Postprandial lipaemia, metabolic syndrome and LDL particle size in urbanised South African blacks with and without coronary artery disease.

BACKGROUND: Postprandial lipaemia, characterised by a rise in triglycerides (TG) after eating, is associated with coronary artery disease (CAD) and metabolic syndrome (MetS). Small, dense, low-density lipoprotein (LDL) particles are implicated in atherogenesis. Little is known about postprandial lipaemia or small, dense LDL particles in urbanised black South Africans. AIMS: Assess postprandial lipaemia in black CAD patients with and without MetS and measure their fasting and postprandial lipid profiles and LDL particles. METHODS: Anthropometric data, biochemical variables and LDL particles were measured in 40 patients and 20 control subjects. Twenty three patients met International Diabetes Federation criteria for MetS and were subdivided according to fasting TG concentration either < or > or = 1.7 mmol/l. Postprandial lipaemia was assessed by an oral fat tolerance test (OFTT) and area under the curve (AUC). RESULTS: CAD patients with and without MetS had similar fasting lipid profiles, postprandial responses during OFTT and AUCs. MetS patients with fasting TG > or = 1.7 mmol/l had greater postprandial responses (P < 0.001) and higher AUC (P < 0.0001) than patients with TG < 1.7 mmol/l. AUC was higher in all patients than controls (P < 0.03). The most significant correlation was between fasting TG and AUC (r = 0.8703; P < 0.0001). Small, dense LDL particles were present in 29 patients (72.5%) and 3 controls (15%) (p = 0.0001). CONCLUSION: Postprandial lipaemia was common in black CAD patients, including patients with MetS. Fasting TG concentration was the strongest determinant. Small, dense LDL particles were highly associated with CAD.

Metabolic syndrome, undiagnosed diabetes mellitus and insulin resistance are highly prevalent in urbanised South African blacks with coronary artery disease.

BACKGROUND: The prevalence of coronary artery disease (CAD) is low in South African blacks, despite increasing westernisation and the accompanying rise in risk factors that are common to CAD and the metabolic syndrome (MS). AIM: To assess the prevalence of the MS and abnormal glucose regulation in black patients with established CAD, who had no previously known diabetes mellitus (DM). METHODS: In 40 patients, anthropometric and biochemical variables were measured by standard methods. MS risk factors were analysed according to the National Cholesterol Education Program Adult Treatment Panel III guidelines. Glucose regulation was assessed by the oral glucose tolerance test, and insulin resistance was evaluated using the hyperinsulinaemic euglycaemic clamp technique (M-value). RESULTS: MS was present in 24 patients (60%) and absent in 16 patients (40%). Abdominal obesity, measured as increased waist circumference (WC), was the risk factor that differentiated the two groups and, together with hypertension and elevated glucose, formed the most frequent risk-factor combination. No significant differences were found in the proportions of males or females above and below the various cut-off points for gender-associated risk factors (WC and HDL cholesterol). There was a significant correlation between WC and M-value (r = -0.3595; p = 0.02). Half the patients had abnormal glucose regulation, comprising impaired glucose tolerance (IGT) in 30% and DM in 20% of the patient cohort. CONCLUSIONS: MS was highly prevalent in our black patients with CAD. Increased WC was the most important risk factor and, together with hypertension and elevated glucose, formed the most frequent risk-factor combination. Abdominal obesity was significantly related to insulin resistance. Previously undiagnosed impaired glucose tolerance (IGT) and DM were common abnormalities.

Adrenocortical function in hospitalised patients with active pulmonary tuberculosis receiving a rifampicin-based regimen -- a pilot study.

OBJECTIVE: To assess whether adrenocortical function was compromised in patients with active tuberculosis (TB) during the first 5 days of therapy with either a rifampicin-based or ciprofloxacin-based regimen. DESIGN: Patients were randomised into two groups of 10 each. Adrenocortical function was compared in both groups by the measurement of biochemical indices, electrolytes, osmolality and pituitary-adrenocortical hormones. Adrenal reserve was assessed by intravenous 250 mug adrenocorticotropin hormone (ACTH) stimulation tests. SETTING: Department of Medicine, Johannesburg Hospital. SUBJECTS: Twenty hospitalised patients who were diagnosed with TB. OUTCOME MEASURES: Respiratory rate, pulse rate and blood pressure were recorded, and urinary sodium and osmolality were measured. Serum ACTH, cortisol, dehydroepiandrosterone- sulphate (DHEA-S) and aldosterone were assayed. RESULTS: None of the patients demonstrated biochemical evidence of overt adrenal insufficiency. There were no significant differences between the two groups before or during therapy for any biochemical indices, electrolytes, hormones or calculated osmolality. Mean basal cortisol concentrations were substantially elevated and DHEA-S levels were consistently subnormal, resulting in a high cortisol/ DHEA-S ratio. In the ciprofloxacin group, cortisol responses to ACTH stimulation on day 1 were not significantly lower than on day 5. In the rifampicin group, cortisol concentrations decreased at each time point on day 5 compared with day 1 (p = 0.001). However, a significantly higher mean incremental rise from the basal cortisol concentration was measured on day 5 at 60 minutes (p = 0.04). In the entire cohort of 20 patients, 40% demonstrated an incremental cortisol rise of < 250 nmol/l after ACTH stimulation on day 1. CONCLUSIONS: Rifampicin did not additionally impair adrenocortical function during the initial period of therapy. The high cortisol/DHEA-S ratio might be of clinical relevance.

Performance of the CardioChek PA and Cholestech LDX point-of-care analysers compared to clinical diagnostic laboratory methods for the measurement of lipids.

Point-of-care (POC) blood testing is intended to provide results more rapidly than can be obtained from a central laboratory. Precision and accuracy of the CardioChek PA and Cholestech LDX analysers were compared to clinical diagnostic laboratory methods. In 100 patients, total cholesterol (TC), triglycerides (TG), HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C) levels were measured by both analysers and compared to those analysed by the National Health Laboratory Service (NHLS) laboratory. Data were evaluated for conformance with National Cholesterol Education Program (NCEP) guidelines. Results were grouped into low, middle and high ranges and were similar to those obtained by the NHLS, except in the high range where TC and LDL-C levels were under-read by both analysers. All analytes measured by both analysers correlated significantly with NHLS (p < 0.0001). With the exception of LDL-C, both analysers showed reasonable compliance with NCEP goals for coefficients of variation and bias measurements. Both analysers met NCEP guidelines for all analytes at two clinical cut-off points. We concluded that, compared to NHLS methods, performance of the CardioChek PA and Cholestech LDX analysers is acceptable and that they offer healthcare professionals a rapid, POC method for the measurement of lipids.

Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy.

Generalised lipodystrophy of the Berardinelli-Seip type (BSCL) is a rare autosomal recessive human disorder with severe adverse metabolic consequences. A gene on chromosome 9 (BSCL1) has recently been identified, predominantly in African-American families. More recently, mutations in a previously undescribed gene of unknown function (BSCL2) on chromosome 11, termed seipin, have been found to be responsible for this disorder in a number of European and Middle Eastern families. We have studied the genotype/phenotype relationships in 70 affected subjects from 44 apparently unrelated pedigrees of diverse ethnic origin. In all subjects, hepatic dysfunction, hyperlipidaemia, diabetes mellitus, and hypertrophic cardiomyopathy were significant contributors to morbidity with no clear differences in their prevalence between subjects with BSCL1 or BSCL2 and those with evidence against cosegregation with either chromosome 9 or 11 (designated BSCLX). BSCL2 appears to be a more severe disorder than BSCL1 with a higher incidence of premature death and a lower prevalence of partial and/or delayed onset of lipodystrophy. Notably, subjects with BSCL2 had a significantly higher prevalence of intellectual impairment than those with BSCL1 or BSCLX (p<0.0001, OR 17.0, CI 3.6 to 79.0). The higher prevalence of intellectual impairment and the increased risk of premature death in BSCL2 compared to BSCL1 emphasise the importance of molecular diagnosis of this syndrome and have clear implications for genetic counselling.

Tandem CAG repeats of the androgen receptor gene and prostate cancer risk in black and white men.

The most common malignancy in men worldwide is cancer of the prostate. Androgens play a direct role in normal and malignant growth of prostate cells via the androgen receptor (AR). This study analyzed the polymorphic CAG repeat sequence in exon 1 of the AR gene to determine if the number of repeats might be an indicator of prostate cancer risk or aggressive disease. DNA was extracted from blood samples of 20 black and 20 white men with well-documented prostate cancer and 40 healthy controls (20 blacks and 20 whites). PCR amplification was followed by gel electrophoresis and DNA sequencing. This region normally contains between 9 and 29 repeats. Patients and controls both had minor variations in the number of repeats, which ranged from 13 to 27 with 21 being the most frequent allele. Black controls and patients both had a mean of 20 +/- 3 repeats; in whites the mean was significantly lower in patients than controls (21 +/- 2 versus 23 +/- 2; p = 0.004). Combined black and white patients also had a lower number than the combined group of controls (20 +/- 3 versus 22 +/- 3; p = 0.02). Similarly, black and white patients with aggressive disease had a lower number than patients whose disease was more slowly progressive (19 +/- 2 versus 22 +/- 3; p = 0.02). We conclude that the small differences in the number of CAG repeats in both black and white patients do not appear to be a strong indicator of risk or aggressive disease but that this size polymorphism may be one of many genetic and environmental risk factors involved in prostate cancer.

Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.

Congenital generalized lipodystrophy, or Berardinelli-Seip syndrome (BSCL), is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biological features include acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia. A locus (BSCL1) has been mapped to 9q34 with evidence of heterogeneity. Here, we report a genome screen of nine BSCL families from two geographical clusters (in Lebanon and Norway). We identified a new disease locus, designated BSCL2, within the 2.5-Mb interval flanked by markers D11S4076 and D11S480 on chromosome 11q13. Analysis of 20 additional families of various ethnic origins led to the identification of 11 families in which the disease cosegregates with the 11q13 locus; the remaining families provide confirmation of linkage to 9q34. Sequence analysis of genes located in the 11q13 interval disclosed mutations in a gene homologous to the murine guanine nucleotide-binding protein (G protein), gamma3-linked gene (Gng3lg) in all BSCL2-linked families. BSCL2 is most highly expressed in brain and testis and encodes a protein (which we have called seipin) of unknown function. Most of the variants are null mutations and probably result in a severe disruption of the protein. These findings are of general importance for understanding the molecular mechanisms underlying regulation of body fat distribution and insulin resistance.

Distribution of autoantibodies to glutamic acid decarboxylase across the spectrum of diabetes mellitus seen in South Africa.

AIMS: This study investigated the association between glutamic acid decarboxylase antibodies (GAD-AB) and Type 1, Type 2, pancreatic and lipoatrophic diabetes mellitus (DM) in South African patients. METHODS: Four groups were selected: group A, 100 Black Type 1 DM patients (age at onset < 35 years, body mass index (BMI) < 27 kg/m2 and insulin dependent within 1 year of presentation); group B, 80 Black Type 2 DM patients (age at onset > 35 years, BMI > 27 kg/m2 and controlled on oral hypoglycaemic agents for at least 1 year after presentation); group C, 10 patients of varying ethnicity with DM or impaired glucose tolerance secondary to chronic pancreatitis; group D, five patients of varying ethnicity with DM associated with total lipodystrophy. Fifty healthy Black control subjects were also studied (group E). Serum GAD-AB and random C-peptide levels were measured by radioimmunoassay. RESULTS: Mean C-peptide concentration was significantly lower in Type 1 DM patients than Type 2 DM patients (P < 0.00001). Forty-four patients with Type 1 DM were GAD-AB-positive compared to two patients with Type 2 DM. Two control subjects were also GAD-AB-positive. No patient in the other groups had a titre > 1 U/ml. Type 1 DM patients who were GAD-AB-positive did not differ from those who were GAD-AB-negative for age at onset, duration of DM or C-peptide concentrations. CONCLUSIONS: Auto-immune beta-cell destruction has an important role in the pathogenesis of Type 1 DM amongst African patients. However, Type 2 African DM patients and other diabetes subtypes are largely GAD-AB-negative.

Circulating endothelium-related adhesion molecules in black South African patients with Graves' disease.

Elevated serum concentrations of endothelium-associated adhesion molecules occur in Graves' disease. However, no data exist in African subjects, among whom the incidence is rising. Therefore, 20 black South Africans with Graves' hyperthyroidism were evaluated and 10 healthy controls were also studied. Quantitative determinations of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and soluble E-Selectin (sE-Selectin) were performed in serum samples by an enzyme-linked immunosorbent assay. Mean levels of sVCAM-1 were significantly increased in the thyrotoxic patients compared to controls, but this did not apply to the other adhesion molecules. The presence of ophthalmopathy in 12 patients did not further increase the mean sVCAM-1 concentration, and the administration of antithyroid medication in 5 patients had no measurable effect. In conclusion, sVCAM-1 appears to be a useful marker of active Graves' disease in black South Africans although it does not seem to reflect the occurrence of eye involvement in such patients.

Thyroid-associated ophthalmopathy in black South Africans with Graves' disease: relationship to serum antibodies reactive against eye muscle and orbital connective tissue autoantigens.

The prevalence of hyperthyroidism owing to Graves' disease is increasing among urban black South Africans. Thyroid-associated ophthalmopathy is often observed in this context, but its pathogenesis remains unclear. No close relationship has been noted between antiflavoprotein (Fp) antibodies or thyrotropin receptor antibodies and ocular involvement in black patients. We measured serum antibodies against eye muscle and orbital connective tissue antigens in black patients with Graves' disease, correlating them with eye signs. Of 11 patients with clinical ophthalmopathy, 2 (18%) had antibodies against collagen type XIII, 3 (27%) against flavine adenine dinucleotide (FAD), 1 (9%) against Fp, and 4 (35%) against G2s. Antibody prevalences in eight patients without clinical ophthalmopathy were 12.5% for collagen XIII, 12.5% for FAD, 25% for Fp and 0% for G2s. These differences were not statistically significant. None of the individual mean antibody levels were significantly different between the two subgroups of thyrotoxic patients. Serum antibody levels were negative in 10 black South African controls. In summary, eye muscle and orbital connective tissue antibodies were found in small proportions of patients with Graves' disease with no close relationship of any antibody to eye signs. Thus, a substantial proportion of black South Africans with overt clinical ophthalmopathy remains in whom currently availabe serologic tests are unhelpful for screening and laboratory confirmation.

Free fatty acids and insulin levels--relationship to leptin levels and body composition in various patient groups from South Africa.

OBJECTIVE: To investigate the relationship between leptin concentrations, various metabolic indices and body composition in six different groups. DESIGN AND MEASUREMENTS: Anthropometric measurements, fasting plasma glucose, serum insulin, C-peptide, FFA and leptin levels were performed. In the obese and diabetic subjects, body composition was analysed with bio-impedance equipment and as a 5 level CT scan. SUBJECTS: Five lipoatrophic diabetes mellitus (LDM) patients, five normal subjects (N), nine white and nine black obese women (WW, BW), and nine white and nine black diabetic women (DWW, DBW) were investigated after an overnight fast. RESULTS: In both ethnic groups there was a positive correlation between leptin and BMI (black group: r=0.8; P<0.0001, white group: r=0.7, P<0.002) and leptin and SC fat mass (black group: r=0.6; P<0.005, white group: r=0.6; P<0.004). CONCLUSIONS: Across the groups, there were positive linear correlations between leptin concentrations, BMI, SC fat mass and FFA levels. Leptin and FFA concentrations are higher and insulin levels lower in both groups of black women compared to the two groups of white women, despite a similar BMI and body fat mass. In the DBW the large increase in visceral fat mass may be indicative of a more complex relationship between compensatory insulin resistance, elevated FFA levels and leptin secretion.

Atherosclerosis seems not to be associated with hyperinsulinaemia in patients with familial hypercholesterolaemia.

OBJECTIVE: To study the relationship between hyperinsulinaemia, insulin resistance, leptin and atherosclerosis in subjects with familial hypercholesterolaemia (FH). DESIGN: Case-control cross-sectional study. SETTING: Lipid clinic, Johannesburg Hospital, South Africa. SUBJECTS AND METHODS: Fasting serum lipid, glucose, insulin and leptin levels were measured in 24 homozygous FH subjects; 20 FH heterozygotes without coronary artery disease (CAD); 22 heterozygotes with documented CAD; and 20 healthy normocholesterolaemic subjects. Insulin resistance was calculated using the homeostasis model assessment (HOMA) formula. RESULTS: Mean glucose and insulin levels were similar in all 4 groups. There was no significant difference in calculated insulin resistance between any of the groups. There was also no relationship between the degree of insulin resistance and total or LDL-cholesterol levels. Using Spearman's correlation coefficient (Rs) calculated insulin resistance correlated with triglyceride (Rs = 0.27; P<0.05) and inversely with HDL-cholesterol (Rs = -0.26; P<0.05). Fasting insulin concentrations and calculated insulin resistance were similar in FH subjects with overt CAD compared to those without. Leptin levels were higher in the FH subjects with CAD. However, these subjects were older and had a larger body mass index (BMI), and when adjusted for age and BMI, only BMI correlated with leptin levels (multiple r = 0.65; P<0.001). CONCLUSIONS: In the absence of other causes of insulin resistance, FH subjects have normal fasting insulin levels and, in general, they are not insulin resistant. Insulin resistance appears to play little role in the pathogenesis of accelerated atherosclerosis in FH.

Thyrotropin receptor antibodies in black South African patients with Graves' disease and their response to medical therapy.

Graves' disease is increasing in incidence amongst urban black South Africans. The pathogenic role of thyrotropin receptor antibodies (TRAb), crucial in other populations, has not been formally evaluated in African communities. We therefore prospectively investigated the prevalence of TRAb in 30 consecutive urban black South African patients with classical Graves' disease at the onset of their illness. This was compared with the frequency of thyroid microsomal and thyroglobulin antibodies in the same patients. Ten patients with euthyroid goitres unrelated to Graves' disease and 10 healthy controls were also studied. Twenty of the hyperthyroid patients were retested 4-6 months after starting carbimazole therapy and ten of them again after 1 year. Initially 83% of patients were positive for TRAb as against 54% for thyroid microsomal and 1 7% for thyroglobulin antibodies. After 4-6 months of treatment, 65% of patients still had elevated (>15% inhibition of binding) TRAb titres, while at 1 year this had dropped to 40% (4 out of 10 patients). All positive patients had relapsed biochemically, while TRAb negative patients were all in remission. We conclude that TRAb are a sensitive and specific marker of Graves' disease in black South Africans and closely parallels the response to medical therapy at 1 year. However, their predictive value for delayed relapse requires the study of a larger cohort of patients over a longer time-frame.

Improved glucose tolerance after effective lipid-lowering therapy with bezafibrate in a patient with lipoatrophic diabetes mellitus: a putative role for Randle's cycle in its pathogenesis?

This report describes a patient with lipoatrophic diabetes mellitus (LDM), which is a rare clinical syndrome characterized by lipoatrophy and severe insulin resistance. Although a genetic abnormality is suspected in the development of LDM, no functional mutations in key domains of the insulin receptor gene were detected. Therapy was directed primarily at decreasing the availability of non-esterified fatty acids (NEFA), and thereby improving glucose tolerance (Randle's cycle), by the administration of a lipid-lowering drug, bezafibrate. Serial changes in fasting levels of the hormones of glucose homeostasis and lipids were measured, as well as glucose and insulin responses to a 75-g oral glucose challenge at onset and following 3 and 6 months of fibrate therapy. Progressive reductions in the patient's levels of triglycerides and NEFA were paralleled by an improvement in beta-cell function, a decrease in insulin resistance, and the attainment of normal glucose homeostasis. We conclude that the pathogenesis of LDM may be related primarily to abnormal regulation of lipid, rather than glucose, metabolism.

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).