Abstract
BackgroundThe hallmark of Type 2 diabetes (T2D) is hyperglycemia, although there are multiple other metabolic abnormalities that occur with T2D, including insulin resistance and dyslipidemia. To advance T2D prevention and develop targeted therapies for its treatment, a greater understanding of the alterations in metabolic tissues associated with T2D is necessary. The aim of this study was to use microarray analysis of gene expression in metabolic tissues from a mouse model of pre-diabetes and T2D to further understand the metabolic abnormalities that may contribute to T2D. We also aimed to uncover the novel genes and pathways regulated by the insulin sensitizing agent (CL-316,243) to identify key pathways and target genes in metabolic tissues that can reverse the diabetic phenotype.MethodsMale MKR mice on an FVB/n background and age matched wild-type (WT) FVB/n mice were used in all experiments. Skeletal muscle, liver and fat were isolated from prediabetic (3 week old) and diabetic (8 week old) MKR mice. Male MKR mice were treated with CL-316,243. Skeletal muscle, liver and fat were isolated after the treatment period. RNA was isolated from the metabolic tissues and subjected to microarray and KEGG database analysis.ResultsSignificant decreases in the expression of mitochondrial and peroxisomal fatty acid oxidation genes were found in the skeletal muscle and adipose tissue of adult MKR mice, and the liver of pre-diabetic MKR mice, compared to WT controls. After treatment with CL-316,243, the circulating glucose and insulin concentrations in the MKR mice improved, an increase in the expression of peroxisomal fatty acid oxidation genes was observed in addition to a decrease in the expression of retinaldehyde dehydrogenases. These genes were not previously known to be regulated by CL-316,243 treatment.ConclusionsThis study uncovers novel genes that may contribute to pharmacological reversal of insulin resistance and T2D and may be targets for treatment. In addition, it explains the lower free fatty acid levels in MKR mice after treatment with CL-316,243 and furthermore, it provides biomarker genes such as ACAA1 and HSD17b4 which could be further probed in a future study.Electronic supplementary materialThe online version of this article (doi:10.1186/s12986-015-0003-8) contains supplementary material, which is available to authorized users.
Highlights
The hallmark of Type 2 diabetes (T2D) is hyperglycemia, there are multiple other metabolic abnormalities that occur with T2D, including insulin resistance and dyslipidemia
Most of the genes in fat tissues related to ether lipid metabolism were found to be down-regulated in MKR compared with WT mice
Pathways related to carbohydrate metabolism such as TCA cycle, pentose phosphate pathway, fructose and mannose metabolism, pyruvate metabolism, and propanoate metabolism were found to be overrepresented only in fat tissues of MKR vs WT mice and not in the fat tissues of CL316,243 treated MKR compared with non-treated MKR
Summary
The hallmark of Type 2 diabetes (T2D) is hyperglycemia, there are multiple other metabolic abnormalities that occur with T2D, including insulin resistance and dyslipidemia. Inter-tissue cross talk between skeletal muscle, adipose tissue, the liver, brain, and pancreatic beta cells may contribute to insulin resistance. Abnormalities in fatty acid metabolism contribute to the accumulation of lipids in tissues such as skeletal muscle and liver and to the development or worsening of insulin resistance [10]. Other molecules, such as myokines and adipokines may contribute to inter-tissue cross talk. Adipose tissue releases multiple adipokines, including leptin, adiponectin and resistin that act through their receptors on many other organs to regulate metabolism
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