Unknown,Transcriptomics,Genomics,Proteomics

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Glycan changes caused by insulin-deficient diabetes in the mouse liver

ABSTRACT: To determine the effect of insulin deficiency on global changes to expression of glycan related genes in the liver. See: Joseph R. Bishop,‡ Erin Foley,‡§ Roger Lawrence,‡ and Jeffrey D. Esko‡1 (2010) Insulin-dependent Diabetes Mellitus in Mice Does Not Alter Liver Heparan Sulfate* J Biol Chem. 2010 May 7; 285(19): 14658–14662. We are studying the glycan changes caused by insulin-deficient diabetes in the mouse liver. We would like to determine whether insulin-deficiency causes global changes to expression of glycan-related genes in the liver. Male C57BL/6 mice (4 weeks of age) were purchased from Jackson Laboratory and maintained in a temperature-controlled (25 °C) facility with a 12-h light/dark cycle. The derivation and genotyping of Ndst1f/fAlbCre+ mice have been described previously (16). Mice were fed laboratory rodent chow (Harlan-Teklad) ad libitum except when fasting blood specimens were obtained. Mice were made diabetic by administering 50 mg/kg body weight of streptozotocin (STZ; Sigma) intraperitoneally for 5 consecutive days. Because of variations in plasma triglycerides in females, only male mice were used in this study. Our preliminary results suggest glycosaminoglycan enzymes may be down-regulated, which may affect the turnover of lipids in the plasma. Liver RNA samples from 3 diabetic mice will be compared to 3 wildtype samples for properly controlled analysis.

ORGANISM(S): Mus musculus

SUBMITTER: Steven Head

PROVIDER: E-GEOD-31989 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:In an effort to reduce hepatic glucose production and lower plasma glucose levels that are characteristics of diabetes, we have devised a treatment whereby we enhance glycolysis in the liver of a type 2 diabetic mouse model (KK/H1J). We achieve this by raising the levels of a potent regulator of glucose metabolism, fructose-2,6-bisphosphate (F26BP). Treating the mice in this way, we have demonstrated amelioration of the diabetic phenotype in terms of lowering plasma glucose and insulin levels. These treated mice also display reduced weight gain, reduced adiposity, and normalized plasma and hepatic lipid levels. These latter metabolic changes brought about by raising F26BP levels are counterintuitive. A concurrent increase in glycolysis and lipogenesis is expected, however, we observe an increase in glycolysis with a concurrent decrease in lipogenesis. Preliminary analysis of gene expression in these mice has revealed alterations in gene expression of several genes that support the therapeutic effect of raising F26BP levels. To further profile F26BP effects on hepatic gene expression, we have applied a comprehensive approach to identify sets of genes and thereby biological pathways that are differentially regulated when hepatic glycolysis is accelerated in diabetic mice. Comparing diabetic and treated animals, we hope to further clarify the molecular and genetic signature of type 2 diabetes and obesity and elucidate how this signature is affected by raising F26BP levels. Our study examining gene array as well as the hepatic proteome has identified multiple gene and protein expression changes. Of particular relevance, we note that fatty acid metabolism and cholesterol metabolism pathways are significantly down-regulated in diabetic mice treated with a PFK-2 mutant engineered to raise F26BP levels, which underlie the changes we see in the metabolic parameters. 6 KK/H1J mice, a polygenic model of type 2 diabetes and obesity, weighing approximately 35g were used in this study. 3 mice were injected with GFP control adenovirus and 3 mice were injected with bisphosphatase deficient PFK-2 adenovirus (BPD). Mice were followed for 7 days before livers were extracted. Total cellular RNA was extracted from each mouse and analyzed by microarray separately.

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Glycan changes caused by insulin-deficient diabetes in the mouse liver

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