Diabetes, Vol 49, Issue 3 399-408, Copyright © 2000 by American Diabetes Association

ARTICLES

Prolonged elevation of plasma free fatty acids impairs pancreatic beta-cell function in obese nondiabetic humans but not in individuals with type 2 diabetes

A Carpentier, SD Mittelman, RN Bergman, A Giacca and GF Lewis
Department of Medicine, University of Toronto, Ontario, Canada.

Our recent in vivo observations in healthy nonobese humans have demonstrated that prolonged elevation of plasma free fatty acids (FFAs) results in diminished glucose-stimulated insulin secretion (GSIS) when the FFA-mediated decrease in insulin sensitivity is taken into account. In the present study, we investigated whether obese individuals and patients with type 2 diabetes are more sensitive than healthy control subjects to the inhibitory effect of prolonged elevation of plasma FFAs on GSIS. In seven patients with type 2 diabetes and seven healthy nondiabetic obese individuals, we assessed GSIS with a programmed graded intravenous glucose infusion on two occasions, 6-8 weeks apart, with and without a prior 48-h infusion of heparin and Intralipid, which was designed to raise plasma FFA concentration approximately twofold over basal. The nondiabetic obese subjects had a significant 21% decrease in GSIS (P = 0.0008) with the heparin and Intralipid infusion, associated with a decrease in whole body insulin clearance. The impairment in GSIS was evident at low (<11 mmol/l) but not at higher plasma glucose concentrations. In contrast, the patients with type 2 diabetes had a slight increase in GSIS (P = 0.027) and no change in insulin clearance, although there was marked interindividual variability in response. Plasma proinsulin concentrations measured in a subset of subjects were not altered in either group by the infusion of heparin and Intralipid. In summary, 1) obese nondiabetic individuals are susceptible to a desensitization of GSIS with heparin and Intralipid infusion, and 2) patients with type 2 diabetes do not demonstrate such susceptibility when FFAs are elevated approximately twofold above basal with heparin and Intralipid. Our results suggest that FFAs could play an important role in the development of beta-cell failure in obese individuals who are at risk for developing type 2 diabetes. They do not, however, seem to further deteriorate the beta-cell function of patients who already have established type 2 diabetes and may even result in a slight increase in GSIS in this latter group.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				K. Mai, T. Bobbert, F. Reinecke, J. Andres, C. Maser-Gluth, S. A. Wudy, M. Mohlig, M. O. Weickert, M. F. Hartmann, H. M. Schulte, et al. Intravenous Lipid and Heparin Infusion-Induced Elevation in Free Fatty Acids and Triglycerides Modifies Circulating Androgen Levels in Women: A Randomized, Controlled Trial J. Clin. Endocrinol. Metab., October 1, 2008; 93(10): 3900 - 3906. [Abstract] [Full Text] [PDF]

				E. Diakogiannaki, H. J Welters, and N. G Morgan Differential regulation of the endoplasmic reticulum stress response in pancreatic {beta}-cells exposed to long-chain saturated and monounsaturated fatty acids J. Endocrinol., June 1, 2008; 197(3): 553 - 563. [Abstract] [Full Text] [PDF]

				V. Poitout and R. P. Robertson Glucolipotoxicity: Fuel Excess and {beta}-Cell Dysfunction Endocr. Rev., May 1, 2008; 29(3): 351 - 366. [Abstract] [Full Text] [PDF]

				C. J. Bloem and A. M. Chang Short-Term Exercise Improves {beta}-Cell Function and Insulin Resistance in Older People with Impaired Glucose Tolerance J. Clin. Endocrinol. Metab., February 1, 2008; 93(2): 387 - 392. [Abstract] [Full Text] [PDF]

				A. C. Carpentier, F. Frisch, P. Brassard, F. Lavoie, A. Bourbonnais, D. Cyr, R. Giguere, and J.-P. Baillargeon Mechanism of insulin-stimulated clearance of plasma nonesterified fatty acids in humans Am J Physiol Endocrinol Metab, March 1, 2007; 292(3): E693 - E701. [Abstract] [Full Text] [PDF]

				T. T. Goh, T. M. Mason, N. Gupta, A. So, T. K. T. Lam, L. Lam, G. F. Lewis, A. Mari, and A. Giacca Lipid-induced beta-cell dysfunction in vivo in models of progressive beta-cell failure Am J Physiol Endocrinol Metab, February 1, 2007; 292(2): E549 - E560. [Abstract] [Full Text] [PDF]

				G. Las, N. Mayorek, K. Dickstein, and J. Bar-Tana Modulation of Insulin Secretion by Fatty Acyl Analogs Diabetes, December 1, 2006; 55(12): 3478 - 3485. [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]

				A. C. Carpentier, F. Frisch, D. Cyr, P. Genereux, B. W. Patterson, R. Giguere, and J.-P. Baillargeon On the suppression of plasma nonesterified fatty acids by insulin during enhanced intravascular lipolysis in humans Am J Physiol Endocrinol Metab, November 1, 2005; 289(5): E849 - E856. [Abstract] [Full Text] [PDF]

				R. Eldor and I. Raz Lipids and Glucose in Type 2 Diabetes: What About the {beta}-Cell and the Mitochondria?: Response to Boden and Laakso Diabetes Care, April 1, 2005; 28(4): 985 - 986. [Full Text] [PDF]

				S. A. Smith, L. E. Porter, N. Biswas, and M. I. Freed Rosiglitazone, But Not Glyburide, Reduces Circulating Proinsulin and the Proinsulin:Insulin Ratio in Type 2 Diabetes J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6048 - 6053. [Abstract] [Full Text] [PDF]

				R. Lupi, S. Del Guerra, L. Marselli, M. Bugliani, U. Boggi, F. Mosca, P. Marchetti, and S. Del Prato Rosiglitazone prevents the impairment of human islet function induced by fatty acids: evidence for a role of PPAR{gamma}2 in the modulation of insulin secretion Am J Physiol Endocrinol Metab, April 1, 2004; 286(4): E560 - E567. [Abstract] [Full Text] [PDF]

				H. Storgaard, C. B. Jensen, M. Bjornholm, X. M. Song, S. Madsbad, J. R. Zierath, and A. A. Vaag Dissociation between Fat-Induced in Vivo Insulin Resistance and Proximal Insulin Signaling in Skeletal Muscle in Men at Risk for Type 2 Diabetes J. Clin. Endocrinol. Metab., March 1, 2004; 89(3): 1301 - 1311. [Abstract] [Full Text] [PDF]

				H. Bays, L. Mandarino, and R. A. DeFronzo 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., February 1, 2004; 89(2): 463 - 478. [Full Text] [PDF]

				M. J. Holness, N. D. Smith, G. K. Greenwood, and M. C. Sugden Acute {omega}-3 Fatty Acid Enrichment Selectively Reverses High-Saturated Fat Feeding-Induced Insulin Hypersecretion But Does Not Improve Peripheral Insulin Resistance Diabetes, February 1, 2004; 53(90001): S166 - 171. [Abstract] [Full Text]

				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]

				M. J. Holness, G. K. Greenwood, N. D. Smith, and M. C. Sugden Diabetogenic Impact of Long-Chain {omega}-3 Fatty Acids on Pancreatic {beta}-Cell Function and the Regulation of Endogenous Glucose Production Endocrinology, September 1, 2003; 144(9): 3958 - 3968. [Abstract] [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]

				C. B. Jensen, H. Storgaard, J. J. Holst, F. Dela, S. Madsbad, and A. A. Vaag Insulin Secretion and Cellular Glucose Metabolism after Prolonged Low-Grade Intralipid Infusion in Young Men J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2775 - 2783. [Abstract] [Full Text] [PDF]

				A. Carpentier, B. Zinman, N. Leung, A. Giacca, A. J.G. Hanley, S. B. Harris, R. A. Hegele, and G. F. Lewis Free Fatty Acid-Mediated Impairment of Glucose-Stimulated Insulin Secretion in Nondiabetic Oji-Cree Individuals From the Sandy Lake Community of Ontario, Canada: A Population at Very High Risk for Developing Type 2 Diabetes Diabetes, June 1, 2003; 52(6): 1485 - 1495. [Abstract] [Full Text] [PDF]

				C. P. Briscoe, M. Tadayyon, J. L. Andrews, W. G. Benson, J. K. Chambers, M. M. Eilert, C. Ellis, N. A. Elshourbagy, A. S. Goetz, D. T. Minnick, et al. The Orphan G Protein-coupled Receptor GPR40 Is Activated by Medium and Long Chain Fatty Acids J. Biol. Chem., March 21, 2003; 278(13): 11303 - 11311. [Abstract] [Full Text] [PDF]

				M. C. Sugden, G. K. Greenwood, N. D. Smith, and M. J. Holness Peroxisome Proliferator-Activated Receptor-{alpha} Activation during Pregnancy Attenuates Glucose-Stimulated Insulin Hypersecretion in Vivo by Increasing Insulin Sensitivity, without Impairing Pregnancy-Induced Increases in {beta}-Cell Glucose Sensing and Responsiveness Endocrinology, January 1, 2003; 144(1): 146 - 153. [Abstract] [Full Text] [PDF]

				E. Qvigstad, I. L. Mostad, K. S. Bjerve, and V. E. Grill Acute lowering of circulating fatty acids improves insulin secretion in a subset of type 2 diabetes subjects Am J Physiol Endocrinol Metab, January 1, 2003; 284(1): E129 - E137. [Abstract] [Full Text] [PDF]

				K. Tordjman, K. N. Standley, C. Bernal-Mizrachi, T. C. Leone, T. Coleman, D. P. Kelly, and C. F. Semenkovich PPAR{alpha} suppresses insulin secretion and induces UCP2 in insulinoma cells J. Lipid Res., June 1, 2002; 43(6): 936 - 943. [Abstract] [Full Text] [PDF]

				R. L. Dobbins, L. S. Szczepaniak, J. Myhill, Y. Tamura, H. Uchino, A. Giacca, and J. D. McGarry The Composition of Dietary Fat Directly Influences Glucose-Stimulated Insulin Secretion in Rats Diabetes, June 1, 2002; 51(6): 1825 - 1833. [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]

				A. J. G. Hanley, G. McKeown-Eyssen, S. B. Harris, R. A. Hegele, T. M. S. Wolever, J. Kwan, and B. Zinman Cross-Sectional and Prospective Associations between Abdominal Adiposity and Proinsulin Concentration J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 77 - 83. [Abstract] [Full Text] [PDF]

				M. Mensink, E. E. Blaak, M. A. van Baak, A. J.M. Wagenmakers, and W. H.M. Saris Plasma Free Fatty Acid Uptake and Oxidation Are Already Diminished in Subjects at High Risk for Developing Type 2 Diabetes Diabetes, November 1, 2001; 50(11): 2548 - 2554. [Abstract] [Full Text] [PDF]

				G. Luef, I. Abraham, E. Trinka, I. Unterberger, F. Hoppichler, G. Bauer, M. Lechleitner, and V. Biton Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy Neurology, August 14, 2001; 57(3): 565 - 566. [Full Text]

				A. Carpentier, B. W. Patterson, K. D. Uffelman, A. Giacca, M. Vranic, M. S. Cattral, and G. F. Lewis The Effect of Systemic Versus Portal Insulin Delivery in Pancreas Transplantation on Insulin Action and VLDL Metabolism Diabetes, June 1, 2001; 50(6): 1402 - 1413. [Abstract] [Full Text]