Regulation of glucose utilization in adipose cells and muscle after long-term experimental hyperinsulinemia in rats.

Abstract

The effects of chronic insulin administration on the metabolism of isolated adipose cells and muscle were studied. Adipose cells from 2 and 6 wk insulin-treated and control rats, fed either chow or chow plus sucrose, were prepared, and insulin binding, 3-0-methylglucose transport, glucose metabolism, and lipolysis were measured at various insulin concentrations. After 2 wk of treatment, adipose cell size and basal glucose transport and metabolism were unaltered, but insulin-stimulated transport and glucose metabolism were increased two-to threefold when cells were incubated in either 0.1 mM glucose (transport rate limiting) or 10 mM glucose (maximum glucose metabolism). Insulin binding was increased by 30%, but no shift in the insulin dose-response curve for transport or metabolism occurred. After 6 wk of treatment, the effects of hyperinsulinemia on insulin binding and glucose metabolism persisted and were superimposed on the changes in cell function that occurred with increasing cell size in aging rats. Hyperinsulinemia for 2 or 6 wk did not alter basal or epinephrine-stimulated lipolysis in adipose cells or the antilipolytic effect of insulin. In incubated soleus muscle strips, insulin-stimulated glucose metabolism was significantly increased after 2 wk of hyperinsulinemia, but these increases were not observed after 6 wk of treatment. We conclude that 2 wk of continuous hyperinsulinemia results in increased insulin-stimulated glucose metabolism in both adipose cells and soleus muscle. Despite increased insulin binding to adipose cells, no changes in insulin sensitivity were observed in adipose cells or muscle. In adipose cells, the increased glucose utilization resulted from both increased transport (2 wk only) and intracellular glucose metabolism (2 and 6 wk). In muscle, after 2 wk of treatment, both glycogen synthesis and total glucose metabolism were increased. These effects of hyperinsulinemia were lost in muscle after 6 wk of treatment, when compared with sucrose-supplemented controls.

Mechanism for enhanced glucose transport response to insulin in adipose cells from chronically hyperinsulinemic rats. Increased translocation of glucose transporters from an enlarged intracellular pool.

“…Table I compares some of the physiological parameters of the insulin-infused and control rats; the values closely concur with those reported by Wardzala et al (9).…”

“…Kobayashi and Olefsky (5,6) increased insulin-stimulated glucose transport in the adipose cell in association with hyperinsulinemia induced in normal rats by subcutaneous insulin injections. Subsequently, similar findings were reported by Trimble et al (8) using intravenous insulin infusion and by Wardzala et al (9) using subcutaneous insulin infusion via osmotic minipumps.…”

“…The possible factors contributing to this alteration in the number of glucose transporters in cells from rats that are naturally (10) or experimentally (5,6,8,9) hyperinsulinemic is of interest. Hyperinsulinemia alone is unlikely to be responsible because in association with obesity (3), impaired glucose tolerance (3), and insulin treatment oftype I diabetes (33) in humans, it is accompanied by insulin resistance in vivo and at the cellular level.…”

Effect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man

“…It generally is thought that insulin resistance represents the primary disturbance, while hyperinsulinaemia is a compensatory response by the beta cells to offset the defect in insulin action and maintain a normal flux of glucose into the cell. However, recent evidence suggests that hyperinsulinaemia per se may lead to the development of insulin resistance [13][14][15][16][17][18].…”

“…Thus, chronic hyperinsulinaemia has been shown to induce insulin resistance in some [13][14][15][16][17][18], but not all [19][20][21] studies. Little information is available concerning the effect of chronic hyperinsulinaemia on insulinmediated glucose metabolism in man [16,17] and the intracellular metabolic pathway(s) responsible for the reduction in insulin-mediated glucose disposal following chronic exposure to the hormone have not been examined.…”