In vivo glucosamine infusion induces insulin resistance in normoglycemic but not in hyperglycemic conscious rats.
Open Access
- 1 July 1995
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 96 (1), 132-140
- https://doi.org/10.1172/jci118013
Abstract
To test the hypothesis that increased flux through the hexosamine biosynthetic pathway can induce insulin resistance in skeletal muscle in vivo, we monitored glucose uptake, glycolysis, and glycogen synthesis during insulin clamp studies in 6-h fasted conscious rats in the presence of a sustained (7-h) increase in glucosamine (GlcN) availability. Euglycemic (approximately 7 mM) insulin (approximately 2,500 pM) clamps with saline or GlcN infusions were performed in control (CON; plasma glucose [PG] = 7.4 +/- 0.2 mM), diabetic (D; PG = 19.7 +/- 1.1), and phlorizin-treated (3-wk) diabetic rats (D + PHL; PG = 7.6 +/- 0.9). 7-h euglycemic hyperinsulinemia with saline did not significantly decrease Rd (360-420 min = 39.2 +/- 3.6 vs. 60-120 min = 42.2 +/- 3.7 mg/kg.min; P = NS). GlcN infusion raised plasma GlcN concentrations to approximately 1.2 mM and increased muscle and liver UDP-GlcNAc levels by 4-5-fold in all groups. GlcN markedly decreased Rd in CON (360-420 min = 30.4 +/- 1.3 vs. 60-120 min = 44.1 +/- 3.5 mg/kg.min; P < 0.01) and D + PHL (360-420 min = 29.4 +/- 2.5 vs. 60-120 min = 43.8 +/- 2.9 mg/kg.min; P < 0.01), but not in D (5-7 h = 21.5 +/- 0.8 vs. 0-2 h = 24.3 +/- 1.1 mg/kg.min; P = NS). Thus, increased GlcN availability induces severe skeletal muscle insulin resistance in normoglycemic but not in chronically hyperglycemic rats. The lack of additive effects of GlcN and chronic hyperglycemia (experimental diabetes) provides support for the hypothesis that increased flux through the GlcN pathway in skeletal muscle may play an important role in glucose-induced insulin resistance in vivo.Keywords
This publication has 36 references indexed in Scilit:
- Skeletal muscle glycogenolysis is more sensitive to insulin than is glucose transport/phosphorylation. Relation to the insulin-mediated inhibition of hepatic glucose production.JCI Insight, 1993
- Mechanism by which hyperglycemia inhibits hepatic glucose production in conscious rats. Implications for the pathophysiology of fasting hyperglycemia in diabetes.JCI Insight, 1993
- Predominant role of gluconeogenesis in the hepatic glycogen repletion of diabetic rats.JCI Insight, 1992
- Relative contribution of glycogen synthesis and glycolysis to insulin-mediated glucose uptake. A dose-response euglycemic clamp study in normal and diabetic rats.JCI Insight, 1990
- Correction of chronic hyperglycemia with vanadate, but not with phlorizin, normalizes in vivo glycogen repletion and in vitro glycogen synthase activity in diabetic skeletal muscle.JCI Insight, 1989
- Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats.JCI Insight, 1987
- Natural Course of Insulin Resistance in Type I DiabetesNew England Journal of Medicine, 1986
- Insulin receptor down-regulation is linked to an insulin-induced postreceptor defect in the glucose transport system in rat adipocytes.JCI Insight, 1985
- Partial pancreatectomy in the rat and subsequent defect in glucose-induced insulin release.JCI Insight, 1983
- Receptor and postreceptor defects contribute to the insulin resistance in noninsulin-dependent diabetes mellitus.JCI Insight, 1981