Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes

• Published in: Diabetologia Vol. 50; no. 4; pp. 752 - 763
• Main Authors: Laybutt, D. R, Preston, A. M, Åkerfeldt, M. C, Kench, J. G, Busch, A. K, Biankin, A. V, Biden, T. J
• Format: Journal Article
• Language: English
• Published: Berlin Berlin/Heidelberg : Springer-Verlag 01.04.2007; Springer; Springer Nature B.V
• Subjects: Animals; Apoptosis; Biological and medical sciences; Blotting, Western; Cell death; Cell Line; chemistry; Diabetes; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Endoplasmic Reticulum; Endoplasmic Reticulum - metabolism; Endoplasmic reticulum stress; Enzymes; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty acids; Gene Expression Regulation; Genes; genetics; Glucose; Heat-Shock Proteins; Heat-Shock Proteins - genetics; Heat-Shock Proteins - physiology; Humans; Immunoglobulins; Insulin resistance; Insulin-Secreting Cells; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Islets; islets of Langerhans; Kinases; Lipids; Lipids - chemistry; Medical research; Medical sciences; metabolism; Mice; Mice, Inbred C57BL; Molecular Chaperones; Molecular Chaperones - genetics; Molecular Chaperones - physiology; noninsulin-dependent diabetes mellitus; Oxidative Stress; pathology; Phosphorylation; physiology; Proteins; RNA, Messenger; RNA, Messenger - metabolism; Transcription factors; Australia; Endocrinopathy; Type 2 diabetes; Pancreatic beta cells; Langerhans islet; Lipids; Metabolic diseases; Fatty acids; Stress; Apoptosis,Endoplasmic reticulum stress, Fatty acids,Islets; Cell death; β Cell; Endoplasmic reticulum; Endocrine pancreas; Apoptosis
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-006-0590-z

Aims/hypothesis 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. Methods 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. Results 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. Conclusions/interpretation Our results provide evidence that ER stress occurs in type 2 diabetes and is required for aspects of the underlying beta cell failure.