Previous studies have suggested that glucagon-like peptide-1 (GLP-1) (7-36 amide) may have the direct effect of increasing insulin sensitivity in healthy man. To evaluate this hypothesis we infused GLP-1 in seven lean healthy men during a hyper insulinaemic (0.8 mU.kg-1.min-1), euglycaemic (5 mmol/l) clamp. Somatostatin (450 micrograms/h was infused to suppress endogenous insulin secretion, and growth hormone (3 ng.kg-1.min-1) and glucagon (0.8 ng.kg-1.min-1) were infused to maintain basal levels. GLP-1 (50 pmol.kg-1.h-1) or 154 mmol/l NaCl (placebo) was infused after 3 h of equilibration, i.e. from 180-360 min. GLP-1 infusion resulted in GLP-1 levels of approximately 40 pmol/l. Plasma glucose, insulin, growth hormone, and glucagon levels were similar throughout the clamps. The rate of glucose infusion required to maintain euglycaemia was similar with or without GLP-1 infusion (7.69 +/- 1.17 vs 7.76 +/- 0.95 mg kg-1.min-1 at 150-180 min and 8.56 +/- 1.13 vs 8.55 +/- 0.68 mg.kg-1.min-1 at 330-360 min) and there was no difference in isotopically determined hepatic glucose production rates (-0.30 +/- 0.23 vs -0.16 +/- 0.22 mg.kg-1.min-1 at 330-360 min). Furthermore, arteriovenous glucose differences across the forearm were similar with or without GLP-1 infusion (1.43 +/- 0.23 vs 1.8 +/- 0.29 mmol/l), (ANOVA; p > 0.60, in all instances). In conclusion, GLP-1 (7-36 amide) administered for 3 h, leading to circulating levels within the physiological range, does not affect insulin sensitivity in healthy man.

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AimsSubgroups of patients with type 2 diabetes mellitus demand large insulin doses to maintain euglycemia. These patients are characterized by severe skeletal muscle insulin resistance and the underlying pathology remains unclear. The purpose of this study was to examine protein expression of the principal glucose transporter, GLUT4, and associated proteins in skeletal muscle from type 2 diabetic patients characterized by severe insulin resistance.MethodsSeven type 2 diabetic patients with severe insulin resistance (mean insulin dose 195 IU/day) were compared with seven age matched type 2 diabetic patients who did not require insulin treatment, and with an age matched healthy control group. Protein expression of GLUT4 and associated proteins was assessed in muscle and fat biopsies using standard western blotting techniques.ResultsGLUT4 protein expression was significantly reduced by ∼30 pct in skeletal muscle tissue from severely insulin resistant type 2 diabetic subjects, compared with both healthy controls and type 2 diabetic subjects that did not require insulin treatment. In fat tissue, GLUT4 protein expression was reduced in both diabetic groups. In skeletal muscle, the reduced GLUT4 expression in severe insulin resistance was associated with decreased ubiquitin-conjugating enzyme 9 (UBC9) expression while expression of GLUT1, TBC1D1 and AS160 was not significantly different among type 2 diabetic patients and matched controls.ConclusionsType 2 diabetic patients with severe insulin resistance have reduced expression of GLUT4 in skeletal muscle compared to patients treated with oral antidiabetic drugs alone. GLUT4 protein levels may therefore play a role in the pathology behind type 2 diabetes mellitus among subgroups of patients, and this may explain the heterogeneous response to insulin treatment. This new finding contributes to the understanding of the underlying mechanisms for the development of extreme insulin resistance.