PDIA1/P4HB is required for efficient proinsulin maturation and ß cell health in response to diet induced obesity
| Autor: | Jing Yong, Peter Arvan, Ming Liu, Juthakorn Poothong, Insook Jang, Adriana Charbono, Jacqueline Lagunas-Acosta, Randal J. Kaufman, Zhouji Chen, Pamela Itkin-Ansari, Anita Pottekat, Donalyn L Scheuner |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Mouse
medicine.medical_treatment PDIA1 Endoplasmic Reticulum beta cell function medicine.disease_cause 0302 clinical medicine Insulin-Secreting Cells Insulin Glucose homeostasis Disulfides Biology (General) Protein disulfide-isomerase Proinsulin Mice Knockout 0303 health sciences geography.geographical_feature_category Chemistry disulfide bond formation General Neuroscience P4HB General Medicine Islet Medicine type 2 diabetes Research Article endocrine system medicine.medical_specialty QH301-705.5 Science Procollagen-Proline Dioxygenase Protein Disulfide-Isomerases Mice Transgenic Oxidative phosphorylation Diet High-Fat General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Internal medicine Glucose Intolerance medicine Animals glucose homeostasis Obesity 030304 developmental biology geography General Immunology and Microbiology Cell Biology Oxidative Stress Endocrinology Diabetes Mellitus Type 2 proinsulin maturation Mitochondrial Swelling 030217 neurology & neurosurgery Oxidative stress |
| Zdroj: | eLife, Vol 8 (2019) eLife |
| ISSN: | 2050-084X |
| DOI: | 10.7554/elife.44528 |
| Popis: | Regulated proinsulin biosynthesis, disulfide bond formation and ER redox homeostasis are essential to prevent Type two diabetes. In ß cells, protein disulfide isomerase A1 (PDIA1/P4HB), the most abundant ER oxidoreductase of over 17 members, can interact with proinsulin to influence disulfide maturation. Here we find Pdia1 is required for optimal insulin production under metabolic stress in vivo. ß cell-specific Pdia1 deletion in young high-fat diet fed mice or aged mice exacerbated glucose intolerance with inadequate insulinemia and increased the proinsulin/insulin ratio in both serum and islets compared to wildtype mice. Ultrastructural abnormalities in Pdia1-null ß cells include diminished insulin granule content, ER vesiculation and distention, mitochondrial swelling and nuclear condensation. Furthermore, Pdia1 deletion increased accumulation of disulfide-linked high molecular weight proinsulin complexes and islet vulnerability to oxidative stress. These findings demonstrate that PDIA1 contributes to oxidative maturation of proinsulin in the ER to support insulin production and ß cell health. |
| Databáze: | OpenAIRE |
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