scholarly journals Chronic consumption of a high-fat/high-fructose diet renders the liver incapable of net hepatic glucose uptake

2010 ◽  
Vol 299 (6) ◽  
pp. E887-E898 ◽  
Author(s):  
Katie Colbert Coate ◽  
Melanie Scott ◽  
Ben Farmer ◽  
Mary Courtney Moore ◽  
Marta Smith ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Glycogen Synthesis ◽  
Large Animal Model ◽  
Oral Glucose ◽  
Large Animal ◽  
High Fructose ◽  
Hepatic Glucose ◽  
Glucose Tolerance Tests ◽  
Hepatic Glucose Uptake ◽  
Average Glucose

The objective of this study was to assess the response of a large animal model to high dietary fat and fructose (HFFD). Three different metabolic assessments were performed during 13 wk of feeding an HFFD ( n = 10) or chow control (CTR, n = 4) diet: oral glucose tolerance tests (OGTTs; baseline, 4 and 8 wk), hyperinsulinemic-euglycemic clamps (HIEGs; baseline and 10 wk) and hyperinsulinemic-hyperglycemic clamps (HIHGs, 13 wk). The ΔAUC for glucose during the OGTTs more than doubled after 4 and 8 wk of HFFD feeding, and the average glucose infusion rate required to maintain euglycemia during the HIEG clamps decreased by ≈30% after 10 wk of HFFD feeding. These changes did not occur in the CTR group. The HIHG clamps included experimental periods 1 (P1, 0–90 min) and 2 (P2, 90–180 min). During P1, somatostatin, basal intraportal glucagon, 4 × basal intraportal insulin, and peripheral glucose (to double the hepatic glucose load) were infused; during P2, glucose was also infused intraportally (4.0 mg·kg−1·min−1). Net hepatic glucose uptake during P1 and P2 was −0.4 ± 0.1 [output] and 0.2 ± 0.8 mg·kg−1·min−1 in the HFFD group, respectively, and 1.8 ± 0.8 and 3.5 ± 1.0 mg·kg−1·min−1 in the CTR group, respectively ( P < 0.05 vs. HFFD during P1 and P2). Glycogen synthesis through the direct pathway was 0.5 ± 0.2 and 1.5 ± 0.4 mg·kg−1·min−1 in the HFFD and CTR groups, respectively ( P < 0.05 vs. HFFD). In conclusion, chronic consumption of an HFFD diminished the sensitivity of the liver to hormonal and glycemic cues and resulted in a marked impairment in NHGU and glycogen synthesis.

Hepatic glucose metabolism during intraduodenal glucose infusion: impact of infection

2000 ◽  
Vol 279 (1) ◽  
pp. E108-E115
Author(s):  
Owen P. McGuinness ◽  
Joseph Ejiofor ◽  
D. Brooks Lacy ◽  
Nancy Schrom
Keyword(s):  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Glycogen Synthesis ◽  
Fibrin Clot ◽  
Glucose Absorption ◽  
Glucose Infusion ◽  
Hepatic Glucose Metabolism ◽  
Hepatic Glucose ◽  
Glycogen Deposition ◽  
Hepatic Glucose Uptake

We previously reported that infection decreases hepatic glucose uptake when glucose is given as a constant peripheral glucose infusion (8 mg · kg−1· min−1). This impairment persisted despite greater hyperinsulinemia in the infected group. In a normal setting, hepatic glucose uptake can be further enhanced if glucose is given gastrointestinally. Thus the aim of this study was to determine whether hepatic glucose uptake is impaired during an infection when glucose is given gastrointestinally. Thirty-six hours before study, a sham (SH, n = 7) or Escherichia coli-containing (2 × 109organisms/kg; INF; n = 7) fibrin clot was placed in the peritoneal cavity of chronically catheterized dogs. After the 36 h, a glucose bolus (150 mg/kg) followed by a continuous infusion (8 mg · kg−1· min−1) of glucose was given intraduodenally to conscious dogs for 240 min. Tracer ([3-3H]glucose and [U-14C]glucose) and arterial-venous difference techniques were used to assess hepatic and intestinal glucose metabolism. Infection increased hepatic blood flow (35 ± 5 vs. 47 ± 3 ml · kg−1· min−1; SH vs. INF) and basal glucose rate of appearance (2.1 ± 0.2 vs. 3.3 ± 0.1 mg · kg−1· min−1). Arterial insulin concentrations increased similarly in SH and INF during the last hour of glucose infusion (38 ± 8 vs. 46 ± 20 μU/ml), and arterial glucagon concentrations fell (62 ± 14 to 30 ± 3 vs. 624 ± 191 to 208 ± 97 pg/ml). Net intestinal glucose absorption was decreased in INF, attenuating the increase in blood glucose caused by the glucose load. Despite this, net hepatic glucose uptake (1.6 ± 0.8 vs. 2.4 ± 0.9 mg · kg−1· min−1; SH vs. INF) and consequently tracer-determined glycogen synthesis (1.3 ± 0.3 vs. 1.0 ± 0.3 mg · kg−1· min−1) were similar between groups. In summary, infection impairs net glucose absorption, but not net hepatic glucose uptake or glycogen deposition, when glucose is given intraduodenally.

Differential effect of amino acid infusion route on net hepatic glucose uptake in the dog

1999 ◽  
Vol 276 (2) ◽  
pp. E295-E302 ◽  
Author(s):  
Mary Courtney Moore ◽  
Po-Shiuan Hsieh ◽  
Paul J. Flakoll ◽  
Doss W. Neal ◽  
Alan D. Cherrington
Keyword(s):  
Amino Acid ◽  
Glucose Uptake ◽  
Glycogen Synthesis ◽  
Hepatic Glycogen ◽  
Acid Infusion ◽  
Amino Acid Infusion ◽  
Arterial Blood ◽  
Hepatic Glucose ◽  
Hepatic Glucose Uptake ◽  
Portal Infusion

Concomitant portal infusion of gluconeogenic amino acids (GNGAA) and glucose significantly reduces net hepatic glucose uptake (NHGU), in comparison with NHGU during portal infusion of glucose alone. To determine whether this effect on NHGU is specific to the portal route of GNGAA delivery, somatostatin, intraportal insulin (3-fold basal) and glucagon (basal), and intraportal glucose (to increase the hepatic glucose load by ∼50%) were infused for 240 min. GNGAA were infused peripherally into a group of dogs (PeAA), at a rate to match the hepatic GNGAA load in a group of dogs that were given the same GNGAA mixture intraportally (PoAA) at 7.6 μmol ⋅ kg−1 ⋅ min−1(9). The arterial blood glucose concentrations and hepatic glucose loads were the same in the two groups, but NHGU (−0.9 ± 0.2 PoAA and −2.1 ± 0.5 mg ⋅ kg−1 ⋅ min−1in PeAA, P < 0.05) and net hepatic fractional extraction of glucose (2.6 ± 0.7% in PoAA vs. 5.9 ± 1.4% in PeAA, P < 0.05) differed. Neither the hepatic loads nor the net hepatic uptakes of GNGAA were significantly different in the two groups. Net hepatic glycogen synthesis was ∼2.5-fold greater in PeAA than PoAA ( P < 0.05). Intraportal, but not peripheral, amino acid infusion suppresses NHGU and net hepatic glycogen synthesis in response to intraportal glucose infusion.

scholarly journals A physiological increase in the hepatic glycogen level does not affect the response of net hepatic glucose uptake to insulin

2009 ◽  
Vol 297 (2) ◽  
pp. E358-E366 ◽  
Author(s):  
Jason J. Winnick ◽  
Zhibo An ◽  
Mary Courtney Moore ◽  
Christopher J. Ramnanan ◽  
Ben Farmer ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Glycogen Synthesis ◽  
Control Period ◽  
In Vivo Studies ◽  
Hepatic Glycogen ◽  
Glycogen Level ◽  
Hepatic Glucose ◽  
Glycogen Deposition ◽  
Hepatic Glucose Uptake

To determine the effect of an acute increase in hepatic glycogen on net hepatic glucose uptake (NHGU) and disposition in response to insulin in vivo, studies were performed on two groups of dogs fasted 18 h. During the first 4 h of the study, somatostatin was infused peripherally, while insulin and glucagon were replaced intraportally in basal amounts. Hyperglycemia was brought about by glucose infusion, and either saline ( n = 7) or fructose ( n = 7; to stimulate NHGU and glycogen deposition) was infused intraportally. A 2-h control period then followed, during which the portal fructose and saline infusions were stopped, allowing NHGU and glycogen deposition in the fructose-infused animals to return to rates similar to those of the animals that received the saline infusion. This was followed by a 2-h experimental period, during which hyperglycemia was continued but insulin infusion was increased fourfold in both groups. During the initial 4-h glycogen loading period, NHGU averaged 1.18 ± 0.27 and 5.55 ± 0.53 mg·kg−1·min−1 and glycogen synthesis averaged 0.72 ± 0.24 and 3.98 ± 0.57 mg·kg−1·min−1 in the saline and fructose groups, respectively ( P < 0.05). During the 2-h hyperinsulinemic period, NHGU rose from 1.5 ± 0.4 and 0.9 ± 0.2 to 3.1 ± 0.6 and 2.5 ± 0.5 mg·kg−1·min−1 in the saline and fructose groups, respectively, a change of 1.6 mg·kg−1·min−1 in both groups despite a significantly greater liver glycogen level in the fructose-infused group. Likewise, the metabolic fate of the extracted glucose (glycogen, lactate, or carbon dioxide) was not different between groups. These data indicate that an acute physiological increase in the hepatic glycogen content does not alter liver glucose uptake and storage under hyperglycemic/hyperinsulinemic conditions in the dog.

scholarly journals Hepatic-Directed Vesicle Insulin: A Review of Formulation Development and Preclinical Evaluation

2009 ◽  
Vol 3 (6) ◽  
pp. 1451-1459 ◽  
Author(s):  
W. Blair Geho ◽  
Hans C. Geho ◽  
John R. Lau ◽  
Theophilus J. Gana
Keyword(s):  
Glucose Uptake ◽  
Evaluation Studies ◽  
Phospholipid Bilayer ◽  
Oral Glucose ◽  
Formulation Development ◽  
Genetic Toxicology ◽  
Preclinical Evaluation ◽  
Hepatic Glucose ◽  
Glucose Output ◽  
Hepatic Glucose Uptake

Hepatic-directed vesicle insulin (HDV-I), a novel investigational vesicle (<150 nm diameter) insulin delivery system that carries insulin and a specific hepatocyte-targeting molecule (HTM) in its phospholipid bilayer and has the ability to mimic a portal vein insulin infusion remotely [subcutaneous (SC) HDV-I] and noninvasively (oral HDV-I), has been developed. This review summarizes formulation development, subsequent refinements, and results of preclinical evaluation studies, including biodistribution, mechanistic, and toxicology studies of predominantly SC HDV-I, in various animal models. Studies conducted to date have confirmed the hepatocyte specificity of HDV and HDV-I and revealed that HDV-I can stimulate the conversion of hepatic glucose output to uptake at a dose that is <1% of the dose of regular insulin (RI) required for liver stimulation; suggest that the enhanced antihyperglycemic effect of HDV-I is due to hepatic glucose uptake; and in pancreatectomized dogs during an oral glucose tolerance test, HDV-I normalized blood glucose curves when compared to control curves in intact dogs and prevented secondary hypoglycemia in contrast to the same dose of RI. A 28-day SC HDV toxicity study in rats revealed no clinical, clinical laboratory, or histopathological findings, and the battery of three genetic toxicology studies was negative. Results support the hypothesis that HDV-I works by stimulating hepatic glucose uptake and/or glycogen storage in insulin-deficient animals. The ability to target the delivery of HDV-I to the liver reestablishes the liver as a major metabolic modulator of glucose metabolism. The future of HDV-I depends on the results of ongoing development and longer term clinical trials.

scholarly journals Chronic overeating impairs hepatic glucose uptake and disposition

2015 ◽  
Vol 308 (10) ◽  
pp. E860-E867 ◽  
Author(s):  
Katie C. Coate ◽  
Guillaume Kraft ◽  
Masakazu Shiota ◽  
Marta S. Smith ◽  
Ben Farmer ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Liver Glycogen ◽  
Hepatic Glucose Metabolism ◽  
Significant Difference ◽  
Hepatic Glucose ◽  
Glycogen Deposition ◽  
Hepatic Glucose Uptake ◽  
Glycogen Phosphorylase Activity

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.

scholarly journals Hepatic glucose uptake and disposition during short-term high-fat vs. high-fructose feeding

2014 ◽  
Vol 307 (2) ◽  
pp. E151-E160 ◽  
Author(s):  
Katie C. Coate ◽  
Guillaume Kraft ◽  
Mary Courtney Moore ◽  
Marta S. Smith ◽  
Christopher Ramnanan ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Glycogen Synthase ◽  
Liver Glycogen ◽  
Glucose Infusion ◽  
High Fat ◽  
Akt Phosphorylation ◽  
High Fructose ◽  
Hepatic Glucose ◽  
Hepatic Glucose Uptake ◽  
The Impact

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.

Neural and pancreatic influences on net hepatic glucose uptake and glycogen synthesis

1996 ◽  
Vol 271 (2) ◽  
pp. E215-E222 ◽  
Author(s):  
M. C. Moore ◽  
L. Rossetti ◽  
M. J. Pagliassotti ◽  
M. Monahan ◽  
C. Venable ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Glycogen Synthesis ◽  
Area Under The Curve ◽  
Glucose Infusion ◽  
Hepatic Glycogen ◽  
Fourfold Increase ◽  
Direct Pathway ◽  
Hepatic Glucose ◽  
Hepatic Glucose Uptake ◽  
Liver Nerves

The role of the liver nerves in the disposition of peripherally administered glucose was examined in seven hepatic innervated (HI) and nine hepatic denervated (HD) 42-h-fasted conscious dogs. After a 40-min basal period, there was a 4-h experimental period during which the hepatic glucose load was increased twofold via peripheral glucose infusion. Somatostatin was infused to suppress pancreatic endocrine secretion, and insulin and glucagon were infused intraportally to produce a fourfold increase in insulin and a gradual decrease (approximately 25%) in glucagon. The area under the curve of net hepatic glucose uptake (NHGU) during the glucose infusion period totaled 483 +/- 82 and 335 +/- 32 mg/kg in HD and HI, respectively (P < 0.05). The area under the curve of the hepatic fractional extraction of glucose was 27% greater in HD (P < 0.05). Net hepatic lactate output was similar in the two groups, and net hepatic glycogen synthesis was 3.8 +/- 0.8 vs. 2.7 +/- 0.5 mg.kg dog wt-1.min-1 in HD and HI, respectively (P = 0.13). The direct pathway of glycogen synthesis was responsible for 54-58% of net hepatic glycogen synthesis in both HI and HD (n = 6 for both). In summary 1) NHGU in response to peripheral glucose infusion was approximately 44% greater in HD than in HI, 2) net hepatic glycogen synthesis was enhanced by 41% in HD although the probability of this change was 0.13, and 3) the contribution of the direct pathway to glycogen synthesis was the same in HD and HI. These data are consistent with a role for the liver nerves in regulating the magnitude of NHGU in response to glucose administration. They also indicate that the absence of liver nerves may reduce glycogen turnover during glucose infusion.

Hepatic glucose disposition during concomitant portal glucose and amino acid infusions in the dog

1998 ◽  
Vol 274 (5) ◽  
pp. E893-E902 ◽  
Author(s):  
Mary Courtney Moore ◽  
Paul J. Flakoll ◽  
Po-Shiuan Hsieh ◽  
Michael J. Pagliassotti ◽  
Doss W. Neal ◽  
...  
Keyword(s):  
Amino Acid ◽  
Glucose Uptake ◽  
Glycogen Synthesis ◽  
Experimental Period ◽  
Hepatic Glycogen ◽  
Blood Concentrations ◽  
Amino Acid Infusion ◽  
Arterial Blood ◽  
Hepatic Glucose ◽  
Hepatic Glucose Uptake

The effect of concomitant intraportal infusion of glucose and gluconeogenic amino acids (AA) on net hepatic glucose uptake (NHGU) and glycogen synthesis was examined in 42-h-fasted dogs. After a basal period, there was a 240-min experimental period during which somatostatin was infused continuously into a peripheral vein and insulin and glucagon (at 3-fold basal and basal rates, respectively) and glucose (18.3 μmol ⋅ kg−1⋅ min−1) were infused intraportally. One group (PoAA, n = 7) received an AA mixture intraportally at 7.6 μmol ⋅ kg−1⋅ min−1, whereas the other group (NoAA, n = 6) did not receive AA. Arterial blood glucose concentrations and hepatic glucose loads were the same in the two groups. NHGU averaged 4.8 ± 2.0 (PoAA) and 9.4 ± 2.0 (NoAA) μmol ⋅ kg−1⋅ min−1( P < 0.05), and tracer-determined hepatic glucose uptake was 4.6 ± 1.6 (PoAA) and 10.0 ± 1.7 (NoAA) μmol ⋅ kg−1⋅ min−1( P < 0.05). AA data for PoAA and NoAA, respectively, were as follows: arterial blood concentrations, 1,578 ± 133 vs. 1,147 ± 86 μM ( P < 0.01); hepatic loads, 56 ± 3 vs. 32 ± 4 μmol ⋅ kg−1⋅ min−1( P < 0.01); and net hepatic uptakes, 14.1 ± 1.4 vs. 5.6 ± 0.4 μmol ⋅ kg−1⋅ min−1( P < 0.01). The rate of net hepatic glycogen synthesis was 7.5 ± 1.9 (PoAA) vs. 10.7 ± 2.3 (NoAA) μmol ⋅ kg−1⋅ min−1( P = 0.1). In a net sense, intraportal gluconeogenic amino acid delivery directed glucose carbon away from the liver. Despite this, net hepatic carbon uptake was equivalent in the presence and absence of amino acid infusion.

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