Harold C. Seftel

Liver damage in heatstroke

The effects of heatstroke on the structure and function of the liver have been studied in thirty-nine Bantu gold miners. Hepatocellular damage was found to be invariable. In a minority of patients (about 10 per cent) the liver damage was severe and may have contributed to a fatal outcome. In the remainder it was mild or moderate and could be detected only on biochemical testing or liver biopsy. The pathologic changes consisted of centrolobular degeneration or necrosis of hepatocytes and congestion; cholestasis and portal venular dilatation were prominent in the fatal cases. In the patients who survived, the histologic and biochemical abnormalities were completely reversible. It is suggested that the hepatic changes are the result of a combination of hypoxia and direct thermal injury.

The heart in heatstroke.

Abstract Evidence of cardiac damage was found in 17 out of 26 Bantu goldminers with heatstroke. Myocardial injury was diagnosed on the basis of serum lactic dehydrogenase (LDH) isoenzyme patterns and electrocardiographically. A significant increase in the percentage of LDH-1 was present in 69 per cent of the patients. Electrocardiographic tracings were abnormal in 58 per cent of the cases. The changes consisted mainly of sinus tachycardia and nonspecific S-T segment and T-wave abnormalities, which were reversible in those patients who were followed up. A good correlation (75 per cent) was found between the isoenzyme and the electrocardiographic evidence of cardiac damage. Pathological examination of the heart in the 2 patients who died in the acute stage showed interstitial edema and degeneration of the muscle fibers. Although myocardial damage occurred in the majority of the cases, in none was it severe enough to cause overt cardiac failure.

The diagnostic and prognostic significance of the serum enzyme changes in heatstroke

Abstract Serum transaminase (SGOT, SGPT), lactic dehydrogenase (LDH) and creatine phosphokinase (CPK) levels were measured serially in 84 Bantu gold-miners with a provisional diagnosis of heatstroke. In 75 patients proved to have heatstroke, SGOT levels were invariably, and SGPT, LDH and CPK values almost invariably, elevated within 24 hours of admission. The levels continued to rise for approximately 48 hours and remained elevated for average periods of 12 to 14 days. In the patients who proved to have acute infections, SGOT, SGPT and LDH values were normal. The serum enzyme changes were therefore useful in confirming or excluding the diagnosis of heatstroke. The degree of elevation of the enzyme levels was also a reliable index of the severity of tissue damage in heatstroke and hence the patients likely outcome. In 15 patients in whom the SGOT level exceeded 1,000 units in the first 24 hours, renal, hepatic and cerebral damage tended to be severe, and death or permanent sequelae were common. In 20 patients with SGOT values of less than 1,000 units, the tissue injury was usually mild or moderate and completely reversible, and there was only 1 death.

PATHOGENESIS OF NONKETOTIC HYPEROSMOLAR DIABETIC COMA

Two concepts are advanced to explain some fo the puzzling biochemical features found in nonketotic hyperosmolar diabetic coma. It is firstly suggested that an insulinised liver (reflecting residual beta-cell secretory activity) coexists with a diabetic periphery, thereby inactivating intrahepatic oxidation of incoming free fatty acids, which are directed largly along nonketogenic metabolic pathways such as triglyceride synthesis. This could account for the lack of hyperketonaemia. Secondly, it is hypothesised that within the liver enhanced neoglucogenesis occurs, due to the prevailing portal-vein into ratio of glucagon to insulin, and is mainly responsible for the development of massive hyperglycaemia.

NIDDM in African-Americans and Black South Africans: Many Similarities but Some Important Differences

The metabolic and clinical features of NIDDM in African-Americans have attracted recent interest because of several unusual characteristics. However, the similarities that exist between the disorder in this community and in black South Africans have not been emphasized. We wish to highlight some of these aspects and to point out important differences, mainly concerning macrovascular complications. While some reviewers have suggested that African-Americans share the same pathogenesis as Western world populations, in that insulin resistance is the initial abnormality preceding NIDDM (1), Banerji and Lebovitz (2,3) have interpreted the situation differently. Their data indicate that NIDDM in African-Americans consists of two distinct metabolic disorders: About half the patients are, indeed, characterized by a genetic abnormality in insulin action producing severe insulin resistance; the other half are associated with a primary defect of P-cell function, insulin resistance developing only as a consequence of obesity or hyperglycemia. Subsequently, they reported that HLA-DQ associations differed in the two variants (4). HLA-DQW7 was more common in the resistant population and HLA-DQW6 more frequent in the insulinsensitive group. Concerning black South Africans, NIDDM may also consist of two metabolic subtypes (5). The majority of patients, however, demonstrate progressive fi-cell failure (6) akin to the insulin-sensitive group of African-Americans. The underlying mechanism appears to be a decrease in the functional (3-cells mass, possibly acquired through perinatal malnutrition (7). Similarities in clinical presentation include epidemiological and clinical features as well as the high prevalence of microvasculopathy. Like African-Americans, urban black South Africans show an escalating incidence of NIDDM (ageadjusted prevalence approaching 7%) such that it is now more common than in whites (7). While NIDDM in most African-Americans appears to evolve insidiously, recent studies have described several unique features. These include the not uncommon presentation in diabetic ketoacidosis (Flatbush diabetes) (8), the high prevalence of obesity in such cases (9), the importance of cessation of prior insulin therapy and infection as precipitating cause (10), and the fact that many such patients go into remission after initial diabetic management (11). Although considered unique for a subset of African-Americans, similar clinical features have now been well recognized in black South Africans. In a recent prospective study involving 50 consecutive patients admitted to Hillbrow Hospital, Johannesburg, South Africa, with diabetic ketoacidosis, —50% had NIDDM, of whom half were overweight (M. Zouvanis, A. Pieterse, H. Seftel, B. Joffe, unpublished observations). Noncompliance and infection were noted to be the major precipitants. Some patients discontinue insulin and remain in remission after initial presentation; insulin may be required again for intercurrent infection (12). Important differences mainly relate to the presence of primary insulin resistance in ~50% of African-Americans with NIDDM. This is observed much less frequently in black South Africans. Although they show diminished glucose disposal on presentation, this normalizes once hyperglycemia and glucose toxicity have been corrected (13). As anticipated, insulin-resistant African-Americans with NIDDM have significantly higher mean serum lipoprotein levels than their insulin-sensitive counterparts (14), whose lipoprotein concentrations resemble those of the overall black South African NIDDM population (Table 1). The exception is fasting triglycerides, which are significantly higher in black South Africans, partly because of dietary factors. This generally favorable lipid profile might explain the continuing low prevalence of myocardial infarction in the latter ethnic group (15). In contrast, AfricanAmericans with NIDDM appear to have a substantial prevalence of coronary artery disease, particularly among women (16). The evidence we have summarized indicates that African-Americans and black South Africans with NIDDM share several unusual clinical features. This can be related to a similar pathogenic mechanism, progressive (3-cell failure. However, unlike black South Africans, African-Americans with NIDDM also encompass a major insulin-resistant variant that resembles the disease in Western world populations with whom they may share genetic links. Alternatively, some West African immigrants to the United States soon acquire insulin resistance (17).

Changes in Glucose Disposal and Cellular Insulin Binding in Obese Black Southern African Patients with Type 2 Diabetes Mellitus Before and After Sulphonylurea Therapy

Peripheral insulin action and cellular insulin binding were studied in 10 newly detected, obese, black, Southern African women with Type 2 diabetes mellitus before and after midterm oral sulphonylurea therapy and in five obese, non‐diabetic controls. Glucose disposal (assessed by the euglycaemic insulin clamp technique) was significantly reduced in diabetic patients compared to control subjects (4.4 ± 0.5 vs 6.4 ± 0.5 mg kg‐1 min‐1, p < 0.05), and increased after 1 and 3 months of sulphonylurea therapy to 6.8 ± 0.6 mg kg‐1 min‐1 (p = 0.01) and 6.3 ± 0.7 mg kg‐1 min‐1 (p = 0.04), respectively. The major change in the binding kinetics of insulin to peripheral monocytes was an increase in the mean receptor concentration in the diabetic patients which was significant after 3 months of therapy (0.2 ± 0.08 to 0.6 ± 0.01 nM, p = 0.05). The basal plasma C‐peptide concentration was significantly lower in the diabetic patients than in the controls and remained so following sulphonylurea therapy, despite significant reductions in fasting glucose and HbA‐1 concentrations. We conclude that newly diagnosed, obese, black Southern Africans with Type 2 diabetes showed diminished peripheral glucose disposal which increased following sulphonylurea therapy. This was accompanied by an increase in insulin receptor concentration but not with changes in basal insulin secretion.

SSCP analysis of the tyrosine kinase domain of the insulin receptor gene: Polymorphisms detected in South African black and white subjects

The frequency of DNA polymorphisms in the tyrosine kinase domain (exons 17–21) of the insulin receptor gene was assessed in 30 black and 30 white South Africans, using single-stranded conformation polymorphism and direct sequencing analysis. A comparison of the frequencies of the normal versus the combined polymosphic alleles, found only in exon 17, showed a significant difference between black and white groups (P = 0.037).

Relationship Between Plasma Insulin and Blood Pressure in South African Black Women in Johannesburg

Objectives To examine the relationship between fasting plasma insulin and blood pressure (BP) in 40 urbanized normotensive South African black women aged 24–60 yr, and to assess the effects of body mass index (BMI) and fasting plasma glucose on BP. Research Design and Methods The women comprised equal numbers of young nonobese nondiabetic subjects, middle-aged nonobese nondiabetic subjects, middle-aged obese nondiabetic subjects, and middle-aged obese newly diagnosed non-insulin-dependent diabetic subjects. Systolic and diastolic BPs were recorded (in duplicate) after 15 min of recumbency, and fasting plasma glucose and insulin levels were determined thereafter. The data were analyzed by simple and multivariate regression. Results There was a wide distribution of individual physical and biochemical features. With simple correlations, systolic BP correlated significantly with age, BMI, and fasting glucose but not with insulin. Diastolic BP correlated significantly with all four variables (r = 0.37, P <0.05). When adjusted for age, BMI, and glucose, however, the significant correlation between diastolic BP and insulin diminished (r = −0.04). Conclusions As in other nonwhite communities, plasma insulin does not appear to play a major role in regulating the BP of South African black women.

Insulin-Receptor Activity in Nondiabetic and Diabetic Urbanized South African Black Women

Objective To evaluate insulin receptor binding characteristics of urbanized South African black women with normal glucose tolerance and of patients with newly diagnosed untreated non-insulin-dependent diabetes mellitus (N1DDM). Research Design and Methods Four groups of 10 subjects each were selected by the following criteria: group A, young (20-39 yr) nonobese (body mass index [BMI] 19.0-24.9 kg/m2) nondiabetic women; group B, middleaged (40–60 yr) nonobese nondiabetic women; group C, middle-aged obese (BMI>30.0 kg/m2) nondiabetic women; and group D, middle-aged obese newly diagnosed but untreated female patients with NIDDM. Insulin binding to monocyte receptors was determined by radioreceptor assay. Fasting plasma samples were analyzed for glucose, insulin, C-pep tide, and nones terified fatty acids. Results In the four groups studied, maximum specific binding and receptor concentration were highest in group A, with a progressive and significant decrease in values through groups B and C to group D. Significant inverse correlations were obtained between maximum specific binding, 50% inhibition dose, and total receptor concentration on the one hand and glucose, insulin, and NEFA on the other. Conclusions Our study of urban South African black women showed decreasing insulin-receptor activity with obesity and glucose intolerance. In patients with NIDDM, hyperglycemia and (β-cell dysfunction were associated with a reduction in receptor concentration. In this regard, our findings in South African blacks are consistent with results of similar studies of NIDDM in other communities.

Metabolic and Hormonal Responses to Salbutamol in Asthma. Evidence of Beta-Adrenergic Overactivity?

The possibility that beta-adrenergic hyposensitivity may be involved in the pathogenesis of bronchial asthma remains a controversial issue. The hormonal, metabolic and cardiovascular responses to selective beta 2-adrenergic stimulation with salbutamol were compared in 11 asthmatic and 11 non-asthmatic subjects. There was no consistent difference between the two groups in the plasma free fatty acid, glucose and potassium responses, or in the cardiovascular variables studied, but the asthmatic patients demonstrated a marked dose-dependent hyperinsulinaemic response to salbutamol. Although this phenomenon cannot be accounted for with certainty, it may be a manifestation of pancreatic beta-adrenergic overactivity which would not be in keeping with the concept of generalised hyposensitivity of beta-adrenergic mechanisms in asthma. The present results provide a clear demonstration of the difficulties involved in attempts to relate extrapulmonary autonomic phenomena to the pathogenesis of bronchial asthma.