Dose-response characteristics of insulin action on glucose metabolism: a non-steady-state approach.
The traditional methods for the assessment of insulin sensitivity yield only a single index, not the whole dose-response curve information. This curve is typically characterized by a maximally insulin-stimulated glucose clearance (Cl(max)) and an insulin concentration at half-maximal response (EC(50)). We developed an approach for estimating the whole dose-response curve with a single in vivo test, based on the use of tracer glucose and exogenous insulin administration (two steps of 20 and 200 mU x min(-1) x m(-2), 100 min each). The effect of insulin on plasma glucose clearance was calculated from non-steady-state data by use of a circulatory model of glucose kinetics and a model of insulin action in which glucose clearance is represented as a Michaelis-Menten function of insulin concentration with a delay (t(1/2)). In seven nondiabetic subjects, the model predicted adequately the tracer concentration: the model residuals were unbiased, and their coefficient of variation was similar to the expected measurement error (approximately 3%), indicating that the model did not introduce significant systematic errors. Lean (n = 4) and obese (n = 3) subjects had similar half-times for insulin action (t(1/2) = 25 +/- 9 vs. 25 +/- 8 min) and maximal responses (Cl(max) = 705 +/- 46 vs. 668 +/- 259 ml x min(-1) x m(-2), respectively), whereas EC(50) was 240 +/- 84 microU/ml in the lean vs. 364 +/- 229 microU/ml in the obese (P < 0.04). EC(50) and the insulin sensitivity index (ISI, initial slope of the dose-response curve), but not Cl(max), were related to body adiposity and fat distribution with r of 0.6-0.8 (P < 0.05). Thus, despite the small number of study subjects, we were able to reproduce information consistent with the literature. In addition, among the lean individuals, t(1/2) was positively related to the ISI (r = 0.72, P < 0.02). We conclude that the test here presented, based on a more elaborate representation of glucose kinetics and insulin action, allows a reliable quantitation of the insulin dose-response curve for whole body glucose utilization in a single session of relatively short duration.
Natali
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Metabolism Unit of the Consiglio Nazionale delle Ricerche Institute of Clinical Physiology and Department of Internal Medicine, University of Pisa, 56126 Pisa, Italy. anatali@ifc.pi.cnr.it
Gastaldelli
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Camastra
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Sironi
A M
AM
Toschi
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Masoni
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Ferrannini
E
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Mari
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D000273:Adipose Tissue; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism*; D001823:Body Composition; D001824:Body Constitution; D003903:Deuterium; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007262:Infusions, Intravenous; D007328:Insulin / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009765:Obesity / Q000097:blood*
D001786:Blood Glucose; D007328:Insulin; D003903:Deuterium