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© 2002 by the American Diabetes Association, Inc.
Banting Lecture 2001
Dysregulation of Fatty Acid Metabolism in the Etiology of Type 2 Diabetes
Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas
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INTRODUCTION |
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Readers of this journal do not need to be reminded of the explosive increase in obesity/type 2 diabetes syndromes and their attendant staggering public health costs that are currently afflicting developed countries. Because of this alarming development and what it portends for the future if left unchecked, the American Diabetes Association, together with its counterparts around the world, as well as the World Health Organization, are faced with the daunting challenge of finding answers to two huge questions. First, what is the pathophysiological basis for these disorders? Second, why is their rate of appearance accelerating so rapidly at this particular juncture of human history, and what, if anything, can we do to intervene? The primary focus of this lecture will be on the first of these issues. I want to emphasize at the outset that I do not plan to dwell exclusively on our own studies in this area. Instead, I shall try to incorporate recent developments from a variety of other laboratories working in the field. Although these will of necessity have to be highly selective, I hope that collectively they will illustrate how we have come to a relatively new and exciting way of thinking about the etiology of type 2 diabetes.
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WHAT CAUSES TYPE 2 DIABETES? |
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It has been said in literary circles that James Joyce’s Ulysses is probably the most frequently opened and least read book that has ever been published. In a similar vein, I sometimes think that the question of what causes type 2 diabetes might be one of the most frequently asked and least satisfactorily answered in the history of diabetes research. This is not meant to be an arrogant statement, nor indeed does it imply that I have a magical solution to the question at hand. Rather, it simply reflects the fact that at the dawn of
The fatty acid–muscle connection.
What is the TG marking?
How are the LCACoAs acting?
What sets the cellular LCACoA level?
Is inefficient fat oxidation a predictor of insulin resistance?
The fatty-acid–ß-cell connection.
Is there a darker side to the FFA–ß-cell interaction?
The fatty acid–liver connection.
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SO WHERE DO ALL OF THE PROBLEMS BEGIN? |
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WHY IS THE INCIDENCE OF TYPE 2 DIABETES INCREASING SO RAPIDLY, AND WHAT CAN BE DONE ABOUT IT? |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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REFERENCES |
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|
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|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
 D. J. Durgan, J. K. Smith, M. A. Hotze, O. Egbejimi, K. D. Cuthbert, V. G. Zaha, J. R. B. Dyck, E. D. Abel, and M. E. Young Distinct transcriptional regulation of long-chain acyl-CoA synthetase isoforms and cytosolic thioesterase 1 in the rodent heart by fatty acids and insulin Am J Physiol Heart Circ Physiol, June 1, 2006; 290(6): H2480 - H2497. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
V. Qvisth, E. Hagstrom-Toft, S. Enoksson, E. Moberg, P. Arner, and J. Bolinder Human Skeletal Muscle Lipolysis Is More Responsive to Epinephrine Than to Norepinephrine Stimulation in Vivo J. Clin. Endocrinol. Metab., February 1, 2006; 91(2): 665 - 670. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Snijder, R. van Dam, M Visser, and J. Seidell What aspects of body fat are particularly hazardous and how do we measure them? Int. J. Epidemiol., February 1, 2006; 35(1): 83 - 92. [Full Text] [PDF]
|
|
|
|
|
|
B. Kiens Skeletal Muscle Lipid Metabolism in Exercise and Insulin Resistance Physiol Rev, January 1, 2006; 86(1): 205 - 243. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Blaschke, Y. Takata, E. Caglayan, R. E. Law, and W. A. Hsueh Obesity, Peroxisome Proliferator-Activated Receptor, and Atherosclerosis in Type 2 Diabetes Arterioscler. Thromb. Vasc. Biol., January 1, 2006; 26(1): 28 - 40. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rodriguez-Lee, G. Ostergren-Lunden, B. Wallin, J. Moses, G. Bondjers, and G. Camejo Fatty Acids Cause Alterations of Human Arterial Smooth Muscle Cell Proteoglycans That Increase the Affinity for Low-Density Lipoprotein Arterioscler. Thromb. Vasc. Biol., January 1, 2006; 26(1): 130 - 135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. M. Lee, J. E. Elliott, and R. W. Brownsey Inhibition of Acetyl-CoA Carboxylase Isoforms by Pyridoxal Phosphate J. Biol. Chem., December 23, 2005; 280(51): 41835 - 41843. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Staiger, N. Stefan, H. Staiger, M. D. Brendel, D. Brandhorst, R. G. Bretzel, F. Machicao, M. Kellerer, M. Stumvoll, A. Fritsche, et al. Adiponectin Is Functionally Active in Human Islets but Does Not Affect Insulin Secretory Function or {beta}-Cell Lipoapoptosis J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6707 - 6713. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. J. Lee, I. K. Lee, H. S. Kim, Y. M. Kim, E. H. Koh, J. C. Won, S. M. Han, M.-S. Kim, I. Jo, G. T. Oh, et al. {alpha}-Lipoic Acid Prevents Endothelial Dysfunction in Obese Rats via Activation of AMP-Activated Protein Kinase Arterioscler. Thromb. Vasc. Biol., December 1, 2005; 25(12): 2488 - 2494. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Assifi, G. Suchankova, S. Constant, M. Prentki, A. K. Saha, and N. B. Ruderman AMP-activated protein kinase and coordination of hepatic fatty acid metabolism of starved/carbohydrate-refed rats Am J Physiol Endocrinol Metab, November 1, 2005; 289(5): E794 - E800. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. D. Oakes, P. Thalen, T. Hultstrand, S. Jacinto, G. Camejo, B. Wallin, and B. Ljung Tesaglitazar, a dual PPAR{alpha}/{gamma} agonist, ameliorates glucose and lipid intolerance in obese Zucker rats Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2005; 289(4): R938 - R946. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Scopinaro, G. M. Marinari, G. B. Camerini, F. S. Papadia, and G. F. Adami Specific Effects of Biliopancreatic Diversion on the Major Components of Metabolic Syndrome: A long-term follow-up study Diabetes Care, October 1, 2005; 28(10): 2406 - 2411. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Lafontan, C. Moro, C. Sengenes, J. Galitzky, F. Crampes, and M. Berlan An Unsuspected Metabolic Role for Atrial Natriuretic Peptides: The Control of Lipolysis, Lipid Mobilization, and Systemic Nonesterified Fatty Acids Levels in Humans Arterioscler. Thromb. Vasc. Biol., October 1, 2005; 25(10): 2032 - 2042. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
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