title: Chronic overeating impairs hepatic glucose uptake and disposition.
abstract: Dogs consuming a hypercaloric high-fat and -fructose diet (52 and 17% of total energy, respectively) or a diet high in either fructose or fat for 4 wk exhibited blunted net hepatic glucose uptake (NHGU) and glycogen deposition in response to hyperinsulinemia, hyperglycemia, and portal glucose delivery. The effect of a hypercaloric diet containing neither fructose nor excessive fat has not been examined. Dogs with an initial weight of ≈25 kg consumed a chow and meat diet (31% protein, 44% carbohydrate, and 26% fat) in weight-maintaining (CTR; n = 6) or excessive (Hkcal; n = 7) amounts for 4 wk (cumulative weight gain 0.0 ± 0.3 and 1.5 ± 0.5 kg, respectively, P < 0.05). They then underwent clamp studies with infusions of somatostatin and intraportal insulin (4× basal) and glucagon (basal). The hepatic glucose load was doubled with peripheral (Pe) glucose infusion for 90 min (P1) and intraportal glucose at 4 mg·kg(-1)·min(-1) plus Pe glucose for the final 90 min (P2). NHGU was blunted (P < 0.05) in Hkcal during both periods (mg·kg(-1)·min(-1); P1: 1.7 ± 0.2 vs. 0.3 ± 0.4; P2: 3.6 ± 0.3 vs. 2.3 ± 0.4, CTR vs. Hkcal, respectively). Terminal hepatic glucokinase catalytic activity was reduced nearly 50% in Hkcal vs. CTR (P < 0.05), although glucokinase protein did not differ between groups. In Hkcal vs. CTR, liver glycogen was reduced 27% (P < 0.05), with a 91% increase in glycogen phosphorylase activity (P < 0.05) but no significant difference in glycogen synthase activity. Thus, Hkcal impaired NHGU and glycogen synthesis compared with CTR, indicating that excessive energy intake, even if the diet is balanced and nutritious, negatively impacts hepatic glucose metabolism.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Katie C
authors.initials: KC
authors.lastname: Coate
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Guillaume
authors.initials: G
authors.lastname: Kraft
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Masakazu
authors.initials: M
authors.lastname: Shiota
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Marta S
authors.initials: MS
authors.lastname: Smith
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Ben
authors.initials: B
authors.lastname: Farmer
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee; Diabetes Research and Training Center, Vanderbilt University School of Medicine, Nashville, Tennessee; and.
authors.forename: Doss W
authors.initials: DW
authors.lastname: Neal
authors.affiliation: Diabetes Research and Training Center, Vanderbilt University School of Medicine, Nashville, Tennessee; and Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Phil
authors.initials: P
authors.lastname: Williams
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee;
authors.forename: Alan D
authors.initials: AD
authors.lastname: Cherrington
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee; genie.moore@vanderbilt.edu.
authors.forename: Mary Courtney
authors.initials: MC
authors.lastname: Moore
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D002908:Chronic Disease; D004285:Dogs; D004435:Eating; D005947:Glucose / Q000493:pharmacokinetics*; D015309:Glucose Clamp Technique; D006963:Hyperphagia / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D015430:Weight Gain
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D005947:Glucose
keywords: glycogen; glycogen phosphorylase; hypercaloric diet; liver