[Effects of angiotensin II type 1 receptor blocker on islet of diabetic db/db mice].

OBJECTIVE

Several epidemiological studies suggested that treatment with angiotensin II type 1 receptor blocker provided a risk reduction of developing type 2 diabetes. The aim of this study was to investigate whether and how chronic candesartan treatment can attenuate the deleterious influence of hyperactive local intra-islet renin-angiotensin system in diabetes state and relieve hyperglycemia using diabetic (db/db) mice.

METHODS

8-week-old db/db mice were randomized to candesartan cilexetil 1 mg/kg, candesartan cilexetil 10 mg/kg, manidipine 10 mg/kg, or placebo via gavage for 6 weeks. Their age-matched nondiabetic littermates db/m mice were given with placebo and acted as non-diabetic controls. After 6 weeks of treatment, intraperitoneal glucose tolerance test, immunohistochemical staining of oxidative stress markers, insulin, and electron microscopy observation of the pancreatic islet cells were performed.

RESULTS

Chronic candesartan treatment provided a slight improvement of glucose tolerance, but greatly rescued islet beta-cell mass. Candesartan treatment also notably decreased staining intensity of oxidative stress markers, as well as candesartan-treated animals exhibited improved granulation and less remarkable endoplasmic reticulum and Golgi bodies. Furthermore, candesartan treatment greatly relieved the swelling of mitochondria to nearly normal.

CONCLUSIONS

After diabetes is initiated, candesartan treatment does not reverse the state of diabetes, but it slightly improves glucose tolerance, and protects beta-cell function by attenuating oxidative stress and ultrastructure disruption. These benefits are independent of blood pressure lowering. The characteristics of candesartan may make itself a novel therapeutic means for protecting from progressive beta-cell failure in diabetes.