Human IAPP-induced pancreatic β cell toxicity and its regulation by autophagy

J Clin Invest. 2014 Aug;124(8):3634-44. doi: 10.1172/JCI69866. Epub 2014 Jul 18.


Pancreatic islets in patients with type 2 diabetes mellitus (T2DM) are characterized by loss of β cells and formation of amyloid deposits derived from islet amyloid polypeptide (IAPP). Here we demonstrated that treatment of INS-1 cells with human IAPP (hIAPP) enhances cell death, inhibits cytoproliferation, and increases autophagosome formation. Furthermore, inhibition of autophagy increased the vulnerability of β cells to the cytotoxic effects of hIAPP. Based on these in vitro findings, we examined the pathogenic role of hIAPP and its relation to autophagy in hIAPP-knockin mice. In animals fed a standard diet, hIAPP had no toxic effects on β cell function; however, hIAPP-knockin mice did not exhibit a high-fat-diet-induced compensatory increase in β cell mass, which was due to limited β cell proliferation and enhanced β cell apoptosis. Importantly, expression of hIAPP in mice with a β cell-specific autophagy defect resulted in substantial deterioration of glucose tolerance and dispersed cytoplasmic expression of p62-associated toxic oligomers, which were otherwise sequestrated within p62-positive inclusions. Together, our results indicate that increased insulin resistance in combination with reduced autophagy may enhance the toxic potential of hIAPP and enhance β cell dysfunction and progression of T2DM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / physiology*
  • Autophagy-Related Protein 7
  • Cell Cycle
  • Cell Line
  • Cell Survival
  • Diabetes Mellitus, Type 2 / etiology
  • Diabetes Mellitus, Type 2 / pathology
  • Diabetes Mellitus, Type 2 / physiopathology
  • Humans
  • Insulin Resistance / physiology
  • Insulin-Secreting Cells / pathology*
  • Insulin-Secreting Cells / physiology*
  • Islet Amyloid Polypeptide / genetics
  • Islet Amyloid Polypeptide / physiology*
  • Islet Amyloid Polypeptide / toxicity
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Microtubule-Associated Proteins / deficiency
  • Microtubule-Associated Proteins / genetics
  • Recombinant Proteins / genetics
  • Recombinant Proteins / toxicity


  • Atg7 protein, mouse
  • Islet Amyloid Polypeptide
  • Microtubule-Associated Proteins
  • Recombinant Proteins
  • Autophagy-Related Protein 7