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Population approaches to estimate minimal model indexes of insulin sensitivity and glucose effectiveness using full and reduced sampling schedules

¹Resource Facility for Population Kinetics, Department of Bioengineering, University of Washington, and ²Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, Veterans Affairs Puget Sound Health Care System, University of Washington, Seattle, Washington

Submitted 28 July 2005 ; accepted in final form 30 March 2006

The intravenous glucose tolerance test (IVGTT) interpreted with the minimal model provides individual indexes of insulin sensitivity (S_I) and glucose effectiveness (S_G). In population studies, the traditional approach, the standard two-stage (STS) method, fails to account for uncertainty in individual estimates, resulting in an overestimation of between-subject variability. Furthermore, in the presence of reduced sampling and/or insulin resistance, individual estimates may be unobtainable, biasing population information. Therefore, we investigated the use of two population approaches, the iterative two-stage (ITS) method and nonlinear mixed-effects modeling (NM), in a population (n = 235) of insulin-sensitive and insulin-resistant subjects under full (FSS, 33 samples) and reduced [RSS(240-min), 13 samples and RSS(180-min), 12 samples] IVGTT sampling schedules. All three population methods gave similar results with the FSS. Using RSS(240), the three methods gave similar results for S_I, but S_G population means were overestimated. With RSS(180), S_I and S_G population means were higher for all three methods compared with their FSS counterparts. NM estimated similar between-subject variability (19% S_G, 53% S_I) with RSS(180), whereas ITS showed regression to the mean for S_G (0.01% S_G, 56% S_I) and STS provided larger population variability in S_I (29% S_G, 91% S_I). NM provided individual estimates for all subjects, whereas the two-stage methods failed in 16–18% of the subjects using RSS(180) and 6–14% using RSS(240). We conclude that population approaches, specifically NM, are useful in studies with a sparsely sampled IVGTT (12 samples) of short duration (3 h) and when individual parameter estimates in all subjects are desired.

NONMEM; two-stage; parameter estimation; minimal model; insulin sensitivity