, Volume 55, Issue 2, pp 392-403
Date: 11 Nov 2011

Autophagy deficiency in beta cells leads to compromised unfolded protein response and progression from obesity to diabetes in mice

Abstract

Aims/hypothesis

The unfolded protein response (UPR) in endoplasmic reticulum (ER) and autophagy are known to be related. We investigated the role of autophagy in UPR of pancreatic beta cells and the susceptibility of autophagy-deficient beta cells to the ER stress that is implicated in the development of diabetes.

Methods

Rat insulin promoter (RIP)-Cre +;autophagy-related 7 (Atg7)F/W mice were bred with ob/w mice to derive RIP-Cre +;Atg7 F/F-ob/ob mice and to induce ER stress in vivo. GFP-LC3 +-ob/ob mice were generated to examine in vivo autophagic activity. Real-time RT-PCR was performed to study the expression of the genes of the UPR machinery. Proteolysis was assessed by determining release of incorporated radioactive leucine.

Results

Production of UPR machinery was reduced in autophagy-deficient beta cells, which was associated with diminished production of p85α and p85β regulatory subunits of phosphoinositide 3-kinase. Because of compromised UPR machinery, autophagy-deficient beta cells were susceptible to ER stressors in vitro. When mice with beta cell-specific autophagy deficiency, which have mild hyperglycaemia, were bred with ob/ob mice to induce ER stress in vivo, severe diabetes developed, which was accompanied by an increase in beta cell death and accumulation of reactive oxygen species. The increased demand for UPR present in obesity was unmet in autophagy-deficient beta cells. Autophagy level and autophagic activity were enhanced by lipid, while proteolysis was reduced.

Conclusions/interpretation

These results suggest that autophagy is important for intact UPR machinery and appropriate UPR in response to lipid injury that increases demand for UPR. Autophagy deficiency in pancreatic beta cells may contribute to the progression from obesity to diabetes.

W. Quan and K. Y. Hur contributed equally to this study.