Modeling the acute effects of exercise on insulin kinetics in type 1 diabetes

• Published in: Journal of pharmacokinetics and pharmacodynamics 2018-12, Vol.45 (6), p.829-845
• Main Authors: Frank, Spencer, Jbaily, Abdulrahman, Hinshaw, Ling, Basu, Rita, Basu, Ananda, Szeri, Andrew J.
• Format: Article
• Language: English
• Subjects: Acute effects; Adult; Algorithms; Artificial intelligence; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Blood Glucose - drug effects; Blood Glucose - metabolism; Capillaries - metabolism; Capillary Permeability; Cohort Studies; Control algorithms; Curve fitting; Decision Support Techniques; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - blood; Diabetes Mellitus, Type 1 - diagnosis; Diabetes Mellitus, Type 1 - drug therapy; Exercise - physiology; Female; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Insulin - administration & dosage; Insulin - pharmacokinetics; Insulin Infusion Systems; Kinetics; Male; Membrane permeability; Middle Aged; Models, Biological; Muscle, Skeletal - blood supply; Muscle, Skeletal - physiology; Muscles; Musculoskeletal system; Original Paper; Pancreas; Pancreas, Artificial; Parameter estimation; Perfusion; Pharmacology/Toxicology; Pharmacy; Skeletal muscle; Support systems; Surface area; Veterinary Medicine/Veterinary Science
• ISSN: 1567-567X; 1573-8744
• DOI: 10.1007/s10928-018-9611-z

Our objective is to develop a physiology-based model of insulin kinetics to understand how exercise alters insulin concentrations in those with type 1 diabetes (T1D). We reveal the relationship between the insulin absorption rate ( k a I ) from subcutaneous tissue, the insulin delivery rate ( k d I ) to skeletal muscle, and two physiological parameters that characterize the tissue: the perfusion rate ( Q ) and the capillary permeability surface area ( PS ), both of which increase during exercise because of capillary recruitment. We compare model predictions to experimental observations from two pump-wearing T1D cohorts [resting subjects ( n = 17 ) and exercising subjects ( n = 12 )] who were each given a mixed-meal tolerance test and a bolus of insulin. Using independently measured values of Q and PS from literature, the model predicts that during exercise insulin concentration increases by 30% in plasma and by 60% in skeletal muscle. Predictions reasonably agree with experimental observations from the two cohorts, without the need for parameter estimation by curve fitting. The insulin kinetics model suggests that the increase in surface area associated with exercise-induced capillary recruitment significantly increases k a I and k d I , which explains why insulin concentrations in plasma and skeletal muscle increase during exercise, ultimately enhancing insulin-dependent glucose uptake. Preventing hypoglycemia is of paramount importance in determining the proper insulin dose during exercise. The presented model provides mechanistic insight into how exercise affects insulin kinetics, which could be useful in guiding the design of decision support systems and artificial pancreas control algorithms.