Clemmensen, Christoffer3; Smajilovic, Sanela6; Smith, Eric P3; Woods, Stephen C4; Bräuner-Osborne, Hans7; Seeley, Randy J3; D'Alessio, David A.3; Ryan, Karen K3
1 Medicinal Chemistry Research, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet2 Department of Drug Design and Pharmacology, Faculty of Pharmaceutical Sciences, Københavns Universitet3 Division of Endocrinology Diabetes and Metabolism, Department of Internal Medicine, University of Cincinnati College of Medicine4 Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine5 Experimental Pharmacology, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet6 Department of Drug Design and Pharmacology, Faculty of Pharmaceutical Sciences, Københavns Universitet7 Experimental Pharmacology, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet
Pharmacological and surgical interventions that increase glucagon-like peptide 1 (GLP-1) action are effective to improve glucose homeostasis in type 2 diabetes mellitus. In light of this, nutritional strategies to enhance postprandial GLP-1 secretion, particularly in the context of diet-induced obesity, may provide an alternative therapeutic approach. Importantly, recent evidence suggests the amino acid l-arginine, a well-known insulin secretagogue, can also stimulate release of GLP-1 from isolated rat intestine. Here we tested the hypothesis that oral l-arginine acts as a GLP-1 secretagogue in vivo, to augment postprandial insulin secretion and improve glucose tolerance. To test this, we administered l-arginine or vehicle by oral gavage, immediately prior to an oral glucose tolerance test in lean and diet-induced obese mice. In both lean and obese mice oral l-arginine increased plasma GLP-1 and insulin and substantially improved glucose clearance. To directly assess the contribution of GLP-1 receptor (GLP-1R)-signaling to these improvements, l-arginine was given to Glp1r knockout mice and their wild-type littermates. In this experiment oral l-arginine significantly augmented insulin secretion and improved glucose clearance in WT mice, but not in Glp1r knockout littermates. Taken together these findings identify l-arginine as a GLP-1 secretagogue in vivo and demonstrate that improvement of glucose tolerance by oral l-arginine depends on GLP-1R-signaling. These findings raise the intriguing possibility that l-arginine-based nutritional and/or pharmaceutical therapies may benefit glucose tolerance by improving the postprandial GLP-1 response in obese individuals.
Endocrinology, 2013, Vol 154, Issue 11, p. 3978-83