Intra-Islet Paracrine Regulation of Glucagon Secretion During Hypoglycemia, Euglycemia, and Hyperglycemia

The regulation of glucagon and insulin secretion, from pancreatic α- and β-cells, respectively, is essential for maintaining blood glucose within the physiological set point. Insulin secretion is stimulated as glucose rises from euglycemia, with incretin hormones modulating the secretion in a glucose-dependent manner. Glucagon secretion is elevated with hypoglycemia but also with hyperglycemia. Within the pancreatic islet, α-cell glucagon output is regulated by complex neuroendocrine and paracrine signals from insulin-releasing β-cells and somatostatin-secreting δ-cells. This network of intra-islet crosstalk tunes glucagon secretion in response to changes in glucose levels. In diabetes, intra-islet paracrine crosstalk between $\alpha$ -, β-, and δ-cells is disrupted. Autoimmune destruction of β-cells or impaired α-cell responsiveness to residual β-cell signals leads to hyperglucagonemia. Conversely, the loss of controlled insulin secretion, along with elevated somatostatin levels, attenuates glucagon responses to hypoglycemia or to prolonged exercise. Antihypoglycemia therapies such as selective somatostatin receptor 2 antagonists have emerged as a novel strategy in managing iatrogenic insulin-induced hypoglycemia. This review summarizes the latest experimental findings on the regulation of glucagon secretion by pancreatic β- and δ-cells, examines how this paracrine regulation of $\alpha$ -cell secretion is affected in diabetes, and highlights potential interventions aimed at restoring physiological glucagon dynamics.