Abstract
Resveratrol (RSV) is a potent anti-diabetic agent when used at high doses. However, the direct targets primarily responsible for the beneficial actions of RSV remain unclear. We used a formulation that increases oral bioavailability to assess the mechanisms involved in the glucoregulatory action of RSV in high-fat diet (HFD)-fed diabetic wild type mice. Administration of RSV for 5 weeks reduced the development of glucose intolerance, and increased portal vein concentrations of both Glucagon-like peptid-1 (GLP-1) and insulin, and intestinal content of active GLP-1. This was associated with increased levels of colonic proglucagon mRNA transcripts. RSV-mediated glucoregulation required a functional GLP-1 receptor (Glp1r) as neither glucose nor insulin levels were modulated in Glp1r-/- mice. Conversely, levels of active GLP-1 and control of glycemia were further improved when the Dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin was co-administered with RSV. In addition, RSV treatment modified gut microbiota and decreased the inflammatory status of mice. Our data suggest that RSV exerts its actions in part through modulation of the enteroendocrine axis in vivo.
Highlights
Type 2 diabetes (T2D), classically arises as a result of defects in insulin secretion and insulin action
Mice fed the high fat diet exhibited reduced levels of Glucagon-like peptid-1 (GLP-1) (Figure 2A), in contrast, RSV almost tripled the concentration of active GLP-1 in the portal vein (Figure 2A) and significantly increased the corresponding intestinal content of both proglucagon mRNA and active GLP-1 (3.4 and 1.8-fold, respectively, Figures 2B, C)
The glucoregulatory actions of RSV depend on a functional GLP-1 receptor and are further improved by a Dipeptidyl peptidase-4 (DPP-4) inhibitor
Summary
Type 2 diabetes (T2D), classically arises as a result of defects in insulin secretion and insulin action. Considerable evidence suggests that low-grade inflammation may exacerbate metabolic control by impairing insulin action and secretion [1]. New mechanisms of action of this well-known biguanide have been described that encompass enhanced secretion and action of Glucagon-like peptid-1 (GLP-1) [6,7] a gut hormone which increases insulin secretion [8,9,10]. This seems to make metformin an ideal oral antidiabetic agent for use alone, or in combination with other agents that exert their glucoregulatory effects through complementary mechanisms of action
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