The Role of cAMP in Beta Cell Stimulus–Secretion and Intercellular Coupling

Abstract

Pancreatic beta cells secrete insulin in response to stimulation with glucose and other nutrients, and impaired insulin secretion plays a central role in development of diabetes mellitus. Pharmacological management of diabetes includes various antidiabetic drugs, including incretins. The incretin hormones, glucagon-like peptide-1 and gastric inhibitory polypeptide, potentiate glucose-stimulated insulin secretion by binding to G protein-coupled receptors, resulting in stimulation of adenylate cyclase and production of the secondary messenger cAMP, which exerts its intracellular effects through activation of protein kinase A or the guanine nucleotide exchange protein 2A. The molecular mechanisms behind these two downstream signaling arms are still not fully elucidated and involve many steps in the stimulus–secretion coupling cascade, ranging from the proximal regulation of ion channel activity to the central Ca2+ signal and the most distal exocytosis. In addition to modifying intracellular coupling, the effect of cAMP on insulin secretion could also be at least partly explained by the impact on intercellular coupling. In this review, we systematically describe the possible roles of cAMP at these intra- and inter-cellular signaling nodes, keeping in mind the relevance for the whole organism and translation to humans.

From Isles of Königsberg to Islets of Langerhans: Examining the Function of the Endocrine Pancreas Through Network Science

“…This seems to be supported by the observation that oscillations in [Ca 2+ ] IC and cAMP are typically in phase or occur with a slight shift. Pharmacological activation of GLP-1 receptors and/or direct activation of adenylate cyclase by forskolin are unable to stimulate beta cells in low glucose but can significantly enhance glucose-stimulated Ca 2+ oscillations ( 180 – 182 ). Indeed, by constructing functional connectivity networks we have recently shown that increasing cAMP levels using forskolin increases beta cell activity as well as enhances synchronicity and coordination of intercellular signaling, evident as denser and more integral networks ( 180 , 183 ).…”

“…Pharmacological activation of GLP-1 receptors and/or direct activation of adenylate cyclase by forskolin are unable to stimulate beta cells in low glucose but can significantly enhance glucose-stimulated Ca 2+ oscillations ( 180 – 182 ). Indeed, by constructing functional connectivity networks we have recently shown that increasing cAMP levels using forskolin increases beta cell activity as well as enhances synchronicity and coordination of intercellular signaling, evident as denser and more integral networks ( 180 , 183 ). While both slow and fast Ca 2+ oscillations rely on periodic entry of Ca 2+ from extracellular space into the beta cells through voltage-activated Ca 2+ channels, the fast Ca 2+ oscillations may also depend on mobilization of intracellular Ca 2+ stores from the endoplasmic reticulum.…”

Skeletal Muscle Uncoupling Proteins in Mice Models of Obesity

“…Glucose influx into pancreatic beta-cells followed by an increase in glucose metabolism elevates cytosolic adenosine triphosphate (ATP) concentration, closing ATP-dependent K+ (KATP) channels and decreasing K+ efflux. Consequent cell membrane depolarization opens voltage-dependent Ca2+ (VDCC) channels and Ca2+ ions influx, which triggers insulin secretion [ 134 , 135 , 136 ]. The predominant UCP in beta-cells is UCP2, which regulates cellular oxidative stress, ROS production, and energy metabolism, and protects mice from aging [ 137 , 138 ].…”

Physiological Role of Bile Acids Modified by the Gut Microbiome

“…The binding of GLP-1 to GLP-1 receptor activates adenylate cyclase, leading to increased cAMP levels. PKA and EPAC are then activated, which induces an increase in intracellular Ca 2+ from the ER and extracellular sources via voltage-dependent Ca 2+ channels [128,129]. Additionally, the activation of PKA by GLP-1 leads to the activation of pancreatic duodenal homeobox-1 protein (PDX-1), which binds to the promoter of the gene encoding insulin and induces the synthesis of insulin [128,130] (Figure 3).…”