Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent
1128 Diabetes Volume 67, June 2018 Adrenaline Stimulates Glucagon Secretion by Tpc2- Dependent Ca2+ Mobilization From Acidic Stores in Pancreatic a-Cells Alexander Hamilton,1 Quan Zhang,1 Albert Salehi,2 Mara Willems,1 Jakob G. Knudsen,1 Anna K. Ringgaard,3,4 Caroline E. Chapman,1 Alejandro Gonzalez-Alvarez,1 Nicoletta C. Surdo,5 Manuela Zaccolo,5 Davide Basco,6 Paul R.V. Johnson,1,7 Reshma Ramracheya,1 Guy A. Rutter,8 Antony Galione,9 Patrik Rorsman,1,2,7 and Andrei I. Tarasov1,7 Diabetes 2018;67:1128–1139 | https://doi.org/10.2337/db17-1102 Adrenaline is a powerful stimulus of glucagon secretion. It The ability of the “fight-or-flight” hormone adrenaline to acts by activation of b-adrenergic receptors, but the down- increase plasma glucose levels by stimulating liver gluconeo- stream mechanisms have only been partially elucidated. genesis is in part mediated by glucagon, the body’sprincipal Here, we have examined the effects of adrenaline in mouse hyperglycemic hormone (1). Glucagon is secreted by the and human a-cells by a combination of electrophysiology, a-cells of the pancreas (2). Reduced autonomic stimulation 2+ imaging of Ca and PKA activity, and hormone release of glucagon secretion may result in hypoglycemia, a serious measurements. We found that stimulation of glucagon and potentially fatal complication of diabetes (3). It has been secretion correlated with a PKA- and EPAC2-dependent estimated that up to 10% of insulin-treated patients die of (inhibited by PKI and ESI-05, respectively) elevation of hypoglycemia (4). Understanding the mechanism by which [Ca2+] in a-cells, which occurred without stimulation of i adrenaline stimulates glucagon secretion and how it becomes ISLET STUDIES electrical activity and persisted in the absence of extracel- perturbed in patients with diabetes is therefore essential.
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