Mechanism of free fatty acid induced insulin resistance in humans

  • Roden M
  • Price T
  • Perseghin G
 et al. 
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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

Author-supplied keywords

  • +/-
  • 13C
  • 31P
  • Acids
  • Concentration
  • Dehydrogenase
  • Fatty
  • Fatty Acid
  • Fatty Acids
  • Free fatty acid
  • Free fatty acids
  • Glucose
  • Glucose 6 phosphate
  • Glucose oxidation
  • Glycogen
  • Human
  • Humans
  • Induce
  • Infusion
  • Inhibit
  • Inhibition
  • Insulin
  • Insulin resistance
  • Lipid
  • Lipids
  • Magnetic resonance
  • Magnetic resonance spectroscopy
  • Mechanism
  • Metabolism
  • Muscle
  • Nuclear
  • Nuclear magnetic resonance
  • Oxidation
  • Oxidative
  • Plasma
  • Pyruvate
  • Rate
  • Reduction
  • Resistance
  • Skeletal
  • Skeletal muscle
  • Spectroscopy
  • Synthesis
  • Uptake

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Authors

  • M Roden

  • T B Price

  • G Perseghin

  • K F Petersen

  • D L Rothman

  • G W Cline

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