Roden, M. et al. Mechanism of free fatty acid-induced insulin resistance in humans. J. Clin. Invest. 97, 2859-2865

Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 06/1996; 97(12):2859-65. DOI: 10.1172/JCI118742
Source: PubMed


To examine the mechanism by which lipids cause insulin resistance in humans, skeletal muscle glycogen and glucose-6-phosphate concentrations were measured every 15 min by simultaneous 13C and 31P nuclear magnetic resonance spectroscopy in nine healthy subjects in the presence of low (0.18 +/- 0.02 mM [mean +/- SEM]; control) or high (1.93 +/- 0.04 mM; lipid infusion) plasma free fatty acid levels under euglycemic (approximately 5.2 mM) hyperinsulinemic (approximately 400 pM) clamp conditions for 6 h. During the initial 3.5 h of the clamp the rate of whole-body glucose uptake was not affected by lipid infusion, but it then decreased continuously to be approximately 46% of control values after 6 h (P < 0.00001). Augmented lipid oxidation was accompanied by a approximately 40% reduction of oxidative glucose metabolism starting during the third hour of lipid infusion (P < 0.05). Rates of muscle glycogen synthesis were similar during the first 3 h of lipid and control infusion, but thereafter decreased to approximately 50% of control values (4.0 +/- 1.0 vs. 9.3 +/- 1.6 mumol/[kg.min], P < 0.05). Reduction of muscle glycogen synthesis by elevated plasma free fatty acids was preceded by a fall of muscle glucose-6-phosphate concentrations starting at approximately 1.5 h (195 +/- 25 vs. control: 237 +/- 26 mM; P < 0.01). Therefore in contrast to the originally postulated mechanism in which free fatty acids were thought to inhibit insulin-stimulated glucose uptake in muscle through initial inhibition of pyruvate dehydrogenase these results demonstrate that free fatty acids induce insulin resistance in humans by initial inhibition of glucose transport/phosphorylation which is then followed by an approximately 50% reduction in both the rate of muscle glycogen synthesis and glucose oxidation.


Available from: Thomas B Price
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    • "During the availability of sufficient amounts of free FA, serum concentrations of ET1 have been reported to increase and insulin resistance is thus observed (e.g. obese and insulin resistant diabetes) [107] [108]. Increasing concentrations of ET1 in the sputum of stable COPD patients have been observed [83] [109] [110] [111] [112]. "

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    • "In this study involving seven healthy adults, it has been demonstrated that four consecutive days of PSD (4.5 h night À1 ) reduced the ability of insulin to stimulate intracellular downstream pathways in subcutaneous adipose tissue by approximately 30% (Broussard et al., 2012). In another study involving 19 young non-diabetic men, PSD for 4 consecutive nights (4.5 h in bed night À1 ) resulted in increased circulating concentrations of free fatty acids (FFAs) (Broussard et al., 2015), which are known to impair insulin-stimulated muscle uptake of glucose in humans (Roden et al., 1996). To what extent such biochemical alterations may have contributed to Table 1 Sleep characteristics of the two experimental sleep conditions "
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    • "Independent of adiposity, both human and animal studies have demonstrated remarkable associations between the degree of lipid accumulation within skeletal muscle and whole body insulin resistance (Jacob et al. 1999; Krssak et al. 1999; McGarry 2002; Pan et al. 1997; Sinha et al. 2002), implying a causal role for lipid accumulation in the development of insulin resistance. Furthermore , lipid accumulation within skeletal muscle often accompanies impaired mitochondrial metabolism in individuals with insulin resistance (Petersen et al. 2003, 2004; Roden et al. 1996). Taken together, defects in mitochondrial fatty acid metabolism appear to play a key role in the development of insulin resistance in skeletal muscle via an impaired lipid oxidation and enhanced lipid accumulation. "
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