Effects of exenatide alone and in combination with daclizumab on beta-cell function in long-standing type 1 diabetes

Abstract

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: For this study, 20 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 crossover 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 >or=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 wt and insulin requirements declined significantly (total daily dose on exenatide 0.48 +/- 0.11 vs. 0.55 +/- 0.13 units x kg(-1) x day(-1) 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.

Trial registration: ClinicalTrials.gov NCT00064714.

Figure 1

Study design (A) and timeline for testing procedures (B): 20 patients entered the optimization period, 16 were randomized, and 14 completed the entire trial. B: A, arginine stimulation test; M, mixed-meal test; T, T-cell proliferation test.

Figure 2

Results of C-peptide responses to arginine stimulation (A and B) and changes of insulin doses and weight according to treatment assignment (C). C-peptide results are shown at screening (basal versus stimulated C-peptide, P < 0.0001) and during run-in period (tests were conducted in months 2, 3, and 4 of run-in period [basal versus stimulated C-peptide, P = 0.0078]) (A) after 6 months of exenatide therapy versus not having received exenatide (irrespective of assignment to daclizumab) (B) with reference to mean results of run-in period. Data are means ± SEM. To convert C-peptide from conventional (ng/ml) to S_i units (nmol/l), multiply by factor 0.333.

Figure 3

Results of mixed-meal testing, conducted according to study timeline (Fig. 1B). Exenatide administered before a mixed meal delayed gastric emptying (A; P = 0.041) and glucose absorption (B; P = 0.052), did not change glucagon levels (C; P = 0.414), and suppressed GLP-1 (D; P = 0.024). P values reflect differences of areas under the curve comparing patients' results on and off exenatide; data are means ± SEM. To convert glucose from conventional (mg/dl) to S_i units (nmol/l), multiply by factor 0.0555.