Mechanism of free fatty acid-induced insulin resistance in humans

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

ABSTRACT 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.

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Available from: Thomas B Price, Sep 26, 2015
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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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    ABSTRACT: The present study sought to investigate whether a single night of partial sleep deprivation (PSD) would alter fasting insulin sensitivity and cephalic phase insulin release (CPIR) in humans. A rise in circulating insulin in response to food-related sensory stimulation may prepare tissues to break down ingested glucose, e.g. by stimulating rate-limiting glycolytic enzymes. In addition, given insulin’s anorexigenic properties once it reaches the brain, the CPIR may serve as an early peripheral satiety signal. Against this background, in the present study 16 men participated in two separate sessions: one night of PSD (4.25-hr sleep) versus one night of full sleep (8.5-hr sleep). In the morning following each sleep condition, subjects’ oral cavity was rinsed with a 1-molar sucrose solution for 45 seconds, preceded and followed by blood sampling for repeated determination of plasma glucose and serum insulin concentrations (-3, +3, +5, +7, +10, and +20 minutes). Our main result was that PSD, compared with full sleep, was associated with significantly higher peripheral insulin resistance, as indicated by a higher fasting homeostasis model assessment of insulin resistance index (+16%, P=0.025). In contrast, no CPIR was observed in any of the sleep conditions. Our findings indicate that a single night of PSD is already sufficient to impair fasting insulin sensitivity in healthy men. Contrarily, brief oral cavity rinsing with sucrose solution did not change serum insulin concentrations, suggesting that a blunted CPIR is an unlikely mechanism through which acute sleep loss causes metabolic perturbations during morning hours in humans.
    Journal of Sleep Research 08/2015; DOI:10.1111/jsr.12340 · 3.35 Impact Factor
    • "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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    ABSTRACT: The prevalence of type 2 diabetes (T2D) has increased dramatically over the past two decades, not only among adults but also among adolescents. T2D is a systemic disorder affecting every organ system and is especially damaging to the cardiovascular system, predisposing individuals to severe cardiac and vascular complications. The precise mechanisms that cause T2D are an area of active research. Most current theories suggest that the process begins with peripheral insulin resistance that precedes failure of the pancreatic β-cells to secrete sufficient insulin to maintain normoglycemia. A growing body of literature has highlighted multiple aspects of mitochondrial function, including oxidative phosphorylation, lipid homeostasis, and mitochondrial quality control in the regulation of peripheral insulin sensitivity. Whether the cellular mechanisms of insulin resistance in adults are comparable to that in adolescents remains unclear. This review will summarize both clinical and basic studies that shed light on how alterations in skeletal muscle mitochondrial function contribute to whole body insulin resistance and will discuss the evidence supporting high-intensity exercise training as a therapy to circumvent skeletal muscle mitochondrial dysfunction to restore insulin sensitivity in both adults and adolescents.
    Biochemistry and Cell Biology 05/2015; DOI:10.1139/bcb-2015-0012 · 2.15 Impact Factor
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