Hormonal Control of Intermediary Metabolism in Obese Hyperglycemic Mice: I. The Sensitivity and Response to Insulin in Adipose Tissue and Muscle in Vitro

Abstract

The sensitivity and response to insulin in vitro of (a) the incorporation of U-C-14-glucose into glycogen in the isolated diaphragm muscle, and (b) the oxidation of l-C-14 glucose in the epididymal fat pad and in adipocytes, has been studied in obese hyperglycemic mice fed ad libitum, in obese mice fasted for twenty-four hours and in obese mice maintained on a restricted diet from weaning and in lean mice, at two to four months of age and at six to eight months of age. In both age groups, there was a significant, although reduced, insulin effect in the muscle from obese mice but this was normal in the six to eight-month-old group of obese mice on a restricted diet. The glucose oxidation in the epididymal fat pad of the obese mice fed ad libitum was very reduced in both age groups. Fasting the obese mice for twenty-four hours did not restore glucose oxidation to normal, but it was normal in fat pads from obese mice kept on a restricted diet. There was no insulin effect on the fat pad of obese mice in either age group even after a twenty-four-hour fast. The response and sensitivity of the tissue to insulin was partially restored in the obese mice on a restricted diet. There were only small differences in sensitivity between adipocytes prepared from obese and lean epididymal fat pads. The maximum response to insulin in adipocytes from obese mice was usually lower than that in adipocytes from lean mice at glucose concentrations of 0.03 per cent but equal or higher at glucose concentrations of 0.2 per cent. The clear responses to low concentrations of insulin of the isolated diaphragm muscle and adipocyte suspension from obese mice on a restricted diet and of the adipocytes from obese mice fed ad libitum, suggest that a decreased sensitivity to insulin at the cellular level is not the primary defect in the obese hyperglycemic syndrome.

Insulin Receptor Deficiency in Genetic and Acquired Obesity

“…The concomitant increase in insulin binding may play an important role in determining the increased cellular response to hormone. During the acute fast, the in vitro and in vivo studies in insulin sensitivity of fat or muscle (41) do not show the increase in insulin binding. The lack of correlation between the insulin binding data and the cellular response to hormone indicate that subsequent regulatory steps may be rate limiting under these circumstances or that the insulin receptor interaction in vivo may be altered due to factors such as acidosis (42) or that the rate of regulation of the receptor in liver is different from that in muscle and fat.…”

Decreased basal, noninsulin-stimulated glucose uptake and metabolism by skeletal soleus muscle isolated from obese-hyperglycemic (ob/ob) mice.

“…Whereas many prior studies have established that insulin-stimulated glucose uptake or metabolism of muscle from the oblob mutation is decreased in vitro (31)(32)(33)(34)(35) Conditions were as described in Tables II, IV, and VI, except that 4% bovine albumin was used. [5-3H]glucose (sum of both glycogen synthesis and glycolysis), and decreased 2-deoxyglucose accumulation, all in the absence of insulin, and after two preincubations to remove whatever insulin might have been present in the tissue at death.…”

Effects of glucagon and insulin on fatty acid synthesis and glycogen degradation in the perfused liver of normal and genetically obese (ob/ob) mice

“…However, if obese mice were deprived of food, to an extent sufficient to keep their weight in the same range as that of the normal mice, the insulin effect returned to normal. Such reversibility is also observed for the decline in the number of insulin receptors in the liver of obese mice (Soll et al, 1975;Le Marchand et al, 1977), for the insulin-resistance observed in adipose tissue and muscle of freely fed genetically obese mice (Abraham & Beloff-Chain, 1971; for reviews see Loten et al, 1974;Czech et al, 1977) and for their increased rates of basal glycogenolysis (Elliott et al, 1971).…”

“…Genetically obese mice provide a model of insulin-resistance in muscle and adipose tissue (Abraham & Beloff-Chain, 1971;see Czech et al, 1977, for review). An investigation of counteraction by insulin of the effects of glucagon should reveal whether the livers of obese mice exhibit insulin-resistance.…”