2014 - Alicante - Spain

PAGE 2014: Drug/Disease modeling - Endocrine
Roberto Bizzotto

Glucose Homeostasis Modeling: Improvement of the Insulin Kinetics Component

Roberto Bizzotto (1), Andrea Natali (2), Amalia Gastaldelli (3), Ralph A. De Fronzo (4), Ele Ferrannini (2), Andrea Mari (1)

(1) Institute of Biomedical Engineering, 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.

Objectives: Models of glucose homeostasis are important for the development of anti-diabetic drugs. Several models have been developed (e.g. [1]); however, the complexity of the processes and the necessity of rich data sets has limited the possibility to account for all mechanisms relevant for glucose homeostasis. One neglected aspect is insulin kinetics, which has typically been assumed to be linear, in contrast to physiological evidence [2]. Aim of this work is to develop a model of insulin kinetics on a data set with a wide insulin span following stimulation of exogenous insulin secretion and endogenous insulin infusion.

Methods: Data were obtained from: A) a frequently-sampled combined hyperglycemic/hyperinsulinemic glucose clamp followed by arginine injection and exogenous insulin infusion in 7 healthy subjects [3]; and B) a euglycemic clamp with one or two-insulin levels in 393 non-diabetic subjects with sampling at steady state [4]. A circulatory model [5] of insulin kinetics was developed including heart and lungs, gut, liver, and extra-hepatic organs lumped together. Extra-hepatic insulin clearance was assumed constant, while saturation in the liver was described using a Michaelis-Menten function [2]. In Study A, insulin secretion was separately computed by deconvolution of plasma C-peptide; in Study B it was considered constant and estimated by simultaneously fitting plasma C-peptide concentrations, using Van Cauter’s model of C-peptide clearance [6]. Parameters were estimated by mixed-effect modeling using Monolix 4.2.2.

Results: The model predicted insulin concentration adequately in both studies. The median hepatic extraction ratio was 0.57 in basal conditions, 0.25 under stimulated insulin secretion (~500 pmol/min/m2) and 0.23 under exogenous insulin infusion (960 pmol/min/m2). Endogenous and peripheral insulin clearance and their dependence from insulin levels were consistent with literature data [2]. Due to hepatic saturation, doubling basal insulin secretion resulted in a threefold increase in peripheral insulin concentration, a remarkable effect.

Conclusions: A new mechanistic model describing insulin kinetics in non-diabetic subjects under both basal and stimulated physiological conditions and exogenous insulin infusion has been developed. Prediction of the effects of drugs enhancing insulin secretion or of subcutaneous insulin infusion may benefit from the use of this new model in the glucose homeostasis representation.

[1] Jauslin PM, Silber HE, Frey N, Gieschke R, Simonsson US, Jorga K, Karlsson MO: An integrated glucose-insulin model to describe oral glucose tolerance test data in type 2 diabetics. J Clin Pharmacol 47:1244-1255, 2007
[2] Ferrannini E, Cobelli C: The kinetics of insulin in man. II. Role of the liver. Diabetes/Metabolism Reviews 3(2):365-397, 1987
[3] Toschi E, Camastra S, Sironi AM, Masoni A, Gastaldelli A, Mari A, Ferrannini E, Natali A: Effect of acute hyperglycemia on insulin secretion in humans. Diabetes 51 Suppl 1:S130-133, 2002
[4] Ferrannini E, Gastaldelli A, Miyazaki Y, Matsuda M, Mari A, DeFronzo RA: β-Cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis. J Clin Endocrinol Metab 90:493-500, 2005
[5] Mari A: Circulatory models of intact-body kinetics and their relationship with compartmental and non-compartmental analysis. J Theor Biol 160:509-531, 1993
[6] Van Cauter E, Mestrez F, Sturis J, Polonsky KS: Estimation of insulin secretion rates from C-peptide levels. Comparison of individual and standard kinetic parameters for C-peptide clearance. Diabetes 41(3):368-377, 1992

This study has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115156, resources of which are composed of financial contributions from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. The DDMoRe project is also financially supported by contributions from Academic and SME partners.

Reference: PAGE 23 (2014) Abstr 3104 [www.page-meeting.org/?abstract=3104]
Poster: Drug/Disease modeling - Endocrine
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