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Alterations of pancreatic islet structure, metabolism and gene expression in diet-induced obese C57BL/6J mice
Journal article   Open access   Peer reviewed

Alterations of pancreatic islet structure, metabolism and gene expression in diet-induced obese C57BL/6J mice

Regan Roat, Vandana Rao, Nicolai M Doliba, Franz M Matschinsky, John W Tobias, Eden Garcia, Rexford S Ahima and Yumi Imai
PloS one, Vol.9(2), pp.e86815-e86815
2014
DOI: 10.1371/journal.pone.0086815
PMCID: PMC3914796
PMID: 24505268
url
https://doi.org/10.1371/journal.pone.0086815View
Published (Version of record) Open Access

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.
 Mitochondrial Proteins - genetics Insulin - blood NADP Transhydrogenase, AB-Specific - genetics Obesity - genetics Hypoxia-Inducible Factor 1 - genetics Insulin-Secreting Cells - metabolism Gene Deletion Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Hyperinsulinism - genetics Hypoxia-Inducible Factor 1 - biosynthesis Hyperinsulinism - metabolism Dietary Fats - adverse effects Obesity - chemically induced Up-Regulation - genetics Transcription Factors - genetics Obesity - metabolism Obesity - pathology Transcription Factors - metabolism Up-Regulation - drug effects Hyperinsulinism - pathology Hyperinsulinism - chemically induced Animals Oxygen Consumption - drug effects Oxygen Consumption - genetics Mice Insulin-Secreting Cells - pathology Oxidative Stress - drug effects

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