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Impaired Regulation of Hepatic Glucose Disposition by High Dietary Fat and Fructose

dc.creatorCoate, Kathryn Eileen Colbert
dc.description.abstractThe goal of this dissertation was to elucidate the metabolic and hepatocellular consequences associated with chronic consumption of a high-fat, high-fructose diet (HFFD), focusing on perturbations in the regulation of HGU and glycogen synthesis (GSYN) by hyperglycemia (HG), hyperinsulinemia (HI), and portal vein glucose (PoG) delivery. We demonstrated that consumption of a HFFD results in impaired glucose tolerance after 4 weeks of feeding, and renders the liver incapable of switching from net glucose output to uptake despite the presence of HI, HG, and PoG delivery. These findings were replicated in a physiologic mixed-meal setting, in which HFFD-fed dogs exhibited excessive postprandial hyperglycemia in association with accelerated gastric emptying and glucose absorption, impaired suppression of lipolysis, and diminished net HGU. These data prompted us to investigate the molecular explanation for impaired HGU associated with HFFD feeding. In normal dogs, PoG delivery in the presence of HI and HG triggered a coordinated cellular response involving an increase in the activity of hepatic glucokinase (GK) and glycogen synthase (GS), which was associated with further augmentation in HGU and GSYN in vivo. In contrast, 4 weeks of HFFD feeding resulted in biochemical insulin resistance, a marked decrease in GK protein content, and loss of the stimulatory effects of PoG delivery on GK and GS activity. These mechanistic defects correlated with diminished HGU and GSYN in vivo. Finally, we determined that both high dietary fat and fructose (in isoenergetic quantities) impair HGU, GSYN, and GK activity, but the defects were significantly greater in high-fructose-fed than in high-fat-fed dogs. In fact, a selective increase in dietary fructose recapitulated nearly all of the metabolic and cellular defects evident in the combination HFFD group. Altogether, our findings suggest that impaired HGU is one of the early metabolic consequences associated with glucose intolerance induced by consumption of a Western diet, and raise the possibility that nutritional modulation of hepatic GK might be causally linked to impaired regulation of HGU in the early stages of diabetes development.
dc.subjectglucokinase regulatory protein
dc.subjectinsulin signaling
dc.subjectinsulin resistance
dc.subjectglucose tolerance
dc.subjectglycogen synthase
dc.subjecthepatic glucose production
dc.titleImpaired Regulation of Hepatic Glucose Disposition by High Dietary Fat and Fructose
dc.contributor.committeeMemberMasakazu Shiota
dc.contributor.committeeMemberAlyssa H. Hasty
dc.contributor.committeeMemberLarry L. Swift
dc.contributor.committeeMemberOwen P. McGuinness
dc.type.materialtext Physiology and Biophysics University
dc.contributor.committeeChairRichard M. O'Brien

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