Indian patients with non-insulin-dependent diabetes mellitus (NIDDM) in whom age of onset was under 35 years and in 760 healthy Indian controls. Increased frequencies of Aw24, B15 and Bw61 were seen in the patients, but the corrected P value was not significant. Among Indians of North Indian origin, however, there was a significant association between B15 and NIDDM (corrected P less than 0,012; relative risk 4,8). In Indians of South Indian origin no clear association with any specific HLA antigens was seen, although there was a slight increase in the frequency of Aw24 (uncorrected P less than 0,007; corrected P greater than 0,05). The findings in this study serve to emphasize the heterogeneity of diabetes mellitus, since no association between NIDDM and HLA antigens has been noted in whites.

HLA A, B, C and DR antigens in young South African Indians with insulin-dependent diabetes mellitus.

The HLA status of South African Indian insulin-dependent diabetic patients in whom the age of onset of diabetes was under 35 years was compared with that of a group of healthy Indian controls. HLA A, B and C antigens were determined in 68 patients and 760 controls, while DR specificities were determined in 35 patients and 235 controls. The diabetic patients showed a significant increase in the frequencies of HLA B8 (19,1% v. 6,8%; relative risk 3,2; corrected P less than 0,04) and Aw24 (42,6% v. 26,8%; relative risk 2,2; corrected P less than 0,04) antigens compared with controls. HLA DR3 was found to be much more common in patients than in controls (31,4% v. 12,8%; relative risk 3,1; corrected P less than 0,035), but DR3/DR4 heterozygosity was associated with a much greater relative risk (7,25). Among patients of North Indian origin a strong association with DR4 was seen (45,5% v. 9,1% (controls); relative risk 8,3).

Nephropathy in Indian patients with non-insulin-dependent diabetes in the young.

In 85 patients diagnosed as having non-insulin-dependent diabetes in the young (NIDDY), 6 were found to have nephropathy. The duration of diabetes ranged from 2 to 17 yr; 5 of the 6 patients had retinopathy as evidenced by fluoroscein angiography (3 with proliferative changes). All 6 patients had a 24-h urinary protein excretion greater than 0.5 g and a glomerular filtration rate less than 80 ml/min. Serum beta 2-microglobulin levels were increased in all 6 patients, while only 3 had increased serum creatinine levels.

Oral hypoglycaemic agents. An update.

Despite the availability of oral hypoglycaemic agents for nearly 30 years, their precise mode of action and role in the management of diabetes mellitus remains poorly defined and controversial. They are regarded by many, though not all, clinicians as helpful adjuncts in the treatment of patients with non-insulin-dependent diabetes who have failed to respond satisfactorily to an adequate programme of dietary treatment. Their initial effectiveness is greatest in those patients who have had diabetes for less than 5 years, are overweight at the time of initiation of therapy, and whose fasting blood glucose levels are not unduly raised (less than 200 mg/dl). If they are receiving treatment with insulin and a shift to oral compounds is contemplated, success in the changeover is more likely if the daily dose has been less than 20 to 30 units daily. While their efficacy in maintaining adequate glycaemic control over the short term in responsive patients is unquestioned, the long term benefit of oral hypoglycaemic agents in reducing morbidity and mortality of late complications remains to be substantiated. In this regard, where long term efficacy is difficult to quantify, physician vigilance for chronic toxicity assumes a special importance. Notwithstanding the potential for interaction between sulphonylureas and numerous other drugs, significant adverse effects are uncommon. Hypoglycaemia is the major health concern associated with the use of sulphonylureas, and lactic acidosis has been the major problem with biguanides. Careful patient selection is thus the key to ensuring efficacy and avoiding toxicity. Recent evidence suggests that while the insulinotropic action of the sulphonylureas may explain the short term hypoglycaemic effect of these compounds, their reported action in enhancing insulin sensitivity, both at the receptor and post-receptor levels, more likely accounts for the long term maintenance of improved carbohydrate tolerance. The relatively new ('second generation') sulphonylurea compounds have not been shown to possess clearly defined advantages over the older preparations; the potentially beneficial effects of gliclazide on the microangiopathic changes of diabetes require considerable further evaluation.

Patterns of diabetes mellitus in young Africans and Indians in Natal.

Young African and Indian patients (age of onset under 35) were studied in order to determine the pattern of diabetes mellitus seen in these groups. Of the 110 African patients 86 had IDDM and 18 NIDDM, whereas of the 101 Indian patients the distribution was 40 and 60 respectively. Tropical diabetes (J-type and Z-type) was rare in both groups. IDDM tended to start at an earlier age in Indians (mean 17 years) compared to Africans (mean 23 years). Onset of the disease tended to be more frequent in winter, particularly in Indian patients. NIDDM was associated with a female predominance (3:1) and obesity in both population groups. A positive family history of diabetes mellitus was obtained from 80% of the Indian and 39% of the African patients with NIDDM.

C-peptide response to a glucose load in young blacks and Indians with insulin-dependent diabetes mellitus.

Residual beta cell function based on C-peptide assays was estimated in 39 patients (27 Blacks, 12 Indians) with insulin-dependent diabetes mellitus and 18 controls (9 Blacks, 9 Indians) using glucose as a stimulus. The diabetic patients showed significantly lower maximal C-peptide values (mean 0,53 +/- 0,08 nmol/l) and delayed peak levels (mean 137 minutes after ingestion of glucose) compared with the controls (mean 2,15 +/- 0,31 nmol/l and 54 minutes respectively). Just over 20% of the patients had no residual beta cell function, this conclusion being made on the basis of undetectable basal C-peptide levels which failed to rise after glucose stimulation. A significant correlation was seen between glycosylated haemoglobin levels and maximal C-peptide levels (r = 0,45, P less than 0,01). C-peptide levels tended to be lower in Black than in Indian patients, but the difference was not significant.

Complications of early-onset insulin-dependent diabetes mellitus in Blacks and Indians.

Blacks and Indians with early-onset insulin-dependent diabetes mellitus (IDDM) were studied in order to assess the prevalence of acute and chronic complications. Of the 92 Blacks almost 70% developed ketoacidotic coma on one or more occasions, whereas 50% of the 41 Indians manifested this complication. Most of the chronic complications were related to duration of IDDM. Retinopathy was found in 14% of the Black and 22% of the Indian patients, nephropathy in 3% and 7% and neuropathy in 22% and 32% respectively. Compared with findings in other studies, IDDM in these population groups is not associated with a particularly high prevalence of chronic complications.

HLA-A, B, C and DR antigens in young South African blacks with Type 1 (insulin-dependent) diabetes mellitus.

The HLA status of South African black Type 1 (insulin-dependent) diabetic patients with age of onset under 35 years was compared with that of healthy black control subjects. HLA-A, B and C antigens were determined in 94 patients and 995 control subjects, while DR typing was carried out on 56 patients and 195 control subjects. There was a significant increase in the frequency of DR4 in patients as compared with control subjects (p less than 0.01; relative risk 3.4). DR3/DR4 heterozygosity was associated with a greater relative risk for developing Type 1 diabetes mellitus (3.7) than the presence of DR3 alone (relative risk 1.6). A significant negative association was observed between the presence of BW42 and Type 1 diabetes in this population sample (p less than 0.04; relative risk 0.3). A similar trend was observed with regard to DR2, the corrected p value just attaining statistical significance (p less than 0.05; relative risk 0.1).

Thyrotoxicosis and asthma. A case report.

A 55-year-old woman with intrinsic asthma that was aggravated by the onset of thyrotoxicosis is described. The possible mechanism for such a relationship is discussed.

The effect of strict control with the artificial beta-cell on plasma lipid levels in insulin-dependent diabetes.

The artificial beta-cell can establish normoglycemia within 2 h in an indifferently controlled diabetic patient. In the present study, the temporal relationship between the achievement of normoglycemia and its effect on plasma lipid concentrations has been examined in 12 insulin-dependent diabetic patients regulated by the artificial beta-cell for 7 days. The fasting values (mean +/- SEM) of blood glucose (BG), triglycerides (TG), total cholesterol (T-chol), HDL-cholesterol (HDL), and the calculated LDL/HDL ratio (obtained while participants were on single or split insulin regimens) were 385 +/- 42 mg/dl, 148 +/- 24 mg/dl, 219 +/- 22 mg/dl, 39 +/- 3.6 mg/dl, and 3.8 +/- 1.04, respectively. Within 12 h of establishing normoglycemia TG levels fell to 87 +/- 10 mg/dl (P less than 0.001), T-chol to 196 +/- 15 mg/dl (P less than 0.005), and HDL to 37 +/- 3 mg/dl (P = NS). The LDL/HDL ratio remained unchanged. After 7 days on the artificial beta-cell, the corresponding values were: 73 +/- 5 mg/dl (P less than 0.001), 169 +/- 9 mg/dl (P less than 0.001), 41 +/- 2.6 mg/dl (P = NS), and 2.6 +/- 0.56 (P less than 0.05). Twenty-four hours after discontinuation of artificial beta-cell therapy, the TG and T-chol concentrations reverted to baseline. These findings underscore the rapidity and effectiveness with which strict control can improve plasma lipid profiles.

The phytohaemagglutinin response and lymphocyte subpopulations in young Blacks and Indians with insulin-dependent diabetes mellitus.

The lymphocyte transformation response to phytohaemagglutinin (PHA) and the relative numbers of T, B and null lymphocytes were studied in 32 insulin-dependent diabetics and 32 healthy matched controls. The mean stimulation index (Sl) of the 18 patients with poorly controlled diabetes mellitus was significantly lower than that of controls. No difference was seen in the mean Sl values of well-controlled diabetics compared with controls. Neither the well-controlled group nor the poorly controlled group showed any significant differences in the mean counts of the various lymphocyte subpopulations when compared with controls.

Insulin response to oral glucose in young African and Indian noninsulin-dependent diabetic patients in Natal.

The insulin response to an oral glucose load was studied in 24 Indian and 14 African patients with NIDDM and 20 controls. The maximal insulin levels attained during the glucose tolerance test were significantly lower, and the peak insulin response occurred later in the diabetic patients compared to controls. The insulinogenic indices were also much lower in the patients. African patients showed lower basal and maximal insulin levels and lower insulinogenic indices than Indian patients, despite similar plasma glucose values. No correlation was seen between the fasting or maximal insulin levels and duration of NIDDM.

The clinical presentation and biochemical diagnosis of acromegaly and gigantism.

Over a 5-year period 14 patients with acromegaly and gigantism were seen at the endocrine clinic of King Edward VIII Hospital: 9 were Blacks and 5 Indians; 8 of the patients were women. The mean age of the patients was 46 years. Surprisingly, only 2 patients complained of acral overgrowth. Symptomatology was varied and not characteristic of the condition. On examination all patients had unequivocal signs of soft-tissue and bony overgrowth, 64% had visual abnormalities and 50% hypertension. Radiologically, 88% showed an enlarged pituitary fossa. On biochemical investigation, the fasting levels of growth hormone (GH) were increased in 12 patients and during oral glucose tolerance tests, the GH levels in these 12 patients were not suppressed. One patient in whom the fasting GH level was not increased had progressed to the stage of panhypopituitarism, in the remaining patient challenge with thyrotrophin-releasing hormone (TRH) led to increased GH levels and L-dopa challenge resulted in a paradoxical decrease in GH levels. Seven patients with increased GH levels who were challenged with L-dopa showed the typical decrease in GH levels found in this condition; in 5 of these patients, challenged with TRH, GH levels increased. The findings emphasize that despite the ease of clinical diagnosis, appropriate biochemical investigations are necessary to confirm the exact status of the disease, which is rare in the population studied.

The insulin and glucose response to an oral glucose load in non-insulin-dependent diabetes in the young.

Non-insulin-dependent diabetes with age of onset under 35 years was studied in 85 Indian patients eighty-one per cent of the group were females, the mean age of onset of diabetes was 27 years while the mean duration was 6.3 years. the mean percentage desirable mass of the patients was 112%, obesity being present in 55% of the group. Eighty-two per cent of patients gave a positive family history; closer analysis revealed that 75% of the propositi had a diabetic parent and 41% a diabetic sibling; while three-generation transmission was present in 7%. Eighty-one patients consented to a 100 g oral glucose load. The insulin and glucose response during a 3-hour period revealed fasting hyperinsulinism with a delayed and attenuated insulin response, a much lower insulin area and higher glucose ares, a lower insulin-glucose ratio and a lower modified Seltzer insulinogenic index when compared with 50 non-diabetic reference subjects. There was no difference in insulin and glucose responses in obese and non-obese diabetics. However, subdivision of the group into those with moderate and those with severe diabetes demonstrated that the latter had significantly higher plasma glucose levels and lower insulin levels at all times, except in the fasting state, during which the insulin levels were not significantly different.

C-peptide response to glucagon in black and Indian insulin-dependent diabetics.

Residual beta cell function was estimated in 35 young diabetic patients (25 Blacks and 10 Indians) and 22 controls by means of C-peptide assays using glucagon as a provocative agent. The basal C-peptide levels (mean 0,32 +/- 0,23 nmol/l) and the 6-minute post-glucagon levels (mean 0,56 +/- 0,47 nmol/l) were significantly lower in the diabetic patients than in the controls (mean values 0,49 +/- 0,20 nmol/l and 1.24 +/- 0,48 nmol/l respectively). None the less, residual beta cell function, as gauged by the presence of significant C-peptide increments in response to glucagon provocation (mean increase 75% of basal level), was present in most of the patients. The Black patients had significantly lower basal and 6-minute post-glucagon C-peptide levels than the Indian patients.