Prophylactic treatment with telmisartan induces tissue-specific gene modulation favoring normal glucose homeostasis in Cohen-Rosenthal diabetic hypertensive rats Firas Younis a , Yoram Oron a , Rona Limor b , Naftali Stern b , Talma Rosenthal a, ⁎ a Department of Physiology and Pharmacology, Hypertension Research Unit, Sackler School of Medicine, Tel Aviv University 69978, Tel Aviv, Israel b Endocrinology, Metabolism and Hypertension Institute, Tel Aviv-Sourasky Medical Center, and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel ARTICLE INFO ABSTRACT Article history: Received 31 January 2011 Accepted 9 June 2011 The objectives were to assess the potential of long-term prophylactic administration of telmisartan, an angiotensin II receptor antagonist and a partial peroxisome proliferator activator receptor (PPAR)γ agonist, in preventing the development of hypertension and hyperglycemia and to demonstrate the alteration in gene expression associated with the development of hyperglycemia and insulin resistance in Cohen-Rosenthal diabetic hypertensive rat, a unique model of hypertension and type 2 diabetes mellitus comorbidity. Cohen-Rosenthal diabetic hypertensive rats were continuously treated with telmisartan (3 mg/[kg d]) starting at age 6 to 8 weeks before developing hypertension or diabetes. Weight changes, blood pressure, blood insulin, adiponectin, glucose tolerance, and insulin sensitivity were monitored. Fat, liver, and muscle messenger RNAs were examined for the expression of genes potentially involved in the onset of insulin resistance. In addition to the expected antihypertensive effect of prophylactic telmisartan, diabetes was blunted, evidenced at the end of the study by a significantly lower glucose level. This was accompanied by improved glucose tolerance, increased sensitivity to insulin, reduction in fasting insulin levels and homeostasis model assessment index, as well as an increase in serum adiponectin. Telmisartan also prevented the increase in serum triglycerides and the associated appearance of lipid droplets in the liver. Diabetes induced tissue-specific changes in messenger RNAs expression of the following selected genes, which were restored by telmisartan treatment: PPARγ, PPARδ, PPARγ coactivator 1α, adiponectin, adiponectin receptor 1, adiponectin receptor 2, phosphotyrosine binding domain and a pleckstrin homology domain-containing adaptor protein, adenosine monophosphate kinase, and glucose translocator 4. Telmisartan blunted the development of hypertension, insulin resistance, and diabetes in prediabetic Cohen-Rosenthal diabetic hypertensive rats through pleiotropic activity, involving specific gene regulation of target organs. © 2012 Elsevier Inc. All rights reserved. METABOLISM CLINICAL AND EXPERIMENTAL 61 (2012) 164 – 174 Authors' contribution: Firas Younis: designed and performed experimental procedures, data analysis, and writing of the paper. Yoram Oron: closely followed each step of the experiment; contributed to data analysis and revising/editing of article writing. Rona Limor: performed part of the experiments; proof-read the paper. Naftali Stern: data analysis and the medical significance of the findings. Talma Rosenthal: closely followed each step of the experiment; contributed to the writing and scientific assessment of the paper. ⁎ Corresponding author. Tel.: +972 3 6406637; fax: +972 3 6960210. E-mail address: rtalma@post.tau.ac.il (T. Rosenthal). 0026-0495/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.metabol.2011.06.007 Available at www.sciencedirect.com Metabolism www.metabolismjournal.com