Selective reversible inhibition of liver carnitine palmitoyl-transferase 1 by teglicar reduces gluconeogenesis and improves glucose homeostasis

Diabetes

Volumn 60, Issue 2, 2011, Pages 644-651

  Conti, Roberto ^a   Mannucci, Edoardo ^b   Pessotto, Pompeo ^a   Tassoni, Emanuela ^a   Carminati, Paolo ^c   Giannessi, Fabio ^a   Arduini, Arduino ^a  

^a Sigma tau spa ^*  (Switzerland)

^b UNIVERSITY OF FLORENCE   (Italy)

^c Sigma Tau SpA   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE AMINOTRANSFERASE; CARNITINE PALMITOYLTRANSFERASE I; DEOXYGLUCOSE; ETOMOXIR; FATTY ACID; FRUCTOSAMINE; GLUCOSE; INSULIN; ISOENZYME; KETONE; TEGLICAR; TRIACYLGLYCEROL; WATER;

ALANINE AMINOTRANSFERASE BLOOD LEVEL; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CELL ISOLATION; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG SELECTIVITY; ENZYME INHIBITION; FATTY ACID BLOOD LEVEL; FLUID INTAKE; FRUCTOSAMINE BLOOD LEVEL; GLUCONEOGENESIS; GLUCOSE BLOOD LEVEL; GLUCOSE HOMEOSTASIS; GLUCOSE METABOLISM; GLUCOSE UTILIZATION; IN VITRO STUDY; INSULIN BLOOD LEVEL; INSULIN SENSITIVITY; INSULINEMIA; LIPID DIET; LIVER CELL; LONG TERM CARE; MALE; MOUSE; NONHUMAN; PRIORITY JOURNAL; RAT; SINGLE DRUG DOSE; TREATMENT DURATION;

ANALYSIS OF VARIANCE; ANIMALS; AREA UNDER CURVE; CARNITINE; CARNITINE O-PALMITOYLTRANSFERASE; DIABETES MELLITUS, TYPE 2; DIETARY FATS; GLUCONEOGENESIS; GLUCOSE; HEART; HEPATOCYTES; HOMEOSTASIS; INSULIN RESISTANCE; LIVER; MALE; MICE; MYOCARDIUM; PPAR ALPHA; RATS; RATS, SPRAGUE-DAWLEY;

EID: 79551605843     PISSN: 00121797     EISSN: 1939327X     Source Type: Journal    
DOI: 10.2337/db10-0346     Document Type: Article

References (42)

1. Basu R, Schwenk WF, Rizza RA. Both fasting glucose production and disappearance are abnormal in people with "mild" and "severe" type 2 diabetes. Am J Physiol Endocrinol Metab 2004;287:E55-E62
2. Boden G, Chen X, Stein TP. Gluconeogenesis in moderately and severely hyperglycemic patients with type 2 diabetes mellitus. Am J Physiol Endocrinol Metab 2001;280:E23-E30
3. DeFronzo RA, Bonadonna RC, Ferrannini E. Pathogenesis of NIDDM. A balanced overview. Diabetes Care 1992;15:318-368
4. Proietto J, Andrikopoulos S. Molecular mechanisms of increased glucose production: identifying potential therapeutic targets. J Investig Med 2004;52:389-393
5. McCormack JG, Westergaard N, Kristiansen M, Brand CL, Lau J. Pharmacological approaches to inhibit endogenous glucose production as a means of anti-diabetic therapy. Curr Pharm Des 2001;7:1451-1474
6. Mandarino L, Tsalikian E, Bartold S, et al. Mechanism of hyperglycemia and response to treatment with an inhibitor of fatty acid oxidation in a patient with insulin resistance due to antiinsulin receptor antibodies. J Clin Endocrinol Metab 1984;59:658-664
7. Ratheiser K, Schneeweiss B, Waldhäusl W, et al. Inhibition by etomoxir of carnitine palmitoyltransferase I reduces hepatic glucose production and plasma lipids in non-insulin-dependent diabetes mellitus. Metabolism 1991;40:1185-1190
8. Hübinger A, Knode O, Susanto F, Reinauer H, Gries FA. Effects of the carnitine-acyltransferase inhibitor etomoxir on insulin sensitivity, energy expenditure and substrate oxidation in NIDDM. Horm Metab Res 1997;29:436-439 (Pubitemid 27454111)
9. Bajaj M, Suraamornkul S, Kashyap S, Cusi K, Mandarino L, DeFronzo RA. Sustained reduction in plasma free fatty acid concentration improves insulin action without altering plasma adipocytokine levels in subjects with strong family history of type 2 diabetes. J Clin Endocrinol Metab 2004;89:4649-4655
10. Boden G, Chen X, Capulong E, Mozzoli M. Effects of free fatty acids on gluconeogenesis and autoregulation of glucose production in type 2 diabetes. Diabetes 2001;50:810-816
11. Walter P. Pyruvate carboxylase: intracellular localization and regulation. In Gluconeogenesis: Its Regulation in Mammalian Species. Hanson RW, Mehlman MA, Eds. New York, John Wiley, 1976, pp. 239-265
12. McGarry JD, Brown NF. The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. Eur J Biochem 1997;244:1-14
13. Loftus TM, Jaworsky DE, Frehywot GL, et al. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 2000;288:2379-2381
14. Hu Z, Cha SH, Chohnan S, Lane MD. Hypothalamic malonyl-CoA as a mediator of feeding behavior. Proc Natl Acad Sci USA 2003;100:12624-12629
15. Obici S, Rossetti L. Minireview: nutrient sensing and the regulation of insulin action and energy balance. Endocrinology 2003;144:5172-5178
16. Bressler R, Gay R, Copeland JG, Bahl JJ, Bedotto J, Goldman S. Chronic inhibition of fatty acid oxidation: new model of diastolic dysfunction. Life Sci 1989;44:1897-1906
17. Dobbins RL, Szczepaniak LS, Bentley B, Esser V, Myhill J, McGarry JD. Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats. Diabetes 2001;50:123-130
18. Giannessi F, Pessotto P, Tassoni E, et al. Discovery of a long-chain carbamoyl aminocarnitine derivative, a reversible carnitine palmitoyltransferase inhibitor with antiketotic and antidiabetic activity. J Med Chem 2003;46:303-309
19. Anderson RC, Balestra M, Bell PA, et al. Antidiabetic agents: a new class of reversible carnitine palmitoyltransferase I inhibitors. J Med Chem 1995;38:3448-3450
20. Deems RO, Anderson RC, Foley JE. Hypoglycemic effects of a novel fatty acid oxidation inhibitor in rats and monkeys. Am J Physiol 1998;274:R524-R528
21. Anderson RC. Carnitine palmitoyltransferase: a viable target for the treatment of NIDDM? Curr Pharm Des 1998;4:1-16
22. Oakes ND, Thalén PG, Jacinto SM, Ljung B. Thiazolidinediones increase plasma-adipose tissue FFA exchange capacity and enhance insulin-mediated control of systemic FFA availability. Diabetes 2001;50:1158-1165
23. Mauvais-Jarvis F, Virkamaki A, Michael MD, et al. A model to explore the interaction between muscle insulin resistance and beta-cell dysfunction in the development of type 2 diabetes. Diabetes 2000;49:2126-2134
24. Berry MN, Edwards AM, Barrit GJ. Isolated Hepatocytes Preparation, Properties and Applications. Amsterdam, Elsevier, 1991
25. Rigoulet M, Leverve XM, Plomp PJ, Meijer AJ. Stimulation by glucose of gluconeogenesis in hepatocytes isolated from starved rats. Biochem J 1987;245:661-668
26. Kraegen EW, James DE, Jenkins AB, Chisholm DJ. Dose-response curves for in vivo insulin sensitivity in individual tissues in rats. Am J Physiol 1985;248:E353-E362
27. Lazarow PB. Assay of peroxisomal beta-oxidation of fatty acids. Methods Enzymol 1981;72:315-319
28. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963;1:785-789
29. Randle PJ. Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metab Rev 1998;14:263-283
30. Schmidt-Schweda S, Holubarsch C. First clinical trial with etomoxir in patients with chronic congestive heart failure. Clin Sci (Lond) 2000;99:27-35
31. Seppälä-Lindroos A, Vehkavaara S, Häkkinen AM, et al. Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab 2002;87:3023-3028
32. Grefhorst A, Hoekstra J, Derks TGJ, et al. Acute hepatic steatosis in mice by blocking b-oxidation does not reduce insulin sensitivity of very-lowdensity lipoprotein production. Am J Physiol Gastrointest Liver Physiol 2005;289:G592-G598
33. Duivenvoorden I, Teusink B, Rensen PC, et al. Acute inhibition of hepatic beta-oxidation in APOE*3Leiden mice does not affect hepatic VLDL secretion or insulin sensitivity. J Lipid Res 2005;46:988-993 (Pubitemid 43309222)
34. Buettner R, Ottinger I, Schölmerich J, Bollheimer LC. Preserved direct hepatic insulin action in rats with diet-induced hepatic steatosis. Am J Physiol Endocrinol Metab 2004;286:E828-E833
35. Heijboer AC, Donga E, Voshol PJ, et al. Sixteen hours of fasting differentially affects hepatic and muscle insulin sensitivity in mice. J Lipid Res 2005;46:582-588
36. Wendel AA, Li LO, Li Y, Cline GW, Shulman GI, Coleman RA. Glycerol-3-phosphate acyltransferase 1 deficiency in ob/ob mice diminishes hepatic steatosis but does not protect against insulin resistance or obesity. Diabetes 2010;59:1321-1329
37. Obici S, Feng Z, Arduini A, Conti R, Rossetti L. Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat Med 2003;9:756-761
38. Coccurello R, Caprioli A, Bellantuono S, et al. Effects of the increase in neuronal fatty acids availability on food intake and satiety in mice. Psychopharmacology (Berl) 2010;210:85-95
39. Bennett MJ, Boriack RL, Narayan S, Rutledge SL, Raff ML. Novel mutations in CPT 1A define molecular heterogeneity of hepatic carnitine palmitoyltransferase I deficiency. Mol Genet Metab 2004;82:59-63
40. Prip-Buus C, Thuillier L, Abadi N, et al. Molecular and enzymatic characterization of a unique carnitine palmitoyltransferase 1A mutation in the Hutterite community. Mol Genet Metab 2001;73:46-54
41. Stoler JM, Sabry MA, Hanley C, Hoppel CL, Shih VE. Successful long-term treatment of hepatic carnitine palmitoyltransferase I deficiency and a novel mutation. J Inherit Metab Dis 2004;27:679-684
42. Foretz M, Hébrard S, Leclerc J, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest 2010;120:2355-2369