Intermittent fasting preserves beta-cell mass in obesity-induced diabetes via the autophagy-lysosome pathway

• Published in: Autophagy 2017-11, Vol.13 (11), p.1952-1968
• Main Authors: Liu, Haiyan, Javaheri, Ali, Godar, Rebecca J., Murphy, John, Ma, Xiucui, Rohatgi, Nidhi, Mahadevan, Jana, Hyrc, Krzysztof, Saftig, Paul, Marshall, Connie, McDaniel, Michael L., Remedi, Maria S., Razani, Babak, Urano, Fumihiko, Diwan, Abhinav
• Format: Article
• Language: English
• Subjects: Animals; Autophagy; Basic Helix-Loop-Helix Transcription Factors - metabolism; Beclin-1 - genetics; beta cells; diabetes; Diabetes Mellitus, Experimental - etiology; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Type 2 - etiology; Diabetes Mellitus, Type 2 - pathology; Fasting; Insulin - metabolism; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; intermittent fasting; Lysosomal-Associated Membrane Protein 2 - genetics; lysosomes; Lysosomes - metabolism; Mice; Mice, Mutant Strains; Mitochondria - pathology; Nerve Tissue Proteins - metabolism; Obesity - complications; Oxidative Stress; Research Paper - Basic Science; Up-Regulation
• ISSN: 1554-8627; 1554-8635
• DOI: 10.1080/15548627.2017.1368596

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.