Impaired insulin action in the liver, but not in adipose tissue or muscle, is a distinct metabolic feature of impaired fasting glucose in obese humans

Metabolism. 2016 May;65(5):757-763. doi: 10.1016/j.metabol.2016.02.010. Epub 2016 Feb 24.


Aim: Elevated basal endogenous glucose production (EGP), impaired suppression of EGP by insulin and reduced insulin-stimulated glucose disposal are cornerstones of the pathogenesis of hyperglycemia in patients with type 2 diabetes. We aimed to determine the contribution of these processes to impaired fasting glucose (IFG) levels in obese non-diabetic adults.

Methods: We included 131 obese non-diabetic adults with normal fasting glucose levels (NFG; fasting glucose <5.6mmol/L; 62 men, 25 women; mean±SEM age 49±1years; median (IQR) BMI 36 (34-41) kg/m(2)) or IFG (fasting glucose 5.6-6.9mmol/L; 35 men, 9 women; age 53±1years; BMI 36 (34-42) kg/m(2)) and studied basal EGP and hepatic, adipose tissue and peripheral insulin sensitivity by two-step euglycemic hyperinsulinemic clamp studies with [6,6-(2)H2]glucose infusion.

Results: Compared to equally obese adults with NFG, individuals with IFG did not differ in basal EGP (9.1±0.2 vs 9.8±0.3μmolkg(-1)min(-1), p=0.082), insulin-mediated suppression of circulating free fatty acid levels (75±1 vs 72±3%, p=0.240) and insulin-stimulated glucose disposal (26.6±1.0 vs 25.2±1.5μmolkg(-1)min(-1), p=0.441). Insulin-mediated suppression of EGP (68±2 vs 55±3%, p<0.001) was markedly reduced in obese subjects with IFG.

Conclusions: Hepatic insulin resistance is a distinct metabolic feature of IFG in obesity. Insulin sensitivity of free fatty acid suppression and skeletal muscle does not differ between obese people with NFG and IFG. Hepatic insulin resistance may contribute to the onset of prediabetes in obese adults.

Keywords: Endogenous glucose production; Glucose disposal; Impaired fasting glucose; Insulin resistance; Prediabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Academic Medical Centers
  • Adipose Tissue, White / metabolism
  • Body Mass Index
  • Cohort Studies
  • Cross-Sectional Studies
  • Fatty Acids, Nonesterified / blood
  • Female
  • Gluconeogenesis
  • Glucose Clamp Technique
  • Glucose Intolerance / blood
  • Glucose Intolerance / epidemiology
  • Glucose Intolerance / etiology
  • Glucose Intolerance / metabolism*
  • Humans
  • Insulin Resistance*
  • Liver / metabolism*
  • Male
  • Middle Aged
  • Muscle, Skeletal / metabolism
  • Netherlands / epidemiology
  • Obesity / physiopathology*
  • Organ Specificity
  • Prediabetic State / blood
  • Prediabetic State / epidemiology
  • Prediabetic State / etiology
  • Prediabetic State / metabolism*
  • Prevalence
  • Risk Factors


  • Fatty Acids, Nonesterified