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

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 Ca(2+) (Ca(V)) channels in which the gamma-4...

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Detalles Bibliográficos
Autores principales: Wu, Rui, Karagiannopoulos, Alexandros, Eliasson, Lena, Renström, Erik, Luan, Cheng, Zhang, Enming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9030882/
https://www.ncbi.nlm.nih.gov/pubmed/35453520
http://dx.doi.org/10.3390/biomedicines10040770
Descripción
Sumario: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 Ca(2+) (Ca(V)) channels in which the gamma-4 subunit (Ca(V)γ4) is required for the beta-cell to maintain its differentiated state. We here aim to explore the involvement of Ca(V)γ4 in controlling glucose homeostasis by employing the Ca(V)γ4(−/−) mice to study in vivo glucose-metabolism-related phenotypes and glucose-stimulated insulin secretion, and to investigate the underlying mechanisms. We show that Ca(V)γ4(−/−) mice exhibit perturbed glucose homeostasis, including IFG and IGT. Glucose-stimulated insulin secretion is blunted in Ca(V)γ4(−/−) mouse islets. Remarkably, Ca(V)γ4 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 Ca(V)γ4(−/−) mice, as well as in INS-1 832/13 cells. Moreover, we prove that CaMKII is responsible for mediating this regulatory pathway linked between Ca(V)γ4 and MafA, which is further confirmed by human islet RNA-seq data. We demonstrate that Ca(V)γ4 is a key player in preserving normal blood glucose homeostasis, which sheds light on Ca(V)γ4 as a novel target for the treatment of prediabetes through correcting the impaired metabolic status.