Mathematical modeling shows exenatide improved beta-cell function in patients
with type 2 diabetes treated with metformin or metformin and a sulfonylurea.
Author(s): Mari A, Nielsen LL, Nanayakkara N, DeFronzo RA, Ferrannini E, Halseth A.
Affiliation(s): National Research Council Institute of Biomedical Engineering, Padova, Italy.
andrea.mari@isib.cnr.it
Publication date & source: 2006, Horm Metab Res. , 38(12):838-44
The incretin mimetic exenatide improved glycemic control and reduced body weight
in patients with type 2 diabetes inadequately controlled with metformin+/-a
sulfonylurea. We assessed postprandial beta-cell function by mathematical
modeling, independent of confounding effects from differing ambient glucose
levels among treatments. Subjects were 63% males, 55+/-10 years, BMI 33+/-6
kg/m2, HbA1C 8.1+/-1.1% (+/- SD) randomized to 5 microg exenatide or placebo
twice daily for 4 weeks. Subsequently, one arm remained at 5 microg twice daily,
one arm escalated to 10 microg twice daily, and one treatment arm remained on
placebo for 26 weeks. Subjects continued metformin+/-a sulfonylurea. A subset
with meal tests at baseline and week 30 were analyzed (n=73). Outcome measures
were the model-based beta-cell function parameters dose-response relating insulin
secretion to glucose concentration, rate sensitivity, and potentiation. Exenatide
reduced postprandial glucose excursions. Modeling predicted an upward shift of
the beta-cell dose-response. Model-predicted insulin secretion rate at a
reference glucose concentration increased 72% (10 microg), increased 40% (5
microg), or decreased 21% (placebo) at week 30 [ p=0.015 (10 microg); p=0.045 (5
microg); vs. placebo]. At week 30, the 2-hour post-meal to basal potentiation
factor ratio was increased to 1.53+/-0.10 (10 microg; p=0.0142 vs. placebo) or
1.40+/-0.08 (5 microg; p=0.0402 vs. placebo) compared with 1.15+/-0.06 (placebo).
Exenatide caused an upward shift of the beta-cell dose-response and enhanced
potentiation of insulin secretion. This model suggests exenatide improved
beta-cell function in patients with type 2 diabetes treated with metformin+/-a
sulfonylurea.
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