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Figure 1: Intracellular effects of soluble mediators are mainly mediated through the interaction with specific receptors that link extracellular signals up to modulation of gene expression. GLP-1 signaling pathway is activated after the binding to its receptor, GLP-1R, and subsequent transactivation of the EGFR. GLP-1’s effects on beta-cell are mainly mediated by the cAMP signaling pathway. GLP-1 potentiates glucose-induced insulin secretion, improves the function of pancreatic beta-cells by promoting neogenesis and proliferation and by decreasing apoptosis signals, increases antioxidant defense, promotes insulin gene transcription, mRNA stability, and biosynthesis, and increases the expression of Pdx-1 and the binding of Pdx-1 to the insulin promoter. Exendin 4, a GLP-1R agonist, potentiates expression of gene products subjected to the UPR in response to ER stress, stimulates GK expression, and prevents depletion of SERCA expression. Metformin enhances the expression of GLP-1R, via a peroxisome proliferator-activated receptor- (PPAR-) α-dependent mechanism, and improves the responsiveness to incretins. The thiazolidinediones (TDZs) act by activating the nuclear receptors PPARγ. TDZs preserve pancreatic beta-cell mass and improve their function, prevent NF-κB activation, improve insulin secretory capacity in patients with diabetes, protect human islets against apoptosis, and maintain the homeostasis of intracellular Ca2+ preventing the loss of SERCA. Extracellular signaling is mediated by cytosolic molecules which can be enzymes, ions, and so on. The PI3K/Akt signaling is a converging pathway in the regulation of beta-cell mass by growth factors, insulin, incretins, and glucose. The health of the beta-cell is also related to the maintenance of its homeostasis during its intensive function. The UPR restores ER homeostasis by decreasing ER protein load and increasing ER folding capacity. Intracellular Ca2+ concentration is important for GSIS, and also for ER function. The enzyme GK, which is considered a “glucose sensor” in pancreatic beta-cells, regulates pancreatic beta cell mass as well as their function. The temporally fluctuating activation of stress signaling is required for the maintenance of beta-cell survival, whereas its persistent activation results in beta-cell dysfunction and apoptosis. Indeed, ROS generation is not only a harmful process but, rather, plays a substantial role in the normal insulin signal transduction and is one of the metabolic signals stimulating insulin secretion. The ROS levels need to be finely regulated to keep good radicals from going bad thus avoiding oxidative damages. The ratio of the oxidized form of glutathione (GSSG) and the reduced form (GSH) is a dynamic indicator of the oxidative stress. The cellular adaptive response to oxidative stress is finely regulated by Nrf2, which upregulates transcription of antioxidant and phase II detoxification enzymes. Regulation of gene transcription is regulated at different biological levels. Recently, miRNAs target genes emerged important for pancreas development, beta-cell proliferation, insulin secretion, and exocytosis. Interestingly, as expression of the transcription factors implicated in the regulation of insulin transcription, such as MafA, Pdx-1, and FoxO1, are controlled by the relationship between themselves for instance, FoxO1 and PDX-1 bind directly to the MafA promoter and mediate MafA transcription, and transcription of the gene coding for PDX-1 is negatively regulated by the binding of FoxO1 to the PDX-1 promoter.