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The pancreatic islets comprising only 1%-2% of the volume are highly vascularized and innervated mini-organs. They contain five endocrine cell types, including β cells that secrete insulin, which is synthesized as a single polypeptide chain, preproinsulin, processed to proinsulin, and finally to insulin and C-peptide. This process is complex and regulated, involving the Golgi complex, the endoplasmic reticulum, and the secretory granules of the β cell.
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SERCA2 regulates proinsulin processing and processing enzyme maturation in pancreatic beta cells.

Hitoshi Iida1,2, Tatsuyoshi Kono3,4,5,6, Chih-Chun Lee3,4,5,6

  • 1Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.

Diabetologia
|August 3, 2023
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Summary

Loss of SERCA2 in beta cells impairs insulin processing by disrupting ER calcium levels and proinsulin trafficking. This leads to glucose intolerance and increased proinsulin, mimicking diabetes conditions.

Keywords:
Beta cell biologyCalcium imagingCalcium signallingEndoplasmic reticulumInsulin secretionInsulin synthesisProinsulin processingProtein trafficking

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Area of Science:

  • Endocrinology
  • Cell Biology
  • Metabolic Diseases

Background:

  • Elevated proinsulin levels are a clinical hallmark of type 1 and type 2 diabetes.
  • Calcium (Ca2+) signaling in beta cells is crucial for insulin processing and secretion.
  • Mechanisms linking impaired Ca2+ signaling to defective insulin maturation are not fully understood.

Purpose of the Study:

  • To investigate the role of sarcoendoplasmic reticulum Ca2+ ATPase-2 (SERCA2) in beta cell function and insulin processing.
  • To elucidate the link between ER Ca2+ homeostasis and proinsulin maturation.

Main Methods:

  • Generated beta cell-specific SERCA2 knockout mice (βS2KO) and used INS-1 cells with SERCA2 deficiency.
  • Performed metabolic phenotyping, Ca2+ imaging, RNA-seq, and protein processing assays.
  • Analyzed human donor islets treated with diabetogenic stressors.

Main Results:

  • βS2KO mice showed glucose intolerance and increased plasma/pancreatic proinsulin.
  • Reduced endoplasmic reticulum (ER) Ca2+ levels and impaired Ca2+ synchronicity were observed in βS2KO islets.
  • Defective proinsulin processing and mis-localization in the ER-Golgi intermediate compartment (ERGIC) and cis-Golgi were identified.

Conclusions:

  • ER Ca2+ homeostasis is critical for proper proinsulin processing and maturation in beta cells.
  • SERCA2 deficiency impairs beta cell function by disrupting ER Ca2+ levels and prohormone trafficking.
  • Findings suggest a novel mechanism contributing to diabetes pathophysiology.