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A High-content In Vitro Pancreatic Islet β-cell Replication Discovery Platform
Published on: July 16, 2016
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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
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.
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.
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