SERCA2 regulates proinsulin processing and processing enzyme maturation in pancreatic beta cells – published online 04/08/2023

Hitoshi Iida, Tatsuyoshi Kono, Chih‑Chun Lee, Preethi Krishnan, Matthew C. Arvin, Staci A. Weaver, Timothy S. Jarvela, Renato C. S. Branco, Madeline R. McLaughlin, Robert N. Bone, Xin Tong, Peter Arvan, Iris Lindberg, Carmella Evans‑Molina

Impaired processing of proinsulin into mature insulin is a key pathological feature of both type 1 and type 2 diabetes. In this issue, Iida and Kono et al (https://doi.org/10.1007/s00125-023-05979-4) investigate the link between endoplasmic reticulum (ER) Ca²⁺ levels and proinsulin processing using a mouse model with beta cell-specific sarcoendoplasmic reticulum Ca²⁺ ATPase-2 (SERCA2) deletion (βS2KO mice). βS2KO mice exhibited age-dependent glucose intolerance and elevated plasma and pancreatic proinsulin levels, whilst, in βS2KO islets, ER Ca²⁺ levels were reduced and glucose-stimulated Ca²⁺ synchronicity was impaired. In addition, expression of connexin-36, which is involved in the coordination of Ca²⁺ oscillations and glucose-stimulated insulin secretion, was reduced in βS2KO islets. Mechanistic studies showed that SERCA2 loss was associated with reduced maturation and activity of proinsulin processing enzymes and resulted in aberrant accumulation of proinsulin in the proximal secretory pathway. Treatment of islets from human donors without diabetes with high glucose and palmitate concentrations partially phenocopied the observations in βS2KO islets. The authors conclude that their findings suggest that chronic ER Ca²⁺ depletion due to SERCA2 deficiency impairs the spatial regulation of prohormone trafficking and processing within the beta cell.

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