Pancreatic islet paracrine crosstalk in systemic glucose homeostasis: implications for diabetes

Abstract

Diabetes mellitus is an endocrine disease with a substantial physiological impact and high prevalence worldwide. Although the aetiology of diabetes is complex, it is now clear that the pancreatic islets play a key role. They are small aggregates of endocrine cells interspersed within the exocrine parenchyma. They play a crucial role in systemic metabolism by secreting several hormones (including insulin from β-cells and glucagon from α-cells) that directly regulate lipid and glucose homeostasis. Understanding intra- and inter-islet crosstalk is essential to understanding the ramifications of endocrine dysfunctions, including diabetes. The incretin hormone GLP-1 (and similar synthetic agonists) are widely used in diabetes therapy. Uniquely, it both stimulates insulin secretion and inhibits glucagon secretion. Paper I compares the effects of GLP-1(7-36) and its metabolite GLP-1(9-36) on pancreatic islet hormone secretion. GLP-1(7-36) stimulates insulin and somatostatin release and inhibits glucagon secretion (in part by a paracrine effect). By contrast, GLP-1(9-36) is without effect on insulin and somatostatin secretion but retains a glucagonostatic effect that is mediated by a direct impact on the α-cells and involves distinct receptors and signalling pathways. Its effect culminates in the activation of an inhibitory GTP-binding protein and the suppression of glucagon secretion by depleting the docked pool of secretory granules in the α-cells. These effects are abolished in α-cells in islets from donors with type-2 diabetes, which may explain why hyperglycaemia in type-2 diabetes is exacerbated by hyperglucagonaemia. In Paper II, the focus is on type-1 diabetes, which involves the autoimmune destruction of the insulin-secreting β-cells and (in addition to the loss of insulin secretion) is associated with dysregulation of α-cell glucagon secretion. In many type-1 diabetes patients, glucagon secretion during hypoglycaemia is impaired. We demonstrate that this results from physiologically inappropriate stimulation of somatostatin-secreting δ-cells at low glucose levels. This is a consequence from the loss of an ‘electric brake’ normally exerted by the β-cells on the δ-cells via electrical coupling that is lost following the destruction of the β-cells. Paper III uses islet optogenetics to explore how δ-cells interact with β-cells, and we describe the possible existence of an electrically “privileged” neighbourhood of cells closer to δ-cells. Via electrical signals, activation of δ-cells leads to a paradoxical stimulation of insulin secretion and an (islet-wide) electrical activity in β-cells. In Paper IV, we identified a subset of α-cells (at least 50%) that are not electrically active at low glucose levels (and thus do not secrete glucagon). We show that this results from increased activity of a ‘mosaic’ of metabolically and hormonally regulated potassium channels that lower electrical excitability. We propose that the fraction of electrically silent α-cells increases as diabetes progresses. Collectively, the findings of these four papers raise awareness of the importance of δ-cells and the exciting possibility of therapeutically targeting non-β-cells to achieve better homeostatic control.