The Calcium Channel Subunit Gamma-4 as a Novel Regulator of MafA in Pancreatic Beta-Cell Controls Glucose Homeostasis

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Abstract
Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are high-risk factors of diabetes development and may be caused by defective insulin secretion in pancreatic beta-cells. Glucose-stimulated insulin secretion is mediated by voltage-gated Ca2+ (CaV) channels in which the gamma-4 subunit (CaVγ4) is required for the beta-cell to maintain its differentiated state. We here aim to explore the involvement of CaVγ4 in controlling glucose homeostasis by employing the CaVγ4−/− mice to study in vivo glucose-metabolism-related phenotypes and glucose-stimulated insulin secretion, and to investigate the underlying mechanisms. We show that CaVγ4−/− mice exhibit perturbed glucose homeostasis, including IFG and IGT. Glucose-stimulated insulin secretion is blunted in CaVγ4−/− mouse islets. Remarkably, CaVγ4 deletion results in reduced expression of the transcription factor essential for beta-cell maturation, MafA, on both mRNA and protein levels in islets from human donors and CaVγ4−/− mice, as well as in INS-1 832/13 cells. Moreover, we prove that CaMKII is responsible for mediating this regulatory pathway linked between CaVγ4 and MafA, which is further confirmed by human islet RNA-seq data. We demonstrate that CaVγ4 is a key player in preserving normal blood glucose homeostasis, which sheds light on CaVγ4 as a novel target for the treatment of prediabetes through correcting the impaired metabolic status.
Funding Information
  • Vetenskapsrådet (Dnr 2009-1039, Dnr 2019-01406, Dnr 2018-03258, Dnr 2019-01567)
  • Stiftelsen för Strategisk Forskning (Dnr IRC 15-0067)
  • Swedish Research Council, Linnaeus Grant (Dnr 349-2006-237)
  • Diabetes Wellness foundation (Dnr 1904-PG)
  • Crafoordska Stiftelsen (Dnr 20190514)

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