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1 Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, USA; Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center, Baltimore, MD, USA
2 Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, USA
3 Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, USA; Division of Endocrinology, University of Cincinnati, Cincinnati, OH, USA
* To whom correspondence should be addressed. E-mail: david.d'alessio{at}uc.edu.
Glucagon-like peptide (GLP-1) is an intestinal hormone that stimulates insulin secretion and decreases glucagon release from the pancreatic islets. It has been hypothesized that GLP-1 also promotes glucose metabolism and reduces glycemia independent of its effect on islet hormones. Based on preliminary evidence that GLP-1 has islet independent actions on endogenous glucose production we undertook a series of experiments that were optimized to address this question. The effect of GLP-1 on endogenous glucose production (Ra) and glucose disposal (Rd) was measured in 8 human volunteers in the setting of fixed insulin and glucagon concentrations while glucose was maintained at the fasting level. This pancreatic clamp was performed using an octreotide infusion to suppress endogenous secretion of islet hormones, and insulin and glucagon were infused at rates adjusted to maintain blood glucose near fasting levels. Following stabilization of plasma glucose and equilibration of 3H-glucose tracer, GLP-1 (30 pmol/kg/h) was given IV for 60 min. In response to exogenous GLP-1 administration, circulating levels increased by ~ 4 fold. Concentrations of insulin, C-peptide, and glucagon were similar before and during the GLP-1 infusion (115 ± 14 v 113 ± 11 pM; 0.153 ± 0.029 v 0.156 ± 0.026 nM; and 64.7 ± 11.5 v 65.8 ± 13.8 ng/L, respectively). With the initiation of GLP-1 plasma glucose decreased in all 8 subjects from steady state levels of 4.8 ± 0.2 to an average of 4.4 ± 0.2 with a nadir value of 4.1 ± 0.2 mM, and was significantly decreased for each time point during the final 50 minutes of GLP-1 administration (p < 0.05). This decrease in plasma glucose was accounted for by a significant, 17 % decrease in Ra, from 22.6 ± 2.8 to 19.1 ± 2.8 umol/kg/min (p < 0.04), with a nadir of 16.6 ± 2.2, with no significant change in Rd (22.2 ± 2.7 and 21.8 ± 2.6 for pre and post GLP-1; p = 0.47). These findings indicate that under fasting conditions GLP-1 decreases endogenous glucose production independent of its actions on islet hormone secretion. This action may play a role in postprandial glucose regulation and is a potential mechanism by which GLP-1 receptor agonists could lower blood glucose in patients with diabetes.
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