Abstract
Type 2 diabetes mellitus is characterized by insulin resistance and failure of pancreatic β-cells producing insulin. Autophagy plays a crucial role in cellular homeostasis through degradation and recycling of organelles such as mitochondria or endoplasmic reticulum (ER). Here we discussed the role of β-cell autophagy in development of diabetes, based on our own studies using mice with β-cell-specific deletion of Atg7 (autophagy-related 7), an important autophagy gene, and studies by others. β-cell-specific Atg7-null mice showed reduction in β-cell mass and pancreatic insulin content. Insulin secretory function ex vivo was also impaired, which might be related to organelle dysfunction associated with autophagy deficiency. As a result, β-cell-specific Atg7-null mice showed hypoinsulinemia and hyperglycemia. However, diabetes never developed in those mice. Obesity and/or lipid are physiological ER stresses that can precipitate β-cell dysfunction. Our recent studies showed that β-cell-specific Atg7-null mice, when bred with ob/ob mice, indeed become diabetic. Thus, autophagy deficiency in β-cells could be a precipitating factor in the progression from obesity to diabetes due to inappropriate response to obesity-induced ER stress.
Highlights
Two major types of cell death are apoptosis and necrosis, recently another type of cell death, autophagy, was defined
When we studied the impact of lipids on endoplasmic reticulum (ER) in our system, we confirmed that lipids induce expression of diverse unfolded protein response (UPR) genes both in insulinoma cells and primary islet cells, showing that lipids are ER stressors and increase demand for UPR by lipids in those cells (Figure 3)
These results show that autophagydeficient β-cells with compromised UPR machinery are more vulnerable to physiological ER stressors as well as pharmacological ER stressors
Summary
Two major types of cell death are apoptosis and necrosis, recently another type of cell death, autophagy, was defined. The close relationship between ER and autophagy was demonstrated by recent reports showing activation of autophagic process by ER stress, which was mediated by induction of Atg12 expression, JNK The significance of such findings is not clear, but may be related to the increased demand for autophagic removal of misfolded proteins in ER lumen in the process of ER stress or accumulation of unfolded proteins.
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