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Disordered Fat Storage and Mobilization in the Pathogenesis of Insulin Resistance and Type 2 Diabetes

Department of Medicine, Division of Endocrinology (G.F.L., A.C., A.G.), Department of Physiology (A.G.), and Department of Laboratory Medicine and Pathobiology (K.A.), University of Toronto, Toronto, Canada M5G 2C4

Correspondence: Address all correspondence and requests for reprints to: Dr. Gary Lewis, Toronto General Hospital, 200 Elizabeth Street, Room EN11-229, Toronto, Ontario, Canada M5G 2C4. E-mail: gary.lewis{at}uhn.on.ca

The primary genetic, environmental, and metabolic factors responsible for causing insulin resistance and pancreatic ß-cell failure and the precise sequence of events leading to the development of type 2 diabetes are not yet fully understood. Abnormalities of triglyceride storage and lipolysis in insulin-sensitive tissues are an early manifestation of conditions characterized by insulin resistance and are detectable before the development of postprandial or fasting hyperglycemia. Increased free fatty acid (FFA) flux from adipose tissue to nonadipose tissue, resulting from abnormalities of fat metabolism, participates in and amplifies many of the fundamental metabolic derangements that are characteristic of the insulin resistance syndrome and type 2 diabetes. It is also likely to play an important role in the progression from normal glucose tolerance to fasting hyperglycemia and conversion to frank type 2 diabetes in insulin resistant individuals. Adverse metabolic consequences of increased FFA flux, to be discussed in this review, are extremely wide ranging and include, but are not limited to: 1) dyslipidemia and hepatic steatosis, 2) impaired glucose metabolism and insulin sensitivity in muscle and liver, 3) diminished insulin clearance, aggravating peripheral tissue hyperinsulinemia, and 4) impaired pancreatic ß-cell function. The precise biochemical mechanisms whereby fatty acids and cytosolic triglycerides exert their effects remain poorly understood. Recent studies, however, suggest that the sequence of events may be the following: in states of positive net energy balance, triglyceride accumulation in "fat-buffering" adipose tissue is limited by the development of adipose tissue insulin resistance. This results in diversion of energy substrates to nonadipose tissue, which in turn leads to a complex array of metabolic abnormalities characteristic of insulin-resistant states and type 2 diabetes. Recent evidence suggests that some of the biochemical mechanisms whereby glucose and fat exert adverse effects in insulin-sensitive and insulin-producing tissues are shared, thus implicating a diabetogenic role for energy excess as a whole. Although there is now evidence that weight loss through reduction of caloric intake and increase in physical activity can prevent the development of diabetes, it remains an open question as to whether specific modulation of fat metabolism will result in improvement in some or all of the above metabolic derangements or will prevent progression from insulin resistance syndrome to type 2 diabetes.

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				C. Lemieux, Y. Gelinas, J. Lalonde, F. Labrie, K. Cianflone, and Y. Deshaies Hypolipidemic action of the SERM acolbifene is associated with decreased liver MTP and increased SR-BI and LDL receptors J. Lipid Res., June 1, 2005; 46(6): 1285 - 1294. [Abstract] [Full Text] [PDF]

				Y. Tamura, Y. Tanaka, F. Sato, J. B. Choi, H. Watada, M. Niwa, J. Kinoshita, A. Ooka, N. Kumashiro, Y. Igarashi, et al. Effects of Diet and Exercise on Muscle and Liver Intracellular Lipid Contents and Insulin Sensitivity in Type 2 Diabetic Patients J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3191 - 3196. [Abstract] [Full Text] [PDF]

				S. Katoh, M. Lehtovirta, J. Kaprio, V. Harjutsalo, M. Koskenvuo, J. Eriksson, N. Tajima, and J. Tuomilehto Genetic and Environmental Effects on Fasting and Postchallenge Plasma Glucose and Serum Insulin Values in Finnish Twins J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2642 - 2647. [Abstract] [Full Text] [PDF]

				R. Carroll, A. N. Carley, J. R. B. Dyck, and D. L. Severson Metabolic effects of insulin on cardiomyocytes from control and diabetic db/db mouse hearts Am J Physiol Endocrinol Metab, May 1, 2005; 288(5): E900 - E906. [Abstract] [Full Text] [PDF]

				D. C. W. Lau, B. Dhillon, H. Yan, P. E. Szmitko, and S. Verma Adipokines: molecular links between obesity and atheroslcerosis Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2031 - H2041. [Abstract] [Full Text] [PDF]

				Y. H. Suh, Y. Kim, J. H. Bang, K. S. Choi, J. W. Lee, W.-H. Kim, T. J. Oh, S. An, and M. H. Jung Analysis of gene expression profiles in insulin-sensitive tissues from pre-diabetic and diabetic Zucker diabetic fatty rats J. Mol. Endocrinol., April 1, 2005; 34(2): 299 - 315. [Abstract] [Full Text] [PDF]

				L. A. Adams, P. Angulo, and K. D. Lindor Nonalcoholic fatty liver disease Can. Med. Assoc. J., March 29, 2005; 172(7): 899 - 905. [Abstract] [Full Text] [PDF]

				A. C. Heijboer, E. Donga, P. J. Voshol, Z.-C. Dang, L. M. Havekes, J. A. Romijn, and E. P. M. Corssmit Sixteen hours of fasting differentially affects hepatic and muscle insulin sensitivity in mice J. Lipid Res., March 1, 2005; 46(3): 582 - 588. [Abstract] [Full Text] [PDF]

				I. Giannopoulou, L. L. Ploutz-Snyder, R. Carhart, R. S. Weinstock, B. Fernhall, S. Goulopoulou, and J. A. Kanaley Exercise Is Required for Visceral Fat Loss in Postmenopausal Women with Type 2 Diabetes J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1511 - 1518. [Abstract] [Full Text] [PDF]

				S. Stan, M. Lambert, E. Delvin, G. Paradis, J. O'Loughlin, J. A. Hanley, and E. Levy Intestinal fatty acid binding protein and microsomal triglyceride transfer protein polymorphisms in French-Canadian youth J. Lipid Res., February 1, 2005; 46(2): 320 - 327. [Abstract] [Full Text] [PDF]

				U. Kintscher and R. E. Law PPAR{gamma}-mediated insulin sensitization: the importance of fat versus muscle Am J Physiol Endocrinol Metab, February 1, 2005; 288(2): E287 - E291. [Abstract] [Full Text] [PDF]

				H. Drexel, S. Aczel, T. Marte, W. Benzer, P. Langer, W. Moll, and C. H. Saely Is Atherosclerosis in Diabetes and Impaired Fasting Glucose Driven by Elevated LDL Cholesterol or by Decreased HDL Cholesterol? Diabetes Care, January 1, 2005; 28(1): 101 - 107. [Abstract] [Full Text] [PDF]

				S. D. Nguyen and D.-E. Sok Preferential inhibition of paraoxonase activity of human paraoxonase 1 by negatively charged lipids J. Lipid Res., December 1, 2004; 45(12): 2211 - 2220. [Abstract] [Full Text] [PDF]

				W. Qiu, R. K. Avramoglu, N. Dube, T. M. Chong, M. Naples, C. Au, K. G. Sidiropoulos, G. F. Lewis, J. S. Cohn, M. L. Tremblay, et al. Hepatic PTP-1B Expression Regulates the Assembly and Secretion of Apolipoprotein B-Containing Lipoproteins: Evidence From Protein Tyrosine Phosphatase-1B Overexpression, Knockout, and RNAi Studies Diabetes, December 1, 2004; 53(12): 3057 - 3066. [Abstract] [Full Text] [PDF]

				G. F. Lewis, M. Naples, K. Uffelman, N. Leung, L. Szeto, and K. Adeli Intestinal Lipoprotein Production Is Stimulated by an Acute Elevation of Plasma Free Fatty Acids in the Fasting State: Studies in Insulin-Resistant and Insulin-Sensitized Syrian Golden Hamsters Endocrinology, November 1, 2004; 145(11): 5006 - 5012. [Abstract] [Full Text] [PDF]

				J. Ran, T. Hirano, and M. Adachi Chronic ANG II infusion increases plasma triglyceride level by stimulating hepatic triglyceride production in rats Am J Physiol Endocrinol Metab, November 1, 2004; 287(5): E955 - E961. [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]

				X. Ma, S. Bacci, W. Mlynarski, L. Gottardo, T. Soccio, C. Menzaghi, E. Iori, R. A. Lager, A. R. Shroff, E. V. Gervino, et al. A common haplotype at the CD36 locus is associated with high free fatty acid levels and increased cardiovascular risk in Caucasians Hum. Mol. Genet., October 1, 2004; 13(19): 2197 - 2205. [Abstract] [Full Text] [PDF]

				N. Ueno, M. G. Dube, A. Inui, P. S. Kalra, and S. P. Kalra Leptin Modulates Orexigenic Effects of Ghrelin and Attenuates Adiponectin and Insulin Levels and Selectively the Dark-Phase Feeding as Revealed by Central Leptin Gene Therapy Endocrinology, September 1, 2004; 145(9): 4176 - 4184. [Abstract] [Full Text] [PDF]

				J. S. Cohn, B. W. Patterson, K. D. Uffelman, J. Davignon, and G. Steiner Rate of Production of Plasma and Very-Low-Density Lipoprotein (VLDL) Apolipoprotein C-III Is Strongly Related to the Concentration and Level of Production of VLDL Triglyceride in Male Subjects with Different Body Weights and Levels of Insulin Sensitivity J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3949 - 3955. [Abstract] [Full Text] [PDF]

				J. Ran, T. Hirano, and M. Adachi Angiotensin II type 1 receptor blocker ameliorates overproduction and accumulation of triglyceride in the liver of Zucker fatty rats Am J Physiol Endocrinol Metab, August 1, 2004; 287(2): E227 - E232. [Abstract] [Full Text] [PDF]

				D. V. Chirieac, H. L. Collins, J. Cianci, J. D. Sparks, and C. E. Sparks Altered triglyceride-rich lipoprotein production in Zucker diabetic fatty rats Am J Physiol Endocrinol Metab, July 1, 2004; 287(1): E42 - E49. [Abstract] [Full Text] [PDF]

				C. S. Olofsson, A. Salehi, C. Holm, and P. Rorsman Palmitate increases L-type Ca2+ currents and the size of the readily releasable granule pool in mouse pancreatic {beta}-cells J. Physiol., June 15, 2004; 557(3): 935 - 948. [Abstract] [Full Text] [PDF]

				A. M. Xydakis, C. C. Case, P. H. Jones, R. C. Hoogeveen, M.-Y. Liu, E. O. Smith, K. W. Nelson, and C. M. Ballantyne Adiponectin, Inflammation, and the Expression of the Metabolic Syndrome in Obese Individuals: The Impact of Rapid Weight Loss through Caloric Restriction J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2697 - 2703. [Abstract] [Full Text] [PDF]

				S. Hummasti, B. A. Laffitte, M. A. Watson, C. Galardi, L. C. Chao, L. Ramamurthy, J. T. Moore, and P. Tontonoz Liver X receptors are regulators of adipocyte gene expression but not differentiation: identification of apoD as a direct target J. Lipid Res., April 1, 2004; 45(4): 616 - 625. [Abstract] [Full Text] [PDF]

				C. Neumann-Haefelin, A. Beha, J. Kuhlmann, U. Belz, M. Gerl, M. Quint, G. Biemer-Daub, M. Broenstrup, M. Stein, E. Kleinschmidt, et al. Muscle-Type Specific Intramyocellular and Hepatic Lipid Metabolism During Starvation in Wistar Rats Diabetes, March 1, 2004; 53(3): 528 - 534. [Abstract] [Full Text] [PDF]