Prediabetes in obese youth: a syndrome of impaired glucose tolerance, severe insulin resistance, and altered myocellular and abdominal fat partitioning

Background Impaired glucose tolerance is common among obese adolescents, but the changes in insulin sensitivity and secretion that lead to this prediabetic state are unknown. We investigated whether altered partitioning of myocellular and abdominal fat relates to abnormalities in glucose homoeostasis in obese adolescents with prediabetes. Methods We studied 14 obese children with impaired glucose tolerance and 14 with normal glucose tolerance, of similar ages, sex distribution, and degree of obesity. Insulin sensitivity and secretion were assessed by the euglycaemichyperinsulinaemic clamp and the hyperglycaemic clamp. Intramyocellular lipid was assessed by proton nuclear magnetic resonance spectroscopy and abdominal fat distribution by magnetic resonance imaging. Findings Peripheral glucose disposal was significantly lower in individuals with impaired than in those with normal glucose tolerance (mean 35•4 [SE 4•0] vs 60•6 [7•2] moles per kg lean body mass per min; p=0•023) owing to a reduction in non-oxidative glucose disposal metabolism (storage). Individuals with impaired glucose tolerance had higher intramyocellular lipid content (3•04 [0•43] vs 1•99 [0•19]%, p=0•03), lower abdominal subcutaneous fat (460 [47] vs 626 [39] cm2, p=0•04), and slightly higher visceral fat than the controls (70 [11] vs 47 [6] cm2, p=0•065), resulting in a higher ratio of visceral to subcutaneous fat (0•15 [0•02] vs 0•07 [0•01], p=0•002). Intramyocellular and visceral lipid contents were inversely related to the glucose disposal and non-oxidative glucose metabolism and positively related to the 2 h plasma glucose concentration. Interpretation In obese children and adolescents with prediabetes, intramyocellular and intra-abdominal lipid accumulation is closely linked to the development of severe peripheral insulin resistance.