Diabetes, Vol 39, Issue 5 570-574, Copyright © 1990 by American Diabetes Association

ARTICLES

Free-fatty acid inhibition of insulin binding, degradation, and action in isolated rat hepatocytes

J Svedberg, P Bjorntorp, U Smith and P Lonnroth
Department of Medicine I, Sahlgren's Hospital, Gothenburg, Sweden.

The effect of free fatty acids (FFAs) on insulin binding and action was investigated in isolated rat hepatocytes. Oleic acid (0.4 mM) added to the cells rapidly (within 45 min) reduced insulin binding and degradation (each by 45%; P less than 0.001, n = 7) without changing the apparent receptor affinity. The effect was concentration dependent; a half-maximal inhibitory effect occurred at 0.150 +/- 0.050 mM (mean +/- SE). Oleic acid exerted no effect on insulin binding in energy-depleted (KCN-treated) cells. Oleic, palmitic, stearic, palmitoleic, and eicosapentaenoic acids were equally effective in reducing insulin binding. FFA did not change insulin binding to partially purified insulin receptors, thus excluding a direct effect on the insulin receptor. Furthermore, binding to partially purified receptors from solubilized cells pretreated with 0.2 mM oleic acid was not changed, indicating the effect of FFA in intact cells is on the rate of receptor internalization and/or recycling. Concomitant with the effect on insulin binding, oleic acid elicited a concentration-dependent reduction in nonstimulated cellular [14C]aminoisobutyric acid uptake (AIB; 29 +/- 8%, P less than 0.05) and decreased the maximal effect of insulin (39 +/- 7%, P less than 0.05). Thus, in a concentration-dependent manner, different fatty acids can reduce the number of binding sites for insulin and the degradation of insulin by isolated liver cells. Basal and insulin-stimulated AIB transport was reduced, suggesting the presence of postbinding perturbations. These data suggest that FFA exerts an important modulating effect on insulin action in the liver.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. P. Kim, K. J. Catalano, I. R. Hsu, J. D. Chiu, J. M. Richey, and R. N. Bergman Nocturnal free fatty acids are uniquely elevated in the longitudinal development of diet-induced insulin resistance and hyperinsulinemia Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1590 - E1598. [Abstract] [Full Text] [PDF]

				S. P. Kim, M. Ellmerer, E. L. Kirkman, and R. N. Bergman beta-Cell "rest" accompanies reduced first-pass hepatic insulin extraction in the insulin-resistant, fat-fed canine model Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1581 - E1589. [Abstract] [Full Text] [PDF]

				X. L. Wang, L. Zhang, K. Youker, M.-X. Zhang, J. Wang, S. A. LeMaire, J. S. Coselli, and Y. H. Shen Free Fatty Acids Inhibit Insulin Signaling-Stimulated Endothelial Nitric Oxide Synthase Activation Through Upregulating PTEN or Inhibiting Akt Kinase. Diabetes, August 1, 2006; 55(8): 2301 - 2310. [Abstract] [Full Text] [PDF]

				H. Yoshii, T. K. T. Lam, N. Gupta, T. Goh, C. A. Haber, H. Uchino, T. T. Y. Kim, V. Z. Chong, K. Shah, I. G. Fantus, et al. Effects of portal free fatty acid elevation on insulin clearance and hepatic glucose flux Am J Physiol Endocrinol Metab, June 1, 2006; 290(6): E1089 - E1097. [Abstract] [Full Text] [PDF]

				V. B. O'Leary, C. M. Marchetti, R. K. Krishnan, B. P. Stetzer, F. Gonzalez, and J. P. Kirwan Exercise-induced reversal of insulin resistance in obese elderly is associated with reduced visceral fat J Appl Physiol, May 1, 2006; 100(5): 1584 - 1589. [Abstract] [Full Text] [PDF]

				R. Abou Samra, N. H. Baba, N. Torbay, L. Dib, and G. E.-H. Fuleihan High Plasma Leptin Is Not Associated with Higher Bone Mineral Density in Insulin-Resistant Premenopausal Obese Women J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2588 - 2594. [Abstract] [Full Text] [PDF]

				M.-E. Piche, S. J. Weisnagel, L. Corneau, A. Nadeau, J. Bergeron, and S. Lemieux Contribution of Abdominal Visceral Obesity and Insulin Resistance to the Cardiovascular Risk Profile of Postmenopausal Women Diabetes, March 1, 2005; 54(3): 770 - 777. [Abstract] [Full Text] [PDF]

				M. Kabir, K. J. Catalano, S. Ananthnarayan, S. P. Kim, G. W. Van Citters, M. K. Dea, and R. N. Bergman Molecular evidence supporting the portal theory: a causative link between visceral adiposity and hepatic insulin resistance Am J Physiol Endocrinol Metab, February 1, 2005; 288(2): E454 - E461. [Abstract] [Full Text] [PDF]

				T. Dai, G. A. Abou-Rjaily, Q. Y. Al-Share', Y. Yang, M. A. Fernstrom, A. M. DeAngelis, A. D. Lee, L. Sweetman, A. Amato, M. Pasquali, et al. Interaction between Altered Insulin and Lipid Metabolism in CEACAM1-inactive Transgenic Mice J. Biol. Chem., October 22, 2004; 279(43): 45155 - 45161. [Abstract] [Full Text] [PDF]

				M. J. Laires, H. Moreira, C. P. Monteiro, L. Sardinha, F. Limao, L. Veiga, A. Goncalves, A. Ferreira, and M. Bicho Magnesium, Insulin Resistance and Body Composition in Healthy Postmenopausal Women J. Am. Coll. Nutr., October 1, 2004; 23(5): 510S - 513S. [Abstract] [Full Text] [PDF]

				M. Lundgren, J. Buren, T. Ruge, T. Myrnas, and J. W. Eriksson Glucocorticoids Down-Regulate Glucose Uptake Capacity and Insulin-Signaling Proteins in Omental But Not Subcutaneous Human Adipocytes J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2989 - 2997. [Abstract] [Full Text] [PDF]

				J. T. Lane Microalbuminuria as a marker of cardiovascular and renal risk in type 2 diabetes mellitus: a temporal perspective Am J Physiol Renal Physiol, March 1, 2004; 286(3): F442 - F450. [Abstract] [Full Text] [PDF]

				M. E. Valera Mora, A. Scarfone, M. Calvani, A. V. Greco, and G. Mingrone Insulin Clearance in Obesity J. Am. Coll. Nutr., December 1, 2003; 22(6): 487 - 493. [Abstract] [Full Text] [PDF]

				D. Eisenberg and R. L. Bell The Impact of Bariatric Surgery on Severely Obese Patients With Diabetes Diabetes Spectr, October 1, 2003; 16(4): 240 - 245. [Abstract] [Full Text] [PDF]

				S. Kashyap, R. Belfort, A. Gastaldelli, T. Pratipanawatr, R. Berria, W. Pratipanawatr, M. Bajaj, L. Mandarino, R. DeFronzo, and K. Cusi A Sustained Increase in Plasma Free Fatty Acids Impairs Insulin Secretion in Nondiabetic Subjects Genetically Predisposed to Develop Type 2 Diabetes Diabetes, October 1, 2003; 52(10): 2461 - 2474. [Abstract] [Full Text] [PDF]

				C.J. Malkin, P.J. Pugh, T.H. Jones, and K.S. Channer Testosterone for secondary prevention in men with ischaemic heart disease? QJM, July 1, 2003; 96(7): 521 - 529. [Full Text] [PDF]

				T. A. Gresl, R. J. Colman, T. C. Havighurst, D. B. Allison, D. A. Schoeller, and J. W. Kemnitz Dietary Restriction and Beta-Cell Sensitivity to Glucose in Adult Male Rhesus Monkeys J. Gerontol. A Biol. Sci. Med. Sci., July 1, 2003; 58(7): B598 - 610. [Abstract] [Full Text] [PDF]

				F. G. Hamel, J. L. Upward, and R. G. Bennett In Vitro Inhibition of Insulin-Degrading Enzyme by Long-Chain Fatty Acids and Their Coenzyme A Thioesters Endocrinology, June 1, 2003; 144(6): 2404 - 2408. [Abstract] [Full Text] [PDF]

				M. I. Goran, G. D. C. Ball, and M. L. Cruz Obesity and Risk of Type 2 Diabetes and Cardiovascular Disease in Children and Adolescents J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1417 - 1427. [Abstract] [Full Text] [PDF]

				K. Eitel, H. Staiger, J. Rieger, H. Mischak, H. Brandhorst, M. D. Brendel, R. G. Bretzel, H.-U. Haring, and M. Kellerer Protein Kinase C {delta} Activation and Translocation to the Nucleus Are Required for Fatty Acid-Induced Apoptosis of Insulin-Secreting Cells Diabetes, April 1, 2003; 52(4): 991 - 997. [Abstract] [Full Text] [PDF]

				M. L. Cruz, R. N. Bergman, and M. I. Goran Unique Effect of Visceral Fat on Insulin Sensitivity in Obese Hispanic Children With a Family History of Type 2 Diabetes Diabetes Care, September 1, 2002; 25(9): 1631 - 1636. [Abstract] [Full Text] [PDF]

				G. F. Lewis, A. Carpentier, K. Adeli, and A. Giacca Disordered Fat Storage and Mobilization in the Pathogenesis of Insulin Resistance and Type 2 Diabetes Endocr. Rev., April 1, 2002; 23(2): 201 - 229. [Abstract] [Full Text] [PDF]

				E. E. Blaak and A. J.M. Wagenmakers The Fate of [U-13C]Palmitate Extracted by Skeletal Muscle in Subjects With Type 2 Diabetes and Control Subjects Diabetes, March 1, 2002; 51(3): 784 - 789. [Abstract] [Full Text] [PDF]

				P. Shah, A. Vella, A. Basu, R. Basu, A. Adkins, W. F. Schwenk, C. M. Johnson, K. S. Nair, M. D. Jensen, and R. A. Rizza Effects of Free Fatty Acids and Glycerol on Splanchnic Glucose Metabolism and Insulin Extraction in Nondiabetic Humans Diabetes, February 1, 2002; 51(2): 301 - 310. [Abstract] [Full Text] [PDF]

				A. E. Sumner, N. M. Farmer, C. S. Cochran, N. G. Sebring, K. Vanevski, J. C. Reynolds, A. Premkumar, and R. C. Boston Obese Premenopausal African-American Women With Normal and Impaired Glucose Tolerance Have a Similar Degree of Insulin Resistance but Differ in {beta}-Cell Function Diabetes Care, November 1, 2001; 24(11): 1978 - 1983. [Abstract] [Full Text] [PDF]

				W. F. DeNino, A. Tchernof, I. J. Dionne, M. J. Toth, P. A. Ades, C. K. Sites, and E. T. Poehlman Contribution of Abdominal Adiposity to Age-Related Differences in Insulin Sensitivity and Plasma Lipids in Healthy Nonobese Women Diabetes Care, May 1, 2001; 24(5): 925 - 932. [Abstract] [Full Text]

				E. E. Blaak, B. H. R. Wolffenbuttel, W. H. M. Saris, M. M. A. L. Pelsers, and A. J. M. Wagenmakers Weight Reduction and the Impaired Plasma-Derived Free Fatty Acid Oxidation in Type 2 Diabetic Subjects J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1638 - 1644. [Abstract] [Full Text]

				B. L. Wajchenberg Subcutaneous and Visceral Adipose Tissue: Their Relation to the Metabolic Syndrome Endocr. Rev., December 1, 2000; 21(6): 697 - 738. [Abstract] [Full Text]

				A. L. Thompson, M. Y.-C. Lim-Fraser, E. W. Kraegen, and G. J. Cooney Effects of individual fatty acids on glucose uptake and glycogen synthesis in soleus muscle in vitro Am J Physiol Endocrinol Metab, September 1, 2000; 279(3): E577 - E584. [Abstract] [Full Text] [PDF]

				R. V. Weber, M. C. Buckley, S. K. Fried, and J. G. Kral Subcutaneous lipectomy causes a metabolic syndrome in hamsters Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2000; 279(3): R936 - R943. [Abstract] [Full Text] [PDF]

				E. E. Blaak, A. J. M. Wagenmakers, J. F. C. Glatz, B. H. R. Wolffenbuttel, G. J. Kemerink, C. J. M. Langenberg, G. A. K. Heidendal, and W. H. M. Saris Plasma FFA utilization and fatty acid-binding protein content are diminished in type 2 diabetic muscle Am J Physiol Endocrinol Metab, July 1, 2000; 279(1): E146 - E154. [Abstract] [Full Text] [PDF]

				C. Schmitz-Peiffer, D. L. Craig, and T. J. Biden Ceramide Generation Is Sufficient to Account for the Inhibition of the Insulin-stimulated PKB Pathway in C2C12 Skeletal Muscle Cells Pretreated with Palmitate J. Biol. Chem., August 20, 1999; 274(34): 24202 - 24210. [Abstract] [Full Text] [PDF]

				A. Carpentier, S. D. Mittelman, R. N. Bergman, A. Giacca, and G. F. Lewis Acute enhancement of insulin secretion by FFA in humans is lost with prolonged FFA elevation Am J Physiol Endocrinol Metab, June 1, 1999; 276(6): E1055 - E1066. [Abstract] [Full Text] [PDF]

				W. C. Duckworth, R. G. Bennett, and F. G. Hamel Insulin Degradation: Progress and Potential Endocr. Rev., October 1, 1998; 19(5): 608 - 624. [Abstract] [Full Text]

				M. DiGirolamo, J. B. Fine, K. Tagra, and R. Rossmanith Qualitative regional differences in adipose tissue growth and cellularity in male Wistar rats fed ad libitum Am J Physiol Regulatory Integrative Comp Physiol, May 1, 1998; 274(5): R1460 - R1467. [Abstract] [Full Text] [PDF]

				P. D. Berk, S.-L. Zhou, C.-L. Kiang, D. Stump, M. Bradbury, and L. M. Isola Uptake of Long Chain Free Fatty Acids Is Selectively Up-regulated in Adipocytes of Zucker Rats with Genetic Obesity and Non-insulin-dependent Diabetes Mellitus J. Biol. Chem., March 28, 1997; 272(13): 8830 - 8835. [Abstract] [Full Text] [PDF]

				S. D. Long and P. H. Pekala Regulation of GLUT4 Gene Expression by Arachidonic Acid J. Biol. Chem., January 12, 1996; 271(2): 1138 - 1144. [Abstract] [Full Text] [PDF]