Abstract
Aims/hypothesisGlucagon-like peptide-1 (GLP-1) receptor agonists are currently used for the treatment of type 2 diabetes. Their main mechanism of action is enhancement of glucose-induced insulin secretion (from increased beta cell glucose sensitivity) and inhibition of glucagon secretion. The latter has been demonstrated to account for about half of their blood glucose-lowering activity. Whereas the effect of GLP-1 on insulin secretion is clearly dependent on ambient glucose concentrations and has been described in detail, the mechanism responsible for the inhibitory effect of GLP-1 on glucagon secretion is heavily debated. Glucagon inhibition is also said to be glucose-dependent, although it is unclear what is meant by this. We hypothesise here that GLP-1 does not inhibit glucagon secretion during hypoglycaemia because the inhibition depends on somatostatin secretion, which in turn is dependent on glucose levels.MethodsWe used the perfused mouse pancreas model to investigate this hypothesis.ResultsWe found that, in this model, GLP-1 was able to significantly inhibit glucagon secretion from pancreatic alpha cells at all glucose levels tested: 6.0, 1.5 and 0.5 mmol/l (−27.0%, −37.1%, and −23.6%, respectively), and the decrease in glucagon secretion was invariably accompanied by an increase in somatostatin secretion (+286.8%, +158.7%, and +118.8%, respectively). Specific blockade of somatostatin receptor 2 increased glucagon secretion (+118.8% at 1.5 mmol/l glucose and +162.9% at 6.0 mmol/l glucose) and completely eliminated the inhibitory effect of GLP-1.Conclusions/interpretationWe have shown here that the glucagon-lowering effect of GLP-1 is entirely mediated through the paracrine actions of somatostatin in the perfused mouse pancreas. However, in this model, the inhibitory effect of GLP-1 was preserved at hypoglycaemic levels, leaving unanswered the question of how this is avoided in vivo in individuals treated with GLP-1 receptor agonists.
Highlights
Type 2 diabetes is a rapidly increasing health issue worldwide
The change in glucose concentration from 1.5 to 6.0 mmol/l did not have a major influence on basal somatostatin secretion, which was very low in these experiments, presumably because of the glucose deprivation in the first part of the experiment
We show here that glucagon-like peptide-1 (GLP-1)-induced suppression of glucagon secretion in the mouse pancreas is eliminated in the presence of an somatostatin receptor 2 (SSTR2) antagonist
Summary
Glucagon-like peptide-1 (GLP-1) analogues and inhibitors of the GLP-1-degrading enzyme dipeptidyl peptidase-4 (DPP-4) have been implemented as treatments for type 2 diabetes [1, 2]. These drugs stimulate insulin secretion but have the advantage that they carry a low risk of causing hypoglycaemia [1, 3], which is a common side effect of insulin treatment. The mechanism of action of GLP-1 analogues is to increase the glucose sensitivity of beta cells, thereby enhancing glucose-induced insulin secretion, but they inhibit glucagon secretion from the alpha cells [4]. The glucose dependency of both the insulin stimulation and the glucagon inhibition is important clinically, as it means that hypoglycaemia does not normally occur during therapy with GLP-1 analogues
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