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GRP94 is an IGF-1R chaperone and regulates beta cell death in diabetes

Do-Sung Kim1, Lili Song1, Wenyu Gou1

  • 1Department of Surgery, Medical University of South Carolina, Charleston, SC, 29425, USA.

Cell Death & Disease
|May 29, 2024
PubMed

Insights

Glucose-regulated protein 94 (GRP94) is crucial for pancreatic beta cell survival and function in diabetes. Its deficiency increases susceptibility to cell death, highlighting its role in preventing beta cell failure.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cellular Stress Response

Background:

  • High workload causes cellular stress, leading to pancreatic beta cell failure, a key feature of type 2 diabetes.
  • Molecular chaperones and stress-response genes are vital for preventing beta cell failure.

Purpose of the Study:

  • To investigate the role of glucose-regulated protein 94 (GRP94) in beta cell adaptation and failure in a mouse model of type 2 diabetes.
  • To identify novel GRP94 clients involved in beta cell survival and function.

Main Methods:

  • Utilized leptin receptor-deficient (db/db) mice to study age-dependent changes in GRP94 expression and function.
  • Assessed GRP94-deficient beta cell susceptibility to diabetogenic stress conditions.
  • Identified GRP94 clients using molecular biology techniques.

Main Results:

  • GRP94 plays a critical role in beta cell adaptation and compensation, or failure, in an age-dependent manner in db/db mice.
  • GRP94-deficient beta cells exhibit increased susceptibility to cell death under diabetogenic stress.
  • Insulin-like growth factor-1 receptor (IGF-1R) was identified as a novel client of GRP94, essential for beta cell survival.

Conclusions:

  • GRP94 is essential for maintaining beta cell function and survival, particularly under conditions of metabolic stress relevant to diabetes.
  • Targeting GRP94 or its client IGF-1R may offer therapeutic strategies for preventing or treating type 2 diabetes by preserving beta cell function.

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