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

Department of Medicine, Endocrinology, and Metabolism, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Cell metabolism (Impact Factor: 17.57). 11/2008; 8(4):325-32. DOI: 10.1016/j.cmet.2008.08.009
Source: PubMed


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.

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Available from: Yoshio Fujitani, Oct 10, 2015
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    • "These mice display impaired glucose tolerance and degenerated islets accompanied by reduced β cell mass and insulin secretion levels. A series of morphological malformations occur in Atg7 mutant β cells, including accumulation of ubiquitinated inclusions, enlargement of mitochondria, and distension of the endoplasmic reticulum (Ebato et al., 2008; Jung et al., 2008). MCK-Cre mice were crossed with Atg7 flox/flox mice for the generation of skeletal muscle cellspecific Atg7 knockout (SMC-Atg7 −/− ) mice. "
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    ABSTRACT: Macroautophagy is an evolutionarily conserved intracellular degradation system used by life ranging from yeasts to mammals. The core autophagic machinery is composed of ATG (autophagy-related) protein constituents. One particular member of the ATG protein family, Atg7, has been the focus of recent research. Atg7 acts as an E1-like activating enzyme facilitating both microtubule-associated protein light chain 3 (LC3)-phosphatidylethanolamine and ATG12 conjugation. Thus, Atg7 stands at the hub of these two ubiquitin-like systems involving LC3 and Atg12 in autophagic vesicle expansion. In this review, I focus on the pleiotropic function of Atg7 in development, maintenance of health, and alternations of such control in disease.
    Protein & Cell 09/2015; DOI:10.1007/s13238-015-0195-8 · 3.25 Impact Factor
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    • "n = 4, ⁄ P < 0.05 vs. control (À). serves as a negative feedback mechanism to clear toxic ubiquitinated protein aggregates in b-cells in diabetic settings including oxidative stress [13] [14]. Therefore, it is presumable that suppression of ROS formation or oxidative stress should inhibit autophagy activation. "
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    ABSTRACT: Nrf2 appears to be a critical regulator of diabetes in rodents. However, the underlying mechanisms as well as the clinical relevance of the Nrf2 signaling in human diabetes remain to be fully understood. Herein, we report that islet expression of Nrf2 is upregulated at an earlier stage of diabetes in both human and mice. Activation of Nrf2 suppresses oxidative stress and oxidative stress-induced β-cell apoptosis while enhancing autophagic clearance in isolated rat islets. Additionally, oxidative stress per se activated autophagy in β-cells. Thus, these results reveal that Nrf2 drives a novel antioxidant independent autophagic clearance for β-cell protection in the setting of diabetes.
    FEBS letters 05/2014; 588(12). DOI:10.1016/j.febslet.2014.04.046 · 3.17 Impact Factor
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    • "On the other hand, human T2D is characterized by both loss of islet mass and function [3], [18]. Prevention of islet mass expansion due to aging or autophagy defects exacerbates hyperglycemia in HF mice [25], [27]. Thus, it is possible that the compensatory increase in islet mass plays a critical role in preventing the worsening of hyperglycemia in HF BL6J mice. "
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    ABSTRACT: The reduction of functional β cell mass is a key feature of type 2 diabetes. Here, we studied metabolic functions and islet gene expression profiles of C57BL/6J mice with naturally occurring nicotinamide nucleotide transhydrogenase (NNT) deletion mutation, a widely used model of diet-induced obesity and diabetes. On high fat diet (HF), the mice developed obesity and hyperinsulinemia, while blood glucose levels were only mildly elevated indicating a substantial capacity to compensate for insulin resistance. The basal serum insulin levels were elevated in HF mice, but insulin secretion in response to glucose load was significantly blunted. Hyperinsulinemia in HF fed mice was associated with an increase in islet mass and size along with higher BrdU incorporation to β cells. The temporal profiles of glucose-stimulated insulin secretion (GSIS) of isolated islets were comparable in HF and normal chow fed mice. Islets isolated from HF fed mice had elevated basal oxygen consumption per islet but failed to increase oxygen consumption further in response to glucose or carbonyl cyanide-4-trifluoromethoxyphenylhydrazone (FCCP). To obtain an unbiased assessment of metabolic pathways in islets, we performed microarray analysis comparing gene expression in islets from HF to normal chow-fed mice. A few genes, for example, those genes involved in the protection against oxidative stress (hypoxia upregulated protein 1) and Pgc1α were up-regulated in HF islets. In contrast, several genes in extracellular matrix and other pathways were suppressed in HF islets. These results indicate that islets from C57BL/6J mice with NNT deletion mutation develop structural, metabolic and gene expression features consistent with compensation and decompensation in response to HF diet.
    PLoS ONE 02/2014; 9(2):e86815. DOI:10.1371/journal.pone.0086815 · 3.23 Impact Factor
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