MINIMAL MODEL OF GLUCOSE-METABOLISM - MODIFIED EQUATIONS AND ITS APPLICATION IN THE STUDY OF INSULIN SENSITIVITY IN OBESE SUBJECTS

As implemented in their program MINMOD, some of the parameters and var iables of the equations representing Bergman and coworkers' minimal mo del of glucose metabolism have no simple rational relationship with th e kinetic constants and constants of proportionality of the minimal mo del as such. In this work we implemented the original version of the m inimal model, which does not suffer from this problem, and used it to investigate the source of insulin resistance among obese but otherwise healthy subjects. A fasting sampled intravenous glucose tolerance (FS IGT) test was performed in 38 healthy subjects of varying degrees of o besity (standard FSIGT test in 21 and tolbutamide FSIGT test in 17 sub jects) in order to compare MINMOD and 'modified' equations (M1). Insul in sensitivity index (S-I) in obese subjects was significantly lower t han in lean subjects (4.58+/-3.5 vs. 11.7+/-4.3.10(-5) min(-1)(pmol.l( -1))(-) 1, P<0.0001). The lower S-I in obese subjects was a consequenc e of a lower p(3) parameter (0.178+/-0.08 vs. 0.440+/-0.26.10(-5) min( -2)(pmol.1(-1))(-1), P<0.01), being p(2) similar between obese and lea n subjects (0.389+/-0.19 vs. 0.376+/-0.19.10(-1) min(-1), NS). S-1 ind ex correlated with p(3) (r=0.73, P<0.0001), but not with p(2) (r=0.01, NS). Using these results and assuming that interstitial insulin is hi gher in obese subjects than in lean subjects, we have demonstrated tha t the proportionality constants of the model (k(4) and k(6)) were lowe r in obese subjects than in lean subjects, but not the rate constant f or insulin transfer across capillaries, k(2). Our results suggest that the modified equations are a better theoretical approach to the minim al model method; and that low insulin sensitivity in obese subjects is due to receptor and/or post-receptor events rather than to slow trans fer of insulin across capillary endothelium into the interstitial spac e. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.