Horm Metab Res 2007; 39(3): 212-217
DOI: 10.1055/s-2007-970421
Original Clinical

© Georg Thieme Verlag KG Stuttgart · New York

Association of Free Fatty Acids (FFA) and Tumor Necrosis Factor-α (TNF-α) and Insulin-resistant Metabolic Disorder

E. Ohmura 1 , 2 , D. Hosaka 1 , M. Yazawa 1 , A. Tsuchida 1 , M. Tokunaga 1 , H. Ishida 1 , S. Minagawa 1 , A. Matsuda 1 , Y. Imai 1 , S. Kawazu 1 , T. Sato 2
  • 1Division of Endocrinology and Diabetes, Department of Medicine, Saitama Medical Center, Saitama Medical University, Kawagoe city, Saitama, Kamisho Health Insurance Center
  • 2Hama-cho, Nihonbashi, Chuo-ku, Tokyo, Japan
Further Information

Publication History

received 13. 6. 2006

accepted 18. 10. 2006

Publication Date:
20 March 2007 (online)

Abstract

The roles of free fatty acids (FFA), tumor necrosis factor-α (TNF-α), and adiponectin in the development of the insulin-resistant metabolic disorder in several subjects have been studied. A total of 70 Japanese male subjects were selected according to the following three sets of criteria: subjects in group A had, (1) a fasting plasma glucose (FPG) ≥110 to <140 mg/dl, (2) a triglyceride (TG) level ≥150 mg/dl, (3) a systolic blood pressure (SBP) ≥140 and/or diastolic blood pressure (DBP) ≥90 mmHg, and (4) a body mass index (BMI) ≥25 kg/m2 (age=53.4±8.5 years, BMI=27.0±1.3 kg/m2, n=16). Subjects in group B had, (1) FPG <110 mg/dl, (2) TG <150 mg/dl, (3) SBP <140 and DBP <90 mmHg, and (4) BMI ≥25 kg/m2 (age=47.2±10.3 years, BMI=26.6±1.31 kg/m2, n=38). Subjects in group C had, (1) FPG <110 mg/dl, (2) TG <150 mg/dl, (3) SBP <140 and DBP <90 mmHg, and (4) 20 ≥BMI <22 kg/m2 (age=50.4±9.3 years, BMI=20.9±0.6 kg/m2, n=16). The homeostasis model assessment of insulin resistance in group A (2.7±1.4) was significantly higher (p<0.0001) than in groups B (1.6±0.7) and C (0.9±0.5). FFA in group A (1.17±0.57 mEq/l) was significantly higher than in groups B (0.62±0.23 mEq/l) and C (0.48±0.16 mEq/l) (p<0.0001). Serum TNF-α in group A (1.36±0.62 pg/ml) was significantly higher than in groups B (0.95±0.35 pg/ml; p=0.003) and C (0.76±0.09 pg/ml; p=0.0013). No significant differences in the serum level of adiponectin were observed between groups A and B or between groups B and C. The results suggest that FFA and possibly TNF-α levels are closely related to the development of insulin resistance in subjects with metabolic disorders.

References

  • 1 Bays H, Mandarino L, DeFronzo RA. Mechanism of endocrine disease: Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: Peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach.  J Clin Endocrinol Metab. 2004;  89 463-478
  • 2 Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults . Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment panel III).  JAMA. 2001;  285 2486-2497
  • 3 Kahn BB, Flier JS. Obesity and insulin resistance.  J Clin Invest. 2000;  106 473-481
  • 4 Havel PJ. Update on adipocyte hormones. Regulation of energy balance and carbohydrate/lipid metabolism.  Diabetes. 2004;  53 S143-S151
  • 5 Pittas AG, Joseph NA, Greenberg AS. Adipocytokines and insulin resistance.  J Clin Endocrinol Metab. 2004;  89 447-452
  • 6 Chandran M, Ciaraldi T, Phillips SA, Henry RR. Adiponectin: More than just another fat cell hormone?.  Diabetes Care. 2003;  26 2442-2450
  • 7 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man.  Diabetologia. 1985;  28 412-419
  • 8 DeFronzo RA. Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetic genes.  Diabetes Rev. 1997;  4 177-269
  • 9 Boden G, Shulman GI. Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and β cell dysfunction.  Eur J Clin Invest. 2002;  32 14-23
  • 10 Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Teitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipotrophy and obesity.  Nat Med. 2001;  7 941-946
  • 11 Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FT, Bihain BE, Lodish HF. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice.  Proc Natl Acad Sci USA. 2001;  98 2005-2010
  • 12 Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N, Kihara S, Funahashi T, Tenner AJ, Tomiyama Y, Matsuzawa Y. Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages.  Blood. 2003;  96 1723-1732
  • 13 Bruun JM, Lihn AS, Verdich C, Pedersen SB, Toubro S, Astrup A, Richelsen B. Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans.  Am J Physiol Endocrinol Metab. 2003;  285 E527-E533
  • 14 Ruan H, Lodish HF. Insulin resistance in adipose tissue: direct and indirect effects of tumor necrosis factor-α.  Cytokine Growth Factor Rev. 2003;  14 447-455
  • 15 Boden G. Effects of free fatty acids (FFA) on glucose metabolism: significance for insulin resistance and type 2 diabetes.  Exp Clin Endocrinol Diabetes. 2003;  1111 121-124
  • 16 Kelley DE, Mandarino LJ. Fuel selection in human skeletal muscle in insulin resistance: a reexamination.  Diabetes. 2000;  49 677-383
  • 17 McGarry JD. Banting Lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes.  Diabetes. 2002;  51 7-18
  • 18 Chen X, Igbal N, Boden G. The effect of free fatty acids on gluconeogenesis and glycogenolysis in normal subjects.  J Clin Invest. 1999;  103 365-372
  • 19 Randle J, 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
  • 20 Boden G, Chen X. Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes.  J Clin Invest. 1995;  96 12612-12618
  • 21 Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline GW, Slezak LA, Andersen DK, Hundal RS, Rothman DL, Petersen KF, Shulman GI. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity.  J Clin Invest. 1999;  103 253-259
  • 22 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
  • 23 Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance.  Science. 1993;  259 87-91
  • 24 Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-α in human obesity and insulin resistance.  J Clin Invest. 1995;  95 2409-2415
  • 25 Miyazaki Y, Pipek R, Mandarino LJ, DeFronzo. Tumor necrosis factor-α and insulin resistance in obese type 2 diabetic patients.  Int J Obesity. 2003;  27 88-94
  • 26 Zinman B, Hanley AJ, Harris SB, Kwan J, Fantus IG. Circulating tumor necrosis factor-α concentrations in a native Canadian population with high rates of type 2 diabetes mellitus.  J Clin Endocrinol Metab. 1999;  84 272-278
  • 27 Feinstein R, Kanety H, Papa MZ, Lunenfeld B, Karasik A. Tumor necrosis factor-α suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates.  J Biol Chem. 1993;  268 26055-26058
  • 28 Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-α and obesity-induced insulin resistance.  Science. 1996;  271 665-668
  • 29 Pellme F, Smith U, Funahashi T, Matsuzawa Y, Brekke H, Wiklund O, Taskinen MR, Jansson PA. Circulating adiponectin levels are reduced in non obese but insulin-resistant first-degree relatives of type 2 diabetic patients.  Diabetes. 2003;  52 1182-1186
  • 30 Cnop M, Havel PJ, Utzschneider KM. Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex.  Diabetologia. 2003;  46 459-469
  • 31 Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia.  J Clin Endocrinol Metab. 2001;  86 1930-1935
  • 32 Kern PA, Di Gregorio GB, Lu T, Rassouli N, Ranganathan G. Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-α expression.  Diabetes. 2003;  52 1779-1785
  • 33 Spranger J, Kroke A, Mohlig M, Hoffmann K, Bergmann MM, Ristow M, Boeing H, Pfeiffer AFH. Adiponectin and protection against type 2 diabetes mellitus.  Lancet. 2003;  361 226-228
  • 34 Lindsay RS, Funahashi T, Hanson RL, Matsuzawa Y, Tanaka S, Tataranni PA, Knowler WC, Krakoff J. Adiponectin and development of type 2 diabetes in the Pima Indian.  Lancet. 2002;  360 57-58
  • 35 Stefan N, Vozarova B, Funahashi T, Matsuzawa Y, Weyer C, Youngren JF, Havel PJ, Pratley RE, Tataranni PA. Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans.  Diabetes. 2002;  51 1884-1888
  • 36 Stefan N, Funahashi T, Stumvoll M, Matsuzawa Y, Vozarova B, Bogardus C, Weyer C, Tataranni PA. Plasma adiponectin and endogenous glucose production in humans.  Diabetes Care. 2003;  26 3315-3319
  • 37 Weiss R, Dufour S, Groszmann A, Petersen K, Dziura J, Taksali SE, Shulman G, Caprio S. Low adiponectin levels in adolescent obesity: A marker of increased intramyocellular lipid accumulation.  J Clin Endocrinol Metab. 2003;  88 2014-2018
  • 38 Abbasi F, Chu JW, Lamendola C, McLaughlin T, Hayden J, Reaven GM, Reaven PD. Discrimination between obesity and insulin resistance in the relationship with adiponectin.  Diabetes. 2004;  53 585-590
  • 39 Abbasi F, Lamendola C, McLaughlin T, Hayden J, Reaven GM, Reaven PD. Plasma adiponectin concentrations do not increase in association with moderate weight loss in insulin-resistant, obese women.  Metabolism. 2004;  53 280-283
  • 40 Baratta R, Amato S, Degano C, Farina MG, Patane G, Vigneri R, Frittitta L. Adiponectin relationship with lipid metabolism is independent of body fat mass: evidence from both cross-sectional and intervention studies.  J Clin Endocrinol Metab. 2004;  89 2665-2671
  • 41 Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K, Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno NH, Shibata Y, Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T, Nagai R, Kadowaki T. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects.  Nature. 2003;  423 762-769
  • 42 Combs TP, Pajvani UB, Berg AH, Lin Y, Jelicks LA, Laplante M, Nawrocki AR, Rajala MW, Parlow AF, Cheeseboro L, Ding YY, Russell RG, Lindemann D, Hartley A, Baker GRC, Obici S, Deshaies Y, Ludgate M, Rossetti L, Scherer PE. A transgenic mouse with a deletion in the collagenous domain of adiponectin displays elevated circulating adiponectin and improved insulin sensitivity.  Endocrinology. 2004;  145 367-383

Correspondence

E. Ohmura

Division of Endocrinology and Diabetes · Department of Medicine · Saitama Medical Center · Saitama Medical University

Kawagoe city

Saitama

Kamisho Health Insurance Center

Hama-cho

Nihonbashi

Chuo-ku

Tokyo

Japan

Phone: +81/49/228 35 64

Fax: +81/49/225 66 49

Email: eioh@saitama-med.ac.jp

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