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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.

1. Modelling analysis of intravenous glucose tolerance test glucose and insulin concentrations can provide measures of insulin sensitivity and metabolism from a single straightforward procedure. However, little is known of the effects of blood arterialization on model-derived parameters. 2. Intravenous glucose tolerance tests were carried out on 18 subjects, with measurement of glucose and insulin concentrations in simultaneously sampled non-arterialized and arterialized blood. Blood oxygen saturation, partial pressure of CO2 and pH were measured on both non-arterialized and arterialized blood during the intravenous glucose tolerance test. Using the minimal models of glucose disappearance and post-hepatic insulin delivery, measures of insulin sensitivity, glucose-dependent glucose disposal, first- and second-phase post-hepatic insulin responsiveness to glucose and plasma insulin elimination rate were derived from intravenous glucose tolerance test glucose and insulin concentrations in both arterialized and non-arterialized blood. 3. During the intravenous glucose tolerance test mean blood oxygen saturation was 6.7% higher, partial pressure of CO2 was 0.3 kPa lower and pH was 0.015 higher in arterialized than non-arterialized blood. Mean parameter values did not differ when derived from measurements made on non-arterialized and arterialized blood. Model-derived parameters were not related to the degree of arterialization, although there was some consistent variation with sampling site for parameters of glucose-dependent glucose disposal (Sg), first-phase post-hepatic insulin responsiveness (phi 1) and insulin elimination (ni). 4. Measurements made on non-arterialized blood are suitable for analyses employing the minimal models of glucose disappearance and post-hepatic insulin delivery. Imprecision in some parameters may be diminished by adherence to a single sampling site.

Relationships between serum Lp(a) levels and insulin metabolism were investigated in 147 healthy nonobese men attending an executive health-screening program. Each subject received an IVGTT with measurement of plasma levels of glucose, insulin, and C-peptide. An inverse relationship was seen with the first-phase plasma insulin response when subjects were stratified into quartile ranges of the serum Lp(a) distribution. This relationship was supported by mathematical modeling analyses of these data, which revealed an inverse relationship between serum Lp(a) levels and first-phase pancreatic insulin secretion and plasma insulin responsiveness to glucose.

Elevated insulin concentrations are independent predictors of coronary heart disease (CHD) and are related to high blood pressure, low serum HDL-cholesterol and elevated serum triglyceride. Insulin resistance is a major determinant of the plasma insulin concentration. Computer modelling of plasma glucose, insulin and C-peptide concentrations during an intravenous glucose tolerance test enables quantification of the determinants of plasma insulin concentration. The association between risk markers of CHD and model-derived measures of determinants of plasma insulin concentration in a group of healthy males has been investigated. In univariate linear regression analysis of the glucose, insulin and C-peptide data, the incremental insulin area during the second phase (10-180 min.) was found to be the strongest predictor of lipid, lipoprotein and blood pressure variables. Variations in insulin sensitivity and hepatic insulin throughput contribute to variation in the insulin response and may be secondary correlates of lipids, lipoproteins and blood pressure.

Plasma corticotrophin (ACTH), cortisol, prolactin and growth hormone (GH) responses to insulin-induced hypoglycaemia were measured in normal healthy subjects of both sexes before and after three weeks' treatment with sodium valproate (Epilim, 200 mg three times a day). The drug had no effect on fasting plasma glucose levels, or the extent of hypoglycaemia induced by insulin (0.15 U/kg). There was no significant difference between pre- and post-treatment values for basal or stress-induced concentrations of ACTH and cortisol (n = 12), prolactin (n = 7) or GH (n = 9). The results suggest that treatment of normal subjects with sodium valproate has no effect on the response of the hypothalamo-pituitary-adrenocortical axis to hypoglycaemia, which is in contrast to its inhibitory effects on ACTH secretion in patients suffering from Nelson's syndrome. This implies that in the disease state, there may be a unique sensitivity to GABA-ergic manipulation.

Using the decay phase of the glucose response during an intravenous tolbutamide test, a minimal model of glucose dynamics was used to calculate a value for an "index of insulin sensitivity". This index describes the efficiency of insulin in accelerating the instantaneous rate of glucose disposal, and provides a measure of insulin resistance. The validity of estimates of the index of insulin sensitivity obtained from the intravenous tolbutamide test have been assessed with reference to estimates of this index derived from the intravenous glucose tolerance test for which the model was originally designed. There were three studies: (A) estimates of the index of insulin sensitivity obtained from the intravenous tolbutamide test in a group of normal, healthy men and women were compared with results obtained in a comparable group of subjects using the intravenous glucose tolerance test. The two methods gave estimates of the index of insulin sensitivity that were identical; (B) A group of patients taking methandienone, an anabolic steroid previously shown to cause marked insulin resistance, were tested whilst taking the steroid and either before, or at least two months after treatment. Each patient was tested by both intravenous tolbutamide test and intravenous glucose tolerance test on both occasions. Estimates of the index of insulin sensitivity from intravenous glucose tolerance or intravenous tolbutamide procedures both on and off treatment were significantly correlated (off treatment: rs = 0.71, n = 9, p less than 0.05; on treatment: rs = 0.69, n = 9, p less than 0.05); (C) A group of patient undergoing investigations for suspected disturbances in carbohydrate metabolism was studied, each patient having had both an intravenous tolbutamide and intravenous glucose tolerance test.(ABSTRACT TRUNCATED AT 250 WORDS)

THE PLASMA GLUCOSE AND BLOOD PYRUVATE LEVELS WERE DETERMINED AFTER ORAL GLUCOSE TOLERANCE TEST IN SIX GROUPS OF WOMEN: non-obese and obese controls and in non-obese and obese women receiving glucocorticoid or oral contraceptive therapy. The mean fasting plasma glucose level was similar in all groups, but glucose tolerance was impaired in the obese controls, non-obese women on oral contraceptives or being treated with glucocorticoids, and appreciably impaired in the obese oral contraceptive and glucocorticoid groups compared with mean levels in non-obese subjects of the same groups. Obesity was associated with abnormally raised blood pyruvate levels in response to a glucose tolerance test in all groups. Striking similarities were observed between the responses of the plasma glucose and blood pyruvate levels to glucose tolerance tests in the obese control and non-obese oral contraceptive and non-obese glucocorticoid-treated groups. It is suggested that these abnormalities result from a common mechanism-namely, glucocorticoid excess.