期刊
DIABETES
卷 64, 期 4, 页码 1444-1458出版社
AMER DIABETES ASSOC
DOI: 10.2337/db14-0632
关键词
-
资金
- NIH [R01-DK-093403, HL-105302, HL-102074, HL-118558]
- NIH from the Centers of Biomedical Research Excellence program of the National Institute of General Medical Sciences [9P20-GM-104934-06]
Protein expression of an antiaging gene, Klotho, was depleted in pancreatic islets in patients with type 2 diabetes mellitus (T2DM) and in db/db mice, an animal model of T2DM. The objective of this study was to investigate whether in vivo expression of Klotho would preserve pancreatic -cell function in db/db mice. We report for the first time that -cell-specific expression of Klotho attenuated the development of diabetes in db/db mice. -Cell-specific expression of Klotho decreased hyperglycemia and enhanced glucose tolerance. The beneficial effects of Klotho were associated with significant improvements in T2DM-induced decreases in number of -cells, insulin storage levels in pancreatic islets, and glucose-stimulated insulin secretion from pancreatic islets, which led to increased blood insulin levels in diabetic mice. In addition, -cell-specific expression of Klotho decreased intracellular superoxide levels, oxidative damage, apoptosis, and DNAJC3 (a marker for endoplasmic reticulum stress) in pancreatic islets. Furthermore, -cell-specific expression of Klotho increased expression levels of Pdx-1 (insulin transcription factor), PCNA (a marker of cell proliferation), and LC3 (a marker of autophagy) in pancreatic islets in db/db mice. These results reveal that -cell-specific expression of Klotho improves -cell function and attenuates the development of T2DM. Therefore, in vivo expression of Klotho may offer a novel strategy for protecting -cells in T2DM.
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