Autophagy Is Important in Islet Homeostasis and Compensatory Increase of Beta Cell Mass in Response to High-Fat Diet

Abstract

Autophagy is an evolutionarily conserved machinery for bulk degradation of cytoplasmic components. Here, we report upregulation of autophagosome formation in pancreatic beta cells in diabetic db/db and in nondiabetic high-fat-fed C57BL/6 mice. Free fatty acids (FFAs), which can cause peripheral insulin resistance associated with diabetes, induced autophagy in beta cells. Genetic ablation of atg7 in beta cells resulted in degeneration of islets and impaired glucose tolerance with reduced insulin secretion. While high-fat diet stimulated beta cell autophagy in control mice, it induced profound deterioration of glucose tolerance in autophagy-deficient mutants, partly because of the lack of compensatory increase in beta cell mass. These findings suggest that basal autophagy is important for maintenance of normal islet architecture and function. The results also identified a unique role for inductive autophagy as an adaptive response of beta cells in the presence of insulin resistance induced by high-fat diet.

Islet beta cell failure in the 60% pancreatectomised obese hyperlipidaemic Zucker fatty rat: severe dysfunction with altered glycerolipid metabolism without steatosis or a falling beta cell mass

“…In support of this possibility, a 12-fold increase in degradation vacuoles in beta cells of Rab3a −/− mice, which are glucoseintolerant because of impaired insulin secretion, has been shown [37]. In addition, high-fat diet has recently been shown to stimulate beta cell autophagy [38].…”

Autophagy at the crossroads of catabolism and anabolism

“…Moreover, during exercise, autophagy is induced in cardiac and skeletal muscles, adipose tissue and pancreatic β-cells, which provides protection against glucose intolerance 101 . Similarly, in pancreatic β-cells, autophagy is important for maintaining glucose tolerance because mice lacking ATG7 in β-cells have reduced serum insulin levels and hyperglycaemia 102,103 . When these mice were fed a high-fat diet they exhibited reduced β-cell numbers and reduced insulin secretion 102 .…”

“…Similarly, in pancreatic β-cells, autophagy is important for maintaining glucose tolerance because mice lacking ATG7 in β-cells have reduced serum insulin levels and hyperglycaemia 102,103 . When these mice were fed a high-fat diet they exhibited reduced β-cell numbers and reduced insulin secretion 102 . In addition to crinophagy, a process involving the direct fusion of secretory granules with lysosomes, autophagy was thought to regulate the secretion of insulincontaining secretory granules to maintain stable insulin levels and thus indirectly contribute to glucose homeostasis 104 .…”

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

“…RNA from paraffin-embedded tissue blocks was prepared using a formalin-fixed paraffin-embedded kit (Qiagen, 56404). cDNA was synthesized using M-MLV reverse transcriptase (Promega, M17013) and oligo(dT) [12][13][14][15][16][17][18] primer. The expression of Atg7, Tnf, Il6, pro-Il1b, Adgre1, Tgfb, Ccl2, Ccl5, Cxcl1 and Actb was assessed by quantitative PCR using specific primer sets.…”

“…11,12 As these results suggest that autophagy deficiency is a proinflammatory condition particularly in relation to inflammasome activation, deficient autophagy can be a factor in the development of T2D associated with low-grade inflammation and inflammasome activation. Although the role of autophagy of diverse tissues in body metabolism has been intensively investigated, [13][14][15][16][17][18][19][20][21] the importance of autophagy of myeloid cells such as Mfs (macrophages) in the regulation of systemic insulin sensitivity and in the development of T2D has not been clearly elucidated. Besides metabolic syndrome, IBD (inflammatory bowel disease) is a prototypic disease associated with autophagy deficiency inducing aggravated tissue inflammation.…”