Improvement of glucose intolerance by combination of pravastatin and olmesartan in type II diabetic KK-A(y) mice.
The effects of the coadministration of pravastatin and an angiotensin type 1 (AT(1)) receptor blocker, olmesartan, on glucose intolerance were examined using type II diabetic mice. Male KK-A(y) mice (8 weeks of age) were treated with pravastatin and/or olmesartan for 2 weeks. An oral glucose tolerance test (OGTT) was performed with an administration of 2 g kg(-1) glucose. Tissue glucose uptake was determined using 2-[(3)H]deoxyglucose. The treatment of mice with pravastatin attenuated the increase in the plasma glucose level during OGTT in a dose-dependent manner, without affecting the plasma insulin level. Pravastatin increased glucose uptake in insulin-sensitive tissue such as the skeletal muscle and adipose tissue after treatment at 5-20 mg kg(-1) day(-1) for 2 weeks, but not at 1 mg kg(-1) day(-1). The combination of a noneffective dose of pravastatin (1 mg kg(-1) day(-1)) and a noneffective dose of olmesartan (0.5 mg kg(-1) day(-1)) synergistically improved OGTT without affecting the plasma insulin level. This combination also increased 2-[(3)H]deoxyglucose uptake in the skeletal muscle and adipose tissue. The effects of pravastatin or olmesartan on OGTT and tissue 2-[(3)H]deoxyglucose uptake were significantly enhanced by an antioxidant, tempol, whereas the effects of a pravastatin-olmesartan combination were not further enhanced by tempol. These results indicate that the combination of pravastatin and olmesartan synergistically improves glucose intolerance through an increase in tissue glucose uptake. The effects seem to be mediated by an increase in insulin sensitivity through the inhibition of oxidative stress.
Kanno
Harumi
H
Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Shitsukawa, Tohon, Ehime 791-0295, Japan.
Iwai
Masaru
M
Inaba
Shinji
S
Senba
Izumi
I
Nakaoka
Hirotomo
H
Sone
Hisako
H
Mogi
Masaki
M
Horiuchi
Masatsugu
M
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D000963:Antimetabolites; D000975:Antioxidants / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology; D003847:Deoxyglucose; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D004359:Drug Therapy, Combination; D018149:Glucose Intolerance / Q000188:drug therapy* / Q000235:genetics; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007093:Imidazoles / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018384:Oxidative Stress / Q000187:drug effects; D017035:Pravastatin / Q000627:therapeutic use*; D013113:Spin Labels; D013777:Tetrazoles / Q000627:therapeutic use*
D047228:Angiotensin II Type 1 Receptor Blockers; D000963:Antimetabolites; D000975:Antioxidants; D001786:Blood Glucose; D003497:Cyclic N-Oxides; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007093:Imidazoles; D007328:Insulin; D013113:Spin Labels; D013777:Tetrazoles; C437965:olmesartan; D003847:Deoxyglucose; D017035:Pravastatin; C001803:tempol