Antiaging Gene Klotho Attenuates Pancreatic β-Cell Apoptosis in Type 1 Diabetes

Diabetes. 2015 Dec;64(12):4298-311. doi: 10.2337/db15-0066. Epub 2015 Sep 4.

Abstract

Apoptosis is the major cause of death of insulin-producing β-cells in type 1 diabetes mellitus (T1DM). Klotho is a recently discovered antiaging gene. We found that the Klotho gene is expressed in pancreatic β-cells. Interestingly, halplodeficiency of Klotho (KL(+/-)) exacerbated streptozotocin (STZ)-induced diabetes (a model of T1DM), including hyperglycemia, glucose intolerance, diminished islet insulin storage, and increased apoptotic β-cells. Conversely, in vivo β-cell-specific expression of mouse Klotho gene (mKL) attenuated β-cell apoptosis and prevented STZ-induced diabetes. mKL promoted cell adhesion to collagen IV, increased FAK and Akt phosphorylation, and inhibited caspase 3 cleavage in cultured MIN6 β-cells. mKL abolished STZ- and TNFα-induced inhibition of FAK and Akt phosphorylation, caspase 3 cleavage, and β-cell apoptosis. These promoting effects of Klotho can be abolished by blocking integrin β1. Therefore, these cell-based studies indicated that Klotho protected β-cells by inhibiting β-cell apoptosis through activation of the integrin β1-FAK/Akt pathway, leading to inhibition of caspase 3 cleavage. In an autoimmune T1DM model (NOD), we showed that in vivo β-cell-specific expression of mKL improved glucose tolerance, attenuated β-cell apoptosis, enhanced insulin storage in β-cells, and increased plasma insulin levels. The beneficial effect of Klotho gene delivery is likely due to attenuation of T-cell infiltration in pancreatic islets in NOD mice. Overall, our results demonstrate for the first time that Klotho protected β-cells in T1DM via attenuating apoptosis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis*
  • Autoimmunity
  • Cell Adhesion
  • Cell Line, Tumor
  • Crosses, Genetic
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / metabolism*
  • Diabetes Mellitus, Type 1 / pathology
  • Diabetes Mellitus, Type 1 / prevention & control
  • Female
  • Genetic Therapy
  • Insulin / blood
  • Insulin / metabolism
  • Insulin Resistance
  • Insulin Secretion
  • Insulin-Secreting Cells / immunology
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice, 129 Strain
  • Mice, Inbred ICR
  • Mice, Inbred NOD
  • Mice, Mutant Strains
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Processing, Post-Translational
  • Recombinant Proteins / metabolism

Substances

  • Insulin
  • Klb protein, mouse
  • Membrane Proteins
  • Recombinant Proteins