Portal Vein Glucose Entry Triggers a Coordinated Cellular Response That Potentiates Hepatic Glucose Uptake and Storage in Normal but Not High-Fat/High-Fructose-Fed Dogs

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.

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A High-Fat, High-Fructose Diet Accelerates Nutrient Absorption and Impairs Net Hepatic Glucose Uptake in Response to a Mixed Meal in Partially Pancreatectomized Dogs

Journal of Nutrition ◽

10.3945/jn.111.145359 ◽

2011 ◽

Vol 141 (9) ◽

pp. 1643-1651 ◽

Cited By ~ 23

Author(s):

Katie Colbert Coate ◽

Guillaume Kraft ◽

Margaret Lautz ◽

Marta Smith ◽

Doss W. Neal ◽

...

Keyword(s):

Glucose Uptake ◽

Nutrient Absorption ◽

High Fat ◽

Mixed Meal ◽

High Fructose Diet ◽

High Fructose ◽

Hepatic Glucose ◽

Pancreatectomized Dogs ◽

Hepatic Glucose Uptake

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Prior exercise increases net hepatic glucose uptake during a glucose load

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.276.6.e1022 ◽

1999 ◽

Vol 276 (6) ◽

pp. E1022-E1029 ◽

Cited By ~ 8

Author(s):

Pietro Galassetti ◽

Robert H. Coker ◽

Drury B. Lacy ◽

Alan D. Cherrington ◽

David H. Wasserman

Keyword(s):

Portal Vein ◽

Glucose Uptake ◽

Control Period ◽

Vena Cava ◽

Experimental Period ◽

Glucose Infusion ◽

Glucose Load ◽

Prior Exercise ◽

Hepatic Glucose ◽

Hepatic Glucose Uptake

The aim of these studies was to determine whether prior exercise enhances net hepatic glucose uptake (NHGU) during a glucose load. Sampling catheters (carotid artery, portal, hepatic, and iliac veins), infusion catheters (portal vein and vena cava), and Doppler flow probes (portal vein, hepatic and iliac arteries) were implanted. Exercise (150 min; n = 6) or rest ( n = 6) was followed by a 30-min control period and a 100-min experimental period (3.5 mg ⋅ kg−1⋅ min−1of glucose in portal vein and as needed in vena cava to clamp arterial blood glucose at ∼130 mg/dl). Somatostatin was infused, and insulin and glucagon were replaced intraportally at fourfold basal and basal rates, respectively. During experimental period the arterial-portal venous (a-pv) glucose gradient (mg/dl) was −18 ± 1 in sedentary and −19 ± 1 in exercised dogs. Arterial insulin and glucagon were similar in the two groups. Net hepatic glucose balance (mg ⋅ kg−1⋅ min−1) shifted from 1.9 ± 0.2 in control period to −1.8 ± 0.2 (negative rates represent net uptake) during experimental period in sedentary dogs (Δ3.7 ± 0.5); with prior exercise it shifted from 4.1 ± 0.3 ( P < 0.01 vs. sedentary) in control period to −3.2 ± 0.4 ( P < 0.05 vs. sedentary) during experimental period (Δ7.3 ± 0.7, P < 0.01 vs. sedentary). Net hindlimb glucose uptake (mg/min) was 4 ± 1 in sedentary animals in control period and 13 ± 2 during experimental period; in exercised animals it was 7 ± 1 in control period ( P < 0.01 vs. sedentary) and 32 ± 4 ( P < 0.01 vs. sedentary) during experimental period. As the total glucose infusion rate (mg ⋅ kg−1⋅ min−1) was 7 ± 1 in sedentary and 11 ± 1 in exercised dogs, ∼30% of the added glucose infusion due to prior exercise could be accounted for by the greater NHGU. In conclusion, when determinants of hepatic glucose uptake (insulin, glucagon, a-pv glucose gradient, glycemia) are controlled, prior exercise increases NHGU during a glucose load due to an effect that is intrinsic to the liver. Increased glucose disposal in the postexercise state is therefore due to an improved ability of both liver and muscle to take up glucose.

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00372.2010 ◽

2010 ◽

Vol 299 (6) ◽

pp. E887-E898 ◽

Cited By ~ 30

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.

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The Importance of the Mechanisms by which Insulin Regulates Meal-Associated Liver Glucose Uptake in the Dog

10.2337/figshare.14242049 ◽

2021 ◽

Author(s):

Guillaume Kraft ◽

Katie C. Coate ◽

Marta Smith ◽

Ben Farmer ◽

Melanie Scott ◽

...

Keyword(s):

Portal Vein ◽

Glucose Uptake ◽

Insulin Action ◽

Insulin Infusion ◽

Insulin Receptors ◽

Postprandial Glucose ◽

Maximal Stimulation ◽

Hepatic Glucose ◽

Healthy Dogs ◽

Hepatic Glucose Uptake

Hepatic glucose uptake (HGU) is critical for maintaining normal postprandial glucose metabolism. Insulin is clearly a key regulator of HGU, but the physiologic mechanisms by which it acts have yet to be established. This study sought to determine the mechanisms by which insulin regulates liver glucose uptake under postprandial-like conditions (hyperinsulinemia, hyperglycemia, and a positive portal vein to arterial glucose gradient). Portal vein insulin infusion increased hepatic insulin levels 5-fold in healthy dogs. In one group (n=7), the physiologic response was allowed to fully occur, while in another (n=7), insulin’s indirect hepatic effects, occurring secondary to its actions on adipose tissue, pancreas, and brain, were blocked. This was accomplished by infusing triglyceride (intravenous), glucagon (portal vein), and inhibitors of brain insulin action (intracerebroventricular) to prevent decreases in plasma free fatty acids or glucagon, while blocking increased hypothalamic insulin signaling for 4h. In contrast to the indirect hepatic effects of insulin, which were previously shown capable of independently generating a half-maximal stimulation of HGU, direct hepatic insulin action was by itself able to fully stimulate HGU. This suggests that under hyperinsulinemic/hyperglycemic conditions insulin’s indirect effects are redundant to direct engagement of hepatocyte insulin receptors.

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Increases in intestinal glucose absorption and hepatic glucose uptake elicited by luminal but not vascular glutamine in the jointly perfused small intestine and liver of the rat

Biochemical Journal ◽

10.1042/bj2830759 ◽

1992 ◽

Vol 283 (3) ◽

pp. 759-765 ◽

Cited By ~ 36

Author(s):

A Gardemann ◽

Y Watanabe ◽

V Große ◽

S Hesse ◽

K Jungermann

Keyword(s):

Small Intestine ◽

Portal Vein ◽

Superior Mesenteric Artery ◽

Glucose Uptake ◽

Mesenteric Artery ◽

Hepatic Uptake ◽

Glucose Absorption ◽

Hepatic Glucose ◽

Intestinal Glucose Absorption ◽

Hepatic Glucose Uptake

1. Previous studies have shown that an arterial-to-portal glucose concentration gradient may be an important signal for insulin-dependent net hepatic glucose uptake. It is not known whether intestinal factors also contribute to the regulation of hepatic glucose utilization. This problem was studied in a newly developed model which allows luminal perfusion of the small intestine via the pyloric sphincter and a combined vascular perfusion of the small intestine via the gastroduodenal artery and superior mesenteric artery, and of the liver via the hepatic artery and portal vein. 2. In both the presence and the absence of 1 mM-glutamine in the vascular perfusate, only about 7% of a luminal bolus of 5500 mumol (1 g) of glucose was absorbed by the small intestine, and nothing was taken up by the liver. 3. With small doses of 75-380 mumol (11-55 mg) of luminal glutamine, but not with 300 mumol of alanine, the intestinal absorption of the luminal glucose bolus was increased almost linearly from 7% to a maximum of 40% and the hepatic uptake from 0% to a maximum of 22%. 4. The increase of hepatic glucose uptake caused by luminal glutamine was only observed when the glucose load was applied into the intestinal lumen, rather than into the superior mesenteric artery. 5. The relative hepatic glucose uptake (uptake/portal supply) was enhanced from 0% to 55% with an increase in portal supply by luminal glutamine, whereas with a similar range of portal glucose supply the relative hepatic uptake by the isolated liver, perfused simultaneously via the hepatic artery and portal vein, was slightly decreased, from 20% to 15%. 6. Addition of various amounts of portal glutamine and/or alterations in the Na+ content of the portal perfusate failed to mimic the luminal glutamine-dependent activation of hepatic glucose uptake. Therefore the luminal-glutamine-elicited activation of hepatic glucose uptake was apparently not caused by a simple increase in the portal-arterial glucose gradient, by glutamine itself or by Na(+)-dependent alterations in hepatic cell volume. The results suggest that luminal glutamine caused not only an increase in intestinal glucose absorption by unknown mechanisms but also the generation of one or more humoral or nervous ‘hepatotropic’ signals in the small intestine which enhanced the hepatic uptake of absorbed glucose.

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Regulation of Hepatic Glucose Uptake and Storage In Vivo

Advances in Nutrition ◽

10.3945/an.112.002089 ◽

2012 ◽

Vol 3 (3) ◽

pp. 286-294 ◽

Cited By ~ 155

Author(s):

Mary Courtney Moore ◽

Katie C. Coate ◽

Jason J. Winnick ◽

Zhibo An ◽

Alan D. Cherrington

Keyword(s):

Glucose Uptake ◽

Hepatic Glucose ◽

Hepatic Glucose Uptake ◽

And Storage

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The Importance of the Mechanisms by which Insulin Regulates Meal-Associated Liver Glucose Uptake in the Dog

10.2337/figshare.14242049.v1 ◽

2021 ◽

Author(s):

Guillaume Kraft ◽

Katie C. Coate ◽

Marta Smith ◽

Ben Farmer ◽

Melanie Scott ◽

...

Keyword(s):

Portal Vein ◽

Glucose Uptake ◽

Insulin Action ◽

Insulin Infusion ◽

Insulin Receptors ◽

Postprandial Glucose ◽

Maximal Stimulation ◽

Hepatic Glucose ◽

Healthy Dogs ◽

Hepatic Glucose Uptake

Hepatic glucose uptake (HGU) is critical for maintaining normal postprandial glucose metabolism. Insulin is clearly a key regulator of HGU, but the physiologic mechanisms by which it acts have yet to be established. This study sought to determine the mechanisms by which insulin regulates liver glucose uptake under postprandial-like conditions (hyperinsulinemia, hyperglycemia, and a positive portal vein to arterial glucose gradient). Portal vein insulin infusion increased hepatic insulin levels 5-fold in healthy dogs. In one group (n=7), the physiologic response was allowed to fully occur, while in another (n=7), insulin’s indirect hepatic effects, occurring secondary to its actions on adipose tissue, pancreas, and brain, were blocked. This was accomplished by infusing triglyceride (intravenous), glucagon (portal vein), and inhibitors of brain insulin action (intracerebroventricular) to prevent decreases in plasma free fatty acids or glucagon, while blocking increased hypothalamic insulin signaling for 4h. In contrast to the indirect hepatic effects of insulin, which were previously shown capable of independently generating a half-maximal stimulation of HGU, direct hepatic insulin action was by itself able to fully stimulate HGU. This suggests that under hyperinsulinemic/hyperglycemic conditions insulin’s indirect effects are redundant to direct engagement of hepatocyte insulin receptors.

Download Full-text