The Study On The Mechanisms Of The Development Of Fat-induced Hepatic Insulin Resistant And Therapeutic Mechanisms Of Berberine On Fat-induced Hepatic Insulin Resistant In Type 2 Diabetic Chinese Hamsters

The "lipotoxicity" hypothesis holds that hepatic insulin resistance induced by ectopic lipid accumulation(fat-induced hepatic insulin resistance) may play a major role in the pathogenesis of type 2 diabetes. Thus,the mechanisms involved in hepatic insulin resistance,especially fat-induced hepatic insulin resistance is a prerequisite to understand pathogenesis of obesity-related type 2 diabetes.Berberine,one of the main bioactive herbal constituents of Rhizoma coptidis,has been reported to have antidiabetic properties.Although more recent studies have demonstrated the molecular mechanisms of antidiabetic action of berberine,the therapeutic mechanisms of berberine on insulin resistance of type 2 diabetes,especially hepatic insulin resistance are not fully understood.Therefore,studying berberine molecular pharmacological mechanisms on hepatic insulin resistance of type 2 diabetes is warranted.Chinese hamsters share genetic susceptibility for diabetes and many characteristic features of human lipid metabolism,thus we have developed insulin-resistant and type 2 diabetic hamster models according to the method previously published.These type 2 diabetic hamsters closely simulate the natural history,metabolic characteristics and clinical symptoms of type 2 diabetes and have satisfied stability.In the present study,we employ microarray technology in berberine-treated and untreated type 2 diabetic hamsters to determine the hepatic gene expression alterations and explore the potential molecular mechanisms involved in therapeutic action of berberine on fat-induced hepatic insulin resistance.Then,according to the results of microarray of type 2 diabetic hamsters,we use the real-time RT-PCR technology in insulin-resistant and type 2 diabetic hamster models to study the alterations in hepatic LXRα,SREBPs and PPARαand their certain target genes and explore their molecular mechanisms involved in fat-induced hepatic insulin resistance during the development of type 2 diabetes.The results suggest that comparing with control hamsters,the increased mRNA levels of SREBPs and the decreased mRNA levels of LXRαand PPARαare observed in insulin-resistant and diabetic hamsters. After treatment,berberine significantly reduces blood glucose and lipid levels and improves fat-induced insulin resistance in our diabetic hamsters,exhibiting same therapeutic effect as metformin and mild pharmacological action.Compared with diabetic hamsters,an increase in the LXRαand PPARαmRNA levels and a decrease in the SREBPs mRNA levels are observed in berberine-treated diabetic hamster. We conclude that the combined changes in expression of hepatic LXRα,SREBPs and PPARαand their certain target genes may contribute to the development of fat-induced hepatic insulin resistance and participate in the therapeutic molecular mechanisms of berberine on fat-induced hepatic insulin resistance of type 2 diabetic hamsters.