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© 2004 The American Society for Nutritional Sciences J. Nutr. 134:3042-3046, November 2004

Nutrient Metabolism

Portal Vein Caffeine Infusion Enhances Net Hepatic Glucose Uptake during a Glucose Load in Conscious Dogs1,2

R. Richard Pencek*,3, Danielle Battram{ddagger}, Jane Shearer*, Freyja D. James*, D. Brooks Lacy{dagger}, Kareem Jabbour**, Phillip E. Williams**, Terry E. Graham{ddagger} and David H. Wasserman*,{dagger}

* Department of Molecular Physiology and Biophysics, {dagger} Diabetes Research and Training Center, and ** Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN 37232-0615, and {ddagger} Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1

3To whom correspondence should be addressed. E-mail: r.r.pencek{at}vanderbilt.edu.


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
We determined whether intraportal caffeine infusion, at rates designed to create concentrations similar to that seen with normal dietary intake, would enhance net hepatic glucose uptake (NHGU) during a glucose load. Dogs (n = 15) were implanted with sampling and infusion catheters as well as flow probes >16 d before the studies. After a basal sampling period, dogs were administered a somatostatin infusion (0–150 min) as well as intraportal infusions of glucose [18 µmol/(kg · min)], basal glucagon [0.5 ng/(kg · min)], and insulin [8.3 pmol/(kg · min)] to establish mild hyperinsulinemia. Arterial glucose was clamped at 10 mmol/L with a peripheral glucose infusion. At 80 min, either saline (Control; n = 7) or caffeine [1.5 µmol/(kg · min); n = 8] was infused into the portal vein. Arterial insulin, glucagon, norepinephrine, and glucose did not differ between groups. In dogs infused with caffeine, NHGU was significantly higher than in controls [21.2 ± 4.3 vs. 11.2 ± 1.6 µmol/(kg · min)]. Caffeine increased net hepatic lactate output compared with controls [12.5 ± 3.8 vs. 5.5 ± 1.5 µmol/(kg · min)]. These findings indicate that physiologic circulating levels of caffeine can enhance NHGU during a glucose load, and the added glucose consumed by the liver is in part converted to lactate.

KEY WORDS: • glycogen • coffee • carbohydrate • methylxanthines

Caffeine decreases glucose disposal in skeletal muscle by impairing insulin action (1). However, the effect of caffeine on liver glucose metabolism remains unknown. The effect of caffeine on glucose disposal at this organ is important given the role of the liver in the maintenance of glucose homeostasis. Of additional importance is that the consumption of caffeinated products results in higher caffeine concentrations at the liver compared with the arterial circulation. Work in which adenosine, a metabolite whose action is antagonized by caffeine, was infused in dogs showed that hepatic glucose output increased and inhibited the suppressive effect of insulin on hepatic glucose output (2).

On the basis of these observations, caffeine could serve as a potential tool for increasing hepatic glucose uptake and the subsequent incorporation of glucose into hepatic glycogen. This is interesting in light of epidemiologic studies showing that coffee consumption may reduce the incidence of type II diabetes (3,4). Therefore, the purpose of this work was to determine the effect of caffeine on hepatic glucose metabolism in the presence of a hyperinsulinemic-hyperglycemic clamp, which promotes the uptake and storage of glucose by the liver.


   MATERIALS AND METHODS
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 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 LITERATURE CITED
 
    Animal care and surgical procedures. Dogs of either sex (n = 15; 25 ± 1 kg) were housed in a facility that met the American Association for the Accreditation of Laboratory Animals Care guidelines. Procedures were approved by the Institutional Animal Care and Use Committee. The dogs were fed a daily diet of meat [60 g dry weight, 300 kcal (1.255 MJ), 44% protein, 17% fat, 6% fiber, and 33% carbohydrate] and dry food [373 g dry weight, 1500 kcal (6.276 MJ), 28% protein, 10% fat, 5% fiber and 47% carbohydrate]. At least 16 d before an experiment, a laparotomy was performed and catheters (artery, portal vein, hepatic vein, peripheral vein) and flow probes (hepatic artery, portal vein) were implanted as previously described (5). The dogs had to meet the laboratory health criteria to be used in an experiment (5).

    Experimental protocol. The experimental protocol is shown in Figure 1. Catheters and flow probes were freed from subcutaneous pockets using incisions made after local administration. Dogs were placed in a Pavlov harness and saline was infused into the arterial catheter throughout the study. At t = –130 min, peripheral infusions of indocyanine green (ICG),4 [3-3H]glucose, and L-[14C]glucose [0.85 kBq/(kg · min)] were initiated. The ICG and [3-3H]glucose (1.75 MBq primer, 17.5 kBq/min constant infusion) infusions were sustained for the entire experiment. At t = 0 min, the peripheral L-[14C]glucose infusion was discontinued. A peripheral somatostatin infusion [0.5 nmol/(kg · min)] was initiated at t = 0 min to suppress insulin and glucagon secretion. Plasma glucagon was maintained at basal levels from t = 0–150 min with a portal glucagon infusion [0.5 ng/(kg · min)]. A physiologic hyperinsulinemia was established with a portal vein insulin infusion [8.3 pmol/(kg · min); t = 0–150 min]. Glucose was infused into the portal vein at 18 mmol/(kg · min). The portal glucose infusion contained trace quantities of L-[14C]glucose. Variable peripheral glucose was used to clamp arterial blood glucose at 10 mmol/L. At t = 80 min, a portal infusion of caffeine [1.5 µmol/(kg · min); n = 8] or saline (n = 7) was initiated and continued for the remainder of the experiment. Arterial, portal vein, and hepatic vein blood samples were taken from t = –30–0 min for the assessment of baseline values. A 100-min interval between the baseline and experimental sampling periods was allotted to establish a steady state. Once a steady state was achieved, arterial, portal vein, and hepatic vein blood samples were taken every 10 min for the remainder of the experiment (t = 100–150 min). Portal vein and hepatic artery flows were measured at the same time blood samples were collected. At t = 150 min dogs were killed with pentobarbital, liver samples were excised and frozen in liquid nitrogen, and the placement of catheters was confirmed.



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  		FIGURE 1 Experimental protocol. After a baseline period, dogs were subjected to a hyperinsulinemic-hyperglycemic clamp. Steady-state samples were taken over the final 50 min of the clamp period in the presence of either a portal vein saline or caffeine infusion.

 
    Analytical methods. Plasma glucose concentration and radioactivity in glucose were determined as previously described (5). Plasma insulin, glucagon, and cortisol were measured as previously described (6). Plasma epinephrine and norepinephrine concentrations were determined by HPLC (7). Liver glycogen concentration and radioactivity were assessed as previously described (8). Liver glycogen phosphorylase and synthase activities were determined as described previously (9). Phosphorylase and synthase activity ratios were determined by dividing the observed enzyme activity by the total enzyme activity. For the determination of hepatic glucose-6-phosphate and fructose-6-phosphate, liver samples were homogenized in 0.8 mol/L perchloric acid and centrifuged (3000 x g, 10 min). Blood glucose and hepatic glycogen (after hydrolysis by amyloglucosidase), glucose-6-phosphate, and fructose-6-phosphate were measured enzymatically (10). Concentrations of substrates were determined by the reduction of NAD+. For the determination of glucose-6-phosphate and fructose-6-phosphate, the level of glucose-6-phosphate was determined. This value was subtracted from the value obtained after treatment of the sample with phosphoglucoisomerase to determine fructose-6-phosphate content. Methylxanthine concentrations were determined using HPLC as previously described (11). Mixing of glucose using L-[14C]glucose in the portal vein was performed as described previously (5).

    Calculations. Net hepatic balance (NHB) was calculated using the equation: NHB = ([H] – [A]) x HAF + ([H] – [P]) x PVF, where [H], [A], and [P] are the hepatic vein, arterial, and portal vein blood concentrations, respectively. HAF and PVF are the hepatic artery and portal vein blood flows. Net hepatic glucose output (NHGO) and uptake (NHGU) are both presented as positive values. Hepatic glucose load (HGL) was calculated as: HGL = [A] x HAF + [P] x PVF. Net hepatic glucose fractional extraction (NHGFE) is the ratio of NHGU to HGL.

Incorporation of glucose into hepatic glycogen stores was calculated as the [3-3H]glucose radioactivity in hepatic glycogen per mass tissue divided by the specific activity of inflowing glucose. The specific activity of inflowing glucose was calculated as (SAA x HAF + SAP x PVF)/(PVF + HAF), where SAA and SAP are the specific activities of glucose in the artery and portal vein. This calculation includes only glucose incorporated into glycogen from the direct pathway (glucose -> UDP-glucose -> glycogen) and assumes that minimal [3-3H]glucose is stored as glycogen before t = 0 min (12).

    Statistics. All data presented are means ± SEM. Two-way repeated-measures ANOVA was performed with Tukey’s tests using SigmaStat 3.0 software to assess differences between groups and baseline and experimental periods for all presented variables except liver biopsy data which was analyzed with t tests. Differences were considered significant if P < 0.05.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 LITERATURE CITED
 
    Concentrations and net hepatic balances of caffeine and breakdown products. Before caffeine infusion, there were no detectable levels of caffeine or its metabolites. The infusion of caffeine resulted in a gradual increase in circulating caffeine (Table 1). Net hepatic uptake of caffeine increased with rising circulating levels (Table 2). The net hepatic uptake of caffeine caused the net hepatic output of caffeine breakdown products; the magnitude of this effect increased over the course of the experimental period. The most prominent breakdown product was theophylline, representing 65% of the total.


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  		TABLE 1 Arterial, portal vein, and hepatic vein concentrations of caffeine and caffeine breakdown products during the insulin clamp in caffeine-infused dogs1, 2

 

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  		TABLE 2 Net hepatic balances of caffeine and caffeine breakdown products during the insulin clamp in caffeine-infused dogs1

 
    Arterial hormones. In saline- and caffeine-infused groups, arterial insulin increased significantly during the experimental period (137 ± 19 and 116 ± 45 pmol/L) compared with the baseline period (59 ± 7 and 38 ± 12 pmol/L). Arterial plasma glucagon (36 ± 9 and 42 ± 6 ng/L), cortisol (68 ± 16 and 67 ± 8 nmol/L), and norepinephrine (1.03 ± 0.16 and 1.30 ± 0.22 nmol/L) did not differ in the baseline period in saline- and caffeine-infused dogs, respectively. During the experimental period, there were no differences in glucagon (28 ± 6 and 38 ± 3 ng/L), cortisol (65 ± 10 and 57 ± 7 nmol/L), or norepinephrine (0.70 ± 0.14 and 1.01 ± 0.22 nmol/L). Arterial epinephrine concentrations did not differ during the baseline (0.91 ± 0.16 and 0.75 ± 0.13 nmol/L) and experimental period (0.80 ± 0.15 and 0.95 ± 0.11 nmol/L) in saline- and caffeine-infused dogs, respectively. However, caffeine infusion caused a small significant increase in epinephrine during the experimental period compared with basal levels within the same group.

    Arterial blood glucose, HGL, and the glucose infusion rate. Arterial blood glucose did not differ in the baseline period in saline- and caffeine-infused dogs (6.1 ± 0.2 and 5.9 ± 0.1 mmol/L, respectively). During the experimental period, arterial blood glucose was increased to and held constant at 9.8 ± 0.2 and 10.2 ± 0.3 mmol/L in the saline- and caffeine-infused groups, respectively. The GIR [µmol/(kg · min)] required to clamp glucose did not differ in saline-(64 ± 7) and caffeine- (73 ± 8) infused dogs.

    Net hepatic glucose balance and fractional extraction. During the baseline period, NHGO was 7.2 ± 1.1 and 10.0 ± 1.1 µmol/(kg · min) in saline and caffeine infused dogs. During the experimental period, the presence of increased insulin and glucose resulted in increased NHGU in both groups (Fig. 2). Caffeine increased NHGU. The increase in NHGU in caffeine-infused dogs was accompanied by an increase in NHGFE compared with saline-infused dogs (0.09 ± 0.02 and 0.05 ± 0.01, respectively).



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  		FIGURE 2 Net hepatic glucose uptake during a hyperinsulinemic-hyperglycemic clamp in caffeine (n = 8) and saline-infused (n = 7) dogs. Data are means ± SEM. *Different from saline, P < 0.05.

 
    Arterial lactate, alanine, glycerol, and NEFA concentrations and hepatic substrate balances. During the baseline period, arterial lactate was lower in saline-than in caffeine-infused dogs (541 ± 84 and 850 ± 91 µmol/L, respectively). During the experimental period, arterial lactate increased in both groups compared with baseline (722 ± 99 vs. 1001 ± 211 µmol/L, respectively). Net hepatic lactate output was significantly higher in dogs infused with caffeine rather than saline during the experimental period [12.5 ± 3.8 and 5.5 ± 1.5 µmol/(kg · min), respectively]. Arterial alanine did not differ in saline- and caffeine-infused dogs during the baseline (298 ± 23 and 393 ± 45 µmol/L, respectively) and experimental (297 ± 21 and 327 ± 41 µmol/L, respectively) periods. Arterial glycerol did not differ in saline- and caffeine-infused dogs during the baseline period (94 ± 10 and 64 ± 13 µmol/L, respectively) and fell to the same extent due to the clamp (32 ± 8 and 31 ± 9 µmol/L, respectively). Arterial NEFA was higher in saline-compared with caffeine-infused dogs during the baseline period (875 ± 56 and 715 ± 59 µmol/L, respectively). NEFA levels fell to similar levels in the saline- and caffeine-infused groups during clamps (170 ± 52 and 194 ± 45 µmol/L, respectively).

    Liver glycogen, glucose-6-phosphate, fructose-6-phosphate, and glycogen synthase/phosphorylase. Liver glycogen (28.4 ± 2.5 and 29.6 ± 3.7 g) as well as the amount of glycogen synthesized (4.2 ± 0.7 and 4.3 ± 0.9 mg/100 g tissue) over the course of the experiment did not differ in saline- and caffeine-infused dogs, respectively. Liver glucose-6-phosphate (20.1 ± 3.1 and 32.8 ± 5.4 µmol/100 g tissue) increased with caffeine infusion, whereas fructose-6-phosphate levels decreased (7.3 ± 0.8 and 4.2 ± 1.2 µmol/100 g tissue), respectively. Enzyme activity ratios for liver glycogen synthase (0.21 ± 0.03 and 0.17 ± 0.03) and phosphorylase (0.62 ± 0.04 and 0.50 ± 0.08) did not differ in saline- and caffeine-infused dogs, respectively.


   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
LITERATURE CITED
 
Caffeine infusion resulted in an increase in NHGU in the presence of a hyperinsulinemic-hyperglycemic clamp. This is consistent with work showing that antagonism of hepatic adenosine receptors promotes insulin action (13). The increased NHGU due to caffeine increased the amount of hepatic glucose-6-phosphate. Some of the additional glucose taken up by the liver was converted to lactate as evidenced by an increase in lactate output which accounted for ~40% of the increase in NHGU. This indicates that the increased glucose taken up by the liver during caffeine infusion is at least in part metabolized glycolytically. The increase in lactate output occurred despite a reduction in liver fructose-6-phosphate. This implies that the oxidative steps downstream of fructose-6-phosphate are upregulated. This oxidative upregulation might outpace the production of fructose-6-phosphate, thereby resulting in a fall in fructose-6-phosphate levels in the liver.

The increase in NHGU did not improve whole-body glucose disposal because the GIR required to clamp glucose was similar in the 2 groups. The improvement in NHGU without a change in GIR suggests that peripheral glucose uptake decreased. Work in humans showed that arterial caffeine concentrations, similar to those seen in this experiment, impaired whole-body and muscle insulin action (1,14,15). In these dog studies, epinephrine increased slightly with caffeine; however, there was no appreciable difference in epinephrine between saline- and caffeine-infused dogs. In contrast, humans have a greater than 2-fold increase in epinephrine with an arterial caffeine concentration of ~45 µmol/L (1). This greater increase in epinephrine in humans could contribute to peripheral glucose intolerance with acute caffeine ingestion (14).

Portal vein caffeine infusions caused a steady increase in circulating caffeine, which was paralleled by an increase in net hepatic caffeine uptake. Fractional extraction of caffeine by the liver was ~10–15%; ~20–30% of caffeine taken up by the liver was converted to theophylline and released. Another ~5–10% of caffeine taken up by the liver was converted to p-xanthine, and an equivalent amount was converted to theobromine. This finding is consistent with previous work in dogs, which showed a marked increase in plasma theophylline after caffeine ingestion (16,17). The primary breakdown product of caffeine in human plasma is p-xanthine (18,19). The differences in caffeine metabolism and the relative proportions of the breakdown products could be attributed to species differences in the cytochrome P450 enzyme that metabolizes caffeine (20).

Epidemiologic work indicates that coffee ingestion can reduce the risk of type II diabetes (3,4). The potential benefit of coffee is separate from the actions of caffeine on skeletal muscle, which cause acute glucose intolerance (1). In addition to the effects of caffeine on the liver, quinides, another component of coffee, were shown to improve insulin action in rats (21). It is therefore possible that habitual coffee ingestion may improve insulin action via the effects of these compounds. This study and our previous work (21) show a mechanistic basis for the epidemiologic reports. Taken together, these findings indicate that caffeine, at levels comparable to those in blood after typical dietary coffee ingestion, increases NHGU in the presence of elevated insulin and glucose concentrations that mimic the postprandial state. The mechanism by which caffeine improves NHGU could be used to improve hepatic glucose disposal in individuals with insulin resistance.


   ACKNOWLEDGMENTS
 
We thank Deanna Bracy and Premila Sathasivam for their valued assistance with the completion of this work as well as the Vanderbilt University Diabetes Center Hormone Assay Core.


   FOOTNOTES
 
1 Data from 6 of the control dogs presented in this work were published previously [Pencek, R. R., James, F., Lacy, D. B., Jabbour, K., Williams, P. E., Fueger, P. T. & Wasserman, D. H.(2003) Interaction of insulin and prior exercise in control of hepatic metabolism of a glucose load. Diabetes 52: 1897–1903]. Back

2 Funded by National Institute of Diabetes and Digestive and Kidney Diseases Grant RO1 DK-50277, Diabetes Center Grant DK-20593, Training Grant 5-T32-DK-7563–08, and the Natural Science and Engineering Research Council (NSERC) of Canada Collaborative Health Research. Back

4 Abbreviations used: [A], arterial concentration; [H], hepatic concentration; HAF, hepatic artery blood flow; HGL, hepatic glucose load; ICG, indocyanine green; NHGFE, net hepatic glucose fractional extraction; NHGO, net hepatic glucose output; NHGU, net hepatic glucose uptake; [P] portal vein concentration; PVF, portal vein blood flow; SAA, arterial specific activity; SAP, portal vein specific activity. Back

Manuscript received 15 March 2004. Initial review completed 8 April 2004. Revision accepted 6 August 2004.


   LITERATURE CITED
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 

1. Greer, F., Hudson, R., Ross, R. & Graham, T. (2001) Caffeine ingestion decreases glucose disposal during a hyperinsulinemic- euglycemic clamp in sedentary humans. Diabetes 50:2349-2354.[Abstract/Free Full Text]

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6. Hamilton, K. S., Gibbons, F. K., Bracy, D. P., Lacy, D. B., Cherrington, A. D. & Wasserman, D. H. (1996) Effect of prior exercise on the partitioning of an intestinal glucose load between splanchnic bed and skeletal muscle. J. Clin. Investig. 98:125-135.[Medline]

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11. Greer, F., Friars, D. & Graham, T. E. (2000) Comparison of caffeine and theophylline ingestion: exercise metabolism and endurance. J. Appl. Physiol. 89:1837-1844.[Abstract/Free Full Text]

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14. Graham, T. E., Sathasivam, P., Rowland, M., Marko, N., Greer, F. & Battram, D. (2001) Caffeine ingestion elevates plasma insulin response in humans during an oral glucose tolerance test. Can J. Physiol. Pharmacol. 79:559-565.[Medline]

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19. Van Soeren, M. H., Sathasivam, P., Spriet, L. L. & Graham, T. E. (1993) Caffeine metabolism and epinephrine responses during exercise in users and nonusers. J. Appl. Physiol. 75:805-812.[Abstract/Free Full Text]

20. Fuhr, U., Doehmer, J., Battula, N., Wolfel, C., Kudla, C., Keita, Y. & Staib, A. H. (1992) Biotransformation of caffeine and theophylline in mammalian cell lines genetically engineered for expression of single cytochrome P450 isoforms. Biochem. Pharmacol. 43:225-235.[Medline]

21. Shearer, J., Farah, A., de Paulis, T., Bracy, D. P., Pencek, R. R., Graham, T. E. & Wasserman, D. H. (2003) Quinides of roasted coffee enhance insulin action in conscious rats. J. Nutr. 133:3529-3532.[Abstract/Free Full Text]




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