title: Losartan increases muscle insulin delivery and rescues insulin's metabolic action during lipid infusion via microvascular recruitment.
abstract: Insulin delivery and transendothelial insulin transport are two discrete steps that limit muscle insulin action. Angiotensin II type 1 receptor (AT1R) blockade recruits microvasculature and increases glucose use in muscle. Increased muscle microvascular perfusion is associated with increased muscle delivery and action of insulin. To examine the effect of acute AT1R blockade on muscle insulin uptake and action, rats were studied after an overnight fast to examine the effects of losartan on muscle insulin uptake (protocol 1), microvascular perfusion (protocol 2), and insulin's microvascular and metabolic actions in the state of insulin resistance (protocol 3). Endothelial cell insulin uptake was assessed, using (125)I-insulin as tracer. Systemic lipid infusion was used to induce insulin resistance. Losartan significantly increased muscle insulin uptake (∼60%, P < 0.03), which was associated with a two- to threefold increase in muscle microvascular blood volume (MBV; P = 0.002) and flow (MBF; P = 0.002). Losartan ± angiotensin II had no effect on insulin internalization in cultured endothelial cells. Lipid infusion abolished insulin-mediated increases in muscle MBV and MBF and lowered insulin-stimulated whole body glucose disposal (P = 0.0001), which were reversed by losartan administration. Inhibition of nitric oxide synthase abolished losartan-induced muscle insulin uptake and reversal of lipid-induced metabolic insulin resistance. We conclude that AT1R blockade increases muscle insulin uptake mainly via microvascular recruitment and rescues insulin's metabolic action in the insulin-resistant state. This may contribute to the clinical findings of decreased cardiovascular events and new onset of diabetes in patients receiving AT1R blockers.
authors.affiliation: Div. of Endocrinology and Metabolism, Dept. of Medicine, Univ. of Virginia Health System, Charlottesville, VA 22908, USA.
authors.forename: Nasui
authors.initials: N
authors.lastname: Wang
authors.forename: Weidong
authors.initials: W
authors.lastname: Chai
authors.forename: Lina
authors.initials: L
authors.lastname: Zhao
authors.forename: Lijian
authors.initials: L
authors.lastname: Tao
authors.forename: Wenhong
authors.initials: W
authors.lastname: Cao
authors.forename: Zhenqi
authors.initials: Z
authors.lastname: Liu
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology*; D008055:Lipids / Q000494:pharmacology*; D019808:Losartan / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D018482:Muscle, Skeletal / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000097:blood / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D008055:Lipids; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D051057:Proto-Oncogene Proteins c-akt; D019808:Losartan; D019331:NG-Nitroarginine Methyl Ester