title: 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.
  
  
  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.
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Hill
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Levy
authors.forename: David R
authors.initials: DR
authors.lastname: Matthews
mesh_terms: D002986:Clinical Trials as Topic; D003198:Computer Simulation; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000503:physiopathology*; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000627:therapeutic use; D007333:Insulin Resistance / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008954:Models, Biological; D000077205:Pioglitazone; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D045162:Thiazolidinediones / Q000627:therapeutic use
chemical_list: D007328:Insulin; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D045162:Thiazolidinediones; D000077205:Pioglitazone
references.citation: Diabetes Metab Res Rev. 2005 Jan-Feb;21(1):31-8
references.pmid: 15624123
references.citation: Am J Physiol. 1986 May;250(5 Pt 1):E591-8
references.pmid: 3518490
references.citation: Diabetes Care. 2006 Oct;29(10):2275-81
references.pmid: 17003306
references.citation: Nat Rev Mol Cell Biol. 2006 Nov;7(11):813-9
references.pmid: 17006434
references.citation: Diabetes Care. 2010 Oct;33(10):2217-24
references.pmid: 20566676
references.citation: Diabet Med. 2005 Apr;22(4):399-405
references.pmid: 15787663
references.citation: Diabetes. 1993 Nov;42(11):1663-72
references.pmid: 8405710
references.citation: Horm Metab Res Suppl. 1990;24:66-71
references.pmid: 2272629
references.citation: Am J Physiol. 1979 Sep;237(3):E214-23
references.pmid: 382871
references.citation: Curr Opin Clin Nutr Metab Care. 2002 Sep;5(5):495-501
references.pmid: 12172472
references.citation: Diabetologia. 1985 Nov;28(11):809-14
references.pmid: 3936738
references.citation: Clin Pharmacol Ther. 2009 May;85(5):513-9
references.pmid: 19129749
references.citation: J Clin Endocrinol Metab. 2004 Dec;89(12):6068-76
references.pmid: 15579760
references.citation: Am J Physiol. 1979 Jun;236(6):E667-77
references.pmid: 443421
references.citation: Arzneimittelforschung. 1990 Apr;40(4):436-40
references.pmid: 2192715
references.citation: Diabetologia. 1985 Jul;28(7):401-11
references.pmid: 3899824
references.citation: Diabetes Care. 2007 Sep;30(9):2411-3
references.pmid: 17726193
references.citation: Int J Clin Pract Suppl. 2001 Sep;(121):13-8
references.pmid: 11594239
references.citation: Diabetes Care. 2004 Jun;27(6):1487-95
references.pmid: 15161807
references.citation: Diabetes Care. 2001 Mar;24(3):539-48
references.pmid: 11289482
references.citation: J Clin Endocrinol Metab. 1977 Nov;45(5):1124-7
references.pmid: 925138
references.citation: Diabetologia. 1985 Jul;28(7):412-9
references.pmid: 3899825
references.citation: Diabetes. 2004 May;53(5):1187-94
references.pmid: 15111485
references.citation: Diabetes Care. 1998 Dec;21(12):2191-2
references.pmid: 9839117
references.citation: Diabetes Care. 2007 Sep;30(9):2414-8
references.pmid: 17726194
references.citation: Diabetes. 1993 Oct;42(10):1536-43
references.pmid: 8375595