期刊
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
卷 23, 期 4, 页码 2890-2900出版社
WILEY
DOI: 10.1111/jcmm.14172
关键词
autophagy; islets; LAMP2; PLIN2; TFEB
资金
- Canadian Diabetes Society
- Canadian Institutes of Health Research
- McGill University
Both type 2 diabetes (T2D) and obesity are characterized by excessive hyperlipidaemia and subsequent lipid droplet (LD) accumulation in adipose tissue. To investigate whether LDs also accumulate in beta-cells of T2D patients, we assessed the expression of PLIN2, a LD-associated protein, in non-diabetic (ND) and T2D pancreata. We observed an up-regulation of PLIN2 mRNA and protein in beta-cells of T2D patients, along with significant changes in the expression of lipid metabolism, apoptosis and oxidative stress genes. The increased LD buildup in T2D beta-cells was accompanied by inhibition of nuclear translocation of TFEB, a master regulator of autophagy and by down-regulation of lysosomal biomarker LAMP2. To investigate whether LD accumulation and autophagy were influenced by diabetic conditions, we used rat INS-1 cells to model the effects of hyperglycaemia and hyperlipidaemia on autophagy and metabolic gene expression. Consistent with human tissue, both LD formation and PLIN2 expression were enhanced in INS-1 cells under hyperglycaemia, whereas TFEB activation and autophagy gene expression were significantly reduced. Collectively, these results suggest that lipid clearance and overall homeostasis is markedly disrupted in beta-cells under hyperglycaemic conditions and interventions ameliorating lipid clearance could be beneficial in reducing functional impairments in islets caused by glucolipotoxicity.
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