cAMP signalling in insulin and glucagon secretion

Abstract

The "second messenger" archetype cAMP is one of the most important cellular signalling molecules with central functions including the regulation of insulin and glucagon secretion from the pancreatic β-and α-cells, respectively. cAMP is generally considered as an amplifier of insulin secretion triggered by Ca 2+ elevation in the β-cells. Both messengers are also positive modulators of glucagon release from α-cells, but in this case cAMP may be the important regulator and Ca 2+ have a more permissive role. The actions of cAMP are mediated by protein kinase A (PKA) and the guanine nucleotide exchange factor Epac. The present review focuses on how cAMP is regulated by nutrients, hormones and neural factors in β-and α-cells via adenylyl cyclase-catalysed generation and phosphodiesterase-mediated degradation. We will also discuss how PKA and Epac affect ion fluxes and the secretory machinery to transduce the stimulatory effects on insulin and glucagon secretion. Finally, we will briefly describe disturbances of the cAMP system associated with diabetes and how cAMP signalling can be targeted to normalize hypo-and hypersecretion of insulin and glucagon, respectively, in diabetic patients. " cAMP is essential not only for neurohormonal amplification of insulin release but also for glucose-stimulated secretion. "As cAMP is generated in response to glucose (see below), the messenger has come into fashion again and must be considered not only when discussing neurohormonal amplification of insulin release but also when analysing glucose-stimulated secretion. There is even a

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

“…Binding of GLP‐1 to GLP‐1R activates adenylyl cyclase, catalyzing the conversion of ATP into cyclic adenosine monophosphate (cAMP; Doyle and Egan ()). In mouse α ‐cells, cAMP has multiple effects that contribute to glucagon secretion (Tengholm and Gylfe ) and GLP‐1 has been reported to increase cytoplasmic cAMP in a subset of α ‐cells (Tian et al. ).…”

“…It has been proposed that the stimulation of glucagon secretion at low glucose is — at least in mouse islets — mediated by cAMP/PKA (Elliott et al. ; Tengholm and Gylfe ). It is therefore of interest that although Rp‐cAMPS abolished the inhibitory effect of GLP‐1, glucagon secretion at 1 mmol/L glucose was unaffected by application of the PKA inhibitor alone (Fig.…”

Insulin/IGF1 signalling mediates the effects of β2‐adrenergic agonist on muscle proteostasis and growth

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Exendin‐4 overcomes cytokine‐induced decreases in gap junction coupling via protein kinase A and Epac2 in mouse and human islets

“…To determine the mechanism of cAMP regulation of Cx36 coupling, we investigated the roles of cAMP‐activated PKA and Epac2, which mediate cAMP‐induced augmentation of glucose stimulated insulin secretion (Tengholm & Gylfe, ). Our results indicate that under the stress of cytokine treatment, PKA plays a role in mediating cAMP regulation of Cx36 in both mouse and human islets.…”