Effects of Exenatide Alone and in Combination With Daclizumab on β-Cell Function in Long-Standing Type 1 Diabetes

Abstract

OBJECTIVEIn patients with long-standing type 1 diabetes, we investigated whether improved β-cell function can be achieved by combining intensive insulin therapy with agents that may 1) promote β-cell growth and/or limit β-cell apoptosis and 2) weaken the anti–β-cell autoimmunity.RESEARCH DESIGN AND METHODSFor 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.RESULTSIn 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 β-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 · kg−1 · 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.CONCLUSIONSIn long-standing type 1 diabetes, which remains an active autoimmune disease even decades after its onset, surviving β-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 β-cells.

Beta cell function during rapamycin monotherapy in long-term type 1 diabetes

“…On the basis of these findings, an intervention combining an anti-IL-2 receptor antibody with the glucagon-like peptide 1 agonist exenatide was performed in long-term type 1 diabetes patients. Although that study demonstrated that such patients have beta cells able to secrete insulin in a physiologically regulated manner [2], there was no improvement in beta cell function after treatment.…”

“…Several studies in patients with type 1 diabetes support the hypothesis that beta cells survive in the long term or that the pancreas has an underappreciated capacity for functional beta cell recovery [1][2][3][4][5]. A significant subset of patients with type 1 diabetes continue to produce Cpeptide, years after their diagnosis [4][5][6][7][8].…”

β‐Cell differentiation and regeneration in type 1 diabetes

“…On the other hand, the Harlan and colleagues showed that a combination of intensified insulin therapy, exenatide and daclizumab did not induce improved function of remaining β-cells. They suggested that the amount of residual β-cells possibly plays a key role as a potential source of new β-cells, especially in younger patients and at an earlier stage of the disease [62]. In this regard, it was recently shown that the addition of exenatide and sitagliptin (a DPP-4 inhibitor) decreased insulin requirements without increasing endogenous insulin production and hypoglycaemic events [63].…”

Diabetes autoinmune (latente) del adulto

“…-Incretino-miméticos: si bien no existen expe riencias con análogos de Glucagon Like Peptide 1 (GLP 1) o inhibidores de DPP IV (glip tinas), su efecto antiapoptótico los convierten en una alternativa a futuro. Sin embargo, en un estudio reciente el uso de exenatide asociado a insulina en diabéticos tipo 1 no logró preserva ción del remanente de secreción pancreática 28 .…”