No abstract

The regeneration of β-cell mass and preservation of its endocrine function under lipotoxicity are long-sought goals in diabetes research. Membrane protein caveolin-1 (Cav-1) is related to β-cell apoptosis and insulin secretion, however, the underlying mechanisms still remains unclear. Our objective is to explore whether Cav-1 depletion protects pancreatic β cells from lipotoxicity and investigate the related mechanisms. Here, we found that Cav-1 silencing significantly promoted β-cell proliferation, inhibited palmitate (PA)-induced apoptosis and enhanced insulin production and secretion. These effects were associated with enhanced phosphorylation of Akt and ERK1/2 protein, which then downregulated the expression of cell cycle inhibitors (FOXO1, GSK3β, P21, P27 and P53) and upregulated Cyclin D2 and Cyclin D3 expression. Subsequent inhibition of PI3K/Akt and ERK/MAPK pathways abolished Cav-1 depletion induced β-cell mass protection. Furthermore,under PA enhanced endoplasmic reticulum (ER) stress, Cav-1 silencing significantly reduced eIF2α phosphorylation and expression of ER stress-responsive markers BiP and CHOP, which mediated the sensitization to lipotoxicity. Our findings suggest the potential application of the Cav-1 molecule as a target for effective T2DM treatment through preservation of lipotoxicity-induced β-cell dysfunction and mass reduction. Disclosure W. Zeng: None. K. Liu: None. J. Tang: None. H. Li: None. H. Xu: None. H. Lu: None. H. Peng: None. C. Lin: None. R. Gao: None. S. Lin: None. K. Lin: None. Y. Jiang: None. L. Zeng: None.

Insulin treatment was confirmed to reduce insulin resistance, but the underlying mechanism remains unknown. Caveolin-1 (Cav-1) is a functional protein of the membrane lipid rafts, known as caveolae, and is widely expressed in mammalian adipose tissue. There is increasing evidence that show the involvement of Cav-1 in the AKT activation, which is responsible for insulin sensitivity. Our aim was to investigate the effect of Cav-1 depletion on insulin sensitivity and AKT activation in glargine-treated type 2 diabetic mice. Mice were exposed to a high-fat diet and subject to intraperitoneal injection of streptozotocin to induce diabetes. Next, glargine was administered to treat T2DM mice for 3 weeks (insulin group). The expression of Cav-1 was then silenced by injecting lentiviral-vectored short hairpin RNA (shRNA) through the tail vein of glargine-treated T2DM mice (CAV1-shRNA group), while scramble virus injection was used as a negative control (Ctrl-shRNA group). The results showed that glargine was able to upregulate the expression of PI3K and activate serine phosphorylation of AKT through the upregulation of Cav-1 expression in paraepididymal adipose tissue of the insulin group. However, glargine treatment could not activate AKT pathway in Cav-1 silenced diabetic mice. These results suggest that Cav-1 is essential for the activation of AKT and improving insulin sensitivity in type 2 diabetic mice during glargine treatment.

Our study aims to access the influence of caveolin1 (CAV1) on β cell expression profiles. We knocked down the expression of CAV1 in both NIT-1 cells and islets isolated from C57BL/6J mice using an RNA interference technique, which was realized by the transfer of an shRNA vector targeting CAV1 mRNA into NIT-1 cells or islets through latent virus infection. First, we identified the change in gene expression profiles in islets, in which the CAV1 expression level was down-regulated, as ascertained by mouse gene expression microarray, and the results showed that pathways related to β cell proliferation and pancreatic secretion functions were significantly influenced. The results of MTT demonstrated that the knockdown of CAV1 expression in NIT-1 cells promoted proliferation. The protein array results showed that pro-apoptotic cytokines were down-regulated in the NIT-1 cell line with CAV1 knockdown. These findings suggest that CAV1 might be involved in apoptosis and proliferation regulation in β cells, and therefore could be a potential target for the development of novel therapies for diabetes mellitus.