The intrauterine environment is a strong determinant of glucose tolerance during the neonatal period, even in prematurity.

The aim of this study was to determine the contribution of birth weight and gestational age to glucose tolerance in premature neonates. The study group consisted of 100 premature and/or small-for-gestational age infants. Anthropometric measurements were performed both at birth and at the time of a standardized milk feed carried out at 19.6 +/- 12.1 d (range, 1-65 d) after birth. Fasting and postprandial glucose and insulin levels were measured. Birth weight, as a proxy mirror of the intrauterine environment, was found to influence the glucose concentration following a standardized milk feed (beta = -0.46; P = 0.01 for birth weight z-score with 60-min glucose level), whereas gestational age did not. Small-for-gestational age neonates had higher 60-min insulin levels than appropriate-for-gestational age neonates (115.4 +/- 9.5 vs. 68.4 +/- 14.2; P < 0.05) despite similar glucose levels. Neonates born of mothers who were on antihypertensive treatment were smaller and had a higher insulin secretory response than neonates from normotensive mothers. Postnatal growth velocity (kilograms per day) correlated with birth weight (beta = -0.65; P < 0.0001) and insulin resistance (beta = -0.31; P = 0.0004), independently of each other. This study shows that glucose tolerance of the neonate is determined by weight attained at birth irrespective of gestational age and that maternal blood pressure may influence insulin sensitivity of the newborn. Furthermore, catch-up growth in neonates is determined by birth weight and insulin sensitivity.

Weight-related differences in glucose metabolism and free fatty acid production in two South African population groups.

OBJECTIVE: The effects of free fatty acids (FFA), leptin, tumour necrosis factor (TNF) alpha and body fat distribution on in vivo oxidation of a glucose load were studied in two South African ethnic groups. DESIGN AND MEASUREMENTS: Anthropometric and various metabolic indices were measured at fasting and during a 7 h oral glucose tolerance test (OGTT). Body composition was measured using bioelectrical impedance analysis and subcutaneous and visceral fat mass was assessed using a five- and two-level CT-scan respectively. Glucose oxidation was evaluated by measuring the ratio of (13)CO(2) to (12)CO(2) in breath following ingestion of 1-(13)C-labelled glucose. SUBJECTS: Ten lean black women (LBW), ten obese black women (OBW), nine lean white women (LWW) and nine obese white women (OWW) were investigated after an overnight fast. RESULTS: Visceral fat levels were significantly higher (P<0.01) in obese white than black women, despite similar body mass indexes (BMIs). There were no ethnic differences in glucose oxidation however; in the lean subjects of both ethnic groups the area under the curve (AUC) was higher than in obese subjects (P<0.05 for both) and was found to correlate negatively with weight (r=-0.69, P<0.01) after correcting for age. Basal TNF alpha concentrations were similar in all groups. Percentage suppression of FFAs at 30 min of the OGTT was 24+/-12% in OWW and -38+/-23% (P<0.05) in OBW, ie the 30 min FFA level was higher than the fasting level in the latter group. AUC for FFAs during the late postprandial period (120--420 min) was significantly higher in OWW than OBW (P<0.01) and LWW (P<0.01) and correlated positively with visceral fat mass independent of age (r=0.78, P<0.05) in the OWW only. Leptin levels were higher (P<0.01) both at fasting and during the course of the OGTT in obese women from both ethnic groups compared to the lean women. CONCLUSIONS: Glucose oxidation is reduced in obese subjects of both ethnic groups; inter- and intra-ethnic differences were observed in visceral fat mass and FFA production and it is possible that such differences may play a role in the differing prevalences of obesity-related disorders that have been reported in these two populations.

Lactate and glycerol release from adipose tissue in lean, obese, and diabetic women from South Africa.

Abnormalities observed in intermediary metabolism may be related to the pathogenesis of obesity-related diseases such as type 2 diabetes. Glycerol and lactate production was estimated in the sc adipose tissue of two anatomical regions of 10 lean (LW), 10 obese (OW), and 10 matched diabetic (DW) black urban women. This was done with the sc microdialysis technique and combined with adipose tissue blood flow (ATBF) rates calculated from (133)Xe clearance. Biochemical measurements were made in the postabsorptive and postprandial state. Bioimpedance and computed tomography scans were used to define body composition. DW present with more visceral fat (DW, 138 +/- 5.0; OW, 66.6 +/- 5.0 cm; P < 0.01). This was associated with elevated free testosterone levels (DW, 1.21 +/- 0.1; OW, 0.75 +/- 0.1 nmol/L; P < 0.05). The fasting FFA, glycerol, and lactate levels increased across the three groups (LW < OW < DW). During the oral glucose tolerance test, glucose levels were elevated in DW, with higher insulin levels [0 h: DW, 207 +/- 8.6; OW, 100 +/- 7.2 pmol/L (P < 0.01); 1 h: DW, 410 +/- 15.2; OW, 320 +/- 10.9 pmol/L (P < 0.05)], but with a flat Cpeptide response (1 h: DW, 932 +/- 40; OW, 1764 +/- 40 pmol/L; P < 0.05). Plasma lactate levels increased significantly in LW and OW at 1 h (P < 0.001), but remained lower in LW vs. OW for all time points. ATBF was highest in LW [abdominal, 0 h: DW, 4.5 +/- 0.2; OW, 1.7 mL/100 g.min (P < 0.01); femoral, 0 h: DW, 3.4 +/- 0.2; OW, 1.8 +/- 0.3 mL/100 g.min (P < 0.01)]. ATBF did not increase in DW during the oral glucose tolerance test. Glycerol release (GR) was used to assess the lipolytic rate and was highest in LW in the abdominal area [0 h: LW, 1.7 +/- 0.2; OW, 1.1 +/- 0.2 micromol/kg.min (P < 0.05); DW, 0.78 +/- 0.05 micromol/kg.min (P < 0.05 vs. OW)]. By contrast, GR was higher in the femoral area of OW (0 h: OW, 1.6 +/- 0.2; LW, 1.15 +/- 0.1 micromol/kg.min; P < 0.05). Regional differences were observed for GR in both OW and DW (femoral > abdominal). Lactate release (LR) was low in DW [abdominal, 0 h: DW, 3.5 +/- 0.4; OW, 7.8 +/- 1.0 micromol/kg.min (P < 0.001); femoral, 0 h: DW, 3.1 +/- 0.3; OW, 9.0 +/- 0.9 micromol/kg.min (P < 0.001)]. LR was appropriately low for body fat mass in LW, with a brisk increase between 0 and 1.5 h. A negative correlation exists between GR (abdominal area) and insulin levels in the postabsorptive state (P < 0.0001). In conclusion, 1) the fasting lipolytic rate is associated with insulin levels; 2) OW and DW have more adipose tissue insulin resistance than LW; 3) OW and DW have a brisker lipolysis in the femoral area; and 4) in DW, higher visceral mass is associated with elevated free testosterone and FFA concentrations. Obesity in the black population is therefore characterized by a marked degree of adipose tissue lipolysis. This degree of resistance together with increasing body fat mass may predispose the obese women to developing type 2 diabetes. Once this disease is established, the onset of adipose tissue vascular insulin resistance will sustain ongoing insulin resistance, even in the presence of relative insulinopenia.

Ethnic differences in lipid metabolism in two groups of obese South African women.

There is a higher prevalence of ischemic heart disease (IHD) in South African white than black women. The objective of this study was to determine biochemical explanations for this prevalence. The study group contained 15 obese black women (OBW) and 14 obese white women (OWW), all premenopausal, who were examined after an overnight fast. Anthropometric measurements and blood concentrations of glucose, non-esterified fatty acids (NEFAs), catecholamines, plasminogen activator inhibitor-1, C-peptide, proinsulin, lipograms, cortisol, growth hormone, and post-heparin lipoprotein lipase activity were measured during an oral glucose tolerance test (OGTT). Body composition was measured using bioelectrical impedance analysis, and subcutaneous and visceral fat mass were assessed with CT-scans. Visceral fat area was higher in OWW (139.7 +/- 10.7 cm(2)) than in OBW (72.3 +/- 3.9 cm(2)) (P < 0.01), as were fasting and 3 h triglyceride concentrations (P < 0.05 for all). OWW also had higher NEFA levels than OBW at 3 and 4 h compared with OBW (P < 0.05 for both). Fasting cortisol (266 +/- 24 vs. 197 +/- 19 nmol/l; P < 0.05) was higher in OWW than in OBW. These data demonstrate that OWW have higher visceral fat mass than OBW, which may lead to a more atherogenic fasting and postprandial lipid profile. The higher cortisol levels of the OWW may promote visceral fat deposition.

Evidence for insulin resistance in black women from South Africa.

OBJECTIVE: The rate of glucose disposal was determined in 10 black and 10 white obese nondiabetic urban women from South Africa to assess insulin resistance. DESIGN AND METHODS: Euglycemic hyperinsulinemic clamp and body composition analysis. RESULTS: Age, body mass index (BMI), anthropometric measurements and body composition were similar in both groups of women. A five-level computed tomography (CT) scan showed a similar mean subcutaneous fat mass in both groups of women (black obese women 555 +/- 9.0 vs white obese women 532 +/- 6.0 cm2), but less visceral fat in black obese women (90 +/- 3.0 vs 121 +/- 3.1 cm2; P< 0.05). Black obese women had higher fasting free fatty acid (997 +/- 69 vs 678 +/- 93 micromol/l; P < 0.05) and lactate concentrations (1,462 +/- 94 vs 1,038 +/- 39 micromol/l; P < 0.05), but lower fasting insulin levels (87 +/- 12 vs 155 +/- 9 pmol/l; P < 0.001). Black obese women also had a more favorable HDL: total cholesterol ratio (30.5% vs 23.0%; P< 0.04). The mean glucose disposal rate (M) and disposal expressed as glucose sensitivity index (M/I) were reduced in the black obese women vs white obese women (M: 7.1 +/- 0.8 vs 13.7 +/- 1.0 mmol/kg min(-1) x 100; P< 0.01, and M/I: 0.12 +/- 0.01 vs 0.24 +/- 0.02 mmol/kg x min(-1)/pmol/1 x 1,000; P < 0.01). Only black obese women showed a significant decrease in C-peptide levels during the clamp (2.9 +/- 0.22 vs 1.2 +/- 0.12 nmol/l; P<0.001). During the euglycemic period, the black obese women had higher lactate levels at all time points, but only the white obese women had increased lactate levels (918 +/- 66 to 1,300 +/- 53 micromol/l; P< 0.05). CONCLUSION: Black obese women demonstrate a higher degree of insulin resistance, despite less visceral fat and a higher HDL: total-cholesterol ratio. In addition, endogenous beta-cell secretory function in black obese women appears to be more sensitive to the suppressive effect of exogenous insulin administration. The significant increase in lactate levels in white obese women confirms that they are more insulin sensitive.

Relation between weight gain and beta-cell secretory activity and non-esterified fatty acid production in 7-year-old African children: results from the Birth to Ten study.

AIMS/HYPOTHESIS: This study aimed to assess the effects of fetal and childhood growth on beta-cell activity and insulin sensitivity in 7-year-old children. METHODS: Insulin, des-31,32 proinsulin, proinsulin, non-esterified fatty acids and glucose concentrations were measured in oral glucose tolerance tests in 152 South African children for whom longitudinal weight data was available. RESULTS: Children with low weights at birth and 7 years (low-low) had relatively low beta-cell activity whereas children with low birth weight and high weight at 7 years (low-high) had relatively high beta-cell activity. The low-low group had higher 30-min glucose concentrations than children with high birth weights. When each insulin-related peptide was expressed as a percentage of all these peptides the low-low children had the highest percentage of insulin but the lowest of the prohormones. The low-high children had the lowest percentage of insulin but the highest of the prohormones. Non-esterified fatty acid concentrations were lowest and their suppression post-glucose load highest in the low-high group. CONCLUSION/INTERPRETATION: Poor fetal and neonatal growth give rise to low beta-cell numbers compensated for by increased efficiency of proinsulin processing to insulin. Poor fetal followed by higher postnatal growth results in low beta-cell numbers and reduced whole-body glucose uptake which leads to reduced efficiency in the processing of proinsulin. Growth in utero and postnatally therefore have profound effects on beta-cell activity and insulin sensitivity with poor fetal coupled with high postnatal growth being detrimental to these processes but not detrimental to the suppression of lipolysis.

Ethnic differences in the responsiveness of adipocyte lipolytic activity to insulin.

OBJECTIVE: The goal of this study was to quantify differences in lipid metabolism and insulin sensitivity in black and white subjects to explain ethnic clinicopathological differences in type 2 diabetes. RESEARCH METHODS AND PROCEDURES: The in vitro lipolytic activity of adipocytes isolated from obese black and white women was measured in the presence of insulin and isoproterenol. Insulin resistance was assessed in vivo using the euglycemic hyperinsulinemic clamp technique. RESULTS: Fasting plasma levels of insulin and nonesterified fatty acid (NEFA) in black and white women were 67 +/- 5 pM vs. 152 +/- 20 pM (p < 0.01) and 863 +/- 93 microM vs. 412 +/- 34 microM (p < 0.01), respectively. Euglycemic hyperinsulinemic clamp studies showed that obese black subjects were more insulin-resistant than their white counterparts (glucose infusion rates: 1.3 +/- 0.2 vs. 2.2 +/- 0.3 mg/kg per min; p < 0.05). Isolated adipocytes from white women were more responsive to insulin than those from black women with 0.7 nM insulin causing a 55 +/- 4% inhibition of isoproterenol-stimulated lipolysis compared with 27 +/- 10% in black women (p < 0.05). DISCUSSION: The low responsiveness of adipocyte lipolytic activity to insulin in black women in the presence of a relative insulinopenia may account for the high plasma NEFA levels seen in these women, which may, in turn, account for their higher in vivo insulin resistance. High NEFA levels may also contribute to the low insulin secretory activity observed in the obese black females. These data suggest that the pathogenesis of insulin resistance and type 2 diabetes within the black obese community is strongly influenced by their adipocyte metabolism.

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.

Lactate and glycerol release from subcutaneous adipose tissue in black and white lean men.

To measure interstitial glycerol and lactate production from the sc adipose tissue of two regions in nine black and nine white lean men, sc microdialysis was performed in combination with adipose tissue blood flow rates measured with 133Xe clearance. In the postabsorptive state, the plasma glucose and insulin levels of the black men and white men were similar. The black men had higher plasma free fatty acids (825+/-97 vs. 439+/-58 micromol/L; P < 0.005), glycerol (99.5+/-5.1 vs. 54.1+/-3.3 micromol/L; P < 0.0001), and lactate (1056+/-95 vs. 729+/-45 micromol/L; P < 0.01). Interstitial glycerol concentrations in the black and white men were 227 vs. 163 micromol/L (P < 0.01) and 230 vs. 162 micromol/L (P < 0.05) in the abdominal and femoral regions. The adipose tissue blood flow rate was higher in the black men in the abdominal (7.9+/-0.9 vs. 3.1+/-0.5 mL/100 g x min; P < 0.01) and femoral area (5.2+/-0.6 vs. 2.8+/-0.3; P < 0.01). Interstitial lactate concentrations in black and white men were 1976 vs. 1364 micromol/L (P < 0.004) and 1953 vs. 1321 micromol/L (P < 0.004) in the abdominal and femoral regions, respectively. Glycerol release was higher in black men vs. white men for abdominal (0.21+/-0.02 vs. 0.14+/-0.02 micromol/100 g x min; P < 0.02) and femoral (0.22+/-0.02 vs. 0.15+/-0.01; P < 0.05) areas. Postprandially, black men had higher plasma glucose levels [1 h, 9.6+/-0.4 vs. 8.2+/-0.5 mmol/L (P < 0.05); 2 h, 8.9+/-0.4 vs. 7.2+/-0.4 mmol/L (P < 0.01)], but lower plasma insulin levels [1 h, 173+/-13 vs. 264+/-48 pmol/L (P < 0.05); 2 h, 136+/-20 vs. 209+/-34 pmol/L (P < 0.05)]. Plasma free fatty acid, lactate, and glycerol levels remained higher in the black men. After 1 h, lactate release was higher in the black men vs. that in the white men for abdominal (20.5+/-1.6 vs. 14.7+/-2.5 micromol/100 g x min;P < 0.05) and femoral (15.6+/-1.1 vs. 12.1+/-1.8; P < 0.03) areas. We conclude that the black men, who are relatively insulinopenic postprandially, have a brisker lipolysis and also release more lactate from sc fat tissue than white men. These differences in adipose tissue metabolism may be related to differences in the lipid profiles and glucose metabolism previously documented in these ethnic groups.

Lactate and glycerol release from the subcutaneous adipose tissue of obese urban women from South Africa; important metabolic implications.

Interstitial glycerol and lactate production was measured in the s.c. adipose tissue of two anatomical regions in 10 obese urban black women (BW) and 10 obese urban white women (WW) matched for age, body mass index, waist-hip ratio, diet, and physical activity. This was done with the s.c. microdialysis technique and combined with adipose tissue blood flow (ATBF) rates calculated from 133Xe clearance. Biochemical measurements were done in the postabsorptive and postprandial state. Bioimpedance and computed tomography scans were used for analyses of body composition. BW responded with lower plasma insulin levels, but higher glucose levels, during the oral glucose tolerance test. BW have higher lactate release from the s.c. adipose tissue, compared with WW, in the postabsorptive state (abdominal: 7.8 +/- 0.9 vs. 2.4 +/- 0.3 micromol/kg x min, P < 0.0001; femoral: 9.1 +/- 0.9 vs. 2.1 +/- 0.3 micromol/kg x min, P < 0.0001) and during the postprandial period (at 1 h, abdominal = 7.3 +/- 0.8 vs. 3.0 +/- 0.4 micromol/kg x min, P < 0.0001, femoral area = 8.1 +/- 1.0 vs. 2.7 +/- 0.4 micromol/kg x min, P < 0.0001; at 2 h, abdominal = 5.7 +/- 0.4 vs. 3.1 +/- 0.3 micromol/kg x min, P < 0.001). The BW also released more glycerol from the sc adipose tissue in the postabsorptive state (abdominal = 1.15 +/- 0.17 vs. 0.65 +/- 0.03 micromol/ kg x min, P < 0.009; femoral = 1.55 +/- 0.19 vs. 0.72 +/- 0.05 micromol/kg x min, P < 0.001) and during the postprandial period (at 1 h, abdominal = 1.05 +/- 0.15 vs. 0.11 +/- 0.02 micromol/kg x min, P < 0.001, femoral = 1.05 +/- 0.12 vs. 0.21 +/- 0.03 micromol/kg x min, P < 0.001; at 2 h, abdominal = 0.31 +/- 0.06 vs. 0.04 +/- 0.01 micromol/kg x min, P < 0.001, femoral = 0.28 +/- 0.07 vs. 0.05 +/- 0.01 micromol/kg x min, P < 0.003). Postprandially, the BW had higher ATBF rates in the abdominal and femoral areas. WW have more visceral fat (150 +/- 2.0 vs. 110 +/- 5.0 cm2, P < 0.05). In conclusion, the insulinopenic BW have a brisker lipolysis and ATBF and release more glycerol and lactate from their sc adipose tissue, both in the postabsorptive state and after an oral glucose tolerance test. These variations in adipose tissue metabolism may contribute to differences observed in the disease profiles of these two groups of women.

Association between poor glucose tolerance and rapid post natal weight gain in seven-year-old children.

A number of studies have shown that glucose tolerance falls with decreasing birth weight and that people with low birth weight and high body mass index (BMI) as adults are those at greatest risk of developing Type II (non-insulin-dependent) diabetes mellitus. No such studies have been carried out in African populations. Therefore we investigated the relation between glucose tolerance and birth weight in a group of 7-year-old black South Africans for whom longitudinal anthropometric data were available. Oral glucose tolerance tests (OGTTs) were carried out on 152 subjects and inverse correlations were found between birth weight and the total amount of insulin secreted during the first 30 min (r = -0.19, p = 0.04) and last 90 min (r = -0.19, p = 0.04) of the oral glucose tolerance test and also between birth weight and the 30 min glucose concentrations (r = -0.20, p = 0.02). Children born with low birth weights but who had high weights at 7 years had higher insulin concentrations and indices of obesity compared with those with low birth weights and low weights at 7 years. There were also positive correlations between weight velocity and BMI (r = 0.24, p = 0.02) and weight velocity and insulin resistance (r = 0.18, p = 0.04) as measured using homeostasis model assessment (HOMA). Thus, low birth weight in conjunction with rapid childhood gains in weight especially as subcutaneous fat, produces poor glucose tolerance in 7-year-old children and can make them susceptible to the development of Type II diabetes later in life.

PIP: A number of studies have shown that glucose tolerance declines with decreasing birth weight and that people with low birth weight and high body mass index (BMI) as adults are at the highest risk of developing type II (non-insulin-dependent) diabetes mellitus. The authors explored the relation between glucose tolerance and birth weight in a group of 7-year old Black South Africans for whom longitudinal anthropometric data were available. Oral glucose tolerance tests (OGTTs) were conducted on 152 subjects and inverse correlations were found between birth weight and the total amount of insulin secreted during the first 30 minutes and last 90 minutes of the oral glucose tolerance test, and also between birth weight and the 30 minute glucose concentrations. Children born with low birth weights, but who had high weights at age 7 years had higher insulin concentrations and indices of obesity compared with those with low birth weights and low weights at age 7 years. Positive correlations were also found between weight velocity and BMI, and weight velocity and insulin resistance as measured through homeostasis model assessment. Therefore, low birth weight together with rapid childhood weight gains, especially in subcutaneous fat, produces poor glucose tolerance in 7-year old children and can make them susceptible to the development of type II diabetes later in life.

An evaluation of clinical laboratory services in sub-Saharan Africa. Ex africa semper aliquid novi?

Pathology services represent the rational, scientific basis of the practice of clinical care. It does not represent deus ex machina, an implausible solution to a complex plot, but rather the way in which clinical care can be audited, controlled, guided and kept appropriate to the funds and the skills available. Arguments are presented to support this statement as well as to analyse what is wrong with health care, from the point of view of laboratory medicine, in sub-Saharan Africa. In most African countries 'first world' technology has to be imported by economies barely able to sustain the basic requirements of human life. Badly needed foreign exchange is obtained by growing export crops at the cost of traditional lifestyle, disenfranchising communities, urbanisation, and even at the cost not being able to grow food. War, corruption, lack of accountability even in the Western sense of being able to go to the polls every so often, lack of empowerment, low literacy rate etc all debase the communities, with minimal exceptions, of Africa. Health care is under the same capricious rule as all other public services: investment in laboratories is poor and most have no access to a professional laboratory at all. More investment, not less; expansion of pathology services not restricting them, is needed throughout the continent.

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.

Beta-cell function in hypopituitary adults before and during growth hormone treatment.

1. We studied beta-cell function in 40 hypopituitary adults and in 36 matched control subjects. Hypopituitary patients were studied again at 1, 3 and 6 months during a double-blind placebo-controlled trial of growth replacement lasting for 6 months. Biosynthetic human growth hormone was given subcutaneously in a daily dose of 0.02-0.05 i.u./kg at bed time. Fasting insulin, intact proinsulin and 32-33 split proinsulin were measured by two-site immunoradiometric assays. 2. Hypopituitary patients were aged 19-67 years and had a body mass index of 27.7 (18.0-41.1) kg/m2. They were receiving replacement thyroxine, adrenal steroids and sex hormones and they were growth hormone deficient. Control subjects were matched for age, sex and body mass index. Hypopituitary patients with normal glucose tolerance and with impaired glucose tolerance were compared separately with subgroups of control subjects matched for age and body mass index. 3. Twenty-six hypopituitary patients had normal glucose tolerance and 14 had impaired glucose tolerance. All control subjects had normal glucose tolerance by World Health Organization criteria. Patients with impaired glucose tolerance were significantly older than those with normal glucose tolerance (P < 0.03). Hypopituitary patients with normal glucose tolerance compared with normal control subjects had a significantly lower fasting plasma glucose concentration (P < 0.01), a lower fasting insulin concentration (P < 0.006), a lower insulin-glucose ratio (P < 0.02) and a lower percentage of insulin to total insulin-like molecules [hypopituitary patients, 90% (81-96%); control subjects, 93% (78-97%); P < 0.02]. Hypopituitary patients with impaired glucose tolerance had similar glucose and insulin concentrations and insulin-glucose ratios as matched control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased secretion of 32,33 split proinsulin after intravenous glucose in glucose-tolerant first-degree relatives of patients with non-insulin dependent diabetes of European, but not Asian, origin.

OBJECTIVE: The aetiology of non-insulin dependent diabetes is unknown, but defective insulin secretion is a feature. The disease also has a strong genetic basis and first-degree relatives of patients have an increased risk of future diabetes. To investigate whether beta-cell dysfunction is an early feature of the disease, we studied insulin secretion in healthy first-degree relatives of patients with non-insulin dependent diabetes. DESIGN: Each subject underwent a 1-hour intravenous glucose tolerance test (0.3 g/kg). PATIENTS: Seventeen first-degree relatives of patients (10 of European and 7 of Asian (Indian subcontinent) origin) with normal glucose tolerance were compared with 17 matched control subjects with no family history of diabetes. MEASUREMENTS: Plasma immunoreactive insulin (IRI) was measured by radioimmunoassay, and specific insulin, intact and 32,33 split proinsulin were measured by specific immunoradiometric assays (IRMA) for the 1st phase (0-10 minutes) and 2nd phase (10-60 minutes) responses. Glucose and intermediary metabolites were measured enzymatically. RESULTS: Fasting concentrations of IRI, IRMA insulin, intact and 32,33 split proinsulin were similar in relatives and controls in each group. Fasting glucose levels were similar in European relatives and controls but lower in Asian relatives compared to their controls (mean +/- SE 4.9 +/- 0.2 vs 5.5 +/- 0.2 mmol/l, P < 0.05). Following intravenous glucose, European relatives had similar IRI and glucose levels to their controls. Secretion of 32,33 split proinsulin was increased in European relatives compared to their controls, significantly so for 2nd phase secretion (1st phase median (range): 71 (7-352) vs 55 (17-118) pmol/l min, NS; 2nd phase: 433 (115-1459) vs 234 (55-745) pmol/l min, P < 0.05). Secretion of IRMA insulin and intact proinsulin were similar in European relatives and controls (IRMA insulin: 1st phase 2757 (700-10,969) vs 2830 (632-4682) pmol/l min; 2nd phase 6387 (3006-15,865) vs 5284 (2060-18,605) pmol/l min; intact proinsulin: 1st phase 31 (13-113) vs 32 (16-72) pmol/l min; 2nd phase: 174 (87-737) vs 159 (97-298) pmol/l min). European relatives had a greater percentage of proinsulin-like molecules (intact + 32,33 split proinsulin) to total insulin (sum of IRMA insulin + intact + 32,33 split proinsulin) during the 2nd phase of secretion (9.1 (5.0-11.8) vs 5.9 (4.3-12.6)%, P < 0.05). In contrast, Asian relatives had similar secretion of IRI, IRMA insulin, intact and 32,33 split proinsulin to their controls. Glucose disappearance (KG) was similar in relatives and controls within each ethnic group (Europeans: relatives 725 +/- 101 vs controls 668 +/- 47/min; Asian: relatives 610 +/- 97 vs controls 783 +/- 936/min). Asian relatives had higher fasting circulating glycerol (65 +/- 7 vs 44 +/- 4 mumol/l, P < 0.05), non-esterified fatty acid (569 +/- 59 vs 375 +/- 64 mumol/l, P < 0.05) and 3-hydroxybutyrate levels (147 (44-187) vs 35 (21-57) mumol/l, P < 0.01) than their controls and this persisted following intravenous glucose. This difference was not observed in the European group. CONCLUSION: First-degree relatives of European patients with NIDDM possess early signs of beta-cell dysfunction, with increased and disproportionate secretion of 32,33 split proinsulin after intravenous glucose, whilst glucose tolerance is still normal.

Genetic analysis of glucokinase and the chromosome 20 diabetes susceptibility locus in families with type 2 diabetes.

Mutations of the glucokinase gene (chromosome 7p) have been shown to cause some cases of familial maturity onset diabetes of youth (MODY) but few, if any, cases of late onset familial Type 2 diabetes. A further single large pedigree with MODY has shown linkage to a marker for the adenosine deaminase gene (ADA, chromosome 20q), although the diabetes susceptibility gene at this locus has not been identified. We have studied members of 19 families with familial Type 2 diabetes (including 10 European families, 6 families from the Indian subcontinent, and 3 families of Afro-Caribbean origin), 2 of which were of MODY type (and both European), with a glucokinase marker and a marker linked to ADA, to examine whether glucokinase, or the unknown defect on chromosome 20, are implicated in diabetes in our pedigrees. Several models were constructed for standard two-point linkage analysis. Glucokinase is not the cause of diabetes in all of these families but was excluded in only one MODY family. It was possible to exclude both loci in the second MODY pedigree. No evidence was found of linkage to either marker in this multi-ethnic population under the models used. At least one further locus is involved in determining susceptibility to MODY.

Serum lipoprotein levels and plasma concentrations of insulin, intact and 32, 33 split proinsulin in normoglycaemic relatives of patients with type 2 diabetes.

Type 2 diabetes is associated with abnormal lipoprotein levels and altered plasma concentrations of insulin, intact and 32, 33 split proinsulin. To investigate whether these are early features of the disease, we studied 36 normoglycaemic first-degree relatives of patients with Type 2 diabetes (13 European, 15 of Asian (Indian-subcontinent), and 8 of Afro-Caribbean origin) and 36 control subjects with no family history of diabetes. Relatives and controls were matched for age (mean +/- S.E. 33 +/- 2 vs 34 +/- 2 years), body mass index (23.7 +/- 0.5 vs 23.7 +/- 0.6 kg m-2), sex (17 M, 19 F) and ethnic origin. After an overnight fast, blood was sampled for measurement of serum lipids, plasma glucose and insulin, intact and 32, 33 split proinsulin by specific immunoradiometric assays. Relatives and controls had similar fasting concentrations of glucose (5.0 +/- 0.1 vs 4.9 +/- 0.1 mmol l-1), total cholesterol (4.51 +/- 0.13 vs 4.54 +/- 0.17 mmol l-1), HDL-cholesterol (1.21 +/- 0.06 vs 1.10 +/- 0.05 mmol l-1), LDL-cholesterol (2.84 +/- 0.14 vs 2.96 +/- 0.14 mmol l-1) and triglyceride (median (range) 0.78 (0.44-2.45) vs 0.83 (0.41-4.03) mmol l-1). Fasting levels of insulin (50.4 (18.9-174.0) vs 51.6 (10.0-118.0) pmol l-1, intact proinsulin (2.8 (0.1-15.0) vs 2.1 (0.6-6.4) pmol l-1 and 32, 33 split proinsulin (2.0(0-23.7) vs 1.6 (0.3-6.0) pmol l-1) were not significantly different between relatives and controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Loss of the first phase insulin response to intravenous glucose in subjects with persistent impaired glucose tolerance.

Loss of the first phase insulin response to intravenous glucose is one of the earliest detectable defects of beta cell dysfunction in Type 2 diabetes mellitus. Impaired glucose tolerance (IGT) is considered a prediabetic condition, therefore loss of first phase insulin secretion in subjects with IGT would suggest beta cell dysfunction as an early lesion in the development of Type 2 diabetes. Three groups of subjects were studied, 7 subjects with persistent IGT (classified as having IGT at two 75 g oral glucose tolerance tests (OGTT) done 6 months apart), 6 subjects with transient IGT (IGT at the first OGTT, but normal glucose tolerance at a repeat OGTT 6 months later), and 7 normal controls. First phase insulin secretion was studied using an intravenous glucose tolerance test with arterialized blood sampling. Fasting, 3, 4 and 5 min samples were assayed for glucose and insulin (specific two-site immunoradiometric assay). The fasting insulin was similar in all three groups, however the 3 min insulin response was significantly lower in those with persistent impaired glucose tolerance (p < 0.02). Thus subjects with persistent impaired glucose tolerance demonstrated loss of the first phase insulin response as an early indicator of beta cell dysfunction while subjects with transient IGT had a normal insulin response to intravenous glucose. During the OGTT, the 30 min glucose was not significantly different (p = 0.1) but the 30 min insulin to glucose ratio was significantly lower in subjects with persistent IGT (p < 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)