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.

OBJECTIVE -The aim of this study was to describe the National Institutes of Health's experience initiating an islet isolation and transplantation center, including descriptions of our first six recipients, and lessons learned.RESEARCH DESIGN AND METHODS -Six females with chronic type 1 diabetes, hypoglycemia unawareness, and no endogenous insulin secretion (undetectable serum Cpeptide) were transplanted with allogenic islets procured from brain dead donors. To prevent islet rejection, patients received daclizumab, sirolimus, and tacrolimus.RESULTS -All patients noted less frequent and less severe hypoglycemia, and one-half were insulin independent at 1 year. Serum C-peptide persists in all but one patient (follow-up 17-22 months), indicating continued islet function. Two major procedure-related complications occurred: partial portal vein thrombosis and intra-abdominal hemorrhage. While we observed no cytomegalovirus infection or malignancy, recipients frequently developed transient mouth ulcers, diarrhea, edema, hypercholesterolemia, weight loss, myelosuppression, and other symptoms. Three patients discontinued immunosuppressive therapy: two because of intolerable toxicity (deteriorating kidney function and sirolimus-induced pneumonitis) while having evidence for continued islet function (one was insulin independent) and one because of gradually disappearing islet function.CONCLUSIONS -We established an islet isolation and transplantation program and achieved a 50% insulin-independence rate after at most two islet infusions. Our experience demonstrates that centers not previously engaged in islet transplantation can initiate a program, and our data and literature analysis support not only the promise of islet transplantation but also its remaining hurdles, which include the limited islet supply, procedure-associated complications, imperfect immunosuppressive regimens, suboptimal glycemia control, and loss of function over time. Diabetes Care 26:3288 -3295, 2003A lthough it is well established that individuals with immune-mediated type 1 diabetes can minimize their risk for long-term complications by maintaining near-normal blood glucose (1,2), it is equally well established that maintaining normal blood glucose concentrations is often quite difficult (3), with one price of such efforts being a threefold greater risk for serious hypoglycemia (4). Currently, pancreas transplantation can restore insulin independence in up to 90% of patients 1 year after surgery, but the procedure is technically demanding and is associated with serious complications and high mortality. In fact, our recent analysis suggests that solitary pancreas transplantation may decrease overall survival for those patients with normal kidney function (4a). Because many of the postsurgical complications are attributable to the non-insulinproducing pancreatic exocrine tissue (5), investigators have asked whether transplanting just the insulin-producing islets might be similarly effective but safer (6,7). Thus, since early reports of islet transplan...

Aim/hypothesis-We measured serum C-peptide in many individuals with chronic type 1 diabetes (T1D) and sought factors that might differentiate those with detectable C-peptide from those without it. Finding no differences, and in view of such subjects' persistent anti-beta cell autoimmunity, we speculated that immunosuppression (to weaken the autoimmune attack) and euglycemia accompanying transplant-based treatments for type 1 diabetes (T1D) might promote recovery of T1D subject's native pancreatic beta cell function.Methods-We performed arginine stimulation tests in 3 islet transplant and 4 whole pancreas transplant recipients, and measured stimulated C-peptide in select venous sampling sites. We differentiated insulin secreted from the individual's native pancreatic beta cells and from allografted beta cells based upon each sampling site's C-peptide concentration and kinetics.Results-Selective venous sampling demonstrated that despite long-standing T1D, all 7 beta cell allograft recipients displayed evidence that their native pancreas was a source for secreted C-peptide. Even so, if chronic immunosuppression coupled with near normal glycemia improved native pancreatic C-peptide production, the magnitude of the effect was quite small.Conclusions/interpretation-While some native pancreatic beta cell function persists even years after disease onset in most with T1D, if prolonged euglycemia plus anti-rejection immunosuppressive therapy promotes improved the subjects' native pancreatic insulin production, the effect is small. We may have underestimated pancreatic regenerative capacity by studying only a limited subject number, or by creating conditions (e.g. high circulating insulin concentrations, or immunosuppressive agents toxic to beta cells) that impair beta cell function.

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