Clinical characteristics and outcome of hyperglycaemic emergencies in Johannesburg Africans.

In this prospective analysis we investigated the clinical characteristics of black South African diabetic patients admitted to hospital with hyperglycaemic emergencies. The study cases were selected from the medical admissions to an urbanized, Johannesburg academic hospital over a period of 12 months. Only patients with severe diabetic ketoacidosis (DKA) or hyperosmolar non-ketotic hyperglycaemia (HNKH) as defined in the text were included. Over the study period, we identified 58 patients with severe DKA (M: 32, F: 26) and 24 with HNKH (M: 14, F:10). Thirty-two of the patients with DKA (55.2%) were classified as having non-insulin dependent (Type 2) diabetes mellitus (NIDDM). Compared to the 26 subjects with insulin-dependent (Type 1) diabetes mellitus (IDDM), the NIDDM patients were older (51.7 vs 27.7 years) and had a significantly higher body mass index (BMI) (29.4 vs 23.5 kg m(-2), p = 0.002), and glucose levels 47.5 vs 34 mmol l(-1) p = 0.004). Mortality from DKA was 6.8 % and from HNKH 16.6%. Infection was the leading precipitating factor for both DKA and HNKH, followed by first presentation and noncompliance. We conclude that the majority of urban African patients admitted to hospital with DKA have NIDDM. Mortality from DKA among the black Africans in Johannesburg is low and comparable to the mortality in western Europe.

Plasma fatty acid levels in South African interethnic male high school pupils at different ultimate risks of coronary heart disease.

While coronary heart disease (CHD) is responsible for about a quarter of deaths in South African white, coloured and Indian populations, the rate is very low in the black population. Dietary risk factors for CHD include high intakes of saturated fatty acids and cholesterol, with low intakes of mono and polyunsaturated fatty acids. In a characterization study, plasma fatty acid profiles have been determined in seven groups of high school pupils aged 16-18 years, namely, white, rural black, urban black and middle-class and lower socio-economic class coloureds and Indians. Plasma fatty acids were measured by gas liquid chromatography in 20 subjects from each group. Contrary to expectation, urban and rural black pupils had the highest mean molar composition of saturated fatty acids, largely myristic (14:0) and palmitic (16:0) acids. Rural blacks and middle-class coloureds had the highest molar percentage composition of monounsaturated fatty acids, primarily oleic acid (18:1). Again unexpectedly, white, coloured and Indian groups had the highest level of polyunsaturated fatty acids, due entirely to linoleic acid (18:2). As the findings are unrelated to proneness to CHD mortality in the particular communities studied, plasma fatty acid levels are not predictive of the disease. Epidemiologically, there are many examples of lack of correlation in serum lipid levels and proneness to CHD.

Comprehensive management of non-insulin-dependent diabetes mellitus. A diabetes clinic revisited.

OBJECTIVE: To 'revisit' the Johannesburg Hospital diabetes clinic to ascertain whether the established risk factors for CAD were being identified and appropriately managed. DESIGN: Body mass indices (BMI), fasting lipograms and glycated haemoglobin (HBA) estimations were done on a random sample of white NIDDM patients aged over 35 years. RESULTS: Eighty-two patients (39 males, 43 females) were tested. The mean age was 60 years (range 36-80 years) and the mean duration of NIDDM 6.2 years (range 1-25 years). The mean HBA value was 10% (normal 4-8%). Obesity was present in 82%; it was moderate (BMI 25-30 kg/m2) in 46% and severe (BMI > 30 kg/m2) in 36%. Hypercholesterolaemia was present in 46%, hypertriglyceridaemia in 68%, and both in 34%. Uncontrolled hypertension was present in 20% of patients, and 27% smoked. CONCLUSIONS: Management of patients at our clinic remains confined to the control of hyperglycaemia. Despite increased awareness of the risk factors for CAD, these factors have largely been ignored.

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 polymorphic alleles, found only in exon 17, showed a significant difference between black and white groups (P = 0.037).

Microalbuminuria is not associated with cardiovascular disease in patients with homozygous familial hypercholesterolaemia.

Microalbuminuria is thought to be a predictor of cardiovascular disease (CVD). A high prevalence of microalbuminuria might therefore be expected in patients with homozygous familial hypercholesterolaemia (HFH), as they develop severe premature atherosclerosis. We tested for this in 15 HFH patients (M = 9, F = 6; mean age 19.3 years). Urinary albumin excretion (UAER) were normal in all patients [corrected]. In addition, there was no difference in the mean urinary albumin excretion rate (UAER) between those with documented CVD (n = 8; UAER = 5.17 micrograms/min) and those without (n = 7; UAER = 3.60 micrograms/min). There is therefore no association between microalbuminuria and CVD in HFH.

Renal and neuromuscular respiratory failure--is this a syndrome associated with cantharidin poisoning?

OBJECTIVE: To describe the clinical and laboratory features of patients with renal and neuromuscular respiratory failure due to suspected cantharidin poisoning. DESIGN: Retrospective record review of cases with neuromuscular respiratory failure. SETTING: Intensive Care Unit (ICU), Hillbrow Hospital, Johannesburg. PATIENTS: Out of a total of 47 patients with neuromuscular respiratory failure admitted to the ICU between January 1983 and December 1990, 10 with suspected cantharidin poisoning were selected and studied further. OUTCOME MEASURES: Description of clinical features, laboratory data, treatment and prognosis. RESULTS: In 10 of the 47 patients, the cause of renal and neuromuscular respiratory failure that which precipitated the need for ICU admission was suspected to be cantharidin poisoning. This was based on the history and clinical and laboratory features. In 4 cases trace amounts of cantharidin were detected in blood and/or urine, strengthening the diagnosis. There were 8 males and 2 females. All had evidence of renal injury and 9 had gastro-intestinal symptoms. All presented with fixed dilated pupils, varying cranial nerve palsies and muscle weakness, usually ascending and progressive, necessitating admission to the ICU. All but 1 of the patients were mechanically ventilated, 5 required significant inotropic support of the blood pressure, and 6 dialysed. Four patients died soon after admission and the remainder survived with relatively complete return of neurological function. CONCLUSION: This study highlights the possibility that cantharidin poisoning may be a cause of a 'Guillain-Barrè-like' syndrome.

Effects of inspired air conditions on catecholamine response to exercise in asthma.

The influence of different inspired air conditions on exercise-induced bronchoconstriction (EIB) is well appreciated. However, the mechanism by which this influence is exerted is uncertain. To determine if varied inspired air conditions during exercise could affect the catecholamine response to physical exercise, we had 13 asthmatic and 6 healthy children (aged 10-18 years) undergo two bouts of cycle ergometry tests under different air conditions. One test was done while breathing cold dry (CD) air (temperature, -20.2 degrees C; relative humidity, 0%) and the other while breathing warm humid (WH) air (temperature, 34.3 degrees C; relative humidity, 100%). Forced expiratory volume in 1 second (FEV1) and plasma catecholamine concentrations were recorded before and after exercise. Marked EIB (48 +/- 5% SEM fall in FEV1 from baseline) developed in all asthmatics after the CD exercise, but no EIB was noted after the WH exercise. Normal controls had no EIB under either test conditions. Plasma levels of catecholamines at rest, and the changes that occurred during and after exercise, were comparable within as well as between the groups in both tests. Catecholamines did not rise in asthmatics following development of EIB. These data demonstrate that inspired air conditions do not influence the sympathoadrenal response to exercise, at least as reflected in plasma catecholamine levels. In fact, this response did not differ between asthmatics and normals, irrespective of the development of EIB. These results are consistent with previous reports about impaired catecholamine response of asthmatics to bronchoconstriction.

Insulin-mediated glucose disposal in black south Africans with essential hypertension.

We used the hyperinsulinaemic euglycaemic clamp method to assess insulin-mediated glucose disposal in ten black South African patients with newly-diagnosed essential hypertension, compared to ten normotensive controls. The patients were all nonobese with normal glucose tolerance. Comparisons were made before and 12 weeks after treatment with a long-acting ACE inhibitor. The mean glucose disposal (M) and disposal expressed as glucose sensitivity index (M/I) were significantly reduced in the hypertensives vs. controls (M: 6.8 +/- 0.9 vs. 9.7 +/- 0.8 mg/kg/min; MI: 7.1 +/- 1.0 vs. 12.5 +/- 1.7 mg/kg/min/mU/l x 100) (p = 0.03 and 0.01, respectively). Following therapy, M/I increased in the patients to values not significantly different to those of the controls. Insulin resistance is an independent feature of essential hypertension in black South African patients, and is partially corrected by treatment with a long-acting ACE inhibitor.

Perindopril and physiologic responses to exercise.

Cardiovascular drugs have varying effects on hemodynamic, metabolic, and hormonal responses to exercise. To evaluate the effects of the novel angiotensin-converting enzyme (ACE) inhibitor, perindopril on these exercise-related responses, we studied 9 healthy volunteers in a double-blind, randomized, placebo-controlled trial. After a week of perindopril 4 mg orally daily or placebo therapy, volunteers performed a treadmill effort test; the sequence was repeated after a 1-week washout period. Perindopril caused a significant reduction in mean resting systolic and diastolic blood pressure (SBP, DBP) without increasing resting heart rate (HR); 15-min post-exercise SBP was also significantly reduced. There were no significant differences between the perindopril and placebo effort tests with respect to metabolic indexes studied (serum K+, plasma glucose, plasma free fatty acids) or plasma hormonal concentrations measured (ACTH and cortisol, norepinephrine (NE) and epinephrine (EPI), glucagon and insulin, growth hormone and prolactin, renin activity). In the perindopril arm of the study, however, there were modest but significant increases in mean serum K+ before exercise to immediately after exercise (0.4 +/- 0.1 mM, p < 0.01) and mean plasma glucose from before exercise to 5 min (0.6 +/- 0.2 mM, p < 0.01) and 15 min (0.5 +/- 0.2 mM, p < 0.05) after exercise. These data show that perindopril does not impair the hormonal changes associated with exercise in healthy subjects but induces a more consistent increase in blood K+ and glucose concentrations.

Lack of effect of high dose vitamin E on xanthoma regression in homozygous familial hypercholesterolaemia.

There is increasing evidence that oxidative modification of low-density lipoprotein (LDL) plays an important role in the pathogenesis of atherosclerosis. Homozygous familial hypercholesterolaemia (HFH) is characterized by premature, severe atherosclerosis. Drugs available at present are ineffective in lowering the markedly elevated LDL levels in this condition; antioxidant therapy to protect the LDL against oxidation may be of benefit. Probucol, the only drug shown to induce xanthoma regression in HFH, is a potent antioxidant, but it also lowers high-density lipoprotein cholesterol (HDL-C) levels, causing some concern. Vitamin E is a naturally occurring antioxidant that does not affect HDL-C levels. We have therefore evaluated the effect of long-term high dose vitamin E on xanthoma regression in HFH. Ten subjects with HFH, mean age 17 years (range 4-34), received vitamin E (400-1000 mg/dl alpha-tocopherol acetate/day) for a period of 23 months (range 12-27). There was a 4.2-fold increase in the mean serum vitamin E level (mean (S.D.) 49.7 (19.9) to 177.9 (45.6) mumol/l; P < 0.005), but no change in serum lipid or lipoprotein concentrations. Although there was an increase in the in vitro resistance of LDL to oxidation as determined by the duration of the lag phase during copper-mediated oxidation (116 (8.34) vs. 141.5 (9.23) min; P < 0.005) there was no xanthoma regression; in fact they progressed in 4 subjects. Unlike probucol, high dose long-term vitamin E has no demonstrable effect on xanthoma regression in HFH.

Selected risk factors for coronary heart disease in male scholars from the major South African population groups.

A number of risk factors for coronary heart disease (CHD) in 7 groups of South African male scholars aged between 15 and 20 years were surveyed. Selection of the groups was based on socioeconomic status and comprised urban and rural blacks, Indians of higher and lower socio-economic status, coloureds of higher and lower socioeconomic status, and middle-class whites. Both Indian groups, both coloured groups and the whites had a much greater prevalence and severity of CHD risk factors than the two black groups. This held for total cholesterol, low-density lipoprotein cholesterol (LDLC), high-density lipoprotein cholesterol (HDLC), the HDLC/LDLC ratio, apolipoprotein B, apolipoprotein A-I, insulin, fibrinogen and mass. One exception was lipoprotein a, levels of which were higher in both black groups. In general the CHD risk factor profile was worse in the higher socio-economic groups, and it also tended to be worse in urban than in rural blacks. These findings stress the need to reduce CHD risk factors in our developed populations and to prevent their emergence in our developing peoples.

Characterization of six patients who are double heterozygotes for familial hypercholesterolemia and familial defective apo B-100.

Familial defective apolipoprotein B-100 (FDB) and familial hypercholesterolemia (FH) are the common causes of monogenic primary hypercholesterolemia. An individual of mixed English and Afrikaner descent with both FDB and the FH Afrikaner-1 low-density lipoprotein receptor mutation was identified in our laboratory. Subsequent analysis of her extended family revealed the presence of heterozygotes for either FH Afrikaner-1, FH Afrikaner-2, or FDB as well as five additional double heterozygotes for FH Afrikaner-1 and FDB and one "complex" heterozygote with all three mutations. The hypercholesterolemic and clinical features of the pure FDB subjects were similar to those of the pure FH heterozygotes. The double heterozygotes with both FH and FDB have lipid levels and clinical features that are intermediate in severity between heterozygous and homozygous FH.

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 mid-term 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 HbA1 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.

Identification and properties of the proline664-leucine mutant LDL receptor in South Africans of Indian origin.

The incidence of familial hypercholesterolemia (FH) is high among South African Indians. The proline664-leucine low density lipoprotein (LDL)-receptor mutation was detected in four apparently unrelated Indian FH families in South Africa. This mutation was originally described in an FH subject (MM) of Indian (Gujerat province) origin (Soutar et al. 1989. Proc. Natl. Acad. Sci. 86: 4166-4170). All four South African families trace their origin to the vicinity of Surat in the Gujerat province of India. Haplotype analyses revealed that both LDL receptor genes in one of the homozygous patients are the same as those in the subject MM. The phenotype of the mutant protein was analyzed in skin fibroblasts of homozygous patients. [35S]methionine pulse-chase experiments revealed that the receptor precursors were slowly processed to mature receptors. Mature mutant receptors were degraded at faster than normal rates. This mutation, which is in the epidermal growth factor (EGF)-precursor-like domain of the LDL receptor, was previously reported to yield binding-defective receptors. Here we report that the affinity of the mutant LDL receptor for both LDL and beta-very low density lipoprotein (beta-VLDL) was normal and that the steady-state level of mutant receptors was about 20% of normal. Thus, the disease FH in these subjects is presumably due to the low steady-state level of receptor molecules that are functionally normal but exhibit accelerated turnover.

Pathogenesis of non-insulin-dependent diabetes mellitus in the black population of southern Africa.

Non-insulin-dependent diabetes mellitus (NIDDM) is an important health problem in the black population of southern Africa. Whether the primary cause of NIDDM is insulin secretory dysfunction or peripheral insulin resistance is unknown. In westernised populations it is believed that insulin resistance and hyperinsulinaemia occur in the early stages of disease, followed later by progressive impairment of insulin secretion. However, we suggest that in the southern African black population a decrease in the mass of functioning beta cells is an important event, making these people vulnerable to the deleterious effects of insulin resistance induced by obesity and other factors. These abnormalities are, in turn, associated with insulin receptor down-regulation. An accelerated decline in beta-cell function then follows in susceptible individuals, ultimately producing striking insulinopenia. Insulinopenic NIDDM in black southern Africans may partly explain why this population has a comparatively low incidence of macrovascular complications and also predicts a short-lived therapeutic response to oral sulphonylureas in most patients.

Relationship between plasma insulin and blood pressure in South African black women in Johannesburg.

OBJECTIVE: 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 less than 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.