The role of somatostatin in GLP-1-induced inhibition of glucagon secretion in mice

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.

Pancreatic islet of Langerhans' cytoarchitecture and ultrastructure in normal glucose tolerance and in type 2 diabetes mellitus

“…Considering the well‐known negative paracrine effect of somatostatin on α‐cell secretion, the reduction of δ‐cells, together with the relative or absolute increase in α‐cell volume, can also play a role in the islet disfunction of T2DM. Considering this paracrine connection, the reduction on δ‐cells together with a reduction in somatostatin secretion, may result in the lack of glucagon secretion inhibition by the α‐cells There are a number of alterations in the cytoarchitecture of the islets of Langerhans in T2DM, including a marked reduction of β‐cells (up to 70%), a reduction in δ‐cells (around 25%‐30%) and relative/(absolute?)…”

“…Considering this paracrine connection, the reduction on δ-cells together with a reduction in somatostatin secretion, may result in the lack of glucagon secretion inhibition by the α-cells. 26 " There are a number of alterations in the cytoarchitecture of the islets of Langerhans in T2DM, including a marked reduction of β-cells (up to 70%), a reduction in δ-cells (around 25%-30%) and relative/(absolute?) increase in α-cells.…”

Stathmin-2 Mediates Glucagon Secretion from Pancreatic α-Cells

“…It has been documented that suppression of glucagon secretion can be mediated at the systemic, paracrine or intrinsic level (8). As a systemic modulator, GLP-1 directly inhibits glucagon secretion from α cells by signaling through the alpha cell GLP-1R (9) (10) (11), or indirectly by increasing inter-islet somatostatin or insulin secretion (12) (9). Glucagon secretion is also suppressed by paracrine signaling through the insulin, somatostatin and GABA A receptors on the α cell (13) (14) (12).…”

“…As a systemic modulator, GLP-1 directly inhibits glucagon secretion from α cells by signaling through the alpha cell GLP-1R (9) (10) (11), or indirectly by increasing inter-islet somatostatin or insulin secretion (12) (9). Glucagon secretion is also suppressed by paracrine signaling through the insulin, somatostatin and GABA A receptors on the α cell (13) (14) (12). At an intrinsic level, glucose directly or indirectly inhibits glucagon secretion from the α cell (15) (16) (17) (18) by altering downstream activities of Ca 2+ channels, K ATP channels (19), and trafficking of secretory granules (20).…”

GLP-1(9-36) mediates the glucagonostatic effect of GLP-1 by promiscuous activation of the glucagon receptor

“…It was therefore postulated that GLP-1 exerts its inhibitory effect on glucagon secretion by a paracrine mechanism mediated by factor(s) secreted by the neighboring β-and δ-cells (e.g. insulin and somatostatin, respectively) within the pancreatic islets (8). Yet, GLP-1 (when tested at nonphysiological nanomolar levels) robustly inhibited glucagon secretion in isolated islets by mechanisms that cannot be accounted for by paracrine signals (5,6).…”