The role of autophagy in β‐cell lipotoxicity and type 2 diabetes

Abstract

Autophagy, a ubiquitous catabolic pathway involved in both cell survival and cell death, has been implicated in many age-associated diseases. Recent findings have shown autophagy to be crucial for proper insulin secretion and β-cell viability. Transgenic mice lacking autophagy in their β-cells showed decreased β-cell mass and suppressed glucose-stimulated insulin secretion. Several studies showed that stress can stimulate autophagy in β-cells: the number of autophagosomes is increased in different in vivo models for diabetes, such as db/db mice, mice fed high-fat diet, pdx-1 knockout mice, as well as in in vitro models of glucotoxicity and lipotoxicity. Pharmacological and molecular inhibition of autophagy increases the susceptibility to cell stress, suggesting that autophagy protects against diabetes-relevant stresses. Recent findings, however, question these conclusions. Pancreases of diabetics and β-cells exposed to fatty acids show accumulation of abnormal autophagosome morphology and suppression of lysosomal gene expression suggesting impairment in autophagic turnover. In this review we attempt to give an overview of the data generated by others and by us in view of the possible role of autophagy in diabetes, a role which depending on the conditions, could be beneficial or detrimental in coping with stress.

Identification of particular groups of microRNAs that positively or negatively impact on beta cell function in obese models of type 2 diabetes

“…Disruption of the signalling pathways involving these two proteins is detrimental for beta cells [23,49]. Moreover, mTOR is an important regulator of autophagy, a process thought to contribute to type 2 diabetes onset [50]. Thus, the toxic effects of miR-199a-3p may be the consequence of diminished expression of mTOR and cMET.…”

Anti-diabetic Action of 7-<i>O</i>-Galloyl-d-sedoheptulose, a Polyphenol from Corni Fructus, through Ameliorating Inflammation and Inflammation-Related Oxidative Stress in the Pancreas of Type 2 Diabetics

“…These results correlate with a previous report showing that anti-diabetic treatment advanced insulin sensitivity and the protection of insulin and C-peptide levels in the pancreas of db/db mice. 38) Oxidative stress is produced under diabetic conditions and is likely implicated in the development of pancreatic β-cell dysfunction found in diabetes as pancreatic β-cells are vulnerable to oxidative stress. For example, when pancreatic β-cells were exposed to oxidative insult, insulin gene expression was markedly suppressed, and when db/db mice were treated with antioxidants, glucose tolerance was diminished.…”

Incretin-based therapy and pancreatic beta cells

“…Autophagy deficiency in beta cells due to a genetic predisposition or other causes such as ageing could be a factor in the progression from obesity to diabetes [34]. On the other hand, recent evidence shows accumulation of abnormal autophagosomes and suppression of lysosomal gene expression, suggesting impairment of autophage turnover in diabetic beta cells and in beta cells treated with FFA [33]. Such impaired autophage flux is also suggested to be a contributing factor to the pathology of disease, even though there is still much to be investigated [33].…”

“…Steady-state autophagy has proved to be important for the physiology as well as viability of pancreatic beta cells. Studies of mice with beta cell-specific deletion of Atg7 (autophagy-related 7), an essential gene for autophagy, reported that beta cells underwent apoptosis and displayed suppression of GSIS [33]. Autophagy deficiency in beta cells due to a genetic predisposition or other causes such as ageing could be a factor in the progression from obesity to diabetes [34].…”

“…Recent studies have shown that autophagy, a lysosomemediated catabolic process implicated in the aetiology of various age-related diseases, is also associated in lipotoxicity and diabetes (see Las and Shirihai for a review [33]). Autophagy plays a crucial role in cellular homoeostasis through the degradation and recycling of organelles such as mitochondria and ER.…”