03-DK-0245 (Effect of AC2993 (synthetic exendin-4) on pancreatic islet function)

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Type 1 diabetes mellitus (T1DM) typically results from immune mediated destruction of pancreatic beta cells. Previous studies indicated that some patients retain the capacity for limited endogenous insulin production. Exendin-4 had been shown in preclinical and in preliminary human studies to have several potentially beneficial antidiabetic actions, including recovery and neogenesis of pancreatic islets. Purpose of this protocol: We investigated whether pancreatic insulin production can be enhanced in patients with long-standing T1DM (more than 5 years) by administering synthetic exendin-4, with or without concomitant immunosuppression (daclizumab). To be eligible, patients had to have evidence of some residual pancreatic insulin production as reflected by measurable circulating C-peptide (between 0.3 ng/ml and < 1.2 ng/ml). All patients received synthetic exendin-4 in a crossover design; half received immunosuppression with daclizumab. We assessed endogenous islet function with repeated arginine-stimulated C-peptide tests. The protocol also monitored glycemia control, insulin requirements, and assays to quantitate anti-islet immune responses. Background information: Considerable evidence, albeit indirect, supports the proposed chronic "race" between the immune system mediated islet destruction and a counter beta cell regenerative process. For instance, it is now well accepted that the anti-islet immune response exists for months and even years prior to T1DM onset. This observation is most intriguing since the immune system typically destroys targets with great efficiency and speed (e.g., the immune response leading to organ allograft rejection). While the gradual beta cell destruction could be due to immune regulatory processes bridling the destructive immune response, the fact that serologic evidence, e.g., anti-glutamic acid decarboxylase (GAD) antibodies persist in many patients with T1DM years after disease onset, suggests some persistence of the target cells driving the immune response. Further, ample data in rodents document that islet cell turnover persists at a low but steady rate throughout life, so islet regeneration can and does occur. Indeed, while controversial, a number of recent studies have demonstrated that a variety of tissues thought to have lost regenerative capacity (e.g., myocytes and neurons) can, under certain circumstances, be induced to proliferate. In 1992, Eng et al reported the isolation and characterization of exendin-4, a novel peptide from lizard venom that displays 52% identity to mammalian glucagon-like peptide (GLP 1). Exendin-4 was subsequently shown to bind the GLP 1 receptor, stimulate glucose-dependent insulin secretion, and increase both cAMP accumulation and insulin gene expression in cultured islet cell lines in vitro. More recently it has been found that GLP 1 induced activation of the GLP 1 receptor resulted in beta cell growth and differentiation by inducing the expression of the homeodomain protein IDX 1 (also known as PDX-1 or IPF-1) and that GLP 1 may lead to differentiation of human pancreatic islet-derived progenitor cells into insulin-producing cells. Though there is a striking homology between lizard exendin-4 and mammalian GLP 1 (a product of posttranslational processing of the proglucagon gene), it was determined that both are distinct peptides encoded by different genes and that there is no human equivalent of exendin-4. So far, all metabolic effects of exendin-4 appear to be mediated via the GLP 1 receptor. Synthetic exendin-4 (exenatide or Byetta (trade name)) has recently been approved for treatment in patients with type 2 diabetes and require insulin. Current protocol status: Using the NIH patient recruitment center, more than 800 patients contacted the NIH patient recruitment center and were sent a questionnaire of which 150 were returned. Seventy-two patients were invited, we screened 43 patients, 23 patients were rejected for clinical reasons, and 20 patients were randomized. Fourteen patients completed the entire trial. Another 6 patients terminated their participation early. First, patients completed the run-in protocol phase during which their baseline C-peptide producing capacity was assessed over 4 months with three arginine stimulation tests while the patients' blood glucose was maintained as closely to normal as possible. Thereafter, the patients entered study period A, then study period B (each 6-month duration) during which they received AC2993 (for 6 months) with or without daclizumab. Then followed a 3-month extension during which the patients remained on the treatment regimen administered in period B. One of our patients has experienced a serious adverse event (diabetic ketoacidosis in association with gastroenteritis). All participants completed their active protocol participation. Results have been summarized in a manuscript published in Diabetes Care. Briefly, 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 in 6 months, 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. We concluded that 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. Further analyses of data and processing of blood specimens are currently underway.