Direct and indirect mechanisms of control of glucagon secretion
The endocrine pancreas plays a key role in glucose homeostasis. It is organized in islets of Langerhans containing three main cell types, β-, α- and δ-cells which secrete insulin, glucagon and somatostatin, respectively. The cross talk between these cells is only partially understood. The mechanisms of control of glucagon secretion are also largely unknown. In particular, it is unclear whether glucose inhibits glucagon release directly or indirectly through the other islet cell types. Evidences from our group and others suggest that somatostatin is strongly involved in the control of glucagon and insulin secretion.
KATP channels are present in α-, β- and δ-cells. Their role in the control of insulin secretion is well established. Their closure transduces an acceleration of β-cell metabolism brought about by glucose into a depolarization of the β-cell and an increase in [Ca2+]c that triggers insulin release. Their role is fully enigmatic in α-cells and partially understood in δ-cells. Using mice with KATP channel deletion specifically in α- or δ-cells, we showed that their closure stimulates exocytosis in both cell types but that the stimulation of somatostatin release attenuates the direct stimulatory effect on glucagon secretion. We also showed that glucose inhibits glucagon secretion independently of KATP channels.
Because glucagon secretion becomes unregulated in diabetes, it was suggested that this defect results from a loss of control by β-cells resulting from the destruction of β-cells (type 1 diabetes) or the installation of insulin-resistance (type 2 diabetes). We studied the role of β-cells in transgenic mice of conditional β-cell ablation. Our results show that β-cells are not required for the control of glucagon release suggesting that the impaired glucagon secretion in diabetes does not result from a β-cell defect.
Philippaert K, Pironet A, Mesuere M, Sones W, Vermeiren L, Kerselaers S, Pinto S, Segal A, Antoine N, Gysemans C, Laureys J, Lemaire K, Gilon P, Cuypers E, Tytgat J, Mathieu C, Schuit F, Rorsman P, Talavera K, Voets T, Vennekens R. Steviol glycosides enhance pancreatic beta-cell function and taste sensation by potentiation of TRPM5 channel activity. Nat Commun 8: 14733 (2017)
Tong X, Kono T, Anderson-Baucum EK, Yamamoto W, Gilon P, Lebeche D, Day RN, Schull GE, Evans-Molina C. SERCA2 deficiency impairs pancreatic β cell function in response to diet-induced obesity. Diabetes 65: 3039-52 (2016)
Gilon P, Chae HY, Rutter GA, Ravier MA. Calcium signaling in pancreatic β-cells in health and in Type 2 diabetes. Cell Calcium 56: 340-361 (2014)
Cheng-Xue R, Gómez-Ruiz A, Antoine N, Noël LA, Chae HY, Ravier MA, Chimienti F, Schuit FC, Gilon P. Tolbutamide controls glucagon release from mouse islets differently than glucose: involvement of KATP channels from both α- and δ-cells. Diabetes 62: 1612-1622 (2013)
Huang YC, Rupnik MS, Karimian N, Herrera PL, Gilon P, Feng ZP, Gaisano HY. In situ electrophysiological examination of pancreatic α-cells in the streptozotocin-induced diabetes model revealing the cellular basis of glucagon hypersecretion. Diabetes 62: 519-530 (2013)