Pharmacogenetic analysis of rosiglitazone-induced hepatosteatosis in new mouse models of type 2 diabetes

Abstract

Although thiazolidinediones suppress hyperglycemia in diabetic (NON × NZO)F1 males, these mice exhibit unusual sensitivity to drug-induced exacerbation of an underlying hepatosteatosis only rarely experienced in human patients. To establish the pharmacogenetic basis for this sensitivity, a panel of recombinant congenic strains (RCSs) with varying degrees of obesity and diabetes was generated by fixing selected NZO HlLt alleles on the diabetes- and hepatosteatosis-resistant NON/Lt background. Four new strains in this panel were exposed to chronic rosiglitazone treatment. Only one, NONcNZO8 (designated RCS8), exhibited an F1-like hepatosteatotic response. In both the F1 and RCS8 males, this adverse effect correlated with rosiglitazone suppression of already impaired hepatic phosphatidyl-choline biosynthetic enzymes in both arms of the biosynthetic pathway, the phosphatidylethanolamine methyl-transferase pathway, and the CDP-choline pathway, including choline kinase and CTP-cholinephosphate cytidylyltransferase. This adverse response was not reproduced by CL316,243, a β3-adrenergic receptor agonist with potent antihyperlipemic effects. Genome comparison showed that RCS8 differed from the other strains in carrying NZO-derived genome on virtually all of chromosome 16 and in smaller segments on chromosomes 6,14, and 17. Thus, these RCSs present a panel of new mouse models exhibiting differential levels of obesity and diabetes as well as different drug responses. This panel can be used to screen for treatments for type 2 diabetes and its complications. © 2005 by the American Diabetes Association.