Insulin sensitivity index in type 1 diabetes and following human islet transplantation: comparison of the minimal model to euglycemic clamp measures

Abstract

Insulin sensitivity is impaired in type 1 diabetes (T1D) and may be enhanced by islet transplantation, an effect best explained by improved metabolic control. While the minimal model index of insulin sensitivity, SI, has been used in studies of T1D, it has not before been evaluated against gold-standard measures derived from the euglycemic clamp. We sought to determine how well minimal model SI derived from an insulin-modified frequently sampled intravenous glucose tolerance (FSIGT) test compared with total body and peripheral insulin sensitivity estimates derived from the hyperinsulinemic-euglycemic clamp in subjects with T1D and following islet transplantation. Twenty-one T1D subjects were evaluated, including a subgroup (n = 12) studied again after intrahepatic islet transplantation, with results compared with normal controls (n = 11 for the FSIGT). The transplant recipients received 9,648 ± 666 islet equivalents/kg with reduction in HbA1c from 7.1 ± 0.2 to 5.5 ± 0.1% (P < 0.01) and 10/12 were insulin independent. FSIGT-derived SI was reduced in T1D pre- compared with posttransplant and with normal [1.76 ± 0.45 vs. 4.21 ± 0.34 vs. 4.45 ± 0.81 × 10(-4)(μU/ml)(-1)·min(-1); P < 0.01 for both]. Similarly, clamp-derived total body, and by the isotopic dilution method with [6,6-(2)H2]glucose, peripheral insulin sensitivity increased in T1D from pre- to posttransplant (P < 0.05 for both). The predictive power (r(2)) between volume-corrected SIC and measures of total and peripheral insulin sensitivity was 0.66 and 0.70, respectively (P < 0.00001 for both). That the minimal model SIC is highly correlated to the clamp-derived measures indicates that the FSIGT is an appropriate methodology for the determination of insulin sensitivity in T1D and following islet transplantation.

Keywords: frequently sampled intravenous glucose tolerance test; glucose effectiveness.

Fig. 1.

Plasma glucose (A) and insulin (B) levels in response to the frequently sampled intravenous glucose tolerance test. Glucose (0.3 g/kg) is injected over 1 min at time (t) = 0, and insulin (0.03 U/kg) is injected over 30 s at t = 20 min. Intravenous glucose tolerance improved in type 1 diabetes (T1D) from pre- to posttransplant (P < 0.01), with posttransplant glucose disappearance not different from normal. The acute insulin response to the injection of glucose, which was absent in T1D pretransplant, was restored posttransplant to levels comparable to normal.

Fig. 2.

Correlations between total body insulin sensitivity estimated by the minimal model [S_I(minmod)], total body insulin sensitivity based on glucose infusion rate, M, from the euglycemic clamp [S_I(clamp); on the left], and peripheral insulin sensitivity based on glucose disposal rate, R_d, from the euglycemic clamp [S_IP(clamp); on the right]. The predictive relationships of S_I(minmod) to S_I(clamp) and S_IP(clamp) were stronger when considering all 21 T1D subjects (A and B) than when considering those not transplanted and those posttransplant (C and D).

Fig. 3.

Correlations between corrected measures of S_IC(minmod) and S_IC(clamp) (on the left), and S_ICP(clamp) (on the right). The minimal model and clamp-derived measures were each independently converted to a common index of insulin sensitivity, S_IC, reflecting the unitary change in insulin to cause a given increment in glucose clearance and expressed ×10² in dl/min per μU/ml. The resulting predictive relationships of S_IC(minmod) to S_IC(clamp) and S_ICP(clamp) were robust both when considering all 21 T1D subjects (A and B), and when considering those not transplanted and those posttransplant (C and D).

Fig. 4.

A and B: correlations between the changes from pre- to posttransplant in uncorrected measures of ΔS_I(minmod) and ΔS_I(clamp) (A), and ΔS_IP(clamp) (B). C and D: correlations between the changes from pre- to posttransplant in the corrected measures of ΔS_IC(minmod) and ΔS_IC(clamp) (C) and ΔS_ICP(clamp) (D).