Overexpression of Glut4 protein in muscle increases basal and insulin-stimulated whole body glucose disposal in conscious mice.

Abstract

The effect of increased Glut4 protein expression in muscle and fat on the whole body glucose metabolism has been evaluated by the euglycemic hyperinsulinemic clamp technique in conscious mice. Fed and fasting plasma glucose concentrations were 172+7 and 78+7 mg/dl, respectively, in transgenic mice, and were significantly lower than that of nontransgenic littermates (208+5 mg/dl in fed; 102±5 mg/dl in fasting state). Plasma lactate concentrations were higher in transgenic mice, (6.5±0.7 mM in the fed and 5.8+1.0 mM in fasting state) compared with that of nontransgenic littermates (4.7+0.3 mM in the fed and 4.2+0.5 mM in fasting state). In the fed state, the rate of whole body glucose disposal was 70% higher in transgenic mice in the basal state, 81 and 54% higher during submaximal and maximal insulin stimulation. In the fasting state, insulinstimulated whole body glucose disposal was also higher in the transgenic mice. Hepatic glucose production after an overnight fast was 24.8+0.7 mg/kg per min in transgenic mice, and 25.4+2.7 mg/kg per min in nontransgenic mice. Our data demonstrate that overexpression of Glut4 protein in muscle increases basal as well as insulin-stimulated whole body glucose disposal. These results suggest that skeletal muscle glucose transport is rate-limiting for whole body glucose disposal and that the Glut4 protein is a potential target for pharmacological or genetic manipulation for treatment of patients with non-insulin-dependent diabetes mellitus. (J. Clin. Invest. 1995. 95:429-432.)

Enhanced glucose cycling and suppressed de novo synthesis of glucose-6-phosphate result in a net unchanged hepatic glucose output in ob/ob mice

“…Previously reported values of endogenous glucose production in C57Bl/6 mice are almost identical to those reported in this study in lean littermates of ob/ob mice [16,17]. Furthermore, endogenous glucose production in C57Bl/6 mice could be suppressed almost completely during hyperinsulinaemic clamp at normal or increased glucose concentrations [16,17] (and unpublished observations, A. Grefhorst et al). The impaired suppression of endogenous glucose production was mainly due to the blunted response of de novo synthesis of G6P to the combined hyperinsulinaemia and hyperglycaemia in ob/ob mice.…”

Deletion of Both Rab-GTPase–Activating Proteins TBC1D1 and TBC1D4 in Mice Eliminates Insulin- and AICAR-Stimulated Glucose Transport

“…Deletion of GLUT4 in these tissues led to a profound reduction in basal glucose transport, whereas overexpression of GLUT4 resulted in a substantial increase in basal uptake of glucose into the cells (42)(43)(44)(45). In contrast, in skeletal muscle and adipose cells from D1KO, D4DO, and D1/4KO mice, basal glucose transport was normal despite substantially reduced abundance of cellular GLUT4 protein.…”

Development of diabetes in obese, insulin-resistant mice: essential role of dietary carbohydrate in beta cell destruction

“…Euglycaemichyperinsulinaemic clamps were performed as previously described [17] in 9-week old, conscious, catheterised mice that had fasted for 16 h. In vivo experiments lasted for 240 min and consisted of a 120-min basal period, directly followed by a 120-min euglycaemic-hyperinsulinaemic clamp. During the basal period a prime-continuous [3] glucose infusion (370 kBq bolus, 3.7 kBq/min) was started and continued to determine rates of whole-body glucose turnover.…”