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Chaperones ameliorate beta cell dysfunction associated with human islet amyloid polypeptide overexpression
Lisa Cadavez1, Joel Montane1, Gema Alcarraz-Vizán1
1Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain.
Plos One
|July 11, 2014
Summary
Molecular chaperones help alleviate endoplasmic reticulum stress caused by human islet amyloid polypeptide (hIAPP) in type 2 diabetes models. Enhancing chaperone function may improve beta-cell function and insulin secretion.
Area of Science:
- Endocrinology
- Cell Biology
- Molecular Medicine
Background:
- Beta-cell dysfunction in type 2 diabetes is linked to toxic islet amyloid aggregates formed by misfolded human islet amyloid polypeptide (hIAPP).
- hIAPP misfolding and aggregation can trigger the unfolded protein response (UPR), disrupting endoplasmic reticulum (ER) homeostasis.
- Molecular chaperones play a crucial role in managing ER stress responses.
Purpose of the Study:
- To investigate the role of molecular chaperones in a cellular model of hIAPP-induced ER stress.
- To determine if chaperones can ameliorate ER stress and improve insulin secretion in beta-cells overexpressing hIAPP.
Main Methods:
- Utilized a rat pancreatic beta-cell line engineered to overexpress hIAPP.
- Induced ER stress using thapsigargin, high glucose, and palmitic acid.
- Administered molecular chaperones (GRP78, PDI) and chemical chaperones (TUDCA, PBA) to assess their effects on ER stress markers and insulin secretion.
Main Results:
- hIAPP overexpression significantly increased ER stress markers compared to control cells.
- Treatment with GRP78, PDI, TUDCA, or PBA reduced ER stress in hIAPP-expressing cells.
- Chaperone treatment also enhanced insulin secretion in these stressed beta-cells.
Conclusions:
- Overexpression of hIAPP exacerbates ER stress in pancreatic beta-cells.
- Both endogenous and exogenous chaperones can mitigate hIAPP-induced ER stress and improve beta-cell function.
- Augmenting chaperone capacity presents a potential therapeutic strategy for type 2 diabetes.
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