Exp Clin Endocrinol Diabetes 2003; 111(3): 121-124
DOI: 10.1055/s-2003-39781
Review

J. A. Barth Verlag in Georg Thieme Verlag Stuttgart · New York

Effects of Free Fatty Acids (FFA) on Glucose Metabolism: Significance for Insulin Resistance and Type 2 Diabetes

G. Boden 1
  • 1Division of Endocrinology/Diabetes/Metabolism and the General Clinical Research Center, Temple University School of Medicine, Philadelphia, PA USA
Further Information

Publication History

Received: July 17, 2002 First decision: October 16, 2002

Accepted: November 17, 2002

Publication Date:
04 June 2003 (online)

Abstract

Most obese individuals have elevated plasma levels of free fatty acids (FFA) which are known to cause peripheral (muscle) insulin resistance. They do this by inhibiting insulin-stimulated glucose uptake and glycogen synthesis. The mechanism involves intramyocellular accumulation of diacylglycerol and activation of protein kinase C. FFAs also cause hepatic insulin resistance. They do this by inhibiting insulin-mediated suppression of glycogenolysis. On the other hand, FFAs support between 30 and 50 % of basal insulin secretion and potentiate glucose-stimulated insulin secretion. The insulin stimulatory action of FFAs is responsible for the fact that the vast majority (∼ 80 %) of obese insulin resistant people do not develop type 2 diabetes. They are able to compensate for their FFA mediated insulin resistance with increased FFA mediated insulin secretion. Individuals who are unable to do this (probably for genetic reasons) eventually develop type 2 diabetes. FFAs have recently been shown to activate the IκB/NFκB pathway which is involved in many inflammatory processes. Thus, elevated plasma levels of FFAs are not only a major cause of insulin resistance in skeletal muscle and liver but may, in addition, play a role in the pathogenesis of coronary artery disease.

References

  • 1 Bevilacqua S, Buzzigoli G, Bonadonna R, Brandi S, Oleggini M, Boni C, Geloni M, Ferrannini E. Operation of Randle's cycle in patients with NIDDM.  Diabetes. 1990;  39 383-389
  • 2 Boden G. Fuel metabolism in pregnancy and in gestational diabetes mellitus.  Obstet Gynecol Clin North Am. 1996;  23 1-10
  • 3 Boden G. Free fatty acids (FFA), a link between obesity and insulin resistance.  Front Biosci. 1998;  3 D169-D175
  • 4 Boden G. Free fatty acids and insulin resistance during pregnancy.  J Clin Endocrinol Metab. 1998;  83 2338-2342
  • 5 Boden G. Free fatty acids - the link between obesity and insulin resistance.  Endocr Pract. 2001;  7 44-51
  • 6 Boden G, Chen X. Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes.  J Clin Invest. 1995;  96 1261-1268
  • 7 Boden G, Chen X. Effects of fatty acids and ketone bodies on basal insulin secretion in type 2 diabetes.  Diabetes. 1999;  48 577-583
  • 8 Boden G, Chen X, Iqbal N. Acute lowering of plasma fatty acids lowers basal insulin secretion in diabetic and nondiabetic subjects.  Diabetes. 1998;  47 1609-1612
  • 9 Boden G, Chen X, Rosner J, Barton M. Effects of a 48-h fat infusion on insulin secretion and glucose utilization.  Diabetes. 1995;  44 1239-1242
  • 10 Boden G, Chen X, Ruiz J, White J V, Rossetti L. Mechanisms of fatty acid-induced inhibition of glucose uptake.  J Clin Invest. 1994;  93 2438-2440
  • 11 Boden G, Cheung P, Stein T P, Kresge K, Mozzoli M. FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis.  Am J Physiol. 2002;  283 E12-E19
  • 12 Boden G, Jadali F, White J, Liang Y, Mozzoli M, Coleman E, Smith C. Effects of fat on insulin-stimulated carbohydrate metabolism in normal men.  J Clin Invest. 1991;  88 960-966
  • 13 Boden G, Lebed B, Schatz M, Homko C, Lemieux S. Effects of acute changes of plasma FFA on intramuscular fat content and insulin resistance in healthy subjects.  Diabetes. 2001;  50 1612-1617
  • 14 Boesch C, Slotboom J, Hoppeler H, Kreis R. In vivo determination of intra-myocellular lipids in human muscle by means of localized 1H - MR spectroscopy.  MRM. 1997;  37 484-493
  • 15 Bollheimer L C, Skelly R H, Chester M W, McGarry D J, Rhodes C J. Chronic exposure to free fatty acids reduced pancreatic β cell insulin content by increasing basal insulin secretion that is not compensated for by a corresponding increase in proinsulin biosynthesis translation.  J Clin Invest. 1998;  101 1094-1118
  • 16 Bronfman M, Morales M N, Orellano A. Diacylglycerol activation of protein kinase C is modulated by long-chain acyl-CoA.  Biochem Biophys Res Commun. 1988;  152 987-992
  • 17 Chin J E, Dickens M, Tavare J M, Roth R A. Overexpression of protein kinase C isoenzymes alpha, beta I, gamma and episilon in cells overexpressing the insulin receptor. Effects on receptor phosphorylation and signaling.  J Biol Chem. 1993;  268 6338-6347
  • 18 Crespin S R, Greenough W B, Steinberg D. Stimulation of insulin secretion by long-chain free fatty acids.  J Clin Invest. 1973;  52 1979-1984
  • 19 DeFea K, Roth R A. Modulation of insulin receptor substrate-1 tyrosine phosphorylation and function by mitogen-activated protein kinase.  J Biol Chem. 1997;  272 31400-31406
  • 20 Dresner A, Laurent D, Marcucci M, Griffin M E, Dufour S, Cline G W, Slezak L A, Andersen D K, Hunal R S, Rothman D L, Petersen K F, Shulman G I. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity.  J Clin Invest. 1999;  103 253-259
  • 21 Edgerton D S, Cardin S, Emshwiller M, Neal D, Chandramouli V, Schuman V C, Landau B R, Rossetti L, Cherrington A D. Small increases in insulin inhibit hepatic glucose production solely caused by an effect on glycogen metabolism.  Diabetes. 2001;  50 1872-1882
  • 22 Fanelli C, Calderone S, Epifano L, DeVincenzo A, Modarelli F, Pampanelli S, Perriello G, DeFeo P, Brunetti P, Gerich J E, Bolli G B. Demonstration of a critical role for free fatty acids in mediating counterregulatory stimulation of gluconeogenesis and suppression of glucose utilization in humans.  J Clin Invest. 1993;  92 1617
  • 23 Farese R V. Protein kinase C. Olefsky J, Taylor SE, LeRoit D Diabetes Mellitus: A Fundamental and Clinical Text. Philadelphia; Lippincott 2000: 239-251
  • 24 Felber J P, Vanotti A. Effects of fat infusions on glucose tolerance and plasma insulin levels.  Med Exp. 1964;  10 153-156
  • 25 Ferrannini E, Barrett E, Bevilacqua S, DeFronzo R. Effect of fatty acids on glucose production and utilization in man.  J Clin Invest. 1983;  72 1737-1747
  • 26 Ferrannini E, Natali A, Bell P, Cavallo-Perin P, Lalic N, Mingrone B. Insulin resistance and hypersecretion in obesity.  J Clin Invest. 1997;  100 1166-1173
  • 27 Gastaldelli A, Toschi E, Pettiti M, Frascerra S, Quinones-Galvan A, Sironi A M, Natali A, Ferrannini E. Effect of physiological hyperinsulinemia on gluconeogenesis in nondiabetic subjects and in type 2 diabetic patients.  Diabetes. 2001;  50 1807-1812
  • 28 Gorden E S. Non-esterified fatty acids in blood of obese and lean subjects.  Am J Clin Nutr. 1960;  8 740-747
  • 29 Itani S I, Ruderman N B, Schmieder F, Boden G. Lipid induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C and IκB-α.  Diabetes. 2002;  51 2005-2011
  • 30 Koyama K, Chen G, Lee Y, Unger R H. Tissue triglycerides, insulin resistance, and insulin production: implications for hyperinsulinemia of obesity.  Am J Physiol. 1997;  273 E708-E713
  • 31 Laybutt D R, Schmitz-Peifffer C, Saha A K, Ruderman N B, Biden T J, Kraegen E W. Muscle lipid accumulation and protein kinase C activation in the insulin-resistant chronically glucose-infused rat.  Am J Physiol. 1999;  277 E1070-E1076
  • 32 Mokdad A H, Serdula M K, Dietz W H, Bowman B A, Marks J S, Koplan J P. The spread of the obesity epidemic in the United States, 1991 - 1998.  JAMA. 1999;  282 1519-1522
  • 33 Nesher M, Boneh A. Effect of fatty acids and their acyl-CoA esters on protein kinase C activity in fibroblasts: possible implications in fatty acid oxidation defects.  Biochim Biophys Acta. 1994;  1221 66-72
  • 34 Oakes N D, Cooney G J, Camilleri S, Chisholm D J, Kraegen E W. Mechanisms of liver and muscle insulin resistance induced by chronic high-fat feeding.  Diabetes. 1997;  46 1768-1774
  • 35 Pan D A, Lillioja S, Kriketos A D, Milner M R, Baur L A, Bogardus C, Jenkins A B, Storlien L H. Skeletal muscle triglyceride levels are inversely related to insulin action.  Diabetes. 1997;  46 983-988
  • 36 Pelkonen R, Miettinen A, Taskinen M-R, Nikkila E A. Effect of acute elevation of plasma glycerol, triglyceride and FFA levels on glucose utilization and plasma insulin.  Diabetes. 1968;  17 76-82
  • 37 Phillips D IW, Caddy S, Ilic V, Fielding B A, Frayn K N, Borthwick A C, Taylor R. Intramuscular triglyceride and muscle insulin sensitivity: evidence for a relationship in nondiabetic subjects.  Metabolism. 1996;  45 947-950
  • 38 Randle P J, Garland P B, Hales C N, Newsholme E A. The glucose-fatty acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus.  Lancet. 1963;  1 785-789
  • 39 Ravichandran L V, Esposito D L, Chen J, Quon M J. Protein kinase C-ζ phosphorylates insulin receptor substrate-1 and impairs its ability to activate phosphatidylinositol 3-kinase in response to insulin.  J Biol Chem. 2000;  276 3543-3549
  • 40 Reaven G M. Role of insulin resistance in human disease.  Diabetes. 1988;  37 1595-1607
  • 41 Reaven G M, Hollenbeck C, Jeng C-Y, Wu M S, Chen Y D. Measurement of plasma glucose, free fatty acid, lactate and insulin for 24 h in patients with NIDDM.  Diabetes. 1988;  37 1020-1024
  • 42 Roden M, Price T B, Perseghin G, Rothman D L, Cline G W, Shulman G I. Mechanisms of free fatty acid induced insulin resistance in humans.  J Clin Invest. 1996;  17 2859-2865
  • 43 Ross R. Atherosclerosis - an inflammatory disease.  N Engl J Med. 1999;  34 115-120
  • 44 Sako Y, Grill V E. A 48-hour lipid infusion in the rat time-dependently inhibits glucose-induced insulin secretion and β-cell oxidation through a process likely coupled to fatty acid oxidation.  Endocrinology. 1990;  127 1580-1589
  • 45 Santomauro A, Boden G, Silva M, Rocha D M, Santos R F, Ursich M JM, Strassman P G, Wajchengerg B L. Overnight lowering of free fatty acids with acipimox improves insulin resistance and glucose tolerance in obese diabetic and non-diabetic subjects.  Diabetes. 1999;  48 1836-1841
  • 46 Simoneau J A, Colberg S R, Thaete F L, Kelley D E. Skeletal muscle glycolytic and oxidative enzyme capacities are determinants of insulin sensitivity and muscle composition in obese women.  FASEB J. 1995;  9 273-278
  • 47 Sivan E, Homko C J, Whittaker P G, Reece A E, Chen X, Boden G. Fatty acids and insulin resistance during pregnancy.  J Clin Endocrinol Metab. 1998;  83 2338-234
  • 48 Storlien L H, Jenks A B, Chisholm D J, Pascoe W S, Khouri S, Kraegen E W. Influence of dietary fat composition on development of insulin resistance in rats. Relationship to muscle triglyceride and ω-3 fatty acids in muscle phospholipid.  Diabetes. 1991;  40 280-289
  • 49 Stumvoll M, Chintalapudi U, Perriello G, Welle S, Gutierrez O, Gerich J. Uptake and release of glucose by the human kidney: postabsorptive rates and responses to epinephrine.  J Clin Invest. 1995;  96 2528-2533
  • 50 Szczepaniak L S, Babcock E E, Schick F, Dobbins R L, Garg A, Burns D K, McGarrry J D, Stein D T. Measurement of intracellular triglyceride stores by 1H spectroscopy: validation in vivo.  Am J Physiol. 1999;  276 E977-E989
  • 51 Zhou Y-P, Grill V E. Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle.  J Clin Invest. 1994;  93 870-876

M. D. Guenther Boden

Temple University Hospital

3401 North Broad Street

Philadelphia, PA 19140

USA

Phone: 2157078984

Fax: 2157071560

Email: bodengh@tuhs.temple.edu

    >