A model of insulin kinetics describing tests with various insulin secretion and infusion patterns by means of a consistent mechanism
Roberto Bizzotto (1), Andrea Natali (2), Amalia Gastaldelli (3), Ralph A. De Fronzo (4), Silva Arslanian (5), Ele Ferrannini (3), Andrea Mari (1)
(1) Institute of Neuroscience, National Research Council, Padova, Italy; (2) Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy; (3) Institute of Clinical Physiology, National Research Council, Pisa, Italy; (4) Department of Medicine, Diabetes Division, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA; (5) Division of Weight Management, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, and Division of Pediatric Endocrinology, Diabetes and Metabolism, Children's Hospital of Pittsburgh, Pittsburgh, PA.
Objectives: Insulin kinetics is an essential component of glucose homeostasis. Due to system complexity and limited data availability, models of this process have typically been linear, in contrast to physiological evidence [1]. In this work, we overcome this limitation developing a nonlinear model that describes a variety of tests with a wide insulin span produced by glucose-stimulated insulin secretion (IS) and insulin infusion.
Methods: Data included: A) tests stimulating IS by different patterns and levels of glucose infusion (6 different studies [2-7], N=204); B) one- or two-step hyperinsulinemic euglycemic clamps with different insulin infusions (4 protocols in 3 studies [8-10], N=150). Subjects had normal, impaired or diabetic glucose tolerance. A circulatory model [11] of insulin kinetics was developed including heart and lungs, gut, liver, and extra-hepatic organs. Insulin clearance (IC) in the liver was described using a saturable function. In studies A, IS was separately computed by deconvolution of plasma C-peptide; in studies B, IS was estimated by simultaneously fitting plasma C-peptide concentrations, using Van Cauter’s model of C-peptide clearance [12]. Parameters were estimated by mixed-effect modeling using Monolix 4.3.2.
Results: In all studies, the model predicted insulin concentration adequately; the parameters were homogeneous across the studies. The typical endogenous IC computed at IS of 100 and 400 pmol/min/m2 (representing basal and glucose-stimulated IS) was 1.46 and 1.16 L/min/m2, respectively. The 4-fold increase in IS produced a 5-fold increase in insulin concentration; the deviation compared to linear kinetics would be 70 pmol/L. For endogenous IC at standardized IS of 100 and 400 pmol/min/m2, significant relationships were found with body mass index (inverse) and insulin sensitivity (direct).
Conclusions: We have developed a unifying mechanistic model describing insulin kinetics in a variety of tests in which a wide range of insulin levels were produced by glucose-stimulated IS and insulin infusion. Using the model, we could calculate IC at standardized insulin secretion levels and determine that the relationships of IC with adiposity and insulin sensitivity were primary and not consequent to an indirect effect of hypersecretion-induced IC saturation. Prediction of the effects of drugs enhancing IS or of subcutaneous insulin infusion may benefit from the use of this new model in the glucose homeostasis representation.
References:
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