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 Presentation

"Mechanisms of nutrient-mediated insulin resistance"

Dr. Meredith Hawkins (biography)
English - 2003-03-28 - 60 minutes
(34 slides)
(14 questions)

Summary :
Obesity plays a central role in the pathogenesis of the insulin resistance syndrome, which in turn confers a heightened risk of diabetes mellitus and atherosclerosis. Besides the health consequences of the increased fat mass per se, excess nutrient availability in obesity also appears to contribute to this syndrome. The nutrient excess refers to increased oral intake and circulating levels of glucose and free fatty acids (FFA). The hexosamine biosynthetic pathway (HBP) provides cellular "satiety" signals with increased availability of such nutrients as glucose and FFA and provided a potential mechanistic link between increased nutrients and the metabolic syndrome. Increased nutrient availability, by increasing HBP flux, enhances glycosylation of important intracellular factors including transcription and thereby affects the expression of many genes, including plasminogen activator inhibitor-1 (PAI-1). Increased circulating levels of PAI-1 accompany the insulin resistance syndrome and probably contribute to the pathogenesis of atherothrombosis. The HBP is active in adipocytes, which are known to secrete PAI-1. It has been demonstrated that increasing plasma FFA levels in lean, nondiabetic individuals results in whole-body insulin resistance, ~2-fold increases in plasma PAI-1 levels, and dramatic increases in adipose PAI-1 gene expression. This suggests that increases plasma FFA levels contribute importantly to the insulin resistance syndrome, by exerting both direct metabolic effects and by altering circulating levels of certain adipocyte-derived proteins which play an important role in the clinical consequences.

Learning objectives :
The pathogenesis of obesity in the insulin resistance syndrome : the role of high plasma FFA levels on metabolism and adipocyte-derived proteins.

Bibliographic references :
Ann N Y Acad Sci 2002 Jun;967:283-98
Fatty acid regulation of gene expression: a genomic explanation for the benefits of the mediterranean diet.

Clarke SD, Gasperikova D, Nelson C, Lapillonne A, Heird WC.

Institute for Cellular and Molecular Biology and Division of Nutritional Sciences, University of Texas, Austin 78712, USA. stevedclarke@mail.utexas.edu

The development of obesity and associated insulin resistance involves a multitude of gene products, including proteins involved in lipid synthesis and oxidation, thermogenesis, and cell differentiation. The genes encoding these proteins are in essence the blueprints that we have inherited from our parents. However, what determines the way in which blueprints are interpreted is largely dictated by a collection of environmental factors. The nutrients we consume are among the most influential of these environmental factors. During the early stages of evolutionary development, nutrients functioned as primitive hormonal signals that allowed the early organisms to turn on pathways of synthesis or storage during periods of nutrient deprivation or excess. As single-cell organisms evolved into complex life forms, nutrients continued to be environmental factors that interacted with hormonal signals to govern the expression of genes encoding proteins involved in energy metabolism, cell differentiation, and cell growth. Nutrients govern the tissue content and activity of different proteins by functioning as regulators of gene transcription, nuclear RNA processing, mRNA degradation, and mRNA translation, as well as functioning as posttranslational modifiers of proteins. One dietary constituent that has a strong influence on cell differentiation, growth, and metabolism is fat. The fatty acid component of dietary lipid not only influences hormonal signaling events by modifying membrane lipid composition, but fatty acids have a very strong direct influence on the molecular events that govern gene expression. In this review, we discuss the influence that (n-9), (n-6), and (n-3) fatty acids exert on gene expression in the liver and skeletal muscle and the impact this has on intra- and interorgan partitioning of metabolic fuels.

J Clin Invest 1997 May 1;99(9):2173-82
Role of the glucosamine pathway in fat-induced insulin resistance.

Hawkins M, Barzilai N, Liu R, Hu M, Chen W, Rossetti L.

Division of Endocrinology and Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

To examine whether the hexosamine biosynthetic pathway might play a role in fat-induced insulin resistance, we monitored the effects of prolonged elevations in FFA availability both on skeletal muscle levels of UDP-N-acetyl-hexosamines and on peripheral glucose disposal during 7-h euglycemic-hyperinsulinemic (approximately 500 microU/ml) clamp studies. When the insulin-induced decrease in the plasma FFA levels (to approximately 0.3 mM) was prevented by infusion of a lipid emulsion in 15 conscious rats (plasma FFA approximately 1.4 mM), glucose uptake (5-7 h = 32.5+/-1.7 vs 0-2 h = 45.2+/-2.8 mg/kg per min; P < 0.01) and glycogen synthesis (P < 0.01) were markedly decreased. During lipid infusion, muscle UDP-N-acetyl-glucosamine (UDP-GlcNAc) increased by twofold (to 53.4+/-1.1 at 3 h and to 55.5+/-1.1 nmol/gram at 7 h vs 20.4+/-1.7 at 0 h, P < 0.01) while glucose-6-phosphate (Glc-6-P) levels were increased at 3 h (475+/-49 nmol/gram) and decreased at 7 h (133+/-7 vs 337+/-28 nmol/gram at 0 h, P < 0.01). To discern whether such an increase in the skeletal muscle UDP-GlcNAc concentration could account for the development of insulin resistance, we generated similar increases in muscle UDP-GlcNAc using three alternate experimental approaches. Euglycemic clamps were performed after prolonged hyperglycemia (18 mM, n = 10), or increased availability of either glucosamine (3 micromol/kg per min; n = 10) or uridine (30 micromol/kg per min; n = 4). These conditions all resulted in very similar increases in the skeletal muscle UDP-GlcNAc (to approximately 55 nmol/gram) and markedly impaired glucose uptake and glycogen synthesis. Thus, fat-induced insulin resistance is associated with: (a) decreased skeletal muscle Glc-6-P levels indicating defective transport/phosphorylation of glucose; (b) marked accumulation of the endproducts of the hexosamine biosynthetic pathway preceding the onset of insulin resistance. Most important, the same degree of insulin resistance can be reproduced in the absence of increased FFA availability by a similar increase in skeletal muscle UDP-N-acetyl-hexosamines. In conclusion, our results support the hypothesis that increased FFA availability induces skeletal muscle insulin resistance by increasing the flux of fructose-6-phosphate into the hexosamine pathway.


Diabetes 2001 Feb;50(2):418-24
Free fatty acids induce peripheral insulin resistance without increasing muscle hexosamine pathway product levels in rats.

Choi CS, Lee FN, Youn JH.

Diabetes Research Center, Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles 90089-9142, USA.

To evaluate the role of the hexosamine biosynthesis pathway (HBP) in fat-induced insulin resistance, we examined whether fat-induced insulin resistance is additive to that induced by increased HBP flux via glucosamine infusion and, if so, whether such additive effects correlate with muscle HBP product levels. Prolonged hyperinsulinemic (approximately 550 pmol/l) euglycemic clamps were conducted in conscious overnight-fasted rats. After the initial 150 min to attain steady-state insulin action, rats received an additional infusion of saline, Intralipid, glucosamine, or Intralipid and glucosamine (n = 8 or 9 for each) for 330 min. At the conclusion of clamps, skeletal muscles (soleus, extensor digitorum longus, and tibialis anterior) were taken for the measurement of HBP product levels. Intralipid and glucosamine infusions decreased insulin-stimulated glucose uptake (Rd) by 38 and 28%, respectively. When the infusions were combined, insulin-stimulated Rd decreased 47%, significantly more than with Intralipid or glucosamine alone (P < 0.05). The glucosamine-induced insulin resistance was associated with four- to fivefold increases in muscle HBP product levels. In contrast, the Intralipid-induced insulin resistance was accompanied by absolutely no increase in HBP product levels in all of the muscles examined. Also, when infused with glucosamine, Intralipid decreased insulin action below that with glucosamine alone without changing HBP product levels. In a separate study, short-term (50 and 180 min) Intralipid infusion also failed to increase muscle HBP product levels. In conclusion, increased availability of plasma free fatty acids induces peripheral insulin resistance without increasing HBP product levels in skeletal muscle.

   


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