Mechanism of Insulin Resistance in the Post Receptor Events in Sheep: 3-O-Methylglucose Transport in Ovine Adipocytes

Summary

A severe resistance to the stimulatory action of insulin on glucose metabolism has been shown in ruminant adipose tissue or isolated adipocytes as compared to that of rats. To elucidate the mechanism of insulin resistance in ruminants, we measured the stimulatory effect of insulin on 3-O-methylglucose transport and on intracellular glucose metabolism in isolated adipocytes from sheep and rats.

At a glucose concentration (0.1 mM) where transport is thought to be rate-limiting for metabolism, lipogenesis from [U-¹⁴C]glucose by ovine adipocytes was markedly less than by rat adipocytes in both the basal state and at all insulin concentrations. The responsiveness to insulin assessed by percent increase above basal was reduced to about 15% of that in rat adipocytes, but the insulin sensitivity was similar, because the insulin concentration giving half-maximal stimulation, ED₅₀, did not differ significantly between ovine and rat adipocytes. The maximal insulin-stimulated 3-O-methylglucose transport in ovine adipocytes per cell was less than 20% of that in rat adipocytes, with a significant lowering in basal rates of transport. However, when data was expressed per 3-O-methylglucose equilibrium space no significant differences were found between ovine and rat in the basal transport rates, but a lowered ability of insulin to stimulate glucose transport was still seen in ovine adipocytes. The dose-response curve for glucose transport was slightly shifted to the right in ovine adipocytes compared to rat adipocytes, indicating a small decrease in insulin sensitivity. The decrease in glucose transport was due to a 60% reduction in the maximum velocity in the insulin-stimulated state, with no change in the Km.

Thus, the decrease in intracellular glucose metabolism was similar in magnitude to the decrease in glucose transport. These results suggest that insulin resistance in sheep is due to conspicuously low capacity in the glucose transport system rather than more distal intracellular processes.

Key words

Ovine Adipocytes - Insulin Resistance - 3-O-Methylglucose Transport - Lipogenesis