Browsing by Author "Farmer, Ben"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Hepatic glucose uptake and disposition during short-term high-fat vs. high-fructose feeding
    (American Physiological Society (APS), 2014-07-15) Coate, Katie C.; Kraft, Guillaume; Moore, Mary Courtney; Smith, Marta S.; Ramnanan, Christopher; Irimia, Jose M.; Roach, Peter J.; Farmer, Ben; Neal, Doss W.; Williams, Phil; Cherrington, Alan D.; Department of Biochemistry & Molecular Biology, IU School of Medicine
    In dogs consuming a high-fat and -fructose diet (52 and 17% of total energy, respectively) for 4 wk, hepatic glucose uptake (HGU) in response to hyperinsulinemia, hyperglycemia, and portal glucose delivery is markedly blunted with reduction in glucokinase (GK) protein and glycogen synthase (GS) activity. The present study compared the impact of selective increases in dietary fat and fructose on liver glucose metabolism. Dogs consumed weight-maintaining chow (CTR) or hypercaloric high-fat (HFA) or high-fructose (HFR) diets diet for 4 wk before undergoing clamp studies with infusion of somatostatin and intraportal insulin (3–4 times basal) and glucagon (basal). The hepatic glucose load (HGL) was doubled during the clamp using peripheral vein (Pe) glucose infusion in the first 90 min (P1) and portal vein (4 mg·kg−1·min−1) plus Pe glucose infusion during the final 90 min (P2). During P2, HGU was 2.8 ± 0.2, 1.0 ± 0.2, and 0.8 ± 0.2 mg·kg−1·min−1 in CTR, HFA, and HFR, respectively (P < 0.05 for HFA and HFR vs. CTR). Compared with CTR, hepatic GK protein and catalytic activity were reduced (P < 0.05) 35 and 56%, respectively, in HFA, and 53 and 74%, respectively, in HFR. Liver glycogen concentrations were 20 and 38% lower in HFA and HFR than CTR (P < 0.05). Hepatic Akt phosphorylation was decreased (P < 0.05) in HFA (21%) but not HFR. Thus, HFR impaired hepatic GK and glycogen more than HFA, whereas HFA reduced insulin signaling more than HFR. HFA and HFR effects were not additive, suggesting that they act via the same mechanism or their effects converge at a saturable step.
  • Thumbnail Image
    Item
    A Soluble Guanylate Cyclase–Dependent Mechanism Is Involved in the Regulation of Net Hepatic Glucose Uptake by Nitric Oxide in Vivo
    (American Diabetes Association, 2010-09-07) An, Zhibo; Winnick, Jason J.; Farmer, Ben; Neal, Doss; Lautz, Margaret; Irimia, Jose M.; Roach, Peter J.; Cherrington, Alan D.; Biochemistry and Molecular Biology, School of Medicine
    OBJECTIVE We previously showed that elevating hepatic nitric oxide (NO) levels reduced net hepatic glucose uptake (NHGU) in the presence of portal glucose delivery, hyperglycemia, and hyperinsulinemia. The aim of the present study was to determine the role of a downstream signal, soluble guanylate cyclase (sGC), in the regulation of NHGU by NO. RESEARCH DESIGN AND METHODS Studies were performed on 42-h–fasted conscious dogs fitted with vascular catheters. At 0 min, somatostatin was given peripherally along with 4× basal insulin and basal glucagon intraportally. Glucose was delivered at a variable rate via a leg vein to double the blood glucose level and hepatic glucose load throughout the study. From 90 to 270 min, an intraportal infusion of the sGC inhibitor 1H-[1,2,4] oxadiazolo[4,3-a] quinoxalin-1-one (ODQ) was given in −sGC (n = 10) and −sGC/+NO (n = 6), whereas saline was given in saline infusion (SAL) (n = 10). The −sGC/+NO group also received intraportal SIN-1 (NO donor) to elevate hepatic NO from 180 to 270 min. RESULTS In the presence of 4× basal insulin, basal glucagon, and hyperglycemia (2× basal ), inhibition of sGC in the liver enhanced NHGU (mg/kg/min; 210–270 min) by ∼55% (2.9 ± 0.2 in SAL vs. 4.6 ± 0.5 in −sGC). Further elevating hepatic NO failed to reduce NHGU (4.5 ± 0.7 in −sGC/+NO). Net hepatic carbon retention (i.e., glycogen synthesis; mg glucose equivalents/kg/min) increased to 3.8 ± 0.2 in −sGC and 3.8 ± 0.4 in −sGC/+NO vs. 2.4 ± 0.2 in SAL (P < 0.05). CONCLUSIONS NO regulates liver glucose uptake through a sGC-dependent pathway. The latter could be a target for pharmacologic intervention to increase meal-associated hepatic glucose uptake in individuals with type 2 diabetes.