Analysis of pathogenic factors of type 2 diabetes mellitus by stable-labeled minimal model approach

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Glucose mass action may be overestimated and insulin sensitivity underestimated in the single compartment minimal model analysis of frequently sampled intravenous glucose tolerance test (FSIGT). Additional use of stable-labeled glucose allows us to precisely estimate indexes for glucose uptake stimulated by insulin (Si^<2*>) and by glucose (Sg^<2*>), and to illustrate time course changes in endogenous glucose production (EGP) in the two compartment model (Diabetes 48 : 1054-1060, 1999). To clarify pathogenic factors responsible for glucose intolerance using this stable-labeled insulin-modified FSIGT, 20 non-obese subjects with type 2 diabetes mellitus (BMI 20.6±0.6kg/m^2 and HbA_1c8.0±0.4%), 8 with impaired glucose tolerance (IGT), and 20 with normal glucose tolerance (NGT) were evaluated. Kg values were 1.93±0.11%/min in NGT, 1.38±0.18 in IGT, and 1.06±0.08 in diabetes (P<0.0001). Acute insulin response to the glucose bolus (AIR) was also deteriorated in this order (P<0.0001). There w … More ere no differences in Si^<2*> and Sg^<2*> among these three groups. Basal EGP was 1.53±0.06mg/kg.min in NGT, 1.69±0.16 in IGT and 1.84±0.08 in diabetes (P=0.0246). There was a linear relationship between basal EGP and fasting plasma glucose (r=0.486, P=0.0005). The initial suppression (0-20min) of EGP was virtually identical between NGT and IGT, but was blunted in diabetes. Thus, in IGT subjects, the decreased net glucose uptake in peripheral tissue, due to the decline in AIR, would be important for the glucose intolerance, since the regulation of EGP was not so impaired. In diabetic subjects, along with the further decline in AIR, the EGP regulation was severely deteriorated. In conclusion, there was no decrease in insulin action and glucose mass action to stimulate glucose uptake in the non-obese glucose intolerant subjects of this study. Together with the progression from IGT to full blown diabetes, the EGP dysregulation came to be evident in concordance with the further decline in AIR. Less