ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2011) 26 S9.3

GLP-1 biology: beyond the pancreas

Darleen Sandoval

Division of Endocrinology, University of Cincinnati, Cincinnati, USA.

Glucagon-like peptide 1 (GLP-1) is a gut hormone that broadly promotes glucose homeostasis through the regulation of islet hormone secretion. Interestingly, GLP-1 has been reported to be both cause and cure of type 2 diabetes mellitus (T2DM). Decreased GLP-1 is thought to cause the progression from impaired glucose tolerance to frank T2DM. Conversely, the GLP-1 system has been successfully targeted as a treatment option for T2DM patients and increases in GLP-1 have been implicated in the rapid resolution of T2DM after bariatric surgery. We have confirmed that animal models of two bariatric surgeries, roux en Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), drastically increase meal-induced GLP-1 and also increase insulin levels, and improve hepatic insulin sensitivity. The benefits of VSG and RYGB on glucose homeostasis may be mediated in part through increased circulating GLP-1. However, there are few, if any, hepatic GLP-1 receptors, which argues for alternative sites of action, at least for regulation of hepatic glucose production. GLP-1 is also synthesized in the brain, where it is thought to primarily regulate food intake. Our work suggests that the CNS GLP-1 system also provides important input to regulate glucose homeostasis. Importantly, we have found that central administration of a GLP-1r antagonist caused relative hyperglycemia during a glucose tolerance test suggesting that activation of CNS GLP-1r contributes to normal post-prandial glucose homeostasis. We have also found direct infusion of GLP-1 into the arcuate, but not the paraventricular nucleus of the hypothalamus reduced hepatic glucose production. Thus, both CNS and peripheral GLP-1 regulate normal glucose homeostasis. We hypothesize that after a meal the coordinated effects of the CNS GLP-1 system are to inhibit glucose production as well as to increase satiation. These CNS effects of GLP-1 may explain the benefits of VSG and RYGB on hepatic insulin sensitivity.

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