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The Journal of Nutrition

Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

A High-Fat, High-Fructose Diet Accelerates

Nutrient Absorption and Impairs Net Hepatic

Glucose Uptake in Response to a Mixed Meal inPartially Pancreatectomized Dogs1,2

Katie Colbert Coate,3* Guillaume Kraft,3 Margaret Lautz,3 Marta Smith,3 Doss W. Neal,3,4

and Alan D. Cherrington3,4

3Department of Molecular Physiology and Biophysics, 4Diabetes Research and Training Center, Vanderbilt University School of

Medicine, Nashville, TN

Abstract

The aim of this study was to elucidate the impact of a high-fat, high-fructose diet (HFFD; fat, 52%; fructose, 17%), in the

presence of a partial (;65%) pancreatectomy (PPx), on the response of the liver and extrahepatic tissues to an orallyadministered, liquid mixed meal. Adult male dogs were fed either a nonpurified, canine control diet (CTR; fat, 26%; no

fructose; n = 5) or a HFFD (n = 5) for 8 wk. Diets were provided in a quantity to maintain neutral or positive energy balance

in CTR or HFFD, respectively. Dogs underwent a sham operation or PPx at wk 0, portal and hepatic vein catheterization at

wk 6, and a mixed meal test at wk 8. Postprandial glucose concentrations were significantly greater in the HFFD group

(14.5 6 2.0 mmol/L) than in the CTR group (9.2 6 0.5 mmol/L). Impaired glucose tolerance in HFFD was due in part to

accelerated gastric emptying and glucose absorption, as indicated by a more rapid rise in arterial plasma acetaminophen

and the rate of glucose output by the gut, respectively, in HFFD than in CTR. It was also attributable to lower net hepatic

glucose uptake (NHGU) in the HFFD group (5.5 6 3.9 mmol kg21

min21) compared to the CTR group (26.6 6 7.0 mmol

kg21 min21), resulting in lower hepatic glycogen synthesis (GSYN) in the HFFD group (10.8 6 5.4 mmol kg21 min21)

than in the CTR group (30.46 7.0mmol kg21 min21). HFFD also displayed aberrant suppression of lipolysis by insulin. In

conclusion, HFFD feeding accelerates gastric emptying and diminishes NHGU and GSYN, thereby impairing glucose

tolerance following a mixed meal challenge. These data reveal a constellation of deleterious metabolic consequences

associated with consumption of a HFFD for 8 wk. J. Nutr. 141: 16431651, 2011.

Introduction

Maintenance of glucose homeostasis during the fasting-tofedtransition is largely dictated by the ability of the liver to switchfrom glucose production to glucose consumption. Several factorshave been reported to influence this dynamic process, includingthe load of glucose delivered to the liver, the concentration ofinsulin in the hepatic sinusoids, and the presence of a portal

glucose-feeding signal (a negative arterial-portal glucose gradientgenerated by the delivery of glucose into the portal vein) (14).Collectively, these factors augment glucose uptake and GSYN5 by

the liver. Thus, under normal conditions, the liver serves as one ofthe principal buffers of perturbations in postprandial glycemia.However, individuals with diabetes display a marked impairmentnot only in the ability of hyperinsulinemia and hyperglycemia tosuppress hepatic glucose production, but also in the ability ofthose postprandial stimuli to activate hepatic glucose uptake andGSYN (58). As a result, diabetic individuals experience frequentbouts of postprandial hyperglycemia, which contributes to theelevation of their hemoglobin A1C and predisposes them to manyof the complications associated with the disease.

Recently, our laboratory demonstrated that consumption of aHFFD has adverse effects on the regulation of whole-bodyglucose metabolism in vivo. For example, 8 wk of HFFD feedingsignificantly impaired glucose tolerance in response to an oralglucose challenge, as indicated by a 123% higher DAUC forplasma glucose compared to baseline studies (9). This was due inpart to a defect in b cell function, given that glucose-stimulatedinsulin secretion (as indicated by theDAUC for c-peptide) was notenhanced relative to that in baseline studies despite a 2-foldgreater increase in the plasma glucose level. Furthermore, 13 wk

1 Supported by NIH RO1-DK18243 and NIH DRTC DK-020593.2 Author disclosures: K. C. Coate, G. Kraft, M. Lautz, M. Smith, D. W. Neal, and

A. D. Cherrington, no conflicts of interest.

* To whom correspondence should be addressed. E-mail: katie.colbert@

vanderbilt.edu.

5 Abbreviations used: CTR, unpurified, canine control diet; GLP-1, glucagon-like

peptide 1; GSYN, glycogen synthesis; HFFD, high-fat, high-fructose diet; HGK,

hepatic glucokinase activity; NHCR, net hepatic carbon retention; NHGU, net

hepatic glucose uptake; non-HGU, nonhepatic glucose uptake; PF, portal vein

blood or plasma flow; PPx, partial (65%) pancreatectomy.

2011 American Society for Nutrition.

Manuscript received May 27, 2011. Initial review completed June 8, 2011. Revision accepted July 1, 2011. 1643First published online July 27, 2011; doi:10.3945/jn.111.145359.

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of HFFD feeding was associated with an inability of the liverto switch from net glucose output to net glucose uptake despitehyperinsulinemia, hyperglycemia, and portal glucose delivery.Thus, the functional consequences of a HFFD on hepatic glucosemetabolism were similar to those observed in diabetic individuals(7,8).

It is important to note that the metabolic consequencesassociated with HFFD feeding were detected in response to aglucose challenge (9), which lacked other meal-associated fac-tors that can influence the gastric emptying rate, insulin and

glucagon secretion, and NHGU (1019). Administration of astandard mixed meal has been proposed as a more physiologicalchallenge to the system. In view of these considerations, weconducted experiments in conscious dogs to determine if 8 wk ofHFFD feeding: 1) impairs NHGU in the context of a mixedmeal; 2) impairs insulin secretion in the presence of other insulinsecretagogues (e.g. amino and fatty acids); 3) affects the acuteprotein and lipid responses to a mixed meal; and 4) altersgastrointestinal function and/or meal macronutrient absorption.

Research Design and Methods

Animals, diets, and surgical procedures. The protocol was

approved by the Vanderbilt University Animal Care and UseCommittee and all facilities met the standards published by theAmerican Association for the Accreditation of LaboratoryAnimal Care. Ten adult male mongrel dogs were randomlyassigned to either a meat (Kal Kan) and CTR (n = 5; LaboratoryCanine Diet 5006, chunk form, PMI Nutrition LabDiet) (20) orto a HFFD (n = 5; High Fructose and Fat Canine Diet 5A4J,short cut pellet form, PMI Nutrition TestDiet) for 8 wk(Table 1). Diets were provided once daily in a quantity (CTR:500 g + 1 can of meat/d; HFFD: 800 g/d) intended to keep thedogs weight stable (CTR body weight; initial: 25 6 2 kg, final:25 6 2 kg) or in positive energy balance (HFFD body weight;initial: 26 6 1 kg; final: 29 6 1 kg) over time. Dogs had free

access to the food that was provided over the course of 24 h.Mean energy intake was greater in HFFD (12.6 6 0.75 MJ/d)than in CTR (8.34 6 0.14 MJ/d) (P , 0.05). Our goal in thepresent study was to investigate the adverse effects of a HFFD onthe response of the liver and extrahepatic tissues to a mixed mealchallenge regardless of whether the defect was attributable toexcess energy consumption or the macro- and micronutrientcontent of the diet. We are currently conducting studies toelucidate the relative contributions of fat, fructose, and excessenergy to impaired hepatic glucose flux in vivo.

Dogs in the CTR or HFFD group underwent a sham or PPx(;65% resection), respectively, at wk 0, as described previously(9). It was not our primary aim to isolate the effect of a PPx perse on metabolism; rather, we wanted to use it as a surgical tool to

compromise endocrine pancreatic function in the hope that,when coupled with a dietary insult, a diabetic phenotype wouldemerge. We have now shown, however, that dogs fed the HFFD,with or without PPx (65%), displayed equivalent glucose intol-erance, whole-body insulin resistance, and defective hepatic glu-cose metabolism, but did not become diabetic (9). Although wethink, therefore, that the data presented herein represent aneffect of the HFFD per se, the possibility cannot be excluded thatfactors secondary to the PPx influenced the results.

Approximately 2 wk before the study (wk 6 of feeding), eachdog underwent a laparotomy under general anesthesia to implantsampling catheters into the femoral artery, the hepatic portal vein,and the left common hepatic vein and to place infusion catheters

into a splenic and jejunal vein (2). At the same time, ultrasonic

flow probes (Transonic Systems) were positioned around the he-patic artery and the portal vein for the assessment of hepatic blood

flow, as previously described (2). After 8 wk of feeding, dogs werechallenged with a mixed meal (see next paragraph) and net gut/hepatic substrate balance (see Calculations) was measured. Alldogs were healthy, as indicated by leukocyte count,18000/mm3,hematocrit .0.35, and good appetite and normal stools.

Experimental design and mixed meal composition. Oralmixed meal tests were carried out in dogs that had been feeddeprived for 24 h. On the morning of the study, a liquid mixedmeal was drawn up into two 60-mL syringes. Following thecontrol period, it was delivered directly into the dogs mouthover the course of 2 min to activate the cephalic response to ameal. Experiments consisted of consecutive 60-min equilibra-

tion (060 min) and control (60120 min) periods, followed by

TABLE 1 Composition of the experimental diets

Nutrient

High-fat, high-fructose

diet composition

Nonpurified

Diet + meat

composition

g/kg diet

Protein1 247 289

Fat2 252 98

Saturated fat 110.9 36.63

Monounsaturated fat 104.2 34.03

Polyunsaturated fat 34.2 13.33

Total carbohydrate 298 355

Starch4 95.9 335

Glucose 0.1 2.3

Fructose 189.3 2.3

Sucrose 7.4 10.8

Lactose 5.6 4.6

Crude fiber5 22 28

Moisture 100 100

Vitamins6 1.7 1.7

Minerals7 73 73

Protein, % energy 21.8 30.7

Fat, % energy 52.0 25.8

Total carbohydrate, % energy 26.2 43.5

Starch 8.5 41.0

Glucose ,0.01 0.3

Fructose 16.7 0.3

Sucrose 0.6 1.3

Lactose 0.5 0.6

Energy density, kJ/g 18.9 17.3

1 Protein sources include porcine meat meal, dehulled soybean meal, corn gluten

meal, wheat middlings, and dried whey.2 Fat sources include lard, porcine animal fat, vegetable shortening, and/or unsalted

butter.3 Corresponds to saturated, monounsaturated, and polyunsaturated fat content of

nonpurified diet only; these data are not provided by the manufacturer for the can of

meat.4 Starch sources include wheat germ and middlings.5 Fiber sources include wheat, beat pulp, and corn.6 Vitamin mix, mg/kg prepared diet: provitamin A carotenoids, 1.0; retinol, 12.0;

cholecalciferol, 0.11; a-tocopherol, 29.4; menadione, 0.3; thiamin hydrocholoride, 8.9;

riboflavin, 4.5; niacin, 78; pantothenic acid, 20; folic acid, 2.8; pyridoxine, 13; biotin,

0.2; vitamin B-12, 27; choline chloride, 1492.7 Mineral mix, g/kg (unless otherwise specified) prepared diet: calcium, 19.2;

phosphorus, 10.6; phosphorus (available), 9.1; potassium, 7.0; magnesium, 1.7;

sulfur, 2.0; sodium, 4.5; chloride, 7.1; fluorine, 48 mg/kg; iron, 390 mg/kg; zinc, 160

mg/kg; manganese, 55 mg/kg; copper, 14 mg/kg; cobalt, 0.5 mg/kg; iodine, 1.7 mg/kg;

chromium, 2.3 mg/kg; selenium, 0.36 mg/kg.

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oral administration of a defined liquid mixed meal and then a270-min postprandial sampling period (120390 min). The testmeal consisted of 20% protein [26.9 g Beneprotein (96 kcal);Nestle Healthcare Nutrition], 56% carbohydrate [67.2 gPolycose (255 kcal); Abbott Nutrition], and 24% fat [25.3 mLMicrolipid (114 kcal); Nestle Healthcare Nutrition]. Benepro-tein and Polycose were dissolved in 60 mL of water along withMicrolipid. Each meal was spiked with acetaminophen (500 mg)to measure the gastric emptying rate during mixed meal testing(21). Blood was drawn every 10 min during the early postpran-

dial period (120150 min) and every 30 min thereafter (180390min).

Processing and analysis of samples. Hematocrit, plasmaglucose, glucagon, insulin, c-peptide, FFA, TG, and active GLP-1concentrations, and blood lactate, alanine, and glycerol concen-trations were measured using standard procedures as previouslydescribed (9,2225). Arterial plasma acetaminophen levels weredetermined using a modified protocol designed for HPLC, aspreviously described (2628).

Calculations. Net hepatic substrate balances were calculatedusing the arteriovenous difference method according to the

following formula: net hepatic substrate balances = loadout loadin, where loadout = [H] 3 HF and loadin = [A] 3 AF + [P] 3PF. [A], [P], and [H] represent substrate concentrations infemoral artery, portal vein, and hepatic vein blood or plasma,respectively, and AF, PF, and HF represent blood or plasma flow(as measured using ultrasonic flow probes) through the hepaticartery, the portal vein, and total liver, respectively. With thiscalculation, positive values reflect net hepatic production andnegative values reflect net hepatic uptake. Net gut balance wasdetermined by multiplying the [A] 2 [P] substrate difference byPF. Net hepatic fractional substrate extraction, hepatic sinusoi-dal hormone concentrations, and non-HGU were calculated aspreviously described (22,29). Net hepatic carbon retention, a

reflection of hepatic GSYN, was calculated as the sum of thehepatic balances of glucose, lactate, alanine 3 2 (to account forthe contribution of amino acids other than alanine), andglycerol, with all factors in glucose equivalents as previouslydescribed and validated (3034).

Statistical analyses. All data are presented as means 6 SEM.Statistical comparisons between groups and over time were car-ried out using 2-way, repeated-measures ANOVA (SigmaPlot11.0, Systat Software). When the F test was significant, theStudent-Newman-Keuls test was conducted. Changes relative tothe basal period only are reported. Differences were consideredsignificant at P , 0.05.

Results

Glucose metabolism and hormone levels. In the CTRgroup, arterial plasma glucose levels rose in response to the mealand remained elevated for the duration of the study, albeit notsignificantly greater than their glucose concentrations during thebasal period (Fig. 1A). A significant increase from basal in netgut output of glucose was evident 1 h after the meal, whichcoincided with an increase in the gastric emptying rate, asindicated by a significant elevation from basal in arterial plasmaacetaminophen concentration in the CTR group (Fig. 1B,C).Glucose output by the gut and arterial plasma acetaminophenlevels eventually plateaued 3 h postmeal delivery in the CTR

group (Fig. 1B,C). In HFFD, on the other hand, arterial plasma

glucose levels increased more rapidly from basal following mealconsumption and were significantly elevated from basal andCTR for 2.5 h postmeal delivery (Fig. 1A). Glucose output by thegut also increased more rapidly from basal in HFFD, albeit for ashorter duration, peaking 1.5 h postmeal administration (P ,0.05 vs. basal period and CTR) and then falling such that duringthe last hour of the experiment, it was significantly lower in theHFFD group than in the CTR group (Fig. 1B). In agreement withtheir gut glucose absorption profile, arterial plasma acetamin-ophen levels were significantly greater in the HFFD group thanin the CTR group during the early postprandial period (Fig. 1C).

In response to the meal, there were 4-fold and 5-fold in-creases from basal in arterial plasma c-peptide (P , 0.05) andinsulin concentrations, respectively, in the CTR group as well asa significant elevation from basal in arterial and portal veinplasma GLP-1 (active form) concentrations 3 h postmeal admin-istration (Fig. 2AC; Table 2). In agreement with a sustainedrate of gastric emptying and delivery of nutrients to the gut,plasma GLP-1 levels tended to remain elevated from basalthroughout the experiment in the CTR group (Fig. 2C; Table 2).In contrast, there were 5-fold and 7-fold increases from basal(P , 0.05) in arterial plasma c-peptide and insulin concentra-tions, respectively, in the HFFD group, which were significantlygreater than those in the CTR group during the experiment (Fig.

2A,B). Likewise, arterial and portal vein plasma GLP-1 levels

FIGURE 1 Arterial plasma glucose (A), net gut glucose balance

(NGGB; B), and arterial plasma acetaminophen (C) concentrations

during the basal (60120 min) and experimental (120390 min) periods

following oral administration of a liquid mixed meal to 24-h feed-

deprived dogs that had been fed a nonpurified, canine control diet

(CTR) or a high-fat, high-fructose diet (HFFD) for 8 wk. Data are mean

6 SEM, n = 5.#

Different from 60 and 120 min (basal), P , 0.05;

*different from control, P, 0.05. D, diet; T, time.

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were significantly greater in the HFFD group than in the CTRgroup 1 h postmeal delivery but returned to basal levels by theend of the study (Fig. 2C; Table 2). There were no significantchanges from the basal period or differences between groups inarterial or hepatic sinusoidal plasma glucagon concentrationsfollowing meal consumption (Table 2).

During the basal period, net hepatic glucose output wascomparable between the CTR and HFFD groups (Fig. 3A). Inresponse to meal consumption, the livers of dogs in the CTRgroup rapidly switched from net glucose output to net glucoseuptake (P , 0.05 vs. basal period and HFFD) and remained inan uptake mode for the duration of the study (Fig. 3A). Incontrast, NHGU was nearly absent in the HFFD group, asevidenced by the lack of a significant change from basal in thenet hepatic glucose balance following meal consumption (Fig.3A). As a result, NHGU was significantly lower in the HFFD

group than in the CTR group during the last 2 h of theexperiment (Fig. 3A). On the other hand, nonhepatic glucoseuptake (non-HGU) in response to meal consumption wasmarkedly higher in the HFFD group than in the CTR group(P , 0.05 vs. basal period and CTR) (Fig. 3C). Given that theratios of non-HGU:arterial insulin (CTR: 0.15 6 0.04, HFFD:0.10 6 0.01) and nonhepatic glucose clearance:arterial insulin(CTR: 0.15 6 0.04, HFFD: 0.09 6 0.01) did not differ betweenthe groups, these data indicate that the muscle was able tocompensate for impaired NHGU in the HFFD group but at theexpense of increased postprandial plasma insulin and glucose.

Lactate metabolism. In both the CTR and HFFD groups,

arterial blood lactate levels increased from basal following mealconsumption (Fig. 4A). In the CTR group, this was consistentwith a robust switch from net hepatic lactate uptake to output(Fig. 4B) and a significant increase from basal in NHCR (Fig.3B), an index of net GSYN. Net hepatic lactate output (Fig. 4B)and GSYN (Fig. 3B) continued for the remainder of the study inthe CTR group. In the HFFD group, on the other hand, therewas only a transient switch from net hepatic lactate uptake tooutput following meal consumption and the rate was signifi-cantly lower in the HFFD group than in the CTR group duringthe experiment (Fig. 4B). This was consistent with a significantlylower rate of NHCR in the HFFD group compared to the CTRgroup (Fig. 3B). These data suggest that in the absence of meal-associated glucose uptake, the livers of dogs in the HFFD groupproduced significantly less lactate and synthesized significantlyless glycogen.

Glycerol, nonesterified fatty acid, and TG metabolism.

During the basal period, arterial blood glycerol levels weresignificantly higher in the HFFD group than in the CTR group(Table 3). Although arterial blood glycerol and plasma FFA

FIGURE 2 Arterial plasma insulin (A), c-peptide (B), and glucagon

like peptide-1 (GLP-1; active) (C) concentrations during the basal (60

120 min) and experimental (120390 min) periods following oral

administration of a liquid mixed meal to 24-h feed-deprived dogs that

had been fed a nonpurified, canine control diet (CTR) or a high-fat,

high-fructose diet (HFFD) for 8 wk. Data are mean 6 SEM, n = 5.#Different from 60 and 120 min (basal), P , 0.05; *different from

control, P, 0.05. D, diet; T, time.

TABLE 2 Portal vein plasma glucagon-like peptide 1 (GLP-1), arterial plasma glucagon, and hepatic sinusoidal plasma glucagonconcentrations during the basal (60120 min) and experimental (120390 min) periods following oral administrationof a liquid mixed meal to 24-h feed-deprived dogs that had been fed a nonpurified, canine control diet (CTR)

or a high-fat, high-fructose diet (HFFD) for 8 wk1

Basal period, min Experimental period, min P value

60120 180 240 300 360 390 Diet Time Diet x time

Portal vein plasma GLP-1, pmol/L NS2 ,0.05 NS

CTR 3.9 6 0.5 5.6 6 0.7 12.761.8 15.662.8# 13.561.4 9.661.1

HFFD 3.1 6 0.3 14.4 6 4.7#* 9.861.4 9.462.8 9.763.8 6.563.0

Arterial plasma glucagon, ng/L NS NS NS

CTR 47.4 6 6.4 40.6 6 4.3 40.964.2 43.264.5 45.265.2 43.863.4

HFFD 31.9 6 6.0 34.4 6 4.1 36.266.0 35.566.4 36.164.0 36.464.2

Hepatic sinusoidal plasma glucagon, ng/L NS NS NS

CTR 51.0 6 7.7 43.5 6 6.8 45.264.6 49.1610.9 47.368.6 49.167.5

HFFD 40.1 6 6.1 43.4 6 4.0 40.663.3 41.265.2 41.264.0 42.266.4

1 Data are mean 6 SEM, n = 5. # Different from basal, P, 0.05; * different from CTR, P, 0.05.2

NS, Nonsignificant, P$ 0.05.

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levels fell rapidly in both groups following meal consumption,glycerol concentrations remained significantly higher in theHFFD group than in the CTR group forthe duration of the study(Table 3). Likewise, arterial plasma FFA concentrations began torise in the HFFD group 3 h postmeal delivery such that by theend of the study, they were similar to basal values and signifi-

cantly greater than those in the CTR group (Table 3). Changes innet hepatic glycerol uptake paralleled those in arterial bloodglycerol; by the end of the study, net hepatic glycerol uptake wassignificantly greater in the HFFD group compared to the CTRgroup (Table 3). Arterial plasma TG concentrations declined inboth groups over the first 3 postprandial hours, after which theyremained low in the CTR group but returned to basal levels inthe HFFD group (Table 3).

Alanine metabolism. Arterial blood alanine levels rose to asignificantly greater extent in the HFFD group than in the CTRgroup 2 h postmeal administration (Table 4). This was partlyattributable to a 5-fold compared to 3-fold increase from basal

in alanine output from the gut in HFFD vs. CTR, respectively,

1 h postmeal delivery, coupled with a lower hepatic fractionalextraction of alanine during the mid- to late-postprandial periodin HFFD compared to CTR (Table 4).

Discussion

The objective of the present study was to investigate whetherchronic consumption of a HFFD, in combination with PPx,alters the response of the liver and extrahepatic tissues to an

orally delivered, liquid mixed meal under nonclamped experi-mental conditions. A HFFD was utilized, because it reflects themacronutrient composition of a Western diet, which containsfoods that are replete with fat and fructose and, when consumedin increasing quantities, has been associated with a heightenedrisk for the development of type 2 diabetes (35,36). We reportherein that 8 wk of HFFD feeding elicited excessive postprandialhyperglycemia due to accelerated gastric emptying and glucoseabsorption as well as diminished NHGU and a reduction in theability of insulin to suppress lipolysis.

Several factors probably contributed to postprandial hyper-glycemia in HFFD-fed animals. For example, the rates of gastricemptying and glucose absorption can influence the timing andmagnitude of postprandial glucose excursions in healthy and

diabetic individuals (37,38). Previously, Davis et al. (39)demonstrated that glucose absorption (and presumably, gastricemptying) occurs very slowly in overnight feed-deprived dogswhen fed a test meal of the same composition as their normaldiet. In the present study, a sustained rate of glucose output bythe gut occurred in CTR following meal consumption, consis-tent with the observations of Davis et al. (39). In contrast, therates of gastric emptying and glucose output by the gut weresignificantly higher in the HFFD group than in the CTR group

FIGURE 3 Net hepatic glucose balance (NHGB; A), net hepatic

carbon retention (NHCR; B), and nonhepatic glucose uptake (Non-HGU;

C) during the basal (60120 min) and experimental (120390 min)

periods following oral administration of a liquid mixed meal to 24-h feed-

deprived dogs that had been fed a nonpurified, canine control diet (CTR)or a high-fat, high-fructose diet (HFFD) for 8 wk. Negative values for net

hepatic glucose balance or net hepatic carbon retention indicate net

hepatic glucose uptake or glycogen synthesis, respectively; positive

values indicate net hepatic glucose output or glycogen breakdown,

respectively. Data are mean 6 SEM, n = 5. #Different from 60 and 120

min (basal), P, 0.05; *different from CTR, P, 0.05. D, diet; T, time.

FIGURE 4 Arterial blood lactate (A) and net hepatic lactate balance

(NHLB;B) during the basal (60120 min) and experimental (120390

min) periods following oral administration of a liquid mixed meal to 24-

h feed-deprived dogs that had been fed a nonpurified, canine control

diet (CTR) or a high-fat, high-fructose diet (HFFD) for 8 wk. Negative

values for net hepatic lactate balance indicate net hepatic lactate

uptake, whereas positive values indicate net hepatic lactate output.

Data are mean 6 SEM, n = 5. #Different from 60 and 120 min (basal),

P, 0.05; *different from control, P, 0.05. D, diet; T, time.




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during the early postprandial period, consistent with excessivepostprandial hyperglycemia in the former. Furthermore, therewas a tendency for alanine production by the gut to be greater inthe HFFD group compared to the CTR group 1 h postmealdelivery, suggesting that accelerated absorption in the HFFDgroup was not exclusive to glucose. By the end of the study,however, temporal differences in gastric emptying and nutrientabsorption between groups were reversed such that net glucoseand alanine output by the gut were significantly greater in theCTR group than in the HFFD group, indicative of acceleratedmeal macronutrient absorption in the latter.

In addition, there was a doubling in arterial and portal veinplasma GLP-1 levels 10 min postmeal delivery in the HFFD

group, whereas there was virtually no change 10 min postmealin the CTR group. GLP-1 is an incretin hormone secreted by theL-cells cells of the distal small intestine primarily in response tonutrient ingestion (40,41). GLP-1 is thought to delay gastric

emptying and potentiate glucose-dependent insulin secretion,thus limiting postprandial hyperglycemia (4251). Previousstudies conducted in our laboratory, however, demonstratedthat a physiologic rise in endogenous GLP-1 is without signif-icant effect on insulin secretion, gastric emptying, and glucoseutilization in dogs (24,28,52). Thus, we think that the temporalchanges in GLP-1 levels in the current study are a reflection ofthe differential gastric emptying rates in the HFFD compared tothe CTR.

Previous studies conducted in individuals in the early stagesof type 2 diabetes or those without autonomic neuropathy alsoreported an accelerated gastric emptying rate following con-sumption of a glucose solution or liquid mixed meal (5360).

Although the mechanisms that mediate differential gastricemptying rates in healthy and diabetic individuals remain poorlydefined, one study (55) attributed augmented gastric emptyingto increased phasic contractility of the proximal stomach in

TABLE 3 Arterial blood glycerol, net hepatic glycerol uptake, and arterial plasma FFA and TG concentrations during the basal(60 to 120 min) and experimental (120 to 390 min) periods following oral administration of a liquid mixed meal

to 24-h feed-deprived dogs that had been fed a nonpurified, canine control diet (CTR) or a high-fat, high-fructosediet (HFFD) for 8 wk1

Basal period min Experimental period min P value


Arterial blood glycerol, mmol/L ,0.01 ,0.001 NS2

CTR 87 6 7 29 6 4# 27 6 3# 31 6 3# 29 6 3# 32 6 3#

HFFD 1136

10* 556

14

#*

566

13

#*

606

15

#*

836

9

#*

806

6

#*

Net hepatic glycerol uptake, mmolkg21min21 NS ,0.001 ,0.01

CTR 1.9 6 0.2 0.7 6 0.1# 0.6 6 0.1# 0.6 6 0.1# 0.5 6 0.1# 0.5 60.1#

HFFD 1.9 6 0.3 1.3 6 0.4# 1.2 6 0.4# 1.4 60.5* 1.6 6 0.2* 1.6 6 0.2*

Arterial plasma FFA, mmol/L NS ,0.001 ,0.05

CTR 926 6 122 144 6 7# 123 6 5# 104 6 12# 81 6 4# 92 6 8#

HFFD 914 6 43 137 6 34# 92 6 21# 137 6 59# 280 6 104#* 402 6 110#*

Arterial plasma TG, mmol/L NS ,0.01 ,0.05

CTR 0.218 6 0.029 0.198 6 0.026 0.182 6 0.114 0.163 6 0.029 0.141 6 0.016# 0.157 6 0.026#

HFFD 0.205 6 0.019 0.188 6 0.021 0.165 6 0.013 0.153 6 0.013 0.183 6 0.014 0.194 6 0.033

1 Data are mean 6 SEM, n = 5. #Different from basal, P, 0.05; *different from CTR, P, 0.05; NS, not significant, P. 0.05.2 NS, Nonsignificant, P$ 0.05.

TABLE 4 Arterial blood alanine, gut production of alanine, net hepatic alanine uptake, and hepatic fractional extractionof alanine during the basal (60120 min) and experimental (120390 min) periods following oral administration of

a liquid mixed meal to 24-h feed-deprived dogs that had been fed a nonpurified, canine control diet (CTR) or ahigh-fat, high-fructose diet (HFFD) for 8 wk1

Basal period, min Experimental period, min P value


Arterial blood alanine, mmol/L NS2

,0.001 NSCTR 284 6 46 350 6 20 321 6 9 313 6 17 307 6 20 311 6 19

HFFD 318 6 35 442 6 25# 452 6 29#* 452 6 46#* 409 6 46# 374 6 63#

Gut production of alanine, mmolkg21min21 NS ,0.001 NS

CTR 1.1 6 0.2 3.5 6 0.4# 3.6 6 0.5# 3.7 6 0.3# 3.9 6 0.4# 3.8 6 0.6#

HFFD 0.9 6 0.1 4.4 6 0.5# 3.7 6 0.4# 2.8 6 0.4# 3.4 6 1.0# 1.1 6 0.4*

Net hepatic alanine uptake, mmolkg21min21 ,0.01 ,0.001 NS

CTR 3.0 6 0.1 5.8 6 0.6# 5.4 6 0.6# 6.5 6 0.1# 5.8 6 0.6# 5.3 6 0.6#

HFFD 1.9 6 0.3 4.9 6 0.7# 4.5 6 0.6# 4.6 6 0.5#* 3.9 6 0.5#* 2.5 6 0.5*

Hepatic fractional extraction of alanine ,0.05 ,0.001 NS

CTR 0.29 6 0.04 0.32 6 0.02 0.33 6 0.02 0.416 0.02# 0.37 6 0.03# 0.35 6 0.03

HFFD 0.22 6 0.02 0.25 6 0.02 0.27 6 0.03 0.326 0.04#* 0.32 6 0.04# 0.25 6 0.03*

1 Data are mean 6 SEM, n = 5. # Different from Basal, P, 0.05; * different from CTR, P, 0.05; NS, not significant, P. 0.05.2

NS, Nonsignificant, P$ 0.05.

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patients with asymptomatic (no autonomic neuropathy) type 2diabetes. It is also possible that the HFFD induced perturbationsin the gut microbiota, which might have elicited an increase inintestinal permeability as a consequence of endotoxemia, aspreviously reported (6166). Future studies will need to beconducted to explore the mechanism(s) responsible for acceler-ated gastric emptying in HFFD-fed animals.

Another factor that contributed to meal-associated glucoseintolerance in the HFFD group was inadequate stimulation ofNHGU. Under normal conditions, the liver is highly responsive

to the route of glucose delivery (peripheral vs. enteral/intra-portal), the hepatic glucose load, and the hepatic sinusoidalinsulin level (2,67,68). However, NHGU was markedly lower inthe HFFD group than in the CTR group despite 1.6- and 2.4-foldgreater increases in peak plasma glucose and insulin levels,respectively. These data suggest that HFFD feeding rendered theliver insensitive to the stimulatory effects of glucose, insulin, andportal glucose delivery on NHGU in the context of a physiologicmixed meal challenge, consistent with our previous findings witha glucose challenge (9).

In agreement with impaired NHGU, net hepatic lactate pro-duction, an index of net glycolytic flux, and NHCR, an indexof net GSYN, were markedly lower in the HFFD group than

in the CTR group following meal consumption. Previously,Basu et al. (7,8) reported that decreased hepatic UDP-glucoseflux in type 2 diabetic individuals during hyperinsulinemia andhyperglycemia is entirely accounted for by a decrease in thecontribution of extracellular glucose to the UDP-glucose pool,suggestive of reduced HGK with diabetes. Moreover, restorationof HGK expression in 20-wk-old Zucker diabetic fatty rats, agenetic model of obese type 2 diabetes, normalized their hepaticglucose flux and the incorporation of glucose into glycogenduring a hyperglycemic clamp (69). Thus, it is likely that HFFDfeeding impaired HGK activity, which resulted in diminishedNHGU and GSYN in response to a mixed meal challenge. Weare currently investigating the mechanism(s) associated with

impaired hepatic glucose flux after HFFD feeding.Interestingly, non-HGU, which is primarily reflective ofglucose uptake in the skeletal muscle (70), was augmented inthe HFFD group compared to the CTR group in response tomeal ingestion. This was due in part to the fact that the skeletalmuscle of dogs in the HFFD group was postprandially exposedto a much higher concentration of glucose and insulin. Thus,through a mass action effect of glucose as well as through thepleiotropic effects of insulin on muscle glucose uptake (7073),the skeletal muscle responded accordingly by increasing itsconsumption of glucose. Indeed, when non-HGU or clearancewas expressed relative to the arterial plasma insulin level inHFFD and CTR, the ratios were similar between groups,suggesting that augmented non-HGU in HFFD was secondary

to elevated insulin and glucose. These data also underscore thepredominance of the defect in hepatic glucose uptake.

Eight weeks of HFFD feeding was also associated with aremarkable resistance to insulin at the level of TG hydrolysiswithin the adipose tissue. This was evident from the fact thatpostprandial blood glycerol concentrations were significantlyhigher in the HFFD group than in the CTR group despite peakarterial plasma insulin concentrations that were 100% greater inthe HFFD group. Conversely, plasma FFA concentrations weresimilar between groups, indicative of a selective impairment inthe ability of insulin to suppress lipolysis, whereas the ability ofhyperinsulinemia and hyperglycemia to stimulate reesterifica-tion of FFA into TG remains intact. The latter is exemplified by

the fact that plasma FFA concentrations began to increase in the

HFFD group toward the end of the study as plasma insulin andglucose concentrations waned.

We cannot ascertain from these data whether relative b cellfailure contributed to meal-associated glucose intolerance in theHFFD group, because we do not know how much insulin wouldhave been secreted in the CTR group had their plasma glucoseconcentrations been matched to those of the HFFD group. Whatwe now know that was not evident at the time when we designedthese experiments is that resection of 65% of the pancreas isinsufficient to exacerbate the glucose intolerance induced by

HFFD feeding (9). This is consistent with previous studiesconducted in rodents in which removal of 8595% of thepancreas was required before diabetes ensued, and even then,there was a heterogeneous hyperglycemic response that corre-lated with the extent of pancreatic resection (74,75). Neverthe-less, the possibility cannot be excluded that in the context of amixed meal, factors associated with a PPx might have influencedthe results in the present study.

This study revealed novel metabolic consequences of a HFFDon the function of the gastrointestinal tract, liver, and adiposetissue in response to a mixed meal. These data highlight the needfor additional studies aimed at elucidating the mechanism(s) bywhich a HFFD per se perturbs the coordinated response of the

aforementioned tissues in the postprandial state.

Acknowledgments

We thank Dr. Mary C. Moore for discussion, critique, and assis-tance in the revision of this manuscript. The authors also extendtheir gratitude to Jon Hastings, Patsy Raymer, and the DiabetesResearch and Training Center Hormone Assay and AnalyticalServices Core for their technical assistance and support. Dr.Cherrington is the Jacquelyn A. Turner and Dr. Dorothy J. TurnerChair in Diabetes Research. K.C.C. wrote the paper; A.D.C.,K.C.C., and G.K. designed the research; M.L., M.S., G.K.,D.W.N., and K.C.C. conducted the research; K.C.C. and A.D.C.analyzed the data; and A.D.C. had primary responsibility for

final content. All authors read and approved the final manuscript.

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