Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits glucagon secretion via somatostatin (receptor subtype 2) in the perfused rat pancreas

Abstract

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.

Roles of the Gut in Glucose Homeostasis

“…An indirect pathway involving GLP1R-dependent stimulation of somatostatin secretion seems likely because somatostatin receptors generally are coupled to inhibition of their target cells. This concept is supported by studies on perfused pancreas that showed a loss of GLP-1-inhibited glucagon release in the presence of somatostatin receptor inhibitors (76).…”

The incretin system and its role in type 2 diabetes mellitus

“…The mechanism whereby GLP-1 inhibits glucagon secretion has been suggested to be indirect relative to its effects on the beta cell (insulin, zinc, glutamate) (58). However, GLP-1 also suppressed glucagon secretion in subjects with type 1 diabetes and no residual beta cell function (59), and recent studies in isolated perfused rat pancreas demonstrated inhibition of glucagon secretion by GLP-1 at glucose levels too low to cause measurable insulin secretion (60) 3) Effects on appetite and food intake. GLP-1 inhibits appetite and food intake in normal subjects(64) as well as in obese subjects with T2DM(65;66), and it is thought that GLP-1 is one of the gastrointestinal hormones that normally regulate food intake(42).…”

Therapy of acromegalic patients exacerbated by concomitant type 2 diabetes requires higher pegvisomant doses to normalise IGF1 levels

“…The latter seems to be under a tonic control by somatostatin. Incretins seem to act within the endocrine pancreas via SSTR2 (33). The early, glucose-induced release of insulin primarily depends on this entero-insular axis.…”

“…Depending on the dose, SSAs inhibit meal-dependent insulin secretion as well as GLP1 secretion. As a result, they also inhibit the protective effects of GLP1 and glucagon on adipogenesis and lipid metabolism (33). The therapeutic use of SSA such as octreotide and lanreotide, which mainly act via an inhibition of SSTR2 and 5, does not lead solely to an inhibition of somatotrophic pituitary cells, but they ubiquitously stimulate the receptors and convey complex metabolic effects which are currently only clarified in part.…”