title: Alterations of pancreatic islet structure, metabolism and gene expression in diet-induced obese C57BL/6J mice.
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.
authors: Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors: Regan
authors: R
authors: Roat
authors: Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors: Vandana
authors: V
authors: Rao
authors: Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors: Nicolai M
authors: NM
authors: Doliba
authors: Department of Biochemistry and Biophysics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors: Franz M
authors: FM
authors: Matschinsky
authors: Bioinformatics Group, Penn Molecular Profiling Facility, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors: John W
authors: JW
authors: Tobias
authors: Department of Internal Medicine, Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, Virginia, United States of America.
authors: Eden
authors: E
authors: Garcia
authors: Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors: Rexford S
authors: RS
authors: Ahima
authors: Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America ; Department of Internal Medicine, Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, Virginia, United States of America.
authors: Yumi
authors: Y
authors: Imai
mesh_terms: D000818:Animals; D004041:Dietary Fats / Q000009:adverse effects*; D017353:Gene Deletion; D006946:Hyperinsulinism / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051793:Hypoxia-Inducible Factor 1 / Q000096:biosynthesis* / Q000235:genetics; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics; D061087:NADP Transhydrogenase, AB-Specific / Q000235:genetics; D009765:Obesity / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics
chemical_list: D004041:Dietary Fats; D051793:Hypoxia-Inducible Factor 1; D007328:Insulin; D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D061087:NADP Transhydrogenase, AB-Specific; C556048:Nnt protein, mouse