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.