Abstract
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 β‐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 β‐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 β‐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 β‐cells under hyperglycaemic conditions and interventions ameliorating lipid clearance could be beneficial in reducing functional impairments in islets caused by glucolipotoxicity.
Highlights
type 2 diabetes (T2D) is characterized by β‐cell failure, insulin resistance, hypergly‐ caemia, and hyperlipidaemia. β‐cells are nutrient sensors that reg‐ ulate insulin secretion in response to elevated levels of glucose and lipids.[1]
We evaluated expression of several genes related to anti‐oxidant defence and apoptosis and found sig‐ nificant up‐regulation of glutathione peroxidase 1 (GPX1, 3.8 ± 0.3 ↑, P < 0.001) and heme oxygenase 1 (HMOX1, 2.2 ± 0.3 ↑, P < 0.01) in T2D pancreata (Figure 3C), which correlated with an increased immunofluorescence for Nrf[2] (Figure S1), a transcription factor regulating GPX1, HMOX1 and other genes involved in oxidant de‐ fense and redox signalling.[29]
Results from this study show that hyperglycaemia and hyperlipi‐ daemia in humans and rat insulin‐producing cells (INS‐1) lead to: (1) an up‐regulation of lipid droplet (LD)‐associated protein PLIN2, (2) a significant decrease in transcription factor EB (TFEB) activity and in lysosomal biomarker lysosome‐associated membrane protein‐2 (LAMP2), con‐ sistent with inhibition of autophagy and (3) dysregulation of genes implicated in lipid metabolism, mitochondrial function and cell survival
Summary
T2D is characterized by β‐cell failure, insulin resistance, hypergly‐ caemia, and hyperlipidaemia. β‐cells are nutrient sensors that reg‐ ulate insulin secretion in response to elevated levels of glucose and lipids.[1]. Perilipin‐2 (PLIN2) is the main housekeeping LD protein that is ubiquitously expressed and used as a marker for LDs in many human and animal tissues.[8] PLIN5 is highly expressed in oxidative tissues and plays multiple metabolic roles such as fatty acid (FA) mobilization and has been shown to regulate post‐prandial insulin secretion in β‐cells.[9,10] High cellular lipid uptake (eg, post‐prandial period) increases PLIN2 (and other PAT proteins) expression and triggers their recruitment to the LD surface.[11] These events temporarily reduce the cytosolic FA concentration. Β‐cell–specific Atg[7] knockout led to islet degeneration in mice, accumulation of protein aggregates and decreased insulin production.[20] β‐cell–spe‐ cific Tsc‐2 knockout, which caused mTORC1 hyperactivation and repression of autophagy, increased mitochondrial oxidation and ER stress, resulting in β‐cell failure.[21] mTORC1 is a central kinase re‐ sponsible for regulating many aspects of metabolism, energy utili‐ zation and cell growth in response to nutrient abundance within the cell. We have suggested that nutrient overload in diabetes causes LD accumulation due to de‐ creased TFEB activation and suppression of autophagy and tested this hypothesis in vitro, using the rat insulinoma β‐cell line INS‐1
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