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Horm Metab Res 2006; 38(12): 838-844
DOI: 10.1055/s-2006-956505
Original Clinical

© Georg Thieme Verlag KG Stuttgart · New York

Mathematical Modeling Shows Exenatide Improved β-Cell Function in Patients with Type 2 Diabetes Treated with Metformin or Metformin and a Sulfonylurea

A. Mari 1 , L. L. Nielsen 2 , N. Nanayakkara 2 , R. A. DeFronzo 3 , E. Ferrannini 4 , A. Halseth 2
  • 1National Research Council Institute of Biomedical Engineering, Padova, Italy
  • 2Amylin Pharmaceuticals, Inc., San Diego CA, USA
  • 3Diabetes Division, University of Texas Health Science Ctr., San Antonio TX, USA
  • 4Department of Internal Medicine and Consiglio Nazionale delle Ricerche Institute of Clinical Physiology, University of Pisa, Pisa, Italy
Further Information

Publication History

Received 23 February 2006

Accepted after revision 17 July 2006

Publication Date:
12 December 2006 (online)

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Abstract

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 β-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 μg exenatide or placebo twice daily for 4 weeks. Subsequently, one arm remained at 5 μg twice daily, one arm escalated to 10 μg 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 β-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 β-cell dose-response. Model-predicted insulin secretion rate at a reference glucose concentration increased 72% (10 μg), increased 40% (5 μg), or decreased 21% (placebo) at week 30 p=0.015 (10 μg); p=0.045 (5 μg); vs. placebo. At week 30, the 2-hour post-meal to basal potentiation factor ratio was increased to 1.53±0.10 (10 μg; p=0.0142 vs. placebo) or 1.40±0.08 (5 μg; p=0.0402 vs. placebo) compared with 1.15±0.06 (placebo). Exenatide caused an upward shift of the β-cell dose-response and enhanced potentiation of insulin secretion. This model suggests exenatide improved β-cell function in patients with type 2 diabetes treated with metformin±a sulfonylurea.

Key words

Exendin-4 - AC2993 - β-cell function - insulin secretion - incretin mimetic - incretin potentiation - BYETTA®
BYETTA® is a registered trademark of Amylin Pharmaceuticals, Inc.

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Correspondence

Andrea MariPh.D. 

Institute of Biomedical Engineering

National Research Council

Corso Stati Uniti 4

35127 Padua

Italy

Phone: +39/049/82 95 75 3

Fax: +39/049/82 95 76 3

Email: andrea.mari@isib.cnr.it