Abstract
Gene expression changes have been associated with type 2 diabetes mellitus (T2DM); however, the alterations are not fully understood. We investigated the effects of anti-diabetic drugs on gene expression in Zucker diabetic fatty (ZDF) rats using oligonucleotide microarray technology to identify gene expression changes occurring in T2DM. Global gene expression in the pancreas, adipose tissue, skeletal muscle, and liver was profiled from Zucker lean control (ZLC) and anti-diabetic drug treated ZDF rats compared with those in ZDF rats. We showed that anti-diabetic drugs regulate the expression of a large number of genes. We provided a more integrated view of the diabetic changes by examining the gene expression networks. The resulting sub-networks allowed us to identify several biological processes that were significantly enriched by the anti-diabetic drug treatment, including oxidative phosphorylation (OXPHOS), systemic lupus erythematous, and the chemokine signaling pathway. Among them, we found that white adipose tissue from ZDF rats showed decreased expression of a set of OXPHOS genes that were normalized by rosiglitazone treatment accompanied by rescued blood glucose levels. In conclusion, we suggest that alterations in OXPHOS gene expression in white adipose tissue may play a role in the pathogenesis and drug mediated recovery of T2DM through a comprehensive gene expression network study after multi-drug treatment of ZDF rats.
Highlights
Type 2 diabetes mellitus (T2DM) is a metabolic disorder that is primarily characterized by insulin resistance and hyperglycemia [1]
Metformin (300 mg/kg/day) and glimepiride (200 mg/kg/day) were administered to 12 week-old Zucker diabetic fatty (ZDF) rats for 2 weeks and rosiglitazone (15 mg/kg/day) was administered for 1 week to evaluate the effect of anti-diabetic drugs on impaired glucose tolerance in ZDF rats [24,25,26]
Blood glucose levels were significantly higher in the ZDF groups at all time-points during the oral glucose tolerance test (OGTT), and the area under the curve (AUC) increased significantly compared to that in normal lean Zucker lean control (ZLC) rats
Summary
Type 2 diabetes mellitus (T2DM) is a metabolic disorder that is primarily characterized by insulin resistance and hyperglycemia [1]. A main component of T2DM is insulin resistance. Insulin does not control glucose utilization in fat and muscle cells in patients with T2DM, which causes hyperglycemia [3]. The pancreas produces more insulin and the cells become even more resistant, resulting in high glucose levels with hyperinsulinemia in patients with T2DM. The molecular pathogenesis causing insulin resistance is not fully understood. Searching for differentially expressed genes involved in the onset of insulin resistance in insulin-sensitive and insulin-producing tissues from patients with diabetes may help us to understand the molecular mechanisms involved in T2DM
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