Hepatic Gene Expression Pattern Of Type 2 Diabetic Rats

Objectives: To compare gene expression in livers of type 2 diabetic rats to matchednon-diabetic controls by cDNA microarray.Methods: (1) Type 2 diabetes was induced by an intraperitoneal injection ofstreptozotocin (STZ, 25mg/kg) and 10 weeks' of high fat dietary.(2)The liver tissuewas evaluated by light microscopy using H.E. and oil-red stains and by transmissionelectron microscopy. (3) Total RNA was isolated from liver tissue and converted tocDNA by reverse transcription .The probes were prepared by labeling normal tissuemRNA and tissue mRNA of diabetic rats with Cy3-dCTP and Cy5-dCTP separately.The array was then hybridized against the cDNA probes mixture and the fluorescentsignals were scanned. (4) Semi-quantitative RT-PCR validation was performed onpart of the microarray results.Results: (1) The body weight, plasma triglycerides, fasting blood glucose, and insulinof the diabetic group were significantly increased and Insulin sensitivity index wasdecreased. The liver histology showed large fat deposition in hepatocytes and electronmicroscopy revealed abnormal mitochondria. (2) Of the 4096 genes on the array, 223were identified with statistically significant changes in the level of expression,including 37 expressed sequence tags (ESTs). 134 genes were up-regulated and 89genes were down-regulated. Gene associated with hepatic glucose production (HGP)and cholesterol synthesis was increased. Gene involved in mitochondria a-oxidationtended to be decreased. Expression of gene involved in oxidative stress was increased.Gene expression of insulin signal transduction, growth factor signaling wassignificantly changed.Conclusion: (1) The rat model of type 2 diabetes was characterized by hyperglycemiaand light impaired insulin secretion accompanied by insulin resistance, whichresembles the clinical manifestationof type 2 diabetes. (2) Abnormalities of HGP andfat metabolism in liver contribute to insulin resistance. Hepatic cholesterol 2metabolism was also impaired .Activation of oxidative stress pathways may play akey role in insulin resistance and the development of type 2 diabetes. Signaltransductionwas also abnormal.