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Objective . Glucagon-like peptide-1 (GLP-1) analogues (e.g., exenatide) increase insulin secretion in diabetes but less is known about their effects on glucose production or insulin-stimulated glucose uptake in peripheral tissues.  Methods . Four groups of Sprague-Dawley rats were studied: nondiabetic (control, C); nondiabetic + exenatide (C + E); diabetic (D); diabetic + exenatide (D + E) with diabetes induced by streptozotocin and high fat diet. Infusion of 3- 3 H-glucose and U- 13 C-glycerol was used to measure basal rates of appearance (R a ) of glucose and glycerol and gluconeogenesis from glycerol (GNG). During hyperinsulinemic-euglycemic clamp, glucose uptake into gastrocnemius muscles was measured with 2-deoxy-D- 14 C-glucose.  Results . In the diabetic rats, exenatide reduced the basal R a  of glucose ( P  < 0.01) and glycerol ( P  < 0.01) and GNG ( P  < 0.001). During the clamp, R a  of glucose was also reduced, whereas the rate of disappearance of glucose increased and there was increased glucose uptake into muscle ( P  < 0.01) during the clamp. In the nondiabetic rats, exenatide had no effect.  Conclusion . In addition to its known effects on insulin secretion, administration of the GLP-1 analogue, exenatide, is associated with increased inhibition of gluconeogenesis and improved glucose uptake into muscle in diabetic rats, implying improved hepatic and peripheral insulin sensitivity.

journal of diabetes research

The GLP-1 Analogue Exenatide Improves Hepatic and Muscle Insulin Sensitivity in Diabetic Rats: Tracer Studies in the Basal State and during Hyperinsulinemic-Euglycemic Clamp