Oskar Alskär (1), Mats O. Karlsson (1), Maria C. Kjellsson (1)
(1) Pharmacometrics research group, Department of Pharmaceutical biosciences, Uppsala University, Sweden
Background and objective: The integrated glucose insulin (IGI) model is a semi-mechanistic model that describes glucose and insulin concentrations in humans during glucose tolerance tests [1]. The objective of this work was to investigate if the model can be scaled to describe intravenous glucose tolerance test (IVGTT) data from several preclinical species.
Methods: Glucose and insulin concentrations from IVGTTs performed in rats, mice, dogs, cats and humans as well as the body weight of each subject was available for analysis [2-7]. In the first step allometric scaling based on body weight was investigated. The most suitable value for the allometric exponent was investigated for all parameters in the model, based on objective function value, parameter uncertainty and model complexity. In the second step species adaptations was investigated by scaling parameters with the weight of organs relevant to that parameter in each species. The cat data showed substantially different glucose and insulin profiles. For this reason the cat data was excluded from model development to not distort the allometric scaling relationship. The glucose and insulin baselines as well as the residual error were estimated for all species.
Results: Estimating one allometric exponent for clearances (0.85), one exponent for volumes (0.9), one exponent for first phase secretion (0.79) and fixing the exponent of rate constants to -0.25 described the data well and kept the scaling complexity low. Estimating an allometric exponent for the power functions for glucose effect on glucose production and insulin secretion (GPRG, IPRG) did not improve the fit and they were fixed to the human values. Dogs showed lower first phase secretion and stronger second phase secretion of insulin than the model predicted and these two parameters (IFST, IPRG) were estimated for dogs. Of the investigated scaling relationships with species specific organ weights only liver weight on insulin clearance improved the fit. The final model was applied to the cat data and IFST and IPRG was estimated and displayed under prediction of glucose concentrations.
Conclusions: The allometrically scaled IGI model can accurately preclinical IVGTT data. The omnivores (mouse, human, rat) show different insulin response to an intravenous glucose bolus dose compared to carnivores (cat, dog). The allometrically scaled IGI model can be used in drug development to facilitate better translations of preclinical research into clinic.
References:
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[4] Ionut, V., et al., Novel canine models of obese prediabetes and mild type 2 diabetes. American Journal of Physiology-Endocrinology and Metabolism, 2010. 298(1): p. E38-E48.
[5] Vicini, P., A. Caumo, and C. Cobelli, The hot IVGTT two-compartment minimal model: indexes of glucose effectiveness and insulin sensitivity. American Journal of Physiology-Endocrinology and Metabolism, 1997. 273(5): p. E1024-E1032.
[6] Vicini, P., et al., Glucose production during an IVGTT by deconvolution: validation with the tracer-to-tracee clamp technique. American Journal of Physiology-Endocrinology and Metabolism, 1999. 276(2): p. E285-E294.
[7] Wilkins, C., et al., Assessment of the influence of fatty acids on indices of insulin sensitivity and myocellular lipid content by use of magnetic resonance spectroscopy in cats. American journal of veterinary research, 2004. 65(8): p. 1090-1099.
Reference: PAGE 24 () Abstr 3521 [www.page-meeting.org/?abstract=3521]
Poster: Drug/Disease modeling - Endocrine