Calcineurin/NFAT signalling regulates pancreatic β-cell growth and function

Abstract

The growth and function of organs such as pancreatic islets adapt to meet physiological challenges and maintain metabolic balance, but the mechanisms controlling these facultative responses are unclear. Diabetes in patients treated with calcineurin inhibitors such as cyclosporin A indicates that calcineurin/nuclear factor of activated T-cells (NFAT) signalling might control adaptive islet responses, but the roles of this pathway in beta-cells in vivo are not understood. Here we show that mice with a beta-cell-specific deletion of the calcineurin phosphatase regulatory subunit, calcineurin b1 (Cnb1), develop age-dependent diabetes characterized by decreased beta-cell proliferation and mass, reduced pancreatic insulin content and hypoinsulinaemia. Moreover, beta-cells lacking Cnb1 have a reduced expression of established regulators of beta-cell proliferation. Conditional expression of active NFATc1 in Cnb1-deficient beta-cells rescues these defects and prevents diabetes. In normal adult beta-cells, conditional NFAT activation promotes the expression of cell-cycle regulators and increases beta-cell proliferation and mass, resulting in hyperinsulinaemia. Conditional NFAT activation also induces the expression of genes critical for beta-cell endocrine function, including all six genes mutated in hereditary forms of monogenic type 2 diabetes. Thus, calcineurin/NFAT signalling regulates multiple factors that control growth and hallmark beta-cell functions, revealing unique models for the pathogenesis and therapy of diabetes.

Inhibition of MafA transcriptional activity and human insulin gene transcription by interleukin-1β and mitogen-activated protein kinase kinase kinase in pancreatic islet beta cells

“…In vitro, reactive oxygen species were shown to inhibit the activity of the calcium/calmodulin-dependent serine/threonine phosphatase calcineurin [35], while recent data demonstrate the pivotal role of calcineurin for beta cell proliferation and human insulin gene transcription [8,9,36]. However, IL-1β did not change calcineurin phosphatase activity in HIT cells (data not shown).…”

Conditional Disruption of Calcineurin B1 in Osteoblasts Increases Bone Formation and Reduces Bone Resorption

“…It has been shown by others that several Cn isoforms are expressed in osteoblasts (14). However, it has been demonstrated that whereas there is redundancy and compensation in response to the inhibition of different CnA catalytic subunits (29), the deletion of the Cnb1 regulatory subunit is sufficient to eliminate all Cn activity in several biological systems (19,30,31). Our results are consistent with these reports and demonstrate that Cnb1 deletion in osteoblasts is not compensated by any of the other Cn isoforms that were reported to be expressed in osteoblasts (Cn A␣, A␤, A␥, and B2).…”

A low-risk ZnT-8 allele (W325) for post-transplantation diabetes mellitus is protective against cyclosporin A-induced impairment of insulin secretion

“…However, because of its well-known diabetogenic effect, its utility is sometimes limited. The suggested mechanisms for the development of CsA-induced diabetes are the following: decreased calcineurin/nuclear factor of activated T-cells-dependent insulin gene transcription, [15][16][17] impairment of priming of the insulin secretory granule, 17,18 decreased b-cell mass 19 and dysfunction of hepatocyte nuclear factor-4a. 20 Although the mechanism by which CsA mediates diabetes is still unclear, CsA ultimately interferes with insulin secretion in b-cells, 21,22 which might contribute to the development of PTDM.…”