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 (NIDDM). 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, middle-aged (40-60 yr) nonobese nondiabetic women; group C, middle-aged obese (BMI greater than 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-peptide, and nonesterified 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 beta-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.

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.

Risk factors for the development of stress fractures during fluoride therapy for osteoporosis.

We attempted to identify risk factors for the development of lower limb stress fractures during fluoride therapy for osteoporosis (OP). We compared 18 patients who developed 41 such fractures (26 periarticular, 6 femoral neck, 5 long bone shaft, 1 greater trochanter and 3 pubic rami fractures) during fluoride therapy, with 24 similarly treated patients who did not develop stress fractures. Treatment consisted of sodium fluoride 0.99 mg/kg per day, elemental calcium 1 g/day, and vitamin D. We obtained a previous fracture history, annual radiographs of the spine (fractures), hands (metacarpal cortical index, MCI) and pelvis (Singh index, femoral cortical index), three-monthly serum fluoride and alkaline phosphatase levels, and pretreatment transiliac bone biopsies (routine histomorphometry). The stress fracture group was found to have, before treatment: lower MCI (p less than 0.05), lower trabecular bone volume (p less than 0.05), a lower number of trabeculae (p less than 0.05), greater trabecular separation (p less than 0.05), less extensive eroded surfaces (p less than 0.05), a lower double/single tetracycline label ratio (p less than 0.05); and during treatment: more new spinal fractures (p less than 0.05) and higher serum alkaline phosphatase levels (p less than 0.01). We conclude that stress fracture patients had more severe trabecular and cortical OP and possibly a poorer bone-forming capacity before therapy than patients without stress fractures. We suspect that fluoride therapy may temporarily further weaken bone and so lead to stress fractures in severely osteoporotic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypoglycemia in hepatocellular carcinoma: failure of short-term growth hormone administration to reduce enhanced glucose requirements.

The mechanism of tumor-associated hypoglycemia was investigated in 10 (six hypoglycemic and four normoglycemic) southern African blacks with hepatocellular carcinoma. The mean basal blood glucose concentration was significantly lower (2.4 +/- 0.1 v 3.6 +/- 0.2 mmol/L; P less than .01) and steady-state exogenous glucose requirements were increased fourfold (3.6 +/- 0.6 v 0.97 +/- 0.2 mg/kg/min; P less than .01) in the hypoglycemic compared with the normoglycemic patients. Plasma insulin and C-peptide levels were suppressed to the lower limit of sensitivity of each of the assays in both groups of patients. The concentrations of insulin-like growth factors (IGF) I and II were lower (19 +/- 1.6 v 25 +/- 4.6 insulin-like growth factors (IGF) I and II were lower (19 +/- 1.6 v 25 +/- 4.6 ng/L) and higher (230 +/- 42 v 173 +/- 40 ng/L), respectively, in the hypoglycemic patients, although the differences were not statistically significant. Of the counterregulatory hormones measured, only the growth hormone (GH) concentration was significantly lower in the hypoglycemic patients (0.9 +/- 0.2 v 18.6 +/- 5.6 micrograms/L; P less than .01). Correction of the plasma GH level into the high-normal physiological range in two hypoglycemic patients failed to reduce steady-state exogenous glucose requirements. However, the glucose requirements were reduced from 2.6 to 1.1 mg/kg/min in the same two patients when "acromegalic" plasma concentrations of GH were achieved. We conclude that steady-state glucose requirements are increased in black patients with hypoglycemia complicating hepatocellular carcinoma, and that short-term correction of the associated hyposomatotropism fails to reduce the enhanced requirements.

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.

Resistance to thyroid hormone in subjects from two unrelated families is associated with a point mutation in the thyroid hormone receptor beta gene resulting in the replacement of the normal proline 453 with serine.

Resistance to thyroid hormone (RTH) is a condition of impaired tissue responsiveness to thyroid hormone characterized by elevated free thyroid hormone levels in serum accompanied by nonsuppressed TSH. RTH has been associated with mutations in the thyroid hormone receptor (TR) beta gene. We report studies carried out in 9 members of a family (F94) of Jewish ethnic origin and a single subject of Mexican origin. All subjects fulfilling the criteria of RTH (6 of family F94 and one of family F27) had the same point mutation in the T3-binding domain on one of the two alleles of the TR beta gene. This mutation resulted in the replacement of the normal proline-453 with serine (P453S). Nevertheless, the clinical characteristics of affected members of each of the two families differed as did the severity of hormonal resistance in terms of responses to the administration of L-T3. Genetic studies indicate that the same mutation occurred independently in each of the two families.

Time-dependent changes in serum gastrin measurements after parathyroidectomy.

A prospective study involving 7 patients with primary hyperparathyroidism and hypergastrinaemia was conducted to assess the time-dependent change in serum gastrin value before and after parathyroidectomy and to determine at which postoperative stage persistent hypergastrinaemia may be indicative of an associated gastrinoma (Zollinger-Ellison syndrome). Five of the 7 patients had hypergastrinaemia in the early postoperative period. One patient had a strikingly high serum gastrin level pre-operatively (1,500 pg/ml). The mean serum gastrin value declined to within the normal range 6 weeks after parathyroidectomy, except in 1 patient who had a gastrinoma. It is concluded that hypergastrinaemia in patients with primary hyperparathyroidism should only be considered significant if pre-operative gastrin levels are strikingly supranormal and/or levels fail to normalise by the 6th postoperative week.

Abnormal cation exchange in insulin-resistant patients with essential hypertension.

OBJECTIVES: To identify important factors that may contribute to abnormal glucose tolerance in elderly patients with treated hypertension with primary reference to changes in the following parameters: calculated insulin resistance, endogenous insulin processing and secretion; platelet cation concentration and membrane ATPase activity. DESIGN: Thirty-nine patients receiving antihypertensive therapy (including low-dose thiazide treatment) were compared to 13 normotensive, normoglycaemic control subjects. Total platelet cation concentration and membrane ATPase activity were measured and, following a 75-g oral glucose test, serum insulin, proinsulin and 31-32 des-proinsulin responses were measured in prospectively defined hypertensive patients with normal glucose tolerance (NG), impaired glucose tolerance (IGT) and diabetes mellitus (DM). RESULTS: Of the total patient cohort, seven patients manifested newly diagnosed DM, 18 had IGT and 14 NG. Among the three groups, no difference in duration of drug use (thiazides and beta-blockers) was noted; BMI and waist-to-hip ratio increased progressively from NG to IGT to overt DM. Compared to NG patients, serum insulin responses were significantly greater in the IGT (all time points) and DM (two-hour measurements) subjects. Proinsulin and 31-32 des-proinsulin serum responses were likewise significantly higher in the IGT and DM groups. The derived measure of insulin resistance in the hypertensive patients showed a significant increase in the progression from NG to IGT and DM. Mean total platelet potassium concentration was reduced in the DM compared to the IGT and the control groups, while platelet sodium, calcium and magnesium concentrations showed no significant differences. Platelet membrane magnesium ATPase activity was significantly higher in the normotensive control versus the hypertensive group. Sodium, potassium and calcium ATPase activity showed no significant differences among the subgroups. CONCLUSION: Our findings support the strong link between essential hypertension, insulin resistance/hyperinsulinaemia and regional adiposity. Beta-cell dysfunction (hypersecretion and abnormal insulin processing) is manifest in the progression from normality to overt diabetes. The use of antihypertensive therapy (low-dose thiazides and cardioselective beta-blockers) possibly added diabetogenic effect(s). The reduction in platelet total potassium concentration paralleled the diabetic state while a reduced membrane magnesium ATPase activity correlated with the hypertensive state.

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.

Bone fragility of the peripheral skeleton during fluoride therapy for osteoporosis.

Bone fragility during fluoride therapy for osteoporosis was observed in 24 (37.5%) of 64 patients treated with sodium fluoride, calcium, and vitamin D for 2.5 years who developed episodes of lower-limb pain during treatment. Eighteen (28%) of these patients had clinical and roentgenographic features of 41 stress fractures and 12 new spinal fractures. There were 26 periarticular, six femoral neck, three pubic rami, three tibia and fibula, one greater trochanter, and two subtrochanteric fractures. Vertebral fractures appeared first, then periarticular, then femoral neck, and lastly long-bone shaft fractures. All fractures were spontaneous in onset. The peripheral fracture rate during treatment was three times that in untreated osteoporosis. Roentgenograms must be repeated at intervals of three to four weeks before the pathognomonic callus becomes visible, and the diagnosis can be made. Trabecular stress fractures tend to occur in the first 18 months of treatment, and cortical stress fractures occur after 30 months of therapy.

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.

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.

Coronary heart disease and urinary albumin excretion rate in type 2 (non-insulin-dependent) diabetic patients.

Associations between overnight urinary albumin excretion rate and prevalent coronary heart disease and its major risk factors were examined in a cross-sectional study of 141 Type 2 (non-insulin-dependent) diabetic patients. Mean albumin excretion rate was higher in men (geometric mean 13.5 micrograms/min; 95% confidence interval 10.3-17.6) than women (7.5 micrograms/min; 5.7-9.8, p less than 0.01). In diabetic men and women mean albumin excretion rate was higher in those with electrocardiographic and/or symptomatic evidence of coronary heart disease than in those without (men, 23.1 micrograms/min; 95% confidence interval 13.7-39.0 versus 10.6 micrograms/min; 7.9-14.2, p less than 0.01, women, 13.7 micrograms/min; 8.0-23.5 versus 5.4 micrograms/min; 4.2-6.8, p less than 0.01). Multiple logistic regression analysis was used to allow for confounding between variables. In the diabetic group as a whole, raised albumin excretion rate (p less than 0.001), gender (p less than 0.05) and systolic blood pressure (p = 0.06) entered the "best" model for coronary heart disease prediction. In women, albumin excretion rate alone (p less than 0.01) and in men albumin excretion rate (p less than 0.01) and age (p = 0.05) entered the "best" models. We conclude that albumin excretion rate is significantly associated with coronary heart disease morbidity after taking into account the confounding effects of raised blood pressure and other cardiovascular risk factors.

Metabolic indices in relation to body composition changes during weight loss on Dexfenfluramine in obese women from two South African ethnic groups.

OBJECTIVE: To characterize differences in metabolic indices as well as body composition in two ethnic groups. SUBJECTS: Eight black and eight white obese urban women were studied. DESIGN: Eight black and eight white obse (BMI > 34) urban women (BW, WW) were matched for age, BMI, WHR, diet and physical activity and investigated before and after 12 weeks of Dexfenfluramine treatment. MEASUREMENTS: Anthropometric measurements; Post 75 g OGTT, plasma glucose, insulin and C-peptide levels were done. FFA and lactate levels were done at onset. Skinfold thickness with Harpenden calipers, bio-impedance for analyses of body composition and CT scan for assessment of regional adiposity (at onset and after 3 months). RESULTS: In the postabsorptive state the WW had significantly higher plasma total cholesterol and triglyceride levels and an unfavourable HDL : total cholesterol ratio. Their FFA levels were significantly lower (324 +/- 51 vs 985 +/- 84 mumol/l; p < 0.0001) and their lactate levels were significantly higher (3045 +/- 245 vs 1938 +/- 358 mumol/l; p < 0.001) as compared with the BW. During a 75 g OGTT the BW had significantly higher glucose levels at 1 h (8.6 +/- 0.8 vs 5.1 +/- 0.4 mmol/l; p < 0.005) and 2 h (7.6 +/- 0.6 vs 4.4 +/- 0.3 mmol/l) but not at fasting. In contrast the BW had lower insulin concentrations (fasting: 77 +/- 9 vs 139 +/- 19 pmol/l; p < 0.04 and 1 h 318 +/- 56 vs 624 +/- 75 pmol/l; p < 0.005), and C-peptide concentrations (fasting: 400 +/- 99 vs 1600 +/- 99 pmol/l; p < 0.000 04, 1 h 1400 +/- 433 vs 5966 +/- 333 pmol/l; p < 0.0007 and 2 h 1266 +/- 333 vs 4066 +/- 366 pmol/l; p < 0.0005). CT scan measurements showed that the WW had significantly more visceral fat than the BW (148.5 +/- 2.0 vs 115.5 +/- 6.9 cm2; p < 0.05) but lost less weight during Dexfenfluramine treatment (-4 kg vs -9 kg). Despite this, the WW lost more visceral fat than the BW (-27.3 cm2/-18.5%; p < 0.03 vs -15.5 cm2/-13.2%; p < 0.04). In contrast the BW had a larger reduction in subcutaneous (SC) fat (-13.9% vs -1.7%; p < 0.01), with the greatest reduction in the SC gluteofemoral adipose tissue (widest hip circumference -20.8% vs -0.2%; p < 0.001) and mid-femur region (-13.1% vs -0.7%; p < 0.08). CONCLUSION: Weight loss in obese black women is associated with a major reduction in SC fat mass with the most active mobilization of fat tissue occurring in the gluteofemoral area. In contrast the WW had more visceral fat that was more readily mobilized. The difference in adipose tissue distribution and pattern of mobilization was associated with lower plasma insulin, C-peptide and triglyceride concentrations in the BW despite increased FFA and glucose levels. These data suggest that plasma insulin concentrations are important in regulating differences in regional adipose tissue metabolism as well as the serum lipid profile.

Fewer bone histomorphometric abnormalities with intermittent than with continuous slow-release sodium fluoride therapy.

To help resolve the uncertainty whether sodium fluoride (NaF) therapy should be given intermittently or continuously, we examined iliac crest bone biopsies (before and after treatment) and fragility fracture rates in 35 intermittently treated (group I) and 69 continuously treated (group C) patients; all received calcium. The following statistically significant results were obtained. Reduction in vertebral fracture rate was similar in the two groups. Trabecular thickness and the structurally more important mineralized thickness increased only in group I. Group I also accumulated less excess osteoid (surface, volume). Mean osteoid thickness did not change in either group because of a bimodal distribution of wide seams with osteoblasts and double tetracycline labels, and thin seams without osteoblasts or labels. Osteoid was lamellar. Osteoid in abnormal sites (within bone marrow or bone, or around osteocytes) was found less frequently in group I. Adjusted apposition rate declined and mineralization lag time increased in both groups because of extended unlabelled osteoid seams. Erosion surface increased only in group C. Hook and/or tunnel erosion was seen less frequently in group I; it was closely associated with osteoid in abnormal sites and correlated with osteoid surface. Extended osteoid surface may have forced osteoclasts to hollow out trabeculae, leaving the empty osteoid shell in marrow. Excess osteoid volume and eroded surface and osteoid and erosion in abnormal sites correlated with bone fragility in group C. We conclude that intermittent therapy is to be preferred because it (1) increased mineralized trabecular thickness, (2) did not cause excessive osteoid accumulation and erosion, (3) showed less osteoid and erosion in abnormal sites and (4) led to a similar reduction in the vertebral fracture rate as did continuous treatment. The question of whether intermittency of therapy has some other effect independent of the cumulative dose of fluoride administered cannot be answered by this study.

Screening for diabetic retinopathy in South Africa with 60 degrees retinal colour photography.

OBJECTIVES: Comparison of 60 degrees mydriatic retinal photography, in screening for diabetic retinopathy, with diabetes clinic doctors, formal ophthalmological assessment, and with one or two 45 degrees fields. DESIGN: Consecutive subjects screened by clinicians and photography, and selected eyes evaluated by an ophthalmologist. Randomized photographs assessed through one or two 45 degrees fields (by masking the slides), and at 60 degrees. SETTING: The first 663 patients attending for routine clinic visits and screened for retinopathy. MAIN OUTCOME MEASURES: The relative diagnostic sensitivity of screening methods, the utility of screening one eye only, and the costs of photographic screening. RESULTS: Compared to an ophthalmologist's assessment, retinal photography had a sensitivity of 93% and a specificity of 89% for any retinopathy, and 100 and 75%, respectively, for severe retinopathy. Photography detected 28% more retinopathy (16% severe) than the clinicians. Compared to a 60 degrees field, one 45 degrees field missed 31%, and 2 x 45 degrees fields 11% of retinopathy. Of 57 patients with retinopathy meeting referral criteria, 31 pairs of eyes had substantially discordant scores. The cost of diagnosis in a patient requiring referral to ophthalmologist was about US $37.00. CONCLUSIONS: 60 degrees retinal photography compares well with an ophthalmologists screening, and is better than clinical and one to two 45 degrees field assessments. Both retinae should be screened. This method is cost-effective in our hands.