Aims/hypothesis The glucose-lowering effect of glucagonlike peptide-1 (GLP-1) is based not only upon its potent insulinotropic actions but also on its ability to restrain glucagon secretion. Surprisingly, the closely related glucose-dependent insulinotropic peptide (GIP) stimulates glucagon release. We examined whether the islet hormone somatostatin, which strongly inhibits glucagon secretion, is involved in this divergent behaviour. Methods At 1.5 mmol/l glucose and therefore minimal insulin secretion, the glucagon, insulin and somatostatin responses to 20 mmol/l glucose, GLP-1, GIP and somatostatin were studied in the presence of a high-affinity monoclonal somatostatin antibody and of a highly specific somatostatin receptor subtype 2 (SSTR2) antagonist (PRL-2903) in the isolated perfused rat pancreas. Results In control experiments, GLP-1 at 1 and 10 nmol/l reduced glucagon secretion significantly to 59.0±6.3% (p<0.004; n=5; SSTR2 series; each vs pre-infusion level) and to 48.0±2.6% (p<0.001; n=6; somatostatin antibody series) respectively. During somatostatin antibody administration, GLP-1 still inhibited glucagon secretion significantly, but the effect was less pronounced than in control experiments (p<0.018). Co-infusion of the SSTR2 antagonist completely abolished the GLP-1-induced suppression of glucagon secretion. In contrast, neither the GIP-induced stimulation of glucagon release nor its inhibition by 20 mmol/l glucose was altered by somatostatin antibody or SSTR2 antagonist administration. Conclusions/interpretationWe conclude that GLP-1 is capable of inhibiting glucagon secretion even in the absence of secretory products from the beta cell. It is highly likely that this is mediated via somatostatin interacting with SSTR2 on rat alpha cells. In contrast, GIP and glucose seem to influence the alpha cell independently of somatostatin secretion.

Glucagon secretion plays an essential role in the regulation of hepatic glucose production, and elevated fasting and postprandial plasma glucagon concentrations in patients with type 2 diabetes (T2DM) contribute to their hyperglycaemia. The reason for the hyperglucagonaemia is unclear, but recent studies have shown lack of suppression after oral but preserved suppression after isoglycaemic intravenous glucose, pointing to factors from the gut. Gastrointestinal hormones that are secreted in response to oral glucose include glucagon-like peptide-1 (GLP-1) that strongly inhibits glucagon secretion, and GLP-2 and GIP, both of which stimulate secretion. When the three hormones are given together on top of isoglycaemic intravenous glucose, glucagon suppression is delayed in a manner similar to that observed after oral glucose. Studies with the GLP-1 receptor antagonist, exendin 9-39, suggest that endogenous GLP-1 plays an important role in regulation of glucagon secretion during fasting as well as postprandially. The mechanisms whereby GLP-1 regulates glucagon secretion are debated, but studies in isolated perfused rat pancreas point to an important role for a paracrine regulation by somatostatin from neighbouring D cells. Clinical studies of the antidiabetic effect of GLP-1 in T2DM suggest that the inhibition of glucagon secretion is as important as the stimulation of insulin secretion.

Understanding the incretin pathway has led to significant advancements in the treatment of type 2 diabetes (T2D). Still, the exact mechanisms are not fully understood. In a randomized, placebocontrolled, four-period, crossover study in 24 patients with T2D, dipeptidyl peptidase-4 (DPP-4) inhibition and its glucose-lowering actions were tested after an oral glucose tolerance test (OGTT). The contribution of GLP-1 was examined by infusion of the GLP-1 receptor (GLP-1r) antagonist exendin-9. DPP-4 inhibition reduced glycemia and enhanced insulin levels and the incretin effect (IE). Glucagon was suppressed, and gastric emptying (GE) was decelerated. Exendin-9 increased glucose levels and glucagon secretion, attenuated insulinemia and the IE, and accelerated GE. With the GLP-1r antagonist, the glucose-lowering effects of DPP-4 inhibition were reduced by ∼50%. However, a significant effect on insulin secretion remained during GLP-1r blockade, whereas the inhibitory effects of DPP-4 inhibition on glucagon and GE were abolished. Thus, in this cohort of T2D patients with a substantial IE, GLP-1 contributed ∼50% to the insulin excursion after an OGTT with and without DPP-4 inhibition. Thus, a significant DPP-4-sensitive glucose-lowering mechanism contributes to glycemic control in T2D patients that may be not mediated by circulating GLP-1.

Glucagon-like peptide (GLP)-