title: Temporal Changes in Skeletal Muscle Capillary Responses and Endothelial-Derived Vasodilators in Obesity-Related Insulin Resistance.
abstract: The inability of insulin to increase skeletal muscle capillary blood volume (CBV) reduces glucose uptake in insulin resistance (IR). We hypothesized that abnormalities in endothelial-derived vasodilator pathways are temporally associated with the development of IR and an impaired ability to increase skeletal muscle CBV. A comprehensive metabolic and vascular screening assessment was performed on 10 adult rhesus macaques at baseline and every 4-6 months for 2 years after starting a high-fat diet supplemented with fructose. Diet changes resulted in an 80% increase in truncal fat by 4 months. Hyperinsulinemia and decreased glucose utilization were observed from 4 to 18 months. At 24 months, pancreatic secretory function and the glucose utilization rate declined. CBV at rest and during an intravenous glucose tolerance test demonstrated a sustained increase from 4 to 18 months and then abruptly fell at 24 months. Nitric oxide bioavailability progressively decreased over 2 years. Conversely, endothelial-derived vasodilators progressively increased over 18 months and then abruptly decreased at 24 months in concert with the CBV. The increase in basal and glucose-mediated CBV early in IR may represent a compensatory response through endothelial-derived vasodilator pathways. The inability to sustain a vascular compensatory response limits glucose-mediated increases in CBV, which correlates with the severity of IR.
authors.affiliation: Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR chadderd@ohsu.edu.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Chadderdon
authors.affiliation: Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR.
authors.forename: J Todd
authors.initials: JT
authors.lastname: Belcik
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Bader
authors.affiliation: Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Peters
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR.
authors.forename: Paul
authors.initials: P
authors.lastname: Kievit
authors.affiliation: Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR.
authors.forename: Nabil J
authors.initials: NJ
authors.lastname: Alkayed
authors.affiliation: Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR.
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Kaul
authors.affiliation: Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Grove
authors.affiliation: Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Lindner
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D015777:Eicosanoids / Q000378:metabolism; D005632:Fructose / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006946:Hyperinsulinism / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008253:Macaca mulatta; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D015777:Eicosanoids; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D005632:Fructose; D009569:Nitric Oxide; D005947:Glucose