Effects of Exenatide Alone and in Combination with Daclizumab on Beta Cell Function in Long-Standing Type 1 Diabetes Mellitus.
Author(s): Rother KI, Spain LM, Wesley RA, Digon BJ 3rd, Baron A, Chen K, Nelson P, Dosch HM, Palmer J, Brooks-Worrell B, Ring M, Harlan DM
Affiliation(s): 1 National Institute of Diabetes, Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland.
Publication date & source: 2009-10-06, Diabetes Care., [Epub ahead of print]
Objective - In patients with long-standing type 1 diabetes, we investigated whether improved beta-cell function can be achieved by combining intensive insulin therapy with agents that may 1) promote beta-cell growth and/or limit beta-cell apoptosis, and 2) weaken the anti-beta-cell autoimmunity. Research Design and Methods - Twenty individuals (mean age 39.5 +/- 11.1 years) with long-standing type 1 diabetes (21.3 +/- 10.7 years) were enrolled in this prospective, open-label, cross-over trial. After achieving optimal blood glucose control, 16 subjects were randomized to exenatide with or without daclizumab. Endogenous insulin production was determined by repeatedly measuring serum C-peptide. Results - In 85% of individuals with long-standing type 1 diabetes who were screened for participation in this trial, C-peptide levels >/= 0.05 ng/mL (0.02 nmol/L) were found. Residual beta-cells responded to physiological (mixed meal) and pharmacological (arginine) stimuli. During exenatide treatment, patients lost 4.1 +/- 2.9 kg body weight, and insulin requirements declined significantly (total daily dose on exenatide 0.48 +/- 0.11 u/kg/d versus 0.55 +/- 0.13 u/kg/d without exenatide; p=0.0062). No signs of further activation of the underlying autoimmune disease were observed. Exenatide delayed gastric emptying, suppressed endogenous incretin levels, but did not increase C-peptide secretion. Conclusions - In long-standing type 1 diabetes, which remains an active autoimmune disease even decades after its onset, surviving beta-cells secrete insulin in a physiologically regulated manner. However, the combination of intensified insulin therapy, exenatide, and daclizumab did not induce improved function of these remaining beta-cells.