Autophagy protects pancreatic beta cell mass and function in the setting of a high-fat and high-glucose diet

Qingfeng Sheng,George K. Gittes,Xiangwei Xiao,Yungching Ming,Congde Chen,Joseph Fusco,David Ricks,Nupur N. Gangopadhyay,Krishna Prasadan

doi:10.1038/s41598-017-16485-0

Abstract

Autophagy is a major regulator of pancreatic beta cell homeostasis. Altered autophagic activity has been implicated in the beta cells of patients with type 2 diabetes, and in the beta cells of obese diabetic rodents. Here, we show that autophagy was induced in beta cells by either a high-fat diet or a combined high-fat and high-glucose diet, but not by high-glucose alone. However, a high-glucose intake alone did increase beta cell mass and insulin secretion moderately. Depletion of Atg7, a necessary component of the autophagy pathway, in beta cells by pancreatic intra-ductal AAV8-shAtg7 infusion in C57BL/6 mice, resulted in decreased beta cell mass, impaired glucose tolerance, defective insulin secretion, and increased apoptosis when a combined high-fat and high-glucose diet was given, seemingly due to suppression of autophagy. Taken together, our findings suggest that the autophagy pathway may act as a protective mechanism in pancreatic beta cells during a high-calorie diet.

Highlights

415 million people live with diabetes worldwide, and the incidence and prevalence continue to rise[1]
We examined autophagy by transmission electron microscopy (TEM)
Beta cells of HF and HF + HG mice showed the formation of large autophagic vacuoles (Fig. 1E). p62, which serves as a link between LC3 and ubiquitinated substrates, was increased in the islets of HF and HF + HG mice compared with STD mice (Fig. 1A,C). p62 and p62-bound polyubiquitinated proteins become incorporated into the autophagosome and are degraded in autolysosomes[18]

Summary

Introduction

415 million people live with diabetes worldwide, and the incidence and prevalence continue to rise[1]. Macroautophagy (referred to hereafter as autophagy) is a fundamental eukaryotic pathway that functions to degrade and recycle aggregated proteins and damaged organelles. It plays a crucial role in the function and survival of pancreatic beta cells[6,7,8,9]. Accumulation of autophagic vacuoles and autophagosomes has been implicated in human type 2 diabetic beta cells[10]. The present study was designed to investigate the effect of a high-calorie diet (high-fat diet, high-glucose water, or the combination of both) on the autophagic activity of pancreatic beta cells in mice. Susceptibility of autophagy-deficient beta cells to energy-dense diet stress was examined in vivo

Methods

Results

Conclusion