B Mc Hugh (1), R Gieschke (1), M Karlsson (2)
(1) Division of Clinical Pharmacology, F. Hoffmann-La Roche, Basel, Switzerland; (2) Department of Pharmacology, Uppsala University, Sweden
Objective: To investigate differences in plasma glucose and insulin levels between volunteers and patients in the absence of drug, i.e., the degree to which insulin effects glucose production/disposition and the degree to which glucose effects insulin secretion/disposition. Beta-cell dysfunction and insulin resistance associated with type 2 diabetes mellitus perturbs the glucose regulatory system, causing postprandial and possibly fasting hyperglycemia. Mathematical models have traditionally been used to investigate the glucose-insulin interaction because they allow a quantitative assessment of physiologically relevant regulatory parameters.
Methods: We implemented 2 Compartment Minimal Models (Cobelli, et al., 1997) in NONMEM for Hot Glucose (disposition), Total Glucose (production), and Insulin (interaction) and considered volunteer data from the literature (Vicini, et al.) and a subset of patient data from a newly developed insulin sensitizer (Hoffmann-La Roche). The subset consisted of pre-dose measurements from type 2 diabetic subjects and post-dose measurements from type 2 diabetic subjects that received placebo. In the insulin modified FSIVGT, a total of 300 mg per kg body weight of a glucose solution enriched with 13± 5% of a stable glucose label [6,6-2H2] was infused over a period of no more than 30 seconds and, starting 20 min after the glucose load, 0.05 U of insulin per kg body weight was administered over 5 min.
Results: Following the FSIVGT, insulin sensitivity was observed to be a factor of 3 lower in the diabetic patients, glucose production was seen to be suppressed in both the volunteers and the patients, and insulin secretion was seen to be virtually unaffected.
Conclusion: We determine how to glucose effects insulin secretion and how insulin effects glucose production. Future work will be directed toward the development of a mathematical description of the glucose/insulin interaction to allow, for example, simultaneous prediction of insulin and glucose levels in the presence of singly and multiply administered anti-diabetic drugs from various classes.
References:
[1] Cobelli C, Vicini P, Toffolo G and Caumo A. The hot IVGTT Minimal Models: Simultaneous assessment of disposal indices and endogenous glucose production. In. Pennington Center Nutrition Series Volume 7: The Minimal Model approach and determinants of glucose tolerance. Bergman RN and Lovejoy JC ed. Louisiana State University Press; Baton Rouge and London.
[2] Vicini P, Caumo A and Cobelli C. The hot IVGTT two-compartment minimal model: indexes of glucose effectiveness and insulin sensitivity. Modeling in Physiology, 1997; E1024-E1032.
Reference: PAGE 12 (2003) Abstr 447 [www.page-meeting.org/?abstract=447]
Poster: poster