| Autor: |
Liu H; a Center for Cardiovascular Research and Division of Cardiology , Washington University School of Medicine , St. Louis , MO , USA.; b John Cochran VA Medical Center , St. Louis , MO , USA., Javaheri A; a Center for Cardiovascular Research and Division of Cardiology , Washington University School of Medicine , St. Louis , MO , USA., Godar RJ; a Center for Cardiovascular Research and Division of Cardiology , Washington University School of Medicine , St. Louis , MO , USA., Murphy J; a Center for Cardiovascular Research and Division of Cardiology , Washington University School of Medicine , St. Louis , MO , USA., Ma X; a Center for Cardiovascular Research and Division of Cardiology , Washington University School of Medicine , St. Louis , MO , USA.; b John Cochran VA Medical Center , St. Louis , MO , USA., Rohatgi N; c Department of Pathology and Immunology , Washington University School of Medicine , St. Louis , MO , USA., Mahadevan J; d Division of Endocrinology , Department of Internal Medicine , Washington University School of Medicine , St. Louis , MO , USA., Hyrc K; e Department of Neurology , Washington University School of Medicine , St. Louis , MO , USA., Saftig P; f Institut für Biochemie, Christian-Albrechts-Universität zu Kiel , Kiel , Germany., Marshall C; c Department of Pathology and Immunology , Washington University School of Medicine , St. Louis , MO , USA., McDaniel ML; c Department of Pathology and Immunology , Washington University School of Medicine , St. Louis , MO , USA., Remedi MS; d Division of Endocrinology , Department of Internal Medicine , Washington University School of Medicine , St. Louis , MO , USA., Razani B; a Center for Cardiovascular Research and Division of Cardiology , Washington University School of Medicine , St. Louis , MO , USA., Urano F; d Division of Endocrinology , Department of Internal Medicine , Washington University School of Medicine , St. Louis , MO , USA., Diwan A; a Center for Cardiovascular Research and Division of Cardiology , Washington University School of Medicine , St. Louis , MO , USA.; b John Cochran VA Medical Center , St. Louis , MO , USA.; g Department of Cell Biology and Physiology , Washington University School of Medicine , St. Louis , MO , USA. |
| Abstrakt: |
Obesity-induced diabetes is characterized by hyperglycemia, insulin resistance, and progressive beta cell failure. In islets of mice with obesity-induced diabetes, we observe increased beta cell death and impaired autophagic flux. We hypothesized that intermittent fasting, a clinically sustainable therapeutic strategy, stimulates autophagic flux to ameliorate obesity-induced diabetes. Our data show that despite continued high-fat intake, intermittent fasting restores autophagic flux in islets and improves glucose tolerance by enhancing glucose-stimulated insulin secretion, beta cell survival, and nuclear expression of NEUROG3, a marker of pancreatic regeneration. In contrast, intermittent fasting does not rescue beta-cell death or induce NEUROG3 expression in obese mice with lysosomal dysfunction secondary to deficiency of the lysosomal membrane protein, LAMP2 or haplo-insufficiency of BECN1/Beclin 1, a protein critical for autophagosome formation. Moreover, intermittent fasting is sufficient to provoke beta cell death in nonobese lamp2 null mice, attesting to a critical role for lysosome function in beta cell homeostasis under fasting conditions. Beta cells in intermittently-fasted LAMP2- or BECN1-deficient mice exhibit markers of autophagic failure with accumulation of damaged mitochondria and upregulation of oxidative stress. Thus, intermittent fasting preserves organelle quality via the autophagy-lysosome pathway to enhance beta cell survival and stimulates markers of regeneration in obesity-induced diabetes. |
