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

Autophagy. 2017;13(11):1952-1968. doi: 10.1080/15548627.2017.1368596. Epub 2017 Nov 25.


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.

Keywords: autophagy; beta cells; diabetes; intermittent fasting; lysosomes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Autophagy*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Beclin-1 / genetics
  • 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*
  • Lysosomal-Associated Membrane Protein 2 / genetics
  • Lysosomes / metabolism*
  • Mice
  • Mice, Mutant Strains
  • Mitochondria / pathology
  • Nerve Tissue Proteins / metabolism
  • Obesity / complications*
  • Oxidative Stress
  • Up-Regulation


  • Basic Helix-Loop-Helix Transcription Factors
  • Beclin-1
  • Becn1 protein, mouse
  • Insulin
  • Lysosomal-Associated Membrane Protein 2
  • Nerve Tissue Proteins
  • Neurog3 protein, mouse