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


CONCLUSIONS
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.
Shao
Jia-qing
JQ
Department of Endocrinology and Metabolism, Nanjing General Hospital of Nanjing Command, Nanjing 210002, China. shaojiaq@hotmail.com
Iwashita
Noseki
N
Du
Hong
H
Wang
Yang-tian
YT
Wang
Yan-yan
YY
Zhao
Ming
M
Wang
Jian
J
Watada
Hirotaka
H
Kawamori
Ryuzo
R
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000473:pathology; D004095:Dihydropyridines / Q000494:pharmacology*; D005260:Female; D005355:Fibrosis / Q000473:pathology; D005951:Glucose Tolerance Test; D007328:Insulin / Q000032:analysis; D050417:Insulin-Secreting Cells / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D007515:Islets of Langerhans / Q000098:blood supply; D008297:Male; D051379:Mice; D009578:Nitrobenzenes; D018384:Oxidative Stress; D010879:Piperazines; D011897:Random Allocation; D012084:Renin-Angiotensin System; D013047:Specific Pathogen-Free Organisms; D013777:Tetrazoles / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D004095:Dihydropyridines; D007328:Insulin; D009578:Nitrobenzenes; D010879:Piperazines; D013777:Tetrazoles; C054218:manidipine; C081643:candesartan