title: 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.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.
authors.forename: Kasper W
authors.initials: KW
authors.lastname: Ter Horst
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.
authors.forename: Pim W
authors.initials: PW
authors.lastname: Gilijamse
authors.affiliation: Department of Clinical Chemistry, Laboratory of Endocrinology, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.
authors.forename: Mariette T
authors.initials: MT
authors.lastname: Ackermans
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.
authors.forename: Maarten R
authors.initials: MR
authors.lastname: Soeters
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.
authors.forename: Max
authors.initials: M
authors.lastname: Nieuwdorp
authors.affiliation: Department of Medicine, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Romijn
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Center, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands. Electronic address: m.j.serlie@amc.nl.
authors.forename: Mireille J
authors.initials: MJ
authors.lastname: Serlie
mesh_terms: D000046:Academic Medical Centers; D052436:Adipose Tissue, White / Q000378:metabolism; D015992:Body Mass Index; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005943:Gluconeogenesis; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000097:blood / Q000453:epidemiology / Q000209:etiology / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism; D009426:Netherlands / Q000453:epidemiology; D009765:Obesity / Q000503:physiopathology*; D009928:Organ Specificity; D011236:Prediabetic State / Q000097:blood / Q000453:epidemiology / Q000209:etiology / Q000378:metabolism*; D015995:Prevalence; D012307:Risk Factors
chemical_list: D005230:Fatty Acids, Nonesterified
keywords: Endogenous glucose production; Glucose disposal; Impaired fasting glucose; Insulin resistance; Prediabetes