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Alexandros Karagiannopoulos

Doctoral student

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

Author

  • Rui Wu
  • Alexandros Karagiannopoulos
  • Lena Eliasson
  • Erik Renström
  • Cheng Luan
  • Enming Zhang

Summary, in English

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.

Department/s

  • EXODIAB: Excellence of Diabetes Research in Sweden
  • NanoLund: Center for Nanoscience
  • Diabetes - Islet Patophysiology
  • Diabetes - Islet Cell Exocytosis

Publishing year

2022

Language

English

Publication/Series

Biomedicines

Volume

10

Issue

4

Document type

Journal article

Publisher

MDPI AG

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Diabetes - Islet Patophysiology
  • Diabetes - Islet Cell Exocytosis

ISBN/ISSN/Other

  • ISSN: 2227-9059