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Progressive reduction in β-cell mass is responsible for the development of type 2 diabetes mellitus, and alteration in insulin receptor substrate 2 (IRS-2) abundance plays a critical role in this process. IRS-2 expression is stimulated by the transcription factor cAMP response element-binding protein (CREB) and we recently demonstrated that Ca 2+ /calmodulin dependent kinase 4 (CaMK4) is upstream of CREB activation in β-cells. This study investigated whether CaMK4 is also a potential target to increase β-cell mass through CREB-mediated IRS-2 expression, by quantifying mouse MIN6 β-cell proliferation and apoptosis following IRS-2 knockdown, CaMKs inhibition and alterations in CaMK4 and CREB expression. Expression of constitutively active CaMK4 (ΔCaMK4) and CREB (CREB DIEDLM ) significantly stimulated β-cell proliferation and survival. In contrast, expression of their corresponding dominant negative forms (Δ K75E CaMK4 and CREB M1 ) and silencing of IRS-2 increased apoptosis and reduced β-cell division. Moreover, CREB DIEDLM  and CREB M1  expression completely abolished the effects of Δ K75E CaMK4 and of ΔCaMK4, respectively. Our results indicate that CaMK4 regulates β-cell proliferation and apoptosis in a CREB-dependent manner and that CaMK4-induced IRS-2 expression is important in these processes.

The CaMK4/CREB/IRS-2 Cascade Stimulates Proliferation and Inhibits Apoptosis of β-Cells