Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes
Increased lipid supply causes beta cell death, which may contribute to reduced beta cell mass in type 2 diabetes. We investigated whether endoplasmic reticulum (ER) stress is necessary for lipid-induced apoptosis in beta cells and also whether ER stress is present in islets of an animal model of diabetes and of humans with type 2 diabetes.
Expression of genes involved in ER stress was evaluated in insulin-secreting MIN6 cells exposed to elevated lipids, in islets isolated from db/db mice and in pancreas sections of humans with type 2 diabetes. Overproduction of the ER chaperone heat shock 70 kDa protein 5 (HSPA5, previously known as immunoglobulin heavy chain binding protein [BIP]) was performed to assess whether attenuation of ER stress affected lipid-induced apoptosis.
We demonstrated that the pro-apoptotic fatty acid palmitate triggers a comprehensive ER stress response in MIN6 cells, which was virtually absent using non-apoptotic fatty acid oleate. Time-dependent increases in mRNA levels for activating transcription factor 4 (Atf4), DNA-damage inducible transcript 3 (Ddit3, previously known as C/EBP homologous protein [Chop]) and DnaJ homologue (HSP40) C3 (Dnajc3, previously known as p58) correlated with increased apoptosis in palmitate- but not in oleate-treated MIN6 cells. Attenuation of ER stress by overproduction of HSPA5 in MIN6 cells significantly protected against lipid-induced apoptosis. In islets of db/db mice, a variety of marker genes of ER stress were also upregulated. Increased processing (activation) of X-box binding protein 1 (Xbp1) mRNA was also observed, confirming the existence of ER stress. Finally, we observed increased islet protein production of HSPA5, DDIT3, DNAJC3 and BCL2-associated X protein in human pancreas sections of type 2 diabetes subjects.
Our results provide evidence that ER stress occurs in type 2 diabetes and is required for aspects of the underlying beta cell failure.
- Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes
Volume 50, Issue 4 , pp 752-763
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- Endoplasmic reticulum stress
- Fatty acids
- Pancreatic beta cells
- Type 2 diabetes
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- Author Affiliations
- 1. Diabetes and Obesity Research Program, Garvan Institute of Medical Research, St Vincent’s Hospital, Sydney, NSW, Australia
- 2. Cancer Research Program, Garvan Institute of Medical Research, St Vincent’s Hospital, Sydney, Australia
- 3. Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia