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

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.

The receptor for advanced glycation endproducts is a mediator of toxicity by IAPP and other proteotoxic aggregates: Establishing and exploiting common ground for novel amyloidosis therapies

“…IAPP is co‐produced and co‐secreted with insulin by pancreatic β‐cells. The biosynthesis of insulin by β‐cells, like that of IAPP, is a multistep process, and mutations in the pre‐proinsulin gene, or disruptions in posttranslational modifications at any major stage, can result in the formation of proteotoxic aggregates and activation of cellular stress mechanisms leading to β‐cell toxicity and diabetes . Insulin is initially translated in the cytosol as a pre‐prohormone (pre‐proinsulin), which is translocated across the ER membrane where it is enzymatically cleaved to form proinsulin .…”

“…Elevated levels of PI have been shown to be correlated to the degree of β‐cell secretory impairment in T2D patients . In the β‐cell, transport‐competent secretory peptide precursors, including PI, are regulated by autophagy, whereas efficient clearance of transport‐incompetent mutated forms of PI by alternative degradative pathways may be necessary to avoid β‐cell proteotoxicity . Insulin resistant Akita and db/db mice, as well as Zucker diabetic fatty rats display increased autophagosome flux, and disrupting autophagy in these models drives β‐cell UPR stress and the progression of diabetes .…”

“…The biosynthesis of insulin by bcells, like that of IAPP, is a multistep process, and mutations in the pre-proinsulin gene, or disruptions in posttranslational modifications at any major stage, can result in the formation of proteotoxic aggregates and activation of cellular stress mechanisms leading to b-cell toxicity and diabetes. [142][143][144][145][146] Insulin is initially translated in the cytosol as a preprohormone (pre-proinsulin), which is translocated across the ER membrane where it is enzymatically cleaved to form proinsulin. 147 Misprocessing during this early step results in the accumulation of preproinsulin in the juxtanuclear compartment and induction of heat shock protein 70 (HSP70), which promotes human b-cell apoptosis.…”

“…151 In the b-cell, transport-competent secretory peptide precursors, including PI, are regulated by autophagy, whereas efficient clearance of transport-incompetent mutated forms of PI by alternative degradative pathways may be necessary to avoid b-cell proteotoxicity. 146,152,153 Insulin resistant Akita and db/db mice, as well as Zucker diabetic fatty rats display increased autophagosome flux, and disrupting autophagy in these models drives b-cell UPR stress and the progression of diabetes. [154][155][156][157] Reduction of PI autophagic degradation increases its residency in the secretory pathway and enhances its secretion in response to stimuli.…”

Up-Regulation Thioredoxin Inhibits Advanced Glycation End Products-Induced Neurodegeneration

“…Although autophagy is typically recognized as a pro-survival mechanism, the consequences of excessive autophagy can lead to cell dysfunction and autophagic cell death, known as type II programmed cell death. Previous studies on the role of autophagy in the pathophysiology of diabetes examined the autophagic process in β cells [29]. Additionally, studies have shown that autophagy plays an important role in neurodegenerative disease [30].…”