The Role of β Cell Glucagon-like Peptide-1 Signaling in Glucose Regulation and Response to Diabetes Drugs

Abstract

SUMMARY Glucagon-like peptide-1 (GLP-1), an insulinotropic peptide released from the intestine after eating, is essential for normal glucose tolerance (GT). To determine whether this effect is mediated directly by GLP-1 receptors (GLP1R) on islet β-cells, we developed mice with β-cell specific knockdown of Glp1r. β-cell Glp1r knockdown mice had impaired GT after intraperitoneal (IP) glucose, and did not secrete insulin in response to IP or intravenous GLP-1. However, they had normal GT after oral glucose, a response that was impaired by a GLP1R antagonist. β-cell Glp1r knockdown mice had blunted responses to a GLP1R agonist, but intact glucose lowering with a DPP-4 inhibitor. Thus, in mice, β-cell Glp1r are required to respond to hyperglycemia and exogenous GLP-1, but other factors compensate for reduced GLP-1 action on the β-cell during meal ingestion. These results support a role for extra-islet GLP1R in oral glucose tolerance and paracrine regulation of β-cells by islet GLP-1.

Autonomic Diabetic Neuropathy Impairs Glucose and Dipeptidyl Peptidase 4 Inhibitor-Regulated Glucagon Concentration in Type 1 Diabetic Patients

“…Hence, a tight relationship is suggested between the autonomic parasympathetic nerve activity and the action of endogenous GLP-1 on glucagon concentration. Our conclusion is also supported by recent data from the literature showing that the deletion of the GLP-1 receptor specifically in the β cells did not impair oral glucose induced insulin secretion in mice [45] further supporting the importance of GLP-1 receptors expressed in other than beta cells. Therefore, as we previously suggested, endogenous GLP-1 may control pancreatic endocrine secretions mainly through neural mechanisms [10,[46][47][48], whereas GLP-1 receptor agonists reaching high circulating concentrations of active agonist would control glycemia through a direct effect on β cells [49].…”

Using miglitol at 30 min before meal is effective in hyperinsulinemic hypoglycemia after a total gastrectomy

“…Octreotide reportedly suppresses plasma GLP-1 and GIP levels and improves early dumping syndrome [9,19]. Recently, Smith et al reported that the incretin effect of GLP-1 is not mediated by the GLP-1 receptor of the pancreatic β cells under normoglycemic conditions [20]. We also reported improvement of glycemic control by a GLP-1 receptor agonist through insulin-independent mechanisms [21].…”

Targeting the gastrointestinal tract to treat type 2 diabetes

“…Complicating this model further, GLP-1 can also act centrally to regulate food intake (Tang-Christensen et al 1996), energy expenditure (Lockie et al 2012), GI function (Seeley et al 2000) and importantly, glucose homeostasis (Knauf et al 2005, Gustavson et al 2008. However, in contrast to these studies, others suggest that the glucoregulatory effects of GLP-1 are primarily mediated by pancreatic GLP-1R activation (Lamont et al 2012, Smith et al 2014. Nonetheless, GLP-1 plays an important role in the regulation of metabolism and glucose homeostasis, and as a result, some of the latest drugs to come onto the market have aimed to exploit the GLP-1R signalling pathway.…”

“…The effects of exenatide on food intake may be mediated by its central action, as exenatide-induced reductions in energy intake in humans have been associated with increased hypothalamic connectivity (Schlogl et al 2013), and intracerebroventricular injection of the GLP-1R antagonist, exendin-9, blocks the inhibitory effects of exenatide on energy intake in rodents (Kanoski et al 2011). However, the effects of exenatide on glucose regulation do not appear to be dependent on central GLP-1R activation (Lamont et al 2012), and evidence suggests that exenatide may exert its effects on glycaemia through direct action on the pancreas (Smith et al 2014). There has also been evidence that the anorexic effects of exenatide are mediated, at least in part, by the activation of GLP-1R expressed on peripheral vagal afferents.…”

“…However, whether liraglutide mediates its glucose-lowering effects through a manner similar to its anorectic effects requires attention. Some studies suggest that liraglutide-induced improvements in glucose tolerance do not require central or vagal GLP-1R (Sisley et al 2014) and that its effects on glycaemia are via direct action on the pancreas (Smith et al 2014). Thus, although the effects of liraglutide on glycaemia appear to be primarily dependent on the activation of pancreatic GLP-1R, central and vagal GLP-1R signalling should not be overlooked given their importance in lowering food intake and body weight, which is a primary treatment strategy for type 2 diabetes.…”