V Wynn’s research while affiliated with National Heart Lung and Blood Institute, National Institutes of Health and other places

Metabolic risk markers for coronary heart disease (CHD) were determined in apparently healthy females of differing racial origins residing in the United Kingdom. The females were of black (n=122), Oriental (n=144), South Asian (n=128), and white (n=271) origin, premenopausal, non-obese, and aged 16-45 years. In comparison to whites, South Asians had lower serum high-density lipoprotein (HDL) cholesterol and HDL2 cholesterol and higher fasting and oral glucose tolerance test plasma insulin responses. Black females had higher fasting plasma and oral glucose tolerance test insulin and lower serum triglyceride and glucose compared with white females. Orientals differed from whites in having higher fasting and oral glucose tolerance test insulin concentrations. Resting systolic or diastolic blood pressures, total serum cholesterol, HDL3 cholesterol, and low-density lipoprotein (LDL) cholesterol did not differ between groups. Whereas previous studies have demonstrated similar differences in representative samples from different ethnic communities, our results clearly demonstrate that differences also exist in young healthy females, individuals considered to have the least risk of CHD.

The Committee on Safety of Medicines and its chairman Professor Michael Rawlins fail to understand the issues raised by their hasty advice to physicians regarding the safety of oral contraceptives containing gestodene and desogestrel. Rawlins has taken on the role of peer reviewer of unpublished information without consultation. The need for consultation is evident in the dissent of John Guillebaud Clifford Kay and W. O. Spitzer. Rawlins dismisses the methodological problems in the studies undermines the importance attached to the accumulating data on stroke and myocardial infarction and denigrates the importance of changes in lipoprotein concentrations induced by oral contraceptives (this last based on a review that hardly discusses the issue). Women of childbearing age are 15 times more likely to die of arterial disease than of venous thromboembolic disease; the third generation pills were introduced specifically to reduce the risks of arterial disease in women using oral contraceptives. This is acknowledged by the deferment of a decision on the safety of third generation pills by the European Committee for Proprietary Medicinal Products. However the single rush to judgement by the Committee on Safety of Medicine may have already damaged any chances of learning about the beneficial effects of these pills and undermined further research and development on oral contraceptives by the pharmaceutical industry.

Data from a previous study, designed to compare metabolic risk markers for cardiovascular disease in non-users and oral contraceptive (OC) users, were analysed to evaluate the influence of OC composition on blood pressure. Healthy, female volunteers (1189 women) either not using OC (non-users) or currently using one of six different combined formulations (users) were compared. Combinations studied contained 30-40 micrograms ethinyl estradiol combined with the progestins levonorgestrel, norethindrone (at two and three different doses, respectively) or desogestrel. After statistical standardisation to account for the significantly greater age of the non-users and longer duration of OC use amongst the levonorgestrel combination users, mean blood pressure was higher, compared with non-users, in users of monophasic or triphasic levonorgestrel combinations (systolic: +4.3 mmHg (p < 0.001) and +2.7 mmHg (p < 0.001), respectively; diastolic: +2.6 mmHg (p < 0.001) and +2.3 mmHg (p < 0.05), respectively). Blood pressures in users of monophasic norethindrone and desogestrel combinations were not significantly raised and there was no increase in the proportion of women with abnormal values. Diastolic and systolic blood pressures were positively associated with oral glucose tolerance test insulin response (r = 0.11 (p < 0.01) and r = 0.15 (p < 0.001), respectively) in users but not in non-users. Currently used OC containing norethindrone or desogestrel progestins have little impact on blood pressure. Their correlated reduction in impact on insulin concentrations, though small, suggests common mechanisms through which OC affect blood pressure and insulin.

Insulin resistance is associated with hypertriglyceridemia and elevated free fatty acid (FFA) concentrations in obese and diabetic individuals, but it is unclear to what extent this relationship is independent of obesity and is present in healthy individuals. We studied 92 healthy middle-aged males selected from the top, middle, and lowest quintiles of the insulin sensitivity index (Si) determined in a group of 182 men using the minimal model of glucose disappearance. Plasma FFA, triglyceride, glucose, insulin, and C-peptide concentrations were measured during a 3-hour intravenous glucose tolerance test (IVGTT). The low-Si (most insulin-resistant) group had more central body fat distribution (subscapular/triceps skinfold thickness) and a higher median body mass index (BMI) of 26.8 (range, 21.1 to 41.1) kg.m-2 compared with the middle- and high-Si groups with BMIs of 24.9 (19.1 to 31.5) and 23.7 (18.8 to 33.2) kg.m-2 (P < .05). Relatively minor glucose intolerance in the low-Si group was no longer significant when central adiposity was accounted for. Glucose tolerance was maintained by increased insulin secretion, leading to IVGTT insulin responses twofold and fourfold higher in the middle- and low-Si groups, respectively, compared with the high-Si group (P < .01). Fasting FFA and triglyceride concentrations were increased in the low-Si group relative to the other groups independent of BMI or central adiposity (P < .01). During the IVGTT, FFA decreased to similar minimum concentrations in all three groups. Triglyceride concentrations during the IVGTT increased above their minimum levels, particularly in the low-Si group (P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)

An intravenous glucose tolerance test (IVGTT) glucose dose of 0.3 g/kg has been adopted for measurement of insulin sensitivity using the minimal model. Traditionally, however, a dose of 0.5 g/kg has been used, which might be expected to improve the IVGTT insulin response and hence the effectiveness of minimal model analysis. In a preliminary study of 5 subjects given 0.3 and 0.5 g/kg IVGTTs, each lasting 120 minutes, we found a 53% increase in IVGTT insulin response at the higher dose, but there was a marked discrepancy in the difference between fasting and final glucose concentrations (-0.17 mmol.l-1 at 0.3 g/kg and -1.01 mmol.l-1 at 0.5 g/kg). Good agreement obtained between estimates of Si derived from 0.3 and 0.5 g/kg IVGTTs (mean Si: 0.3 g/kg test = 6.0 min-1.microU-1.ml, 0.5 g/kg test = 5.8 min-1.microU-1.ml: r = 0.97, p < 0.001) providing the final IVGTT glucose concentration rather than the fasting concentration was taken as the basal level for modelling analysis. These findings were confirmed and extended in two further studies; firstly in an analysis of the effects of choice of basal glucose concentration and the application of various modelling constraints in a cross-section of 66 subjects with a wide range of insulin sensitivities; then in a further study in which seven subjects were each given two 0.3 g/kg IVGTTs and one 0.5 g/kg IVGTT, with each test being prolonged to 300 minutes. Agreement between estimates of Si at the two different doses was again only achieved by taking the final IVGTT glucose concentration as basal (mean Si: 0.3 g/kg test = 4.7 min-1.microU-1.ml, 0.5 g/kg test = 3.8 min-1.microU-1.ml: r = 0.75, p < 0.05), although one anomalous test required that a constraint be applied to the modelling process for this agreement to obtain. Closest agreement between the 300 minute 0.3 and 0.5 g/kg IVGTTs was found when tests were modelled up to 180 minutes. An IVGTT duration of 180 minutes appears to be optimum for re-establishing the basal concentration necessary for effective modelling analysis. Application of constraints can markedly affect certain analyses and may introduce some bias; their use should be carefully monitored, although their effect on large datasets is likely to be small.

We have carried out intravenous glucose tolerance tests with measurement of plasma glucose, insulin and C-peptide concentrations on 66 premenopausal and 92 postmenopausal non-obese caucasian women. After adjustment for the effects of a number of possible confounding variables, including age and body mass index, there was little difference between pre and postmenopausal women in glucose and insulin concentrations either fasting or in response to intravenous glucose. Mathematical modelling analysis of the resultant plasma concentration profiles was used to obtain measures of insulin sensitivity, secretion and elimination, and non-insulin dependent glucose disposal. We found reciprocal differences in mean insulin sensitivity (increased by 50%) and non-insulin dependent glucose disposal (decreased by 30%). Plasma C-peptide response and pancreatic insulin secretion were markedly lower in the postmenopausal group (-35% and -51% respectively). However, the rate constant for insulin elimination was also lower in these women. As a result, intravenous glucose tolerance test plasma insulin concentrations were not significantly different between the two groups. We conclude that, despite the occurrence of little or no variation in plasma glucose and insulin concentrations, the menopause is associated with significant changes in insulin metabolism.