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.
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.
['Ter Horst|Kasper W|KW|', 'Gilijamse|Pim W|PW|', 'Ackermans|Mariette T|MT|', 'Soeters|Maarten R|MR|', 'Nieuwdorp|Max|M|', 'Romijn|Johannes A|JA|', 'Serlie|Mireille J|MJ|']
D000046:Academic Medical Centers D052436:Adipose Tissue, White D015992:Body Mass Index D015331:Cohort Studies D003430:Cross-Sectional Studies D005230:Fatty Acids, Nonesterified D005260:Female D005943:Gluconeogenesis D015309:Glucose Clamp Technique D018149:Glucose Intolerance D006801:Humans D007333:Insulin Resistance D008099:Liver D008297:Male D008875:Middle Aged D018482:Muscle, Skeletal D009426:Netherlands D009765:Obesity D009928:Organ Specificity D011236:Prediabetic State D015995:Prevalence D012307:Risk Factors
Impaired fasting glucose Endogenous glucose production Glucose disposal Insulin resistance Prediabetes