Antiaging gene klotho attenuates pancreatic β-cell apoptosis in type 1 diabetes

Yi Lin, Zhongjie Sun

Research output: Contribution to journalArticle

31 Citations (Scopus)

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 TNFa-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 b1. Therefore, these cell-based studies indicated that Klotho protected β-cells by inhibiting β-cell apoptosis through activation of the integrin b1-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.

Original languageEnglish (US)
Pages (from-to)4298-4311
Number of pages14
JournalDiabetes
Volume64
Issue number12
DOIs
StatePublished - Dec 1 2015

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Type 1 Diabetes Mellitus
Apoptosis
Genes
Caspase 3
Insulin
Experimental Diabetes Mellitus
Integrins
Phosphorylation
Inbred NOD Mouse
Glucose Intolerance
Streptozocin
Plasma Cells
Islets of Langerhans
Cell Adhesion
Hyperglycemia
Cause of Death
Cultured Cells
Collagen
T-Lymphocytes
Glucose

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Antiaging gene klotho attenuates pancreatic β-cell apoptosis in type 1 diabetes. / Lin, Yi; Sun, Zhongjie.

In: Diabetes, Vol. 64, No. 12, 01.12.2015, p. 4298-4311.

Research output: Contribution to journalArticle

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