Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca2+ Mobilization From Acidic Stores in Pancreatic α-Cells

Abstract

Adrenaline is a powerful stimulus of glucagon secretion. It acts by activation of β-adrenergic receptors, but the downstream mechanisms have only been partially elucidated. Here, we have examined the effects of adrenaline in mouse and human α-cells by a combination of electrophysiology, imaging of Ca and PKA activity, and hormone release measurements. We found that stimulation of glucagon secretion correlated with a PKA- and EPAC2-dependent (inhibited by PKI and ESI-05, respectively) elevation of [Ca] in α-cells, which occurred without stimulation of electrical activity and persisted in the absence of extracellular Ca but was sensitive to ryanodine, bafilomycin, and thapsigargin. Adrenaline also increased [Ca] in α-cells in human islets. Genetic or pharmacological inhibition of the Tpc2 channel (that mediates Ca release from acidic intracellular stores) abolished the stimulatory effect of adrenaline on glucagon secretion and reduced the elevation of [Ca] Furthermore, in Tpc2-deficient islets, ryanodine exerted no additive inhibitory effect. These data suggest that β-adrenergic stimulation of glucagon secretion is controlled by a hierarchy of [Ca] signaling in the α-cell that is initiated by cAMP-induced Tpc2-dependent Ca release from the acidic stores and further amplified by Ca-induced Ca release from the sarco/endoplasmic reticulum.

GLP-1 suppresses glucagon secretion in human pancreatic alpha-cells by inhibition of P/Q-type Ca2+ channels

“…Human α ‐cells can be identified by the occurrence of spontaneous [Ca 2+ ] i oscillations in 1 mmol/L glucose that are stimulated by adrenaline (Hamilton et al. ). Whereas GLP‐1 was without any major effect on [Ca 2+ ] i oscillation amplitude (Fig.…”

Epinephrine responsiveness is reduced in livers from trained mice

“…In addition to having direct effects on the liver, epinephrine also impacts the secretion of the pancreatic hormones such as glucagon (Hamilton et al, ) and insulin (Han & Bonen, ; Peterhoff et al, ). There were main effects of both exercise and epinephrine to increase circulating glucagon and reduce insulin.…”

“…Furthermore, wheel running-mediated adaptations in skeletal muscle and/ or adipose tissue could also play a role in the reduced glucose response to an epinephrine challenge. In addition to having direct effects on the liver, epinephrine also impacts the secretion of the pancreatic hormones such as glucagon (Hamilton et al, 2018) and insulin (Han & Bonen, 1998;Peterhoff et al, 2003). There were main effects of both exercise and epinephrine to increase circulating glucagon and reduce insulin.…”

“…In addition to having direct effects on the liver, epinephrine increases glucagon while reducing serum insulin (Hamilton et al, 2018;Sherwin & Sacca, 1984;Zhang, Wan, Liu, Hua, & Sun, 2018). As insulin suppresses, and glucagon increases, hepatic glycogenolysis and hepatic gluconeogenesis (Heyworth, Wallace, & Houslay, 1983;Petersen, Laurent, Rothman, Cline, & Shulman, 1998;Wasserman et al, 1989), we wanted to determine if the blunted epinephrine-mediated increase in blood glucose and liver glycogenolysis in exercised mice could be related to differences in these hormones.…”

“…In adipose tissue, increases in PKA activity stimulates lipolysis through the phosphorylation of perilipin proteins and multiple lipases such as hormone sensitive lipase (Anthonsen, Rönnstrand, Wernstedt, Degerman, & Holm, 1998;Strålfors et al, 1984). In the pancreas, epinephrine stimulates glucagon secretion from the α-cells of the pancreas, and inhibits insulin release from β-cells (Hamilton et al, 2018;Han & Bonen, 1998;Peterhoff et al, 2003). cAMP-PKA signaling is attenuated by cyclic nucleotide phosphodiesterases (PDE), which can be activated in response to various cellular signals including protein kinase B (AKT) and 5′AMP-activated protein kinase (AMPK) (Berger et al, 2009;Johanns et al, 2016).…”