Angiotensin II receptor blocker provides pancreatic beta-cell protection independent of blood pressure lowering in diabetic db/db mice.

Abstract

AIM:

Several epidemiological studies have 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 the hyperactive local intra-islet renin-angiotensin system in the diabetes state.

METHODS:

Eight-week-old db/db mice were randomized to candesartan 1 mg/kg, candesartan 10 mg/kg, manidipine 10 mg/kg, or placebo via gavage for 6 weeks. Their age-matched nondiabetic littermates db/m mice were treated with placebo and acted as nondiabetic controls. After 6 weeks' treatment, an intraperitoneal glucose tolerance test, immunohistochemical staining of oxidative stress markers, insulin, CD31, azan staining and an electron microscopy observation were performed.

RESULTS:

Chronic candesartan treatment provided an improvement of glucose tolerance, and greatly rescued islet beta-cell mass. Candesartan treatment also notably decreased staining intensity of oxidative stress markers, as well as attenuating intra-islet fibrosis and improving blood supply in the islet. In the electron microscopy observation, 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. Both the benefits of reducing oxidative stress and ultrastructure protection were in a dose-dependent and blood pressure-independent manner.

CONCLUSION:

After diabetes was initiated, candesartan treatment could not reverse the state of diabetes, but it effectively improved glucose tolerance and protected beta-cell function by attenuating oxidative stress, islet fibrosis, sparsity of blood supply and ultrastructure disruption in a dose-dependent and blood pressure-independent manner.

• Authors: Jia-qing Shao, Noseki Iwashita, Hong Du, Yang-tian Wang, Yan-yan Wang, Ming Zhao, Jian Wang, Hirotaka Watada, Ryuzo Kawamori
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 28 Issue 2 Pg. 246-57 (Feb 2007) ISSN: 1671-4083 [Print] United States
• PMID: 17241528 (Publication Type: Journal Article, Retracted Publication)

Chemical References

• Angiotensin II Type 1 Receptor Blockers
• Antihypertensive Agents
• Benzimidazoles
• Biphenyl Compounds
• Dihydropyridines
• Insulin
• Nitrobenzenes
• Piperazines
• Tetrazoles
• manidipine
• candesartan

Topics

• Angiotensin II Type 1 Receptor Blockers (pharmacology)
• Animals
• Antihypertensive Agents (pharmacology)
• Benzimidazoles (pharmacology)
• Biphenyl Compounds
• Diabetes Mellitus, Experimental (drug therapy, pathology)
• Dihydropyridines (pharmacology)
• Female
• Fibrosis (pathology)
• Glucose Tolerance Test
• Insulin (analysis)
• Insulin-Secreting Cells (chemistry, drug effects, pathology, ultrastructure)
• Islets of Langerhans (blood supply)
• Male
• Mice
• Nitrobenzenes
• Oxidative Stress
• Piperazines
• Random Allocation
• Renin-Angiotensin System
• Specific Pathogen-Free Organisms
• Tetrazoles (pharmacology)