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The impact of mathematical modeling on the understanding of diabetes and related complications.

ABSTRACT: Diabetes is a chronic and complex multifactorial disease caused by persistent hyperglycemia and for which underlying pathogenesis is still not completely understood. The mathematical modeling of glucose homeostasis, diabetic condition, and its associated complications is rapidly growing and provides new insights into the underlying mechanisms involved. Here, we discuss contributions to the diabetes modeling field over the past five decades, highlighting the areas where more focused research is required.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e54; doi:10.1038/psp.2013.30; advance online publication 10 July 2013.

SUBMITTER: Ajmera I

PROVIDER: S-EPMC3731829 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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The impact of mathematical modeling on the understanding of diabetes and related complications.

Ajmera I I Swat M M Laibe C C Le Novère N N Chelliah V V

CPT: pharmacometrics & systems pharmacology 20130710

Diabetes is a chronic and complex multifactorial disease caused by persistent hyperglycemia and for which underlying pathogenesis is still not completely understood. The mathematical modeling of glucose homeostasis, diabetic condition, and its associated complications is rapidly growing and provides new insights into the underlying mechanisms involved. Here, we discuss contributions to the diabetes modeling field over the past five decades, highlighting the areas where more focused research is r ...[more]

PMID: 23842097

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Project description:In contrast to heart failure (HF) with reduced ejection fraction (HFrEF), effective interventions for HF with preserved ejection fraction (HFpEF) have proven elusive, in part because it is a heterogeneous syndrome with incompletely understood pathophysiology. This study utilized mathematical modeling to evaluate mechanisms distinguishing HFpEF and HFrEF. HF was defined as a state of chronically elevated left ventricle end diastolic pressure (LVEDP > 20mmHg). First, using a previously developed cardiorenal model, sensitivities of LVEDP to potential contributing mechanisms of HFpEF, including increased myocardial, arterial, or venous stiffness, slowed ventricular relaxation, reduced LV contractility, hypertension, or reduced venous capacitance, were evaluated. Elevated LV stiffness was identified as the most sensitive factor. Large LV stiffness increases alone, or milder increases combined with either decreased LV contractility, increased arterial stiffness, or hypertension, could increase LVEDP into the HF range without reducing EF. We then evaluated effects of these mechanisms on mechanical signals of cardiac outward remodeling, and tested the ability to maintain stable EF (as opposed to progressive EF decline) under two remodeling assumptions: LV passive stress-driven vs. strain-driven remodeling. While elevated LV stiffness increased LVEDP and LV wall stress, it mitigated wall strain rise for a given LVEDP. This suggests that if LV strain drives outward remodeling, a stiffer myocardium will experience less strain and less outward dilatation when additional factors such as impaired contractility, hypertension, or arterial stiffening exacerbate LVEDP, allowing EF to remain normal even at high filling pressures. Thus, HFpEF heterogeneity may result from a range of different pathologic mechanisms occurring in an already stiffened myocardium. Together, these simulations further support LV stiffening as a critical mechanism contributing to elevated cardiac filling pressures; support LV passive strain as the outward dilatation signal; offer an explanation for HFpEF heterogeneity; and provide a mechanistic explanation distinguishing between HFpEF and HFrEF.

Dataset Information

The impact of mathematical modeling on the understanding of diabetes and related complications.

Publications

The impact of mathematical modeling on the understanding of diabetes and related complications.

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