Insulin sensitivity of adipose tissue in vitro and the response to exogenous insulin in obese human subjects.

The effect of varying concentrations of insulin on 1-14C-glucose conversion to 14CO2 was measured in subcutaneous adipose tissue samples obtained from 16 obese human subjects (10 nondiabetic, 6 diabetic). An index of insulin sensitivity in vitro, Kins, was calculated as the concentration of insulin stimulating one-half maximal 14CO2 production. An index of insulin sensitivity in vivo, Kitt, was calculated as the rate constant for decrease in blood glucose after rapid intravenous administration of 0.05 U/kg insulin. There was, over-all, a significant correlation between Kins and Kitt, indicating that insulin sensitivity of 1-14C-glucose oxidation by adipose tissue in vitro reflects the general state of sensitivity of glucose metabolism to insulin in vivo in obese human subjects. The mean values for both Kins and Kitt in the nondiabetic subjects were significantly different from those in the diabetic subjects, indicating greater sensitivity to insulin in the former group. The nondiabetic group was also distinguished by a significantly greater plasma insulin:blood glucose ratio in the oral glucose tolerance test. These results support the view that tissue insulin sensitivity as well as pancreatic beta cell response play an important role in determining glucose tolerance in obesity.

The effects of mazindol and 46-034 (Sandoz) on glucose oxidation and insulin binding by rat isolated fat cells.

1. The anorexic agent mazindol and its major metabolite 46-034 (Sandoz) in high concentrations ( greater than 0-4 mM) abolished basal and insulin-stimulated conversion of 1-14C-glucose to 14CO2 by rat isolated fat cells. 2. High concentrations (1mM) also inhibited specific binding of 125 I-insulin to fat cells. 3. The observed effects appeared to be due in part to perturbation of the plasma membrane since there was a rise in the lactate dehydrogenase content of the incubation medium, increased 125I-insulin degradation and a reduction in cellular tritiated water space. 4. These effects are unlikely to be relevant to the therapeutic action of mazindol.

Cell size and glucose oxidation rate in adipose tissue from non-diabetic and diabetic obese human subjects.

1. The rate of oxidation of [1-14C]glucose to 14CO2 was examined in subcutaneous adipose tissue from fifteen obese non-diabetic subjects and from eleven obese maturity-onset diabetic patients. Production of 14CO2, measured in the basal state and in the presence of insulin, was significantly correlated with mean cell size in both the non-diabetic and the diabetic subjects, independent of age, relative weight and fasting plasma insulin concentration. 2. Comparison of the regressions of glucose oxidation rates on mean cell size indicated: (i) that insulin produced a significant increase in activity over the basal value in both groups, and (ii) that basal and insulin-stimulated activity were both significantly lower in diabetic than in non-diabetic adipose tissue.

Effects of mazindol on carbohydrate and insulin metabolism in obesity.

Oral administration of a single dose of the anorectic agent mazindol to obese subjects led to a significant improvement in oral glucose tolerance and a concomitant reduction in insulin secretion, but had no effect on the blood glucose and plasma insulin responses to glucose given intravenously. Mazindol, when given to obese subjects in conjunction with a hypocaloric diet, was associated with progressive weight loss and reduction in the fasting levels of blood glucose, plasma insulin, serum triglyceride, and serum cholesterol. When oral glucose tolerance was retested after 16-20 wk, blood glucose and plasma insulin responses were significantly decreased compared with initial control values. It is concluded that one effect of mazindol, when given acutely, is to impair absorption of glucose from the gut. Changes in carbohydrate metabolism after chronic administration of mazindol are entirely consistent with weight loss, although a separate effect of the drug cannot be excluded.