HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: 289/6/E1039    most recent 00247.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Camacho, R. C. Articles by Wasserman, D. H. Search for Related Content PubMed PubMed Citation Articles by Camacho, R. C. Articles by Wasserman, D. H.

5-Aminoimidazole-4-carboxamide-1--D-ribofuranoside renders glucose output by the liver of the dog insensitive to a pharmacological increment in insulin

Department of Molecular Physiology and Biophysics and Diabetes Research and Training Center, Vanderbilt University School of Medicine, Nashville, Tennessee

Submitted 1 June 2005 ; accepted in final form 21 July 2005

	ABSTRACT

TOP ABSTRACT RESEARCH DESIGN AND METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
This study aimed to test whether stimulation of net hepatic glucose output (NHGO) by increased concentrations of the AMP analog, 5-aminoimidazole-4-carboxamide-1--D-ribosyl-5-monophosphate, can be suppressed by pharmacological insulin levels. Dogs had sampling (artery, portal vein, hepatic vein) and infusion (vena cava, portal vein) catheters and flow probes (hepatic artery, portal vein) implanted >16 days before study. Protocols consisted of equilibration (–130 to –30 min), basal (–30 to 0 min), and hyperinsulinemic-euglycemic (0–150 min) periods. At time (t) = 0 min, somatostatin was infused, and basal glucagon was replaced via the portal vein. Insulin was infused in the portal vein at either 2 (INS2) or 5 (INS5) mU·kg^–1·min^–1. At t = 60 min, 1 mg·kg^–1·min^–1 portal venous 5-aminoimidazole-4-carboxamide-1--D-ribofuranoside (AICAR) infusion was initiated. Arterial insulin rose 9- and 27-fold in INS2 and INS5, respectively. Glucagon, catecholamines, and cortisol did not change throughout the study. NHGO was completely suppressed before t = 60 min. Intraportal AICAR stimulated NHGO by 1.9 ± 0.5 and 2.0 ± 0.5 mg·kg^–1·min^–1 in INS2 and INS5, respectively. AICAR stimulated tracer-determined endogenous glucose production similarly in both groups. Intraportal AICAR infusion significantly increased hepatic acetyl-CoA carboxylase (ACC, Ser⁷⁹) phosphorylation in INS2. Hepatic ACC (Ser⁷⁹) phosphorylation, however, was not increased in INS5. Thus intraportal AICAR infusion renders hepatic glucose output insensitive to pharmacological insulin. The effectiveness of AICAR in countering the suppressive effect of pharmacological insulin on NHGO occurs even though AICAR-stimulated ACC phosphorylation is completely blocked.

hepatic glucose production; glycogenolysis; AMP-activated protein kinase; adenosine 5'-monophosphate; 5-aminoimidazole-4-carboxamide-1--D-ribosyl-5-monophosphate

The compound 5-aminoimidazole-4-carboxamide-1--D-ribofuranoside (AICAR) is taken up by cells and phosphorylated to become the AMP analog, 5-aminoimidazole-4-carboxamide-1--D-ribosyl-5-monophosphate (ZMP). Intraportal AICAR infusion (1 mg·kg^–1·min^–1) stimulates hepatic glycogenolysis and glucose output by the liver in the presence of basal intraportal glucagon, high physiological insulin, and either euglycemia or hypoglycemia (6). Moreover, it causes a dose-dependent stimulation of net hepatic glucose output (NHGO) when the liver is in what normally would be a glucose uptake mode (in the presence of hyperinsulinemia, a negative arterial-portal venous glucose gradient, and hyperglycemia; see Ref. 25). In light of the prevalence of insulin-induced hypoglycemia, it is notable that AICAR is effective despite high physiological levels of insulin. The hypothesis tested in the present study was that AICAR renders NHGO insensitive to a pharmacological increase in insulin. To this end, AICAR was infused intraportally at rates 10% of those used in rodent models (to minimize extrahepatic effects; see Refs. 3, 4, 29) during euglycemic clamps in which somatostatin (SRIF) was infused, glucagon was replaced at basal rates, and insulin was replaced at high physiological or pharmacological rates.

	RESEARCH DESIGN AND METHODS

TOP ABSTRACT RESEARCH DESIGN AND METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
Animals and surgical procedures. Experiments were performed on a total of 19 overnight-fasted mongrel dogs (mean weight 22.2 ± 0.5 kg) of either sex that had been fed a standard diet (7). Protocols were approved by the Vanderbilt University Animal Care Committee. Surgical procedures used in this study have been previously described (7). Dogs meeting the established health criteria (7) were studied after an 18-h overnight fast.

Experimental procedures. Experiments consisted of tracer equilibration (–130 to –30 min) and basal (–30 to 0 min), and hyperinsulinemic euglycemic clamp (0–150 min) periods. A primed (40 µCi) infusion (0.2 µCi/min) of HPLC purified [3-³H]glucose was initiated at time (t) = –130 min. The tracer infusion rate was tripled at t = 0 min. A SRIF infusion (0.8 µg·kg^–1·min^–1) was started at t = 0 min to inhibit insulin and glucagon secretion. Concurrent with SRIF infusion was basal intraportal glucagon replacement (0.5 ng·kg^–1·min^–1). An intraportal insulin infusion of 2 (INS2, n = 7) or 5 (INS5, n = 12) mU·kg^–1·min^–1 was also initiated at this time. Six dogs in INS2 comprise a group published previously (6). A group of dogs treated identically to INS2 except without AICAR from a previous publication (6) is included for comparison in Figs. 1 and 3. Arterial glucose was clamped at euglycemic levels (105 mg/dl). A portal venous AICAR infusion (1 mg·kg^–1·min^–1) was initiated at t = 60 min. Portal vein and hepatic artery blood flows were monitored on-line throughout the experiments. At the end of the experiment, animals were killed with pentobarbital sodium and liver biopsies were frozen in liquid nitrogen. An autopsy was performed to confirm catheter placement.

View larger version (22K): [in this window] [in a new window]   Fig. 1. Net hepatic glucose output (NHGO) in the presence of a 2 mU·kg–1·min–1 (INS2, n = 7, ) and 5 mU·kg–1·min–1 (INS5, n = 12, ) hyperinsulinemic insulin infusion during the basal period (–30 to 0 min) and hyperinsulinemic euglycemic clamp period (0 to 150 min) in the presence of intraportal 5-aminoimidazole-4-carboxamide-1--D-ribofuranoside (AICAR) from 60 to 150 min. The dotted line represents the normal response of NHGO in the presence of hyperinsulinemia alone (data from Ref. 6). Inset: area under the curve (AUC) of NHGO after time (t) = 60 min. Data are means ± SE. *Significantly different from saline (P < 0.05).

View larger version (12K): [in this window] [in a new window]   Fig. 3. Quantification of the phosphorylated form of acetyl-CoA carboxylase (ACC, Ser79) from livers after a 2 mU·kg–1·min–1 hyperinsulinemic infusion with a portal venous saline (Sal) infusion (n = 5, gray bar, from Ref. 6), and portal venous AICAR-treated dogs in the presence of 2 mU·kg–1·min–1 (n = 7, filled bar) and 5 mU·kg–1·min–1 (n = 5, open bar) insulin. Data are means ± SE. *Significantly different from saline and INS5 (P < 0.05).

Western blotting. Protein from liver lysates (30 µg; see Ref. 6) was run on a SDS-PAGE gel and transferred to a polyvinyldine fluoride membrane. Membranes were treated with rabbit -phospho-AMP-activated protein kinase (AMPK, Thr¹⁷²) or -phospho-acetyl-CoA carboxylase (ACC, Ser⁷⁹; Cell Signaling, Beverly, MA) and then incubated with -rabbit-horseradish peroxidase (Promega, Madison, WI). Chemiluminescence was detected with a WesternBreeze kit from Invitrogen (Carlsbad, CA). Densitometry was performed using Scion Image software (Frederick, MD).

Calculations. Endogenous glucose production (R_a) and utilization (R_d) were determined by isotope dilution (20).

Statistical analysis. Statistical comparisons between groups and over time were made using ANOVA designed to account for repeated measures. Specific time points were examined for significance using contrasts solved by univariate repeated measures. Liver purine nucleotides were compared using ANOVA designed to account for repeated measures. Liver glycogen was compared using t-tests. AMPK and ACC phosphorylation was compared using one-tailed t-tests. Statistics are reported in Table 1 and Figs. 1–3. Data are presented as means ± SE. Statistical significance was defined as P < 0.05.

	RESULTS

TOP ABSTRACT RESEARCH DESIGN AND METHODS RESULTS DISCUSSION GRANTS REFERENCES

Glucose kinetics. NHGO was similar during the basal period and fell similarly during the first 60 min of hyperinsulinemia in each group (Fig. 1). AICAR increased NHGO similarly in INS2 (–0.2 ± 0.2 at t = 60 min to 1.8 ± 0.6 mg·kg^–1·min^–1 at t = 150 min, P < 0.05) and INS5 (–0.9 ± 0.3 at t = 60 min to 1.1 ± 0.6 mg·kg^–1·min^–1 at t = 150 min, P < 0.05). In contrast, NHGO remained suppressed when saline was infused instead of AICAR (Fig. 1).

Endogenous R_a was similar during the basal period and fell during the first 60 min of hyperinsulinemia in each group (Fig. 2A). AICAR increased R_a in both INS2 (0.9 ± 0.2 at t = 60 min to 2.1 ± 0.7 mg·kg^–1·min^–1 at t = 140 min) and INS5 (–1.7 ± 0.4 at t = 60 min to 1.4 ± 0.6 mg·kg^–1·min^–1 at t = 140 min, P < 0.05). R_d was similar during the basal period and rose similarly during the first 30 min of hyperinsulinemia in each group (Fig. 2B). R_d was significantly greater in INS5 compared with INS2 from t = 40–140 min.

View larger version (23K): [in this window] [in a new window]   Fig. 2. Endogenous Ra (A) and Rd (B) in the presence of a 2 mU·kg–1·min–1 (n = 7, ) and 5 mU·kg–1·min–1 (n = 12, ) hyperinsulinemic infusion during the basal period (–30 to 0 min) and hyperinsulinemic euglycemic clamp period (0 to 150 min) in the presence of intraportal AICAR from 60 to 150 min. Data are means ± SE. *Significantly different from 5 mU·kg–1·min–1 (P < 0.05).

Tissue analyses. At t = 150 min, liver glycogen was 47 ± 4, 41 ± 3, and 35 ± 4 mg/g liver in a portal venous saline-infused group (from Ref. 6), INS2, and INS5, respectively (P < 0.05, INS5 vs. saline). Liver ZMP was not detectable, 3.51 ± 0.38, and 4.34 ± 0.46 µmol/g liver in saline-infused dogs (from Ref. 6), INS2, and INS5, respectively (P < 0.05, INS2 and INS5 vs. saline). Phosphorylation of hepatic AMPK (Thr¹⁷²) was similar in all groups (data not shown). Phosphorylation of hepatic ACC (Ser⁷⁹) was significantly greater in INS2 vs. INS5 and saline-infused dogs (P < 0.05, Fig. 3).

	DISCUSSION

TOP ABSTRACT RESEARCH DESIGN AND METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
These studies show that intraportal infusion of AICAR at a rate of 1 mg·kg^–1·min^–1 renders hepatic glucose output blind to the suppressive effects of pharmacological insulin. Although it has previously been shown that intraportal AICAR stimulates hepatic glucose output (6, 25), it was unknown if the effect was because of AMPK activation [and the subsequent activation of glycogen-phosphorylase kinase (8) and phosphorylase (31)] and/or allosteric activation of glycogen phosphorylase by ZMP (12, 19, 28). These studies show that 1) AICAR is equally effective in stimulating hepatic glucose output at physiological and pharmacological insulin levels and that 2) AICAR does not require an increase in AMPK activity (as reflected by ACC phosphoylation) to exert this effect.

Several studies have examined the hepatic effects of administering AICAR in vivo. Intracerebroventricular infusion of AICAR increases endogenous R_a in 5-h-fasted mice (26) and overnight-fasted rats (21). Iglesias et al. (16) showed that a 250 mg/kg intraperitoneal injection of AICAR caused a marked increment in net hepatic glycogen breakdown in the 5-h-fasted rat. Our laboratory has shown that, in the presence of hyperinsulinemia, basal glucagon, and either hypoglycemia, euglycemia (6), or hyperglycemia (25), an intraportal AICAR infusion (1 mg·kg^–1·min^–1) increases hepatic glucose output in the 18-h-fasted dog. This AICAR infusion results in hepatic ZMP concentrations of 3 µmol/g liver, and an increase in hepatic AMPK activity, reflected by an increase in hepatic ACC phosphorylation (6, 25). These studies were in contrast to those of Bergeron et al., who showed that primed (100 mg/kg) systemic AICAR infusions of 7.5 (4) and 10 (3) mg·kg^–1·min^–1 suppressed R_a in overnight-fasted rats. The differences between the studies of Bergeron et al. and the previously mentioned studies showing an AICAR stimulation of glucose production can be attributed to differences in glycogen content, since an overnight fast virtually glycogen depletes rats. Consistent with differences in hepatic glycogen levels being responsible for these differences is the fact that the marked stimulation of NHGO from an intraportal AICAR infusion was lost when given to a 42-h-fasted dog in which liver glycogen was markedly reduced (Camacho and Wasserman, unpublished observation).

Intraportal AICAR infusion was associated with significant decreases in hepatic glycogen (9 ± 4 and 12 ± 4 mg/g tissue in INS2 and INS5, respectively). This coupled with the fact that there were no differences in net hepatic alanine, glycerol, or lactate uptake indicates that an increase in glycogenolysis was responsible for the rise in hepatic glucose output. The differences in hepatic glycogen correspond to rates of net hepatic glycogenolysis of 3.3 ± 1.2 and 4.7 ± 1.5 mg·kg^–1·min^–1 in INS2 and INS5, respectively. Because endogenous R_a tends to be underestimated (as reflected by negative rates) under hyperinsulinemic euglycemic clamp conditions (14), we focused on NHGO. However, it is noteworthy that intraportal AICAR stimulated endogenous R_a to rise to a similar rate (2 mg·kg^–1·min^–1) in both INS2 and INS5. Net hepatic glycogenolysis exceeded NHGO by twofold, indicating that 50% of the glucose 6-phosphate formed by glycogenolysis has a fate other than glucose release. Because insulin stimulates pyruvate dehydrogenase, pyruvate oxidation is likely to be an alternative fate (24).

The liver of the AICAR-infused dog appears to be resistant to the suppressive effects of high physiological concentrations of insulin on hepatic glucose output (6, 25). This suggests that a compound with similar liver actions could be effectively exploited to combat insulin-induced hypoglycemia, which is the single most frequent complication in diabetic patients (10). Both increased AMP/ZMP concentrations (12, 19, 28) and increased AMPK activity (8, 31) have been shown to result in activation of glycogen phosphorylase. Even small increments (11) in insulin potently inhibit glycogen phosphorylase in vivo (5) via its regulation of cAMP (13). This is one of the few studies to investigate insulin's regulation of hepatic AMPK.

Intracerebroventricular infusion of insulin reduces ₂-AMPK activity in all hypothalamic regions in mice (22). Chronic insulin treatment normalizes hypothalamic ₂-AMPK hyperactivity in streptozotocin-induced diabetic rats (23). Beauloye et al. (2) showed that insulin antagonizes AMPK activity (Thr¹⁷² phosphorylation) induced by ischemia or anoxia in rat hearts. Gamble and Lospaschuk (15), as well as Witters and Kemp (30), have shown that AMPK inhibition and ACC activation are equally sensitive to insulin and that AMPK may be the major target for insulin regulation of ACC. One way in which AMPK is activated is by phosphorylation of the Thr¹⁷² residue by an upstream kinase, AMPKK, or LKB1 (17). However, another study showed that AICAR does not activate AMPK by stimulating LKB1 (27). Given that AMPK activity is regulated by both allosteric interactions and phosphorylation (9), phosphorylation of ACC is a more sensitive marker of AMPK activity in vivo (1, 6, 25). Although there was no apparent increase in phosphorylation of the Thr¹⁷² residue of AMPK, the downstream target of AMPK, ACC (Ser⁷⁹), showed increased phosphorylation in the presence of intraportal (physiological) insulin and AICAR infusions (Fig. 3). This notion is supported by other work that showed that AICAR treatment resulted in a clear increase in the phosphorylation of ACC, but not in that of AMPK (19). The low AICAR dose used in this study may not be high enough to cause covalent modification (phosphorylation) of AMPK, yet may be sufficient to cause allosteric activation (19).

When the intraportal insulin infusion was increased to 5 mU·kg^–1·min^–1, ACC (Ser⁷⁹) phosphorylation was not different from that of saline-infused dogs, confirming that insulin inhibits AMPK activation (2, 15, 22, 30). Because AMPK was not activated in the presence of a 5 mU·kg^–1·min^–1 intraportal insulin infusion and the increase in glucose output remained, it is clear that AICAR is stimulating net hepatic glycogen breakdown via an AMPK-independent mechanism. This is consistent with the assertion that AICAR increases hepatic glucose output in vivo (6, 25) via allosteric activation of glycogen phosphorylase (12, 19, 28).

In summary, results show that, in the presence of basal glucagon, an intraportal infusion of AICAR stimulates endogenous glucose output equally well regardless of whether insulin concentrations are in the high physiological or pharmacological range. The present results combined with earlier studies (6, 25) have numerous important implications. First, because purine nucleotides are a natural constituent of all cells, including hepatocytes, they may comprise part of an endogenous pathway involved in physiological activation of hepatic glucose output. Second, understanding hepatic insulin resistance caused by AICAR may provide insight into basic mechanisms underlying this liver pathology. Third, AMPK-independent actions of AICAR are a potent component of its glucoregulatory actions. Fourth, mechanisms that increase hepatic purine nucleotide concentrations may be effective in countering insulin-induced hypoglycemia. The fact that AICAR counters even pharmacological levels of insulin, and that hypoglycemia potentiates the glycogenolytic effect of AICAR (6), adds further weight to this last point. This suggests that a compound with similar hepatic actions could effectively be exploited to combat insulin-induced hypoglycemia, which is the single most frequently occurring complication in diabetes.

	GRANTS

TOP ABSTRACT RESEARCH DESIGN AND METHODS RESULTS DISCUSSION GRANTS REFERENCES

 
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant RO1 DK-50277 and Diabetes Research and Training Center Grant DK-20593.

	ACKNOWLEDGMENTS

 
We thank the Hormone Assay and Animal Resources Cores of the Vanderbilt Diabetes Research and Training Center for providing the hormone and catecholamine data provided.

	FOOTNOTES

 

Address for reprint requests and other correspondence: R. Camacho, Dept. of Medicine, Division of Endocrinology, Belfer 701, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461 (e-mail: rcamacho{at}aecom.yu.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

	REFERENCES

TOP ABSTRACT RESEARCH DESIGN AND METHODS RESULTS DISCUSSION GRANTS REFERENCES

 

1. Al-Khalili L, Krook A, Zierath JR, and Cartee GD. Prior serum and AICAR-induced AMPK activation in primary human myocytes does not lead to subsequent increase in insulin-stimulated glucose uptake. Am J Physiol Endocrinol Metab 287: E553–E557, 2004.[Abstract/Free Full Text]
2. Beauloye C, Marsin AS, Bertrand L, Krause U, Hardie DG, Vanoverschelde JL, and Hue L. Insulin antagonizes AMP-activated protein kinase activation by ischemia or anoxia in rat hearts, without affecting total adenine nucleotides. FEBS Lett 505: 348–352, 2001.[CrossRef][ISI][Medline]
3. Bergeron R, Previs SF, Cline GW, Perret P, Russell RR, 3rd Young LH, and Shulman GI. Effect of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside infusion on in vivo glucose and lipid metabolism in lean and obese Zucker rats. Diabetes 50: 1076–1082, 2001.[Abstract/Free Full Text]
4. Bergeron R, Russell RR III, Young LH, Ren JM, Marcucci M, Lee A, and Shulman GI. Effect of AMPK activation on muscle glucose metabolism in conscious rats. Am J Physiol Endocrinol Metab 276: E938–E944, 1999.[Abstract/Free Full Text]
5. Bishop JS, Goldberg ND, and Larner J. Insulin regulation of hepatic glycogen metabolism in the dog. Am J Physiol 220: 499–506, 1971.[Free Full Text]
6. Camacho RC, Pencek RR, James F, Lacy DB, and Wasserman DH. Portal venous 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside overcomes hyperinsulinemic suppression of endogenous glucose output. Diabetes 54: 373–382, 2005.[Abstract/Free Full Text]
7. Camacho RC, Pencek RR, Lacy DB, James FD, and Wasserman DH. Suppression of endogenous glucose production by mild hyperinsulinemia during exercise is determined predominantly by portal venous insulin. Diabetes 53: 285–293, 2004.[Abstract/Free Full Text]
8. Carling D and Hardie DG. The substrate and sequence specificity of the AMP-activated protein kinase. Phosphorylation of glycogen synthase and phosphorylase kinase. Biochim Biophys Acta 1012: 81–86, 1989.[Medline]
9. Corton JM, Gillespie JG, Hawley SA, and Hardie DG. 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? Eur J Biochem 229: 558–565, 1995.[ISI][Medline]
10. Cryer PE. Hypoglycaemia: the limiting factor in the glycaemic management of Type I and Type II diabetes. Diabetologia 45: 937–948, 2002.[CrossRef][ISI][Medline]
11. Edgerton DS, Cardin S, Emshwiller M, Neal D, Chandramouli V, Schumann WC, Landau BR, Rossetti L, and Cherrington AD. Small increases in insulin inhibit hepatic glucose production solely caused by an effect on glycogen metabolism. Diabetes 50: 1872–1882, 2001.[Abstract/Free Full Text]
12. Ercan-Fang N, Gannon MC, Rath VL, Treadway JL, Taylor MR, and Nuttall FQ. Integrated effects of multiple modulators on human liver glycogen phosphorylase a. Am J Physiol Endocrinol Metab 283: E29–E37, 2002.[Abstract/Free Full Text]
13. Exton JH, Lewis SB, Ho RJ, Robison GA, and Park CR. The role of cyclic AMP in the interaction of glucagon and insulin in the control of liver metabolism. Ann NY Acad Sci 185: 85–100, 1971.[ISI][Medline]
14. Finegood DT, Bergman RN, and Vranic M. Estimation of endogenous glucose production during hyperinsulinemic-euglycemic glucose clamps. Comparison of unlabeled and labeled exogenous glucose infusates. Diabetes 36: 914–924, 1987.[Abstract]
15. Gamble J and Lopaschuk GD. Insulin inhibition of 5' adenosine monophosphate-activated protein kinase in the heart results in activation of acetyl coenzyme A carboxylase and inhibition of fatty acid oxidation. Metabolism 46: 1270–1274, 1997.[CrossRef][ISI][Medline]
16. Iglesias MA, Ye JM, Frangioudakis G, Saha AK, Tomas E, Ruderman NB, Cooney GJ, and Kraegen EW. AICAR administration causes an apparent enhancement of muscle and liver insulin action in insulin-resistant high-fat-fed rats. Diabetes 51: 2886–2894, 2002.[Abstract/Free Full Text]
17. Lizcano JM, Goransson O, Toth R, Deak M, Morrice NA, Boudeau J, Hawley SA, Udd L, Makela TP, Hardie DG, and Alessi DR. LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J 23: 833–843, 2004.[CrossRef][ISI][Medline]
18. Lloyd B, Burrin J, Smythe P, and Alberti KG. Enzymatic fluorometric continuous-flow assays for blood glucose, lactate, pyruvate, alanine, glycerol, and 3-hydroxybutyrate. Clin Chem 24: 1724–1729, 1978.[Abstract/Free Full Text]
19. Longnus SL, Wambolt RB, Parsons HL, Brownsey RW, and Allard MF. 5-Aminoimidazole-4-carboxamide-1--D-ribofuranoside (AICAR) stimulates myocardial glycogenolysis by allosteric mechanisms. Am J Physiol Regul Integr Comp Physiol 284: R936–R944, 2003.[Abstract/Free Full Text]
20. Mari A. Estimation of the rate of appearance in the non-steady state with a two-compartment model. Am J Physiol Endocrinol Metab 263: E400–E415, 1992.[Abstract/Free Full Text]
21. McCrimmon RJ, Fan X, Ding Y, Zhu W, Jacob RJ, and Sherwin RS. Potential role for AMP-activated protein kinase in hypoglycemia sensing in the ventromedial hypothalamus. Diabetes 53: 1953–1958, 2004.[Abstract/Free Full Text]
22. Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, Foufelle F, Ferre P, Birnbaum MJ, Stuck BJ, and Kahn BB. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428: 569–574, 2004.[CrossRef][Medline]
23. Namkoong C, Kim MS, Jang PG, Han SM, Park HS, Koh EH, Lee WJ, Kim JY, Park IS, Park JY, and Lee KU. Enhanced hypothalamic AMP-activated protein kinase activity contributes to hyperphagia in diabetic rats. Diabetes 54: 63–68, 2005.[Abstract/Free Full Text]
24. Parker JC and Jarett L. Insulin mediator stimulates pyruvate dehydrogenase of intact liver mitochondria. Diabetes 34: 92–97, 1985.[Abstract]
25. Pencek RR, Shearer J, Camacho RC, James FD, Lacy DB, Fueger PT, and Wasserman DH. 5'-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside causes acute hepatic insulin resistance in vivo. Diabetes 54: 355–360, 2005.[Abstract/Free Full Text]
26. Perrin C, Knauf C, and Burcelin R. Intracerebroventricular infusion of glucose, insulin and the AMP-activated kinase activator AICAR controls muscle glycogen synthesis. Endocrinology 145: 4025–4033, 2004.[Abstract/Free Full Text]
27. Sakamoto K, Goransson O, Hardie DG, and Alessi DR. Activity of LKB1 and AMPK-related kinases in skeletal muscle: effects of contraction, phenformin, and AICAR. Am J Physiol Endocrinol Metab 287: E310–E317, 2004.[Abstract/Free Full Text]
28. Shang J and Lehrman MA. Activation of glycogen phosphorylase with 5-aminoimidazole-4-carboxamide riboside (AICAR). Assessment of glycogen as a precursor of mannosyl residues in glycoconjugates. J Biol Chem 279: 12076–12080, 2004.[Abstract/Free Full Text]
29. Shearer J, Fueger PT, Vorndick B, Bracy DP, Rottman JN, Clanton JA, and Wasserman DH. AMP kinase-induced skeletal muscle glucose but not long-chain fatty acid uptake is dependent on nitric oxide. Diabetes 53: 1429–1435, 2004.[Abstract/Free Full Text]
30. Witters LA and Kemp BE. Insulin activation of acetyl-CoA carboxylase accompanied by inhibition of the 5'-AMP-activated protein kinase. J Biol Chem 267: 2864–2867, 1992.[Abstract/Free Full Text]
31. Young ME, Radda GK, and Leighton B. Activation of glycogen phosphorylase and glycogenolysis in rat skeletal muscle by AICAR-an activator of AMP-activated protein kinase. FEBS Lett 382: 43–47, 1996.[CrossRef][ISI][Medline]

This article has been cited by other articles:

				C. Rantzau, M. Christopher, and F. P. Alford Contrasting effects of exercise, AICAR, and increased fatty acid supply on in vivo and skeletal muscle glucose metabolism J Appl Physiol, February 1, 2008; 104(2): 363 - 370. [Abstract] [Full Text] [PDF]

				M. Christopher, C. Rantzau, Z.-P. Chen, R. Snow, B. Kemp, and F. P. Alford Impact of in vivo fatty acid oxidation blockade on glucose turnover and muscle glucose metabolism during low-dose AICAR infusion Am J Physiol Endocrinol Metab, November 1, 2006; 291(5): E1131 - E1140. [Abstract] [Full Text] [PDF]

				R. C. Camacho, E. P. Donahue, F. D. James, E. D. Berglund, and D. H. Wasserman Energy state of the liver during short-term and exhaustive exercise in C57BL/6J mice Am J Physiol Endocrinol Metab, March 1, 2006; 290(3): E405 - E408. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 289/6/E1039    most recent 00247.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Camacho, R. C. Articles by Wasserman, D. H. Search for Related Content PubMed PubMed Citation Articles by Camacho, R. C. Articles by Wasserman, D. H.