Physiologic modeling of the intravenous glucose tolerance test in type 2 diabetes: A new approach to the insulin compartment

The minimal model of Bergman et al has been used to yield estimates of insu lin sensitivity (Si) and glucose effectiveness (Sg) in type 2 diabetes by i ncorporating exogenous insulin protocols into the regular intravenous gluco se tolerance test (IVGTT). These estimates, however, are influenced by the degree to which the dose of exogenous insulin is greater than the physiolog ic response to a glucose load. Moreover, most studies have related to type 2 diabetes subjects whose diabetes was relatively mild in terms of therapeu tic requirements. To develop a "minimal disturbance" approach in estimating Si and Sg in type 2 diabetes, we have used a reduced glucose load (200 mg/ kg) and a "physiologic" insulin infusion throughout the IVGTT in a series o f 8 patients, 5 of whom were insulin-requiring. Data from this approach wer e analyzed using the modelling program CONSAM to apply the Bergman model, e ither unmodified (BMM), or incorporating an additional delay element betwee n the plasma and "remote" insulin compartments (MMD). Application of the MM D and extension of the IVGTT from 3 to 5 hours improved successful resoluti on of Si and Sg from 37.5% (BMM, 3-hour IVGTT) to 100% (MMD, 5-hour IVGTT). Si was reduced in these type 2 diabetes patients compared with normal subj ects (1.86 +/- 0.60 v 8.65 +/- 2.27 min(-1) . muU(-1) . mL x 10(4) P < .01) . The results were validated in the type 2 diabetes group using a 2-stage e uglycemic clamp ((Si)CLAMP = 2.02 +/- 0.42 min(-1) . <mu>U-1 . mL x 10(4) P > .4). Sg was not significantly reduced (2.00 +/- 0.25 type 2 diabetes v 1 .55 +/- 0.26 normal min(-1) x 10(2)). Data from a group of normal nondiabet ic subjects was then analyzed using the MMD, but this approach did not enha nce the fit of the model compared with the BMM. This result indicates that the delay in insulin action in type 2 diabetes represents an abnormality wh ereby the onset of insulin action cannot be described as a single phase in the transfer of insulin from plasma to the remote compartment. It is postul ated that the physiologic basis for this delayed action may relate to trans capillary endothelial transfer of insulin, this process limiting the rate o f onset of insulin action. Copyright (C) 2001 by W.B. Saunders Company.