Impaired ability of glycated insulin to regulate plasma glucose and stimulate glucose transport and metabolism in mouse abdominal muscle

Previous studies have shown that glycated insulin is secreted from pancreat ic beta-cells under conditions of hyperglycaemia. This study has investigat ed the effects of monoglycated insulin on plasma glucose homeostasis and in vitro cellular glucose transport and metabolism by isolated abdominal musc le of mice. Monoglycated insulin was prepared under hypeglycaemic reducing conditions, purified by RP-HPLC and identified by electrospray ionisation m ass spectrometry (5971.1 Dal. When administered to mice at an intraperitone al dose of 7 nmoles/kg body weight, insulin (non-glycated) decreased plasma glucose concentrations and substantially reduced the glycaemic excursion i nduced by conjoint intraperitoneal injection of 2 g glucose/kg body weight. In comparison, the same dose of monoglycated insulin decreased plasma gluc ose concentrations to a lesser extent (P < 0.05), corresponding to an appro x. 20% reduction of glucose lowering potency. Using isolated abdominal musc le, insulin (10(-9)-10(-7) M) stimulated dose-dependent increases in cellul ar 2-deoxy-D-[1(-3)H]glucose uptake, D-[U-14C]glucose oxidation and glycoge n production. Monoglycated insulin was approx. 20% less effective than nati ve insulin in stimulating glucose uptake and both indices of metabolism, ge nerally requiring 10-fold greater concentrations to achieve significant sti mulatory effects. These data indicate that the impaired biological activity of glycated insulin may contribute to glucose intolerance of diabetes. (C) 2000 Elsevier Science B.V. All rights reserved.