Glucose controls glucagon secretion with minor changes in alpha cell [Ca2+]c whereas sulfonylureas control glucagon secretion by increasing alpha cell [Ca2+]c and via somatostatin

BACKGROUND AND AIMS: The mechanisms by which glucose (G) and KATP channels control glucagon release are poorly understood. A rise in [Ca2+]c is considered as a signal triggering glucagon secretion. However, the effects of glucose and KATP channels on α-cell [Ca2+]c are hotly debated. In the present study, we tested the effects of glucose and KATP channel blockers (sulfonylureas) on α-cell [Ca2+]c using mice expressing the Ca2+indicator, GCAMP6f, specifically in α-cells, and we studied the correlation between α-cell [Ca2+]c and glucagon secretion. We also investigated the paracrine influence of somatostatin (SST) using Sst-/- mice. [...

In vitro and fully mature in vivo function of human induced pluripotent stem cell-derived beta cells

Background and aims: Pancreatic β-cell failure is central in the pathogenesis of diabetes. In vitro differentiation of human induced pluripotent stem cells (iPSCs) into β-cells represents a novel cell source for diabetes research. Here we differentiated iPSC-β-cells and tested their function in vitro and in vivo in humanized mice [...

SGLT2 is not expressed in pancreatic alpha and beta cells and its inhibition does not directly affect glucagon and insulin secretion in rodents and humans

BACKGROUND AND AIMS: SGLT2 inhibitors (SGLT2i), such as dapagliflozin and empagliflozin, are effective glucose-lowering medications with a unique, insulin-independent mechanism that is to promote glycosuria. SGTL2i-induced glycosuria is associated with metabolic responses including increases in fatty acid mobilization, hepatic glucose and ketone body production, and circulating glucagon levels. These metabolic adaptations are considered causative for rare cases of euglycemic ketoacidosis reported for SGLT2i. One potential cause of euglycemic ketoacidosis is the SGLT2i-mediated increase in glucagonemia and drop in insulinemia. It has been suggested that direct inhibition of α-cell SGLT2 stimulates glucagon release. Here, we investigated the potential role of SGLT1 and SGLT2 in the control of glucagon and insulin secretion from rat, mouse and human islets [...