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.
- SourceAvailable from: Yoshio Fujitani[Show abstract] [Hide abstract]
ABSTRACT: Autophagy is a tightly regulated self-digestion system. As in other cell types, autophagy plays an essential role in the homeostasis of pancreatic beta cells. However, the mechanisms involved in the deterioration of beta cell function caused by autophagic failure have not yet been fully elucidated. To gain insight into its mechanisms, we compared the protein expression of islets from beta cell-specific Atg7-deficient mice (Atg7(Δbeta-cell) mice) and their controls (Atg7(f/f) mice). Liquid chromatography/mass spectrometry after 1-dimensional electrophoresis identified the increased expression of ERp57/GRP58 in islets isolated from Atg7(Δbeta-cell) mice compared with those from Atg7(f/f) mice. The expression level of ERp57 was also elevated in rat insulinoma INS-1 cells by inducible knock-down of the atg7-gene. In Atg7 knock-down INS-1 cells, the suppression of ERp57 expression by siRNA resulted in an increase in the level of cleaved Caspase-3 protein and a decrease in the number of live cells. Furthermore, cell cycle analyses demonstrated that the suppressed expression of ERp57 increased the sub-G1 population. These data reveal that increased expression of ERp57 may contribute to the protection from beta cell death caused by autophagic failure.Biochemical and Biophysical Research Communications 09/2014; · 2.28 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Quercetin can reverse high glucose-induced inhibition of neural cell proliferation, and therefore may have a neuroprotective effect in diabetic peripheral neuropathy. It is difficult to obtain primary Schwann cells and RSC96 cells could replace primary Schwann cells in studies of the role of autophagy in the mechanism underlying diabetic peripheral neuropathy. Here, we show that under high glucose conditions, there are fewer autophagosomes in immortalized rat RSC96 cells and primary rat Schwann cells than under control conditions, the proliferative activity of both cell types is significantly impaired, and the expression of Beclin-1 and LC3, the molecular markers for autophagy, is significantly lower. After intervention with quercetin, the autophagic and proliferative activity of both cell types is rescued. These results suggest that quercetin can alleviate high glucose-induced damage to Schwann cells by autophagy.Neural Regeneration Research 06/2014; 9(12):1195-203. · 0.23 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Autophagy is an essential cellular pathway by which protein aggregates, long-lived proteins, or defective organelles are sequestered in double membrane vesicles and then degraded upon fusion of those vesicles with lysosomes. Although autophagy plays a critical role in maintaining intracellular homeostasis and keeping the cell in a healthy state, this key pathway can become dysregulated in various cardiometabolic disorders, such as; obesity, dyslipidemia, inflammation, and insulin resistance. In these conditions, autophagy may actually worsen the pathological state instead of protecting the cell or organism. In this review, we discuss how dysregulated autophagy may be linked to increases in cardiovascular risk factors, and how manipulation of the autophagic machinery might reduce those risks.Reviews in Endocrine and Metabolic Disorders 09/2014; · 4.58 Impact Factor