Disease progression in the integrated glucose-insulin model in subjects with impaired glucose tolerance
Siti M. S. Ghadzi1,2, Mats O. Karlsson1, Vanessa D. de Mello3, Matti Uusitupa3, Maria C. Kjellsson1; Finnish Diabetes Prevention Study Group
1Department of Pharmaceutical Biosciences, Uppsala University, Sweden 2Universiti Sains Malaysia, Ministry of Education Malaysia, Malaysia 3Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio Campus, Kuopio, Finland
Objectives: Silber et. al1 published an integrated glucose-insulin (IGI) model, describing glucose and insulin after various glucose loads in healthy subjects and in patients with type 2 diabetes. This model does not include disease progression (DP) from prediabetes, i.e. impaired glucose tolerance, to overt diabetes, which is driven by decreased insulin sensitivity and relative beta cell failure. The objective of this project was to develop the IGI model to include DP model for glucose and insulin in subjects with impaired glucose tolerance.
Methods: Data was obtained from a substudy of the Finnish Diabetes Prevention Study2,3, consisting of 101 subjects with impaired glucose tolerance; randomly assigned to control group and lifestyle intervention group with intensive counselling on diet, weight reduction and exercise. At the start and end of the study most subjects underwent a frequently sampled intravenous glucose tolerance test (FSIGT): 87 subjects at year 0 and 52 subjects at year 4. All subjects also underwent yearly an oral glucose tolerance test (OGTT). Subjects who developed diabetes were excluded from the study at the time of diagnosis. Intense blood sampling was performed after the FSIGT and sparse (0, 30 min, 120 min) after OGTT. Combination of intravenous and oral IGI model was used to fit the data for baseline until the fourth year, incorporating prior information on the parameters from published models using PRIOR functionality in NONMEM4. The DP model was investigated on the pathophysiologically most reasonable parameters e.g. insulin-dependent glucose clearance (CLGI). The impact of diet and exercise intervention on the DP was investigated. The best model was chosen based on objection function value, diagnostic plots, and visual predictive check.
Results: For the control group, first phase insulin secretion (IFST), CLGI, and maximum incretin effect (EMAX) were decreased by 7.5%/year, 4.7%/year and 7.4%/year as a consequence of DP. For the intervention group, IFST was marginally decreased by 1.3%. Instead CLGI was increased by 3.1% indicating an improvement of insulin sensitivity, while the DP based on EMAX was similar to the control group.
Conclusions: The DP was successfully included in the IGI model to describe difference seen in a population with impaired glucose tolerance with or without lifestyle intervention. In particular, insulin dependent glucose clearance improved after intensive lifestyle intervention.
 Silber HE, Jauslin PM, Frey N, Karlsson MO. An integrated model for glucose and insulin system. Basic Clin Pharmacol Toxicol. 2010;106(3):189-194.
 Eriksson J, Lindstrom J, Valle T, Aunola S, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanneiemi, Laakso M, Lauhkonen M, Lehto P, Lehtonen A, Louheranta A, Mannelin M, Martikkala V, Rastas M, Sundvall J, Turpeinen A, Viljanen T, Uusitupa M, Tuomilehto J, Finnish Diabetes Prevention Study Group. Prevention of Type II diabetes in subjects with impaired glucose tolerance: the Diabetes Prevention Study (DPS) in Finland. Study design and 1-year interim report on the feasibility of the lifestyle intervention programme. Diabetologia. 1999; 42:793-801.
 Uusitupa M, Lindi V, Louheranta A, Salopuro T, Lindstrom J, Tuomilehto J, the Finnish Prevention Study Group, Long-term imporovement in insulin sensitivity by changing lifestyles of people with impaired glucose tolerance: 4-year results from the Finnish Diabetes Prevention Study. Diabetes. 2003;52:2532-2538.
 Gisleskog PO, Karlsson MO, Beal SL. Use of prior information to stabilize a population data analysis. Journal of pharmacokinetics and pharmacodynamic. 2002;29(5):473-505.
Acknowledgement: This work was supported by the DDMoRe (www.ddmore.eu) project. Travelling grant to PAGE meeting was provided by Apotekarsocietitien, Sweden.