In pancreatic β cells, various hormones, neurotransmitters, nucleotides, and fatty acids including GLP-1 [55–57], glucose-dependent insulinotropic polypeptide (GIP) [55,57], vasoactive intestinal polypeptide (VIP) , pituitary adenylate cyclase-activating polypeptide (PACAP) , adrenaline, ATP/ADP, lysophosphatidylcholine (LPC) , and oleoylethanolamide (OEA)  activate their specific receptors (Table 7.1). These receptors when coupled with Gs-protein activate adenylate cyclase and increase cAMP production. These cAMP-increasing ligands potentiate both the 1st phase and 2nd phase of GIIS .
cAMP is mediated by protein kinase A (PKA)-independent as well as by PKA-dependent mechanisms, the former involving the cAMP-binding protein Epac2 (now called Epac2A) [47,62,63]. The effect of Epac2A on GIIS is mediated not only by its guanine nucleotide exchange (GEF) activity toward small G-protein Rap  but also by interactions with several other proteins, including the KATP channel regulatory subunit SUR1 [47,65,66], small G-protein Rab3 effector Rim2α [41,47,63], and Piccolo . Epac2A/Rap1 signaling mediates the potentiation of the 1st phase of GIIS by cAMP . It has been proposed that activation of Epac2A/Rap1 signaling increases the size of RRP and/or recruitment of insulin granules from RRP, while PKA signaling increases the size of RP and/or recruitment of insulin granules from RP (Figure 7.3(b)) . Epac2A is also thought to be involved in mobilization of Ca2+ from intracellular Ca2+ stores in pancreatic β cells . The effect of Epac2A is mediated by ryanodine receptors . In addition, Epac2A is a direct target of antidiabetic drug sulfonylureas and is required for the effect of sulfonylureas on stimulation of insulin secretion [70–72].
PKA phosphorylation of Kir6.2, VDCC α-subunits, and GLUT2 influences their activities [73–75]. PKA phosphorylation of snapin, which interacts with SNAP25 , increases the interaction among insulin granule-associated proteins, thereby potentiating GIIS . The subcellular localization of PKA via A-kinase anchoring proteins (AKAPs) is also critical for the stimulatory effect of cAMP-elevating agents on insulin secretion .
The incretin hormones GLP-1 and GIP are released from enteroendocrine L cells and K cells, respectively, in response to ingestion of nutrients [55,57]. Both hormones potentiate insulin secretion in a glucose concentration-dependent manner [79,80]. The potentiating effects of GLP-1 and GIP occur at glucose concentrations higher than 5mM in vivo in humans . Long-term treatment with GLP-1 promotes β-cell proliferation and protects from apoptosis, thereby maintaining β-cell mass in rodent pancreatic β cells and β-cell lines . GLP-1 also has an anti-apoptotic effect on primary cultured human pancreatic islets . However, the proliferative capacity of human pancreatic β cells and its modulation by GLP-1 is still unclear.
GIP also stimulates β-cell proliferation and has an inhibitory effect on β-cell apoptosis in rodents . It has been suggested that defects in potentiation of insulin secretion by exogenous GIP is associated with reduced expression of the GIP receptor in pancreatic β cells [83–85]. Incretin-related drugs such as dipeptidyl peptidase-4 inhibitors, which block degradation of GLP-1 and GIP, and GLP-1 receptor agonists have been developed for treatment of patients with type 2 diabetes .
Glucagon receptors are expressed on pancreatic β cells and glucagon stimulates insulin secretion [86,87]. The binding of glucagon to its receptor activates the Gs and Gq-proteins . GIIS is enhanced in pancreatic islets that are rich in glucagon compared to that from islets containing fewer pancreatic α cells , which indicates that glucagon is important for the insulin secretory response to glucose. However, the contribution of glucagon receptors to β-cell function remains to be established.
GPR119, which is a receptor for fatty acid, is expressed in β cells and in pancreatic polypeptide (PP) cells [89,90]. Activation of GPR119 by lysophosphatidylcholine (LPC)  and oleoylethanolamide (OEA)  increases cAMP production and stimulates insulin secretion in a glucose-dependent manner [60,89,90].
Gq-protein stimulates phospholipase Cβ to produce IP3 and DAG . IP3 triggers the release of Ca2+ from the endoplasmic reticulum, whereas DAG activates protein kinase C (PKC). Activation of PKC by phorbol ester, a mimic for DAG, stimulates insulin secretion in the presence of raised intracellular Ca2+. It has been proposed that PKCϵ stimulates insulin secretion through the amplification of glucose metabolism . Pancreatic β cells express several Gq/11-protein-coupled receptors  including the M3 muscarinic acetylcholine (ACh) receptor (M3R) and receptors for fatty acids (GPR40), cholecystokinin (CCKA), arginine vasopressin (V1b), and extracellular nucleotides (P2Y1 and P2Y6).The M3 muscarinic receptor is involved in the regulation of insulin secretion by the vagal nerve system. ACh has a stimulatory effect on insulin secretion in pancreatic β cells through vagal nerves, an effect that mediates the cephalic phase response to food ingestion induced by the activity of efferent vagal nerves and not by the absorbed nutrients . In mouse, parasympathetic and sympathetic fibers innervate islets cells including β, α, and δ cells, while in human, islets endocrine cells are shown to be barely innervated .Thus, hormone secretion in human pancreatic islets may be modulated by the autonomic nervous system via sympathetic input controlling blood flow within the islets.
GPR40 is activated by fatty acids, including docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid, and potentiates GIIS [94,95]. GPR40 has been suggested to mediate the major effect of fatty acids on insulin secretion from pancreatic β cells [94,95]. GPR40 agonists also stimulate GLP-1 and GIP secretion from enteroendocrine cells, thereby amplifying GIIS from mouse pancreatic islets . A GPR40 agonist has recently been developed as a potential glucose-lowering medication by stimulating insulin secretion .
Somatostatin, noradrenaline, and ghrelin inhibit insulin secretion through the activation of PTX-sensitive Gi/o-protein [92,98,99], which suppresses adenylate cyclase activity. Somatostatin, which is released from pancreatic δ cells in pancreatic islets, exerts its inhibitory effect in pancreatic β cells upon binding to its specific GPCRs. There are five somatostatin receptor subtypes (SSTR1-5) [100–102]. Activation of SSTRs induces membrane repolarization and results in the reduction of action potential and Ca2+ influx [103,104]. SSTR2 is expressed predominantly in human pancreatic β cells . α2-adrenoceptors activated by noradrenaline inhibit cAMP production and open K+ channels. Repolarization by K+ efflux induces the closure of VDCC and the consequent inhibition of insulin secretion [92,105].
Ghrelin has an inhibitory effect on insulin secretion in rodents and humans [99,106,107]. Circulating ghrelin is produced in X/A-like cells in rat (known as P/D1 cells in human), which is distributed predominantly in the oxyntic mucosa of stomach [108,109]. Ghrelin is also expressed in pancreatic islets in humans and released into pancreatic microcirculations. Ghrelin in β cells activates growth hormone (GH) secretagogue receptor (GHS-R) that is coupled with PTX-sensitive G-protein Gi2, decreases cAMP production, and attenuates membrane excitability via activation of voltage-dependent K+ channels (Kv2.1 subtype), consequently suppressing Ca2 + influx and insulin secretion [106,107]. It remains to be clarified how ghrelin is released from the pancreas.