Disordered Fat Storage and Mobilization in the Pathogenesis of Insulin Resistance and Type 2 Diabetes
Gary F. Lewis,
André Carpentier,
Khosrow Adeli and
Adria Giacca
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 responsiblefor causing insulin resistance and pancreatic ß-cellfailure and the precise sequence of events leading to the developmentof type 2 diabetes are not yet fully understood. Abnormalitiesof triglyceride storage and lipolysis in insulin-sensitive tissuesare an early manifestation of conditions characterized by insulinresistance and are detectable before the development of postprandialor fasting hyperglycemia. Increased free fatty acid (FFA) fluxfrom adipose tissue to nonadipose tissue, resulting from abnormalitiesof fat metabolism, participates in and amplifies many of thefundamental metabolic derangements that are characteristic ofthe insulin resistance syndrome and type 2 diabetes. It is alsolikely to play an important role in the progression from normalglucose tolerance to fasting hyperglycemia and conversion tofrank type 2 diabetes in insulin resistant individuals. Adversemetabolic consequences of increased FFA flux, to be discussedin this review, are extremely wide ranging and include, butare not limited to: 1) dyslipidemia and hepatic steatosis, 2)impaired glucose metabolism and insulin sensitivity in muscleand liver, 3) diminished insulin clearance, aggravating peripheraltissue hyperinsulinemia, and 4) impaired pancreatic ß-cellfunction. The precise biochemical mechanisms whereby fatty acidsand cytosolic triglycerides exert their effects remain poorlyunderstood. Recent studies, however, suggest that the sequenceof events may be the following: in states of positive net energybalance, triglyceride accumulation in "fat-buffering" adiposetissue is limited by the development of adipose tissue insulinresistance. This results in diversion of energy substrates tononadipose tissue, which in turn leads to a complex array ofmetabolic abnormalities characteristic of insulin-resistantstates and type 2 diabetes. Recent evidence suggests that someof the biochemical mechanisms whereby glucose and fat exertadverse effects in insulin-sensitive and insulin-producing tissuesare shared, thus implicating a diabetogenic role for energyexcess as a whole. Although there is now evidence that weightloss through reduction of caloric intake and increase in physicalactivity can prevent the development of diabetes, it remainsan open question as to whether specific modulation of fat metabolismwill result in improvement in some or all of the above metabolicderangements or will prevent progression from insulin resistancesyndrome to type 2 diabetes.
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A. Charbonneau, A. Melancon, C. Lavoie, and J.-M. Lavoie Alterations in hepatic glucagon receptor density and in Gs{alpha} and Gi{alpha}2 protein content with diet-induced hepatic steatosis: effects of acute exercise
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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
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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
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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?
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J. Ran, T. Hirano, and M. Adachi Chronic ANG II infusion increases plasma triglyceride level by stimulating hepatic triglyceride production in rats
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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
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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
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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
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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
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