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.

We studied the effects of chronic angiotensin 1-7 (Ang 1-7) treatment in an experimental model of the metabolic syndrome, i.e., rats given high-fructose/low-magnesium diet (HFrD). Rats were fed on HFrD for 24 weeks with and without Ang 1-7 (576 µg/kg/day, s.c., Alzet pumps). After 6 months, Ang 1-7-treated animals had lower body weight (-9.5%), total fat mass (detected by magnetic resonance imaging), and serum triglycerides (-51%), improved glucose tolerance, and better insulin sensitivity. Similar metabolic effects were also evident, albeit in the absence of weight loss, in rats first exposed to HFrD for 5 months and then subjected to short-term (4 weeks) treatment with Ang 1-7. Six months of Ang 1-7 treatment were associated with lower plasma renin activity (-40%) and serum aldosterone (-48%), less hepatosteatatitis, and a reduction in epididymal adipocyte volume. The marked attenuation of macrophage infiltration in white adipose tissue (WAT) was associated with reduced levels of the pP65 protein in the epididymal fat tissue, suggesting less activation of the nuclear factor-κB (NFκB) pathway in Ang 1-7-treated rats. WAT from Ang 1-7-treated rats showed reduced NADPH-stimulated superoxide production. In single muscle fibers (myofibers) harvested and grown ex vivo for 10 days, myofibers from HFrD rats gave rise to 20% less myogenic cells than the Ang 1-7-treated rats. Fully developed adipocytes were present in most HFrD myofiber cultures but entirely absent in cultures from Ang 1-7-treated rats. In summary, Ang 1-7 had an ameliorating effect on insulin resistance, hypertriglyceridemia, fatty liver, obesity, adipositis, and myogenic and adipogenic differentiation in muscle tissue in the HFrD rats.