Horm Metab Res 2014; 46(06): 390-396
DOI: 10.1055/s-0034-1372600
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

Nicotinic Acid Effects on Insulin Sensitivity and Hepatic Lipid Metabolism: An In Vivo to In Vitro Study

E. Blond
1   Research Centre in Human Nutrition Rhône-Alpes and CENS (Centre of ­European Nutrition Safety and Health), Hospices Civils de Lyon, Pierre Bénite, France
2   INSERM U1060, CarMeN Laboratory, Lyon 1 University, INRA 1235, Oullins, France
,
J. Rieusset
2   INSERM U1060, CarMeN Laboratory, Lyon 1 University, INRA 1235, Oullins, France
,
M. Alligier
2   INSERM U1060, CarMeN Laboratory, Lyon 1 University, INRA 1235, Oullins, France
,
S. Lambert-Porcheron
1   Research Centre in Human Nutrition Rhône-Alpes and CENS (Centre of ­European Nutrition Safety and Health), Hospices Civils de Lyon, Pierre Bénite, France
,
N. Bendridi
2   INSERM U1060, CarMeN Laboratory, Lyon 1 University, INRA 1235, Oullins, France
,
L. Gabert
2   INSERM U1060, CarMeN Laboratory, Lyon 1 University, INRA 1235, Oullins, France
,
M. Chetiveaux
3   INSERM U915 and Nantes Research Centre in Human Nutrition, 44000, Nantes, France
,
C. Debard
2   INSERM U1060, CarMeN Laboratory, Lyon 1 University, INRA 1235, Oullins, France
,
M.-A. Chauvin
2   INSERM U1060, CarMeN Laboratory, Lyon 1 University, INRA 1235, Oullins, France
,
S. Normand
1   Research Centre in Human Nutrition Rhône-Alpes and CENS (Centre of ­European Nutrition Safety and Health), Hospices Civils de Lyon, Pierre Bénite, France
,
H. Roth
4   Research Centre in Human Nutrition Rhône-Alpes, Centre Hospitalier ­Universitaire Grenoble, Grenoble, France
,
A.-C. de Gouville
5   GlaxoSmithKline, Les Ulis, France
,
M. Krempf
3   INSERM U915 and Nantes Research Centre in Human Nutrition, 44000, Nantes, France
,
H. Vidal
1   Research Centre in Human Nutrition Rhône-Alpes and CENS (Centre of ­European Nutrition Safety and Health), Hospices Civils de Lyon, Pierre Bénite, France
2   INSERM U1060, CarMeN Laboratory, Lyon 1 University, INRA 1235, Oullins, France
,
J. Goudable
1   Research Centre in Human Nutrition Rhône-Alpes and CENS (Centre of ­European Nutrition Safety and Health), Hospices Civils de Lyon, Pierre Bénite, France
2   INSERM U1060, CarMeN Laboratory, Lyon 1 University, INRA 1235, Oullins, France
,
M. Laville
1   Research Centre in Human Nutrition Rhône-Alpes and CENS (Centre of ­European Nutrition Safety and Health), Hospices Civils de Lyon, Pierre Bénite, France
2   INSERM U1060, CarMeN Laboratory, Lyon 1 University, INRA 1235, Oullins, France
,
on behalf of “Niacin” Study Group › Author Affiliations
Further Information

Publication History

received 18 September 2013

accepted 13 March 2014

Publication Date:
07 May 2014 (online)

Abstract

Our aim was to characterize the effects and the underlying mechanisms of the lipid-regulating agent Niaspan® on both insulin action and triglyceride decrease in 20 nondiabetic, dyslipidemic men with metabolic syndrome receiving Niaspan® (2 g/day) or placebo for 8 weeks in a randomized, cross-over study. The effects on plasma lipid profile were characterized at the beginning and the end of each treatment period; insulin sensitivity was assessed using the 2-step euglycemic hyperinsulinemic clamp and VLDL-triglyceride turnover by measuring plasma glycerol enrichment, both at the end of each treatment period. The mechanism of action of nicotinic acid was studied in HuH7 and mouse primary hepatocytes. Lipid profile was improved after Niaspan® treatment with a significant−28% decrease in triglyceride levels, a+17% increase in HDL-C concentration and unchanged levels of fasting nonesterified fatty acid. VLDL-tri­glyceride production rate was markedly reduced after Niaspan® (−68%). However, the treatment induced hepatic insulin resistance, as assessed by reduced inhibition of endogenous glucose production by insulin (0.7±0.4 vs. 1.0±0.5 mg/kg · min, p<0.05) and decrease in fasting hepatic insulin sensitivity index (4.8±1.8 vs. 3.2±1.6, p<0.05) in the Niaspan® condition. Nicotinic acid also reduced insulin action in HuH7 and primary hepatocytes, independently of the activation of hepatic PKCε. This effect was associated with an increase in diacylglycerol and a decrease in tri­glyceride contents that occurred in the absence of modification of DGAT2 expression and activity. Eight weeks of Niaspan® treatment in dyslipidemic patients with metabolic syndrome induce hepatic insulin resistance. The mechanism could involve an accumulation of diacylglycerol and an alteration of insulin signaling in hepatocytes.

 
  • References

  • 1 Knopp RH, Paramsothy P, Atkinson B, Dowdy A. Comprehensive lipid management versus aggressive low-density lipoprotein lowering to reduce cardiovascular risk. Am J Cardiol 2008; 101: 48B-57B
  • 2 McKenney J. New perspectives on the use of niacin in the treatment of lipid disorders. Arch Intern Med 2004; 164: 697-705
  • 3 Vega GL, Cater NB, Meguro S, Grundy SM. Influence of extended-release nicotinic acid on nonesterified fatty acid flux in the metabolic syndrome with atherogenic dyslipidemia. Am J Cardiol 2005; 95: 1309-1313
  • 4 Wise A, Foord SM, Fraser NJ, Barnes AA, Elshourbagy N, Eilert M, Ignar DM, Murdock PR, Steplewski K, Green A, Brown AJ, Dowell SJ, Szekeres PG, Hassall DG, Marshall FH, Wilson S, Pike NB. Molecular identification of high and low affinity receptors for nicotinic acid. J Biol Chem 2003; 278: 9869-9874
  • 5 Tunaru S, Kero J, Schaub A, Wufka C, Blaukat A, Pfeffer K, Offermanns S. PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. Nat Med 2003; 9: 352-355
  • 6 Karpe F, Frayn KN. The nicotinic acid receptor – a new mechanism for an old drug. Lancet 2004; 363: 1892-1894
  • 7 Poynten AM, Gan SK, Kriketos AD, O’Sullivan A, Kelly JJ, Ellis BA, Chisholm DJ, Campbell LV. Nicotinic acid-induced insulin resistance is related to increase circulating fatty acids and fat oxidation but not muscle lipid content. Metabolism 2003; 52: 699-704
  • 8 Kang I, Kim SW, Youn JH. Effects of nicotinic acid on gene expression: potential mechanisms and implications for wanted and unwanted effects of the lipid-lowering drug. J Clin Endocrinol Metab 2011; 96: 3048-3055
  • 9 Choi S, Yoon H, Oh KS, Oh YT, Kim YI, Kang I, Youn JH. Widespread effects of nicotinic acid on gene expression in insulin-sensitive tissues: implications for unwanted effects of nicotinic acid treatment. Metabolism 2011; 60: 134-144
  • 10 Lauring B, Taggart AK, Tata JR, Dunbar R, Caro L, Cheng K, Chin J, Colletti SL, Cote J, Khalilieh S, Liu J, Luo WL, Maclean AA, Peterson LB, Polis AB, Sirah W, Wu TJ, Liu X, Jin L, Wu K, Boatman PD, Semple G, Behan DP, Connolly DT, Lai E, Wagner JA, Wright SD, Cuffie C, Mitchel YB, Rader DJ, Paolini JF, Waters MG, Plump A. Niacin lipid efficacy is independent of both the niacin receptor GPR109A and free fatty acid suppression. Sci Transl Med 2012; 4: 148ra115
  • 11 Ganji SH, Tavintharan S, Zhu D, Xing Y, Kamanna VS, Kashyap ML. Niacin noncompetitively inhibits DGAT2 but not DGAT1 activity in HepG2 cells. J Lipid Res 2004; 45: 1835-1845
  • 12 Le Bloc’h J, Leray V, Chetiveaux M, Freuchet B, Magot T, Krempf M, Nguyen P, Ouguerram K. Nicotinic acid decreases apolipoprotein B100-containing lipoprotein levels by reducing hepatic very low density lipoprotein secretion through a possible diacylglycerolacyltransferase 2 inhibition in obese dogs. J Pharmacol Exp Ther 2010; 334: 583-589
  • 13 Hu M, Chu WC, Yamashita S, Yeung DK, Shi L, Wang D, Masuda D, Yang Y, Tomlinson B. Liver fat reduction with niacin is influenced by DGAT-2 polymorphisms in hypertriglyceridemic patients. J Lip Res 2012; 53: 802-809
  • 14 Fabbrini E, Mohammed BS, Korenblat KM, Magkos F, McCrea J, Patterson BW, Klein S. Effect of Fenofibrate and Niacin on Intrahepatic Trigly­ceride Content, Very Low-Density Lipoproteins Kinetics, and Insulin Action in Obese Subjects with Nonalcoholic Fatty Liver Disease. J Clin Endocrinol Metab 2010; 95: 2727-2735
  • 15 Birkenfeld AL, Lee HY, Majumdar S, Jurczak MJ, Camporez JP, Jornayvaz FR, Frederick DW, Guigni B, Kahn M, Zhang D, Weismann D, Arafat AM, Pfeiffer AF, Lieske S, Oyadomari S, Ron D, Samuel VT, Shulman GI. Influence of the hepatic eukaryotic initiation factor 2alpha (eIF2alpha) endoplasmic reticulum (ER) stress response pathway on insulin-mediated ER stress and hepatic and peripheral glucose metabolism. J Biol Chem 2011; 286: 36163-36170
  • 16 Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, Romanelli AJ, Shulman GI. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem 2004; 279: 32345-32453
  • 17 Kumashiro N, Erion DM, Zhang D, Kahn M, Beddow SA, Chu X, Still CD, Gerhard GS, Han X, Dziura J, Petersen KF, Samuel VT, Shulman GI. Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proc Natl Acad Sci USA 2011; 108: 16381-16385
  • 18 Magkos F, Su X, Bradley D, Fabbrini E, Conte C, Eagon JC, Varela JE, Brunt EM, Patterson BW, Klein S. Intrahepatic diacylglycerol content is associated with hepatic insulin resistance in obese subjects. Gastroenterology 2012; 142: 1444.e2-1446.e2
  • 19 Alberti KG, Zimmet P, Shaw J. IDF Epidemiology Task Force Consensus Group . The metabolic syndrome – a new worldwide definition. Lancet 2005; 366: 1059-1062
  • 20 Laville M, Rigalleau V, Riou JP, Beylot M. Respective role of plasma nonesterified fatty acid oxidation and total lipid oxidation in lipid-induced insulin resistance. Metabolism 1995; 44: 639-644
  • 21 Ferrannini E. The theoretical bases of indirect calorimetry: a review. Metabolism 1988; 37: 287-301
  • 22 Pouteau E, Ferchaud-Roucher V, Zair Y, Paintin M, Enslen M, Auriou N, Macé K, Godin JP, Ballèvre O, Krempf M. Acetogenic fibers reduce fasting glucose turnover but not peripheral insulin resistance in metabolic syndrome patients. Clin Nutr 2010; 29: 801-807
  • 23 Rabasa-Lhoret R, Bastard JP, Jan V, Ducluzeau PH, Andreelli F, Guebre F, Bruzeau J, Louche-Pellissier C, MaItrepierre C, Peyrat J, Chagné J, Vidal H, Laville M. Modified quantitative insulin sensitivity check index is better correlated to hyperinsulinemic glucose clamp than other fasting-based index of insulin sensitivity in different insulin-resistant states. J Clin Endocrinol Metab 2003; 88: 4917-4923
  • 24 Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 1999; 22: 1462-1470
  • 25 Wang W, Basinger A, Neese RA, Shane B, Myong SA, Christiansen M, Hellerstein MK. Effect of nicotinic acid administration on hepatic very low density lipoprotein-triglyceride production. Am J Physiol Endocrinol Metab 2001; 280: E540-E547
  • 26 Schwarze E, Tolleshaug H, Seglen O. Uptake and degradation of asialo-orosomucoid in hepatocytes from carcinogen-treated rats. Carcinogenesis 1985; 6: 777-782
  • 27 Rieusset J, Chauvin MA, Durand A, Bravard A, Laugerette F, Michalski MC, Vidal H. Reduction of endoplasmic reticulum stress using chemical chaperones or Grp78 overexpression does not protect muscle cells from palmitate-induced insulin resistance. Biochem Biophys Res Commun 2012; 417: 439-445
  • 28 Alligier M, Meugnier E, Debard C, Lambert-Porcheron S, Chanseaume E, Sothier M, Loizon E, Hssain AA, Brozek J, Scoazec JY, Morio B, Vidal H, Laville M. Subcutaneous adipose tissue remodeling during the initial phase of weight gain induced by overfeeding in humans. J Clin Endocrinol Metab 2012; 97: E183-E192
  • 29 Ciuclan L, Ehnert S, Ilkavets I, Weng HL, Gaitantzi H, Tsukamoto H, Ueberham E, Meindl-Beinker NM, Singer MV, Breitkopf K, Dooley S. TGF-beta enhances alcohol dependent hepatocyte damage via down-regulation of alcohol dehydrogenase I. J Hepatol 2010; 52: 407-416
  • 30 Stone SJ, Koliwad S, Harris C, Farese Jr RV. Thematic review series: glycerolipids. DGAT enzymes and triacylglycerol biosynthesis. J Lipid Res 2008; 49: 2283-2301
  • 31 Kamanna VS, Kashyap ML. Mechanism of action of niacin. Am J Cardiol 2008; 101: 20B-26B
  • 32 Liu Y, Millar JS, Cromley DA, Graham M, Crooke R, Billheimer JT, Rader DJ. Knockdown of acyl-CoA:diacylglycerol acyltransferase 2 with antisense oligonucleotide reduces VLDL TG and ApoB secretion in mice. Biochim Biophys Acta 2008; 1781: 97-104
  • 33 Guyton JR, Goldberg AC, Kreisberg RA, Sprecher DL, Superko HR, O’Connor CM. Effectiveness of once-nightly dosing of extended-release niacin alone and in combination for hypercholesterolemia. Am J Cardiol 1998; 82: 737-743
  • 34 Grundy SM, Vega GL, McGovern ME, Tulloch BR, Kendall DM, Fitz-Patrick D, Ganda OP, Rosenson RS, Buse JB, Robertson DD, Sheehan JP. Diabetes Multicenter Research Group . Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the assessment of diabetes control and evaluation of the efficacy of niaspan trial. Arch Intern Med 2002; 162: 1568-1576
  • 35 Choi CS, Savage DB, Kulkarni A, Yu XX, Liu ZX, Morino K, Kim S, Distefano A, Samuel VT, Neschen S, Zhang D, Wang A, Zhang XM, Kahn M, Cline GW, Pandey SK, Geisler JG, Bhanot S, Monia BP, Shulman GI. Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. J Biol Chem 2007; 282: 22678-22688
  • 36 Yu XX, Murray SF, Pandey SK, Booten SL, Bao D, Song XZ, Kelly S, Chen S, McKay R, Monia BP, Bhanot S. Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice. Hepatology 2005; 42: 362-371