Atf6α-null mice are glucose intolerant due to pancreatic β-cell failure on a high-fat diet but partially resistant to diet-induced insulin resistance
| Autor: | Suguru Yamaguchi, Yoshitomo Oka, Hisamitsu Ishihara, Masahiro Usui, Ryu Tominaga, Manabu Fukumoto, Yasushi Ishigaki, Hideki Katagiri, Yasuhiro Tanji, Kazutoshi Mori |
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| Rok vydání: | 2011 |
| Předmět: |
Blood Glucose
medicine.medical_specialty Endocrinology Diabetes and Metabolism Hyperlipidemias Mice Inbred Strains Diet High-Fat Endoplasmic Reticulum Real-Time Polymerase Chain Reaction Mice Endocrinology Insulin resistance Internal medicine Diabetes mellitus Insulin-Secreting Cells Genetic model medicine Diabetes Mellitus Glucose homeostasis Animals Homeostasis Obesity RNA Messenger Triglycerides Mice Knockout biology Type 2 Diabetes Mellitus medicine.disease Activating Transcription Factor 6 Fatty Liver Mice Inbred C57BL biology.protein Unfolded protein response Glucose-6-Phosphatase Female Insulin Resistance Sterol Regulatory Element Binding Protein 1 Diet-induced obese Glucose 6-phosphatase |
| Zdroj: | Metabolism: clinical and experimental. 61(8) |
| ISSN: | 1532-8600 |
| Popis: | Activating transcription factor 6α (ATF6α) is essential for the endoplasmic reticulum (ER) stress response. Since recent studies suggested that ER stress is involved in the pathogenesis of type 2 diabetes mellitus, we have analyzed Atf6α-null (Atf6α(-/-)) mice challenged with metabolic overload or genetic manipulations. Atf6α(-/-) mice were fed a high-fat diet to create diet-induced obese (DO) mice, and were subjected to examination of glucose homeostasis with biochemical and morphological analysis of the pancreatic β-cell and liver tissues. Atf6α-null mice were also crossed with genetic models of diabetes caused either by insulin resistance (Agouti obese mice) or by impaired insulin secretion (Ins2(WT/C96Y) mice). Atf6α(-/-) DO mice were less glucose tolerant with blunted insulin secretion compared to littermates on a high-fat diet. Pancreatic insulin content was lower in Atf6α(-/-) DO mice with the swollen β-cell ER, a typical feature of cells with ER stress. In the liver of Atf6α(-/-) DO mice, XBP-1 splicing was increased, suggesting that higher ER stress was present. ATF6-deficient mice showed increased mRNA expressions of glucose-6-phosphatase and SREBP1c associated with a tendency for a higher degree of steatosis in the liver. However, Atf6α(-/-) DO mice exhibited higher insulin sensitivity with lower serum triglyceride levels. Similar phenotypes were observed in ATF6α-deficient Agouti mice. In addition, ATF6α-deficiency accelerated reduction in pancreatic insulin content in Ins2(WT/C96Y) mice. These data suggested that ATF6α contributes to both prevention and promotion of diabetes; it protects β-cells from ER stress and suppresses hepatosteatosis, but plays a role in the development of hyperlipidemia and insulin resistance. |
| Databáze: | OpenAIRE |
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