Schematic showing the role of the CaMK4-CREB pathway in the regulation of β-cell mass.

<p>Glucose enters β-cells via GLUT-2 transporters, and its metabolism generates an increase in the intracellular ATP/ADP ratio (1), which leads to closure of ATP-dependent potassium (K⁺_ATP) channels, generating plasma membrane depolarisation (2). Calcium enters through voltage-dependent calcium channels and binds to calmodulin (CaM), and this complex activates CaMKKs/CaMKs signalling cascades (3). Upon its activation, CaMKK phosphorylates CaMK4, which translocates to the nucleus and phosphorylates the cAMP response element binding protein (CREB) on serine 133 (4). This phosphorylation is responsible for CREB activation which, in turn, binds to the cAMP response element (CRE) on the IRS-2 promoter to increase IRS-2 gene expression (5). IRS-2 maintains β-cell mass by stimulating proliferation and inhibiting apoptosis (6). In addition to this CaMK4/CREB-mediated pathway, calcium/calmodulin-induced activation of CaMK2 and CaMK4 stimulate insulin secretion and insulin gene expression (7) and this results in an autocrine/paracrine activation of the β-cell insulin signalling cascade (8), which ultimately increases β-cell proliferation and reduces apoptosis, at least in part, in an IRS-2-dependent manner (9).