Expansion of the homeostasis model assessment of β-cell function and insulin resistance to enable clinical trial outcome modeling through the interactive adjustment of physiology and treatment effects: iHOMA2

Abstract

Objective: To describe and make available an interactive, 24-variable homeostasis model assessment (iHOMA2) that extends the HOMA2 model, enabling the modeling of physiology and treatment effects, to present equations of the HOMA2 and iHOMA2 models, and to exemplify iHOMA2 in two widely differing scenarios: changes in insulin sensitivity with thiazolidinediones and changes in renal threshold with sodium glucose transporter 2 (SGLT2) inhibition.

Research design and methods: iHOMA2 enables a user of the available software to examine and modify the mathematical functions describing the organs and tissues involved in the glucose and hormonal compartments. We exemplify this with SGLT2 inhibition modeling (by changing the renal threshold parameters) using published data of renal effect, showing that the modeled effect is concordant with the effects on fasting glucose from independent data.

Results: iHOMA2 modeling of thiazolidinediones effect suggested that changes in insulin sensitivity in the fasting state are predominantly hepatic. SGLT2 inhibition modeled by iHOMA2 resulted in a decrease in mean glucose of 1.1 mmol/L. Observed data showed a decrease in glucose of 0.9 mmol/L. There was no significant difference between the model and the independent data. Manipulation of iHOMA2's renal excretion threshold variable suggested that a decrease of 17% was required to obtain a 0.9 mmol/L decrease in mean glucose.

Conclusions: iHOMA2 is an extended mathematical model for the assessment of insulin resistance and β-cell function. The model can be used to evaluate therapeutic agents and predict effects on fasting glucose and insulin and on β-cell function and insulin sensitivity.

Figure 1

The iHOMA2 model is represented in three different ways: A) as a cartoon displaying the organs and tissues involved; B) showing the dose response curves as graphs modeled for each organ or tissue; and C) providing the equations that govern the organs and tissues functioning in the model. B₁ and B₂ are modifiable for the brain, PE₁–PE₅ for the periphery, R₁–R₄ for the kidneys, G₁ and G₂ for the gut, L₁–L₅ for the liver, and P₁–P₅ for the pancreas (see Table 1).

Figure 2

Three hypotheses of action of pioglitazone on β-cell function and insulin sensitivity analyzed by iHOMA2. Gray lines are the unaltered functions in iHOMA2. Black lines are the altered variable functions modeled. Hypothesis 1, increase of whole-body sensitivity and an increase in β-cell function; hypothesis 2, increase in liver insulin sensitivity only with an increase in β-cell function; and hypothesis 3, increase in peripheral insulin sensitivity only and an increase in β-cell function.