HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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.
AuthorsRegan Roat, Vandana Rao, Nicolai M Doliba, Franz M Matschinsky, John W Tobias, Eden Garcia, Rexford S Ahima, Yumi Imai
JournalPloS one (PLoS One) Vol. 9 Issue 2 Pg. e86815 ( 2014) ISSN: 1932-6203 [Electronic] United States
PMID24505268 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Dietary Fats
  • Hypoxia-Inducible Factor 1
  • Insulin
  • Mitochondrial Proteins
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Transcription Factors
  • NADP Transhydrogenase, AB-Specific
  • Nnt protein, mouse
Topics
  • Animals
  • Dietary Fats (adverse effects)
  • Gene Deletion
  • Hyperinsulinism (chemically induced, genetics, metabolism, pathology)
  • Hypoxia-Inducible Factor 1 (biosynthesis, genetics)
  • Insulin (blood)
  • Insulin-Secreting Cells (metabolism, pathology)
  • Mice
  • Mitochondrial Proteins (genetics)
  • NADP Transhydrogenase, AB-Specific (genetics)
  • Obesity (chemically induced, genetics, metabolism, pathology)
  • Oxidative Stress (drug effects)
  • Oxygen Consumption (drug effects, genetics)
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Transcription Factors (genetics, metabolism)
  • Up-Regulation (drug effects, genetics)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: