title: Calcium channel blocker azelnidipine reduces glucose intolerance in diabetic mice via different mechanism than angiotensin receptor blocker olmesartan.
abstract: The potential combined effect and mechanism of calcium channel blockers (CCB) and angiotensin II type 1 receptor blockers (ARB) to improve insulin resistance were investigated in type 2 diabetic KK-Ay mice, focusing on their antioxidative action. Treatment of KK-Ay mice with a CCB, azelnidipine (3 mg/kg/day), or with an ARB, olmesartan (3 mg/kg/day), for 2 weeks lowered the plasma concentrations of glucose and insulin in the fed state, attenuated the increase in plasma glucose in the oral glucose tolerance test (OGTT), and increased 2-[(3)H]deoxy-d-glucose (2-[(3)H]DG) uptake into skeletal muscle with the increase in translocation of glucose transporter 4 (GLUT4) to the plasma membrane. Both blockers also decreased the in situ superoxide production in skeletal muscle. The decrease in plasma concentrations of glucose and insulin in the fed state and superoxide production in skeletal muscle, as well as GLUT4 translocation to the plasma membrane, after azelnidipine administration was not significantly affected by coadministration of an antioxidant, 2,2,6,6-tetramethyl-1-piperidinyloxy (tempol). However, those changes caused by olmesartan were further improved by tempol. Moreover, olmesartan enhanced the insulin-induced tyrosine phosphorylation of insulin receptor substrate-1 induced in skeletal muscle, whereas azelnidipine did not change it. Coadministration of azelnidipine and olmesartan further decreased the plasma concentrations of glucose and insulin, improved OGTT, and increased 2-[(3)H]DG uptake in skeletal muscle. These results suggest that azelnidipine improved glucose intolerance mainly through inhibition of oxidative stress and enhanced the inhibitory effects of olmesartan on glucose intolerance, as well as the clinical possibility that the combination of CCB and ARB could be more effective than monotherapy in the treatment of insulin resistance.
authors.affiliation: Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Shitsukawa, Tohon, Ehime 791-0295, Japan.
authors.forename: Masarsu
authors.initials: M
authors.lastname: Iwai
authors.forename: Huan-Sheng
authors.initials: HS
authors.lastname: Li
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Shiuchi
authors.forename: Lan
authors.initials: L
authors.lastname: Wu
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Min
authors.forename: Jian-Mei
authors.initials: JM
authors.lastname: Li
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tsuda
authors.forename: Jun
authors.initials: J
authors.lastname: Suzuki
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Tomono
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tomochika
authors.forename: Masaki
authors.initials: M
authors.lastname: Mogi
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003497:Cyclic N-Oxides / Q000494:pharmacology; D003847:Deoxyglucose / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D004095:Dihydropyridines / Q000494:pharmacology*; D018149:Glucose Intolerance / Q000188:drug therapy*; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000963:Antimetabolites; D000975:Antioxidants; D001786:Blood Glucose; D002121:Calcium Channel Blockers; D003497:Cyclic N-Oxides; D004095:Dihydropyridines; D051275:Glucose Transporter Type 4; D007093:Imidazoles; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D013113:Spin Labels; D013777:Tetrazoles; D013481:Superoxides; D001383:Azetidinecarboxylic Acid; C437965:olmesartan; D003847:Deoxyglucose; C061679:azelnidipine; C001803:tempol