Receptors and Signaling Pathways Controlling Beta-Cell Function and Survival as Targets for Anti-Diabetic Therapeutic Strategies

Abstract

Preserving the function and survival of pancreatic beta-cells, in order to achieve long-term glycemic control and prevent complications, is an essential feature for an innovative drug to have clinical value in the treatment of diabetes. Innovative research is developing therapeutic strategies to prevent pathogenic mechanisms and protect beta-cells from the deleterious effects of inflammation and/or chronic hyperglycemia over time. A better understanding of receptors and signaling pathways, and of how they interact with each other in beta-cells, remains crucial and is a prerequisite for any strategy to develop therapeutic tools aimed at modulating beta-cell function and/or mass. Here, we present a comprehensive review of our knowledge on membrane and intracellular receptors and signaling pathways as targets of interest to protect beta-cells from dysfunction and apoptotic death, which opens or could open the way to the development of innovative therapies for diabetes.

Keywords: apoptosis; diabetes; insulin secretion; pancreatic beta-cell; receptors; signaling pathways; therapeutic strategies.

Figure 1

Insulin secretion induced by glucose in the beta-cell. Insulin secretion follows variations in plasma glucose concentrations. Glucose enters the beta-cells through glucose transporters (GLUT1/2). The stimulatory effect of glucose on insulin secretion depends on its metabolism in beta-cells, through glycolysis in the cytosol and KREBS cycle in the mitochondria, and is mediated by triggering and amplifying pathways. The increase in cytosolic ATP concentration ([ATP]) causes the closure of membrane K⁺/ATP channels, leading to membrane depolarization, and the opening of voltage-dependent calcium channels (VDCCs). The entry of calcium triggers the insulin secretion through a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNAREs)-mediated fusion of a readily releasable pool of insulin-containing vesicles within the plasma membrane. This triggering pathway is responsible for the first phase of insulin secretion (or the early peak of insulin, 5–10 min). The second phase, also known as the amplifying pathway, is late, more sustained (30–60 min), relies on K⁺/ATP channel-independent mechanisms, and involves several metabolites including glucose metabolism products (NAD(P)H), and associated products (Glutamate and Malonyl-CoA).

Figure 2

GPCRs regulating beta-cell function. GPCRs stimulate or inhibit insulin secretion in beta-cells. GPCRs coupled to Gαs lead to cAMP production through adenylate cyclase, the subsequent activation of PKA and Epac signaling pathways, and the potentiation of insulin secretion. GPCRs coupled to Gαq lead to inositol triphosphate (IP₃) and diacylglycerol (DAG) production through phospholipase C, the activation of PKC and calcium (Ca²⁺) release from the endoplasmic reticulum (ER), and the potentiation of insulin secretion. GPCRs coupled to Gαi inhibit insulin secretion by preventing cAMP production.

Figure 3

Insulin and IGF-1 receptors regulating beta-cells. Adaptor proteins of the insulin receptor (IR) and insulin like growth factor-1 receptor (IGF-1R) are the insulin receptor substrates 1/2 (IRS-1/2), src homology domain containing proteins (Shc), growth factor receptor-bound protein 2 (Grb2), and son of sevenless (SoS). Following activation by their ligands, IR and IGF-1R interact with these adaptor proteins. Once bound to and phosphorylated by the receptor, the adaptor proteins engage downstream and distinct signaling pathways. Following IR-IRS associations, IRS adaptor proteins interact with the p85 regulatory subunit of PI3 kinase, activating the catalytic subunit p110, which in turn promotes the production of phosphatidylinositol-3,4,5-trisphosphate (PiP₃). PiP₃ recruits the phosphoinositide-dependent protein kinase-1 (PDK1), and activates protein kinase B (PKB/Akt). Following IR-Shc/Grb2 association, the ERK1/2 pathway is also induced. Diamonds and star symbols mark the positions of the important tyrosine residues in the transmembrane β subunits, and which are phosphorylated following receptor activation by their ligand.

Figure 4

Cytokine receptors regulating beta-cell function and survival. Pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) induce the apoptosis and dysfunction of beta-cells through the activation of membrane receptors, intracellular protein kinases (i.e. serine/threonine kinase mammalian sterile 20-like kinase 1 (MST1), serine/threonine kinase transforming growth factor-β activated kinase-1 (TAK1, or MAP3kinase 7), tumor progression locus 2 kinase (TPL2, or MAP3kinase 8), cellular abelson tyrosine kinase (c-Abl), mitogen-activated protein kinases (MAPKs) such as c-Jun N-terminal kinases (JNK)), and nuclear factor-kappa B (NFκB) transcription factor. IFNγ and type I IFN induce the apoptosis and dysfunction of beta-cells through the activation of the membrane receptors, mammalian janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2), respectively, and signal transducer and activator of transcription (STAT). These signaling pathways lead to mitochondrial alterations and the release of death signals, endoplasmic reticulum (ER) stress, and the regulation of gene transcription.