The basic hypothesis underlying this project is that the native pancreas in individuals with even long-standing T1DM has the capacity to recover meaningful insulin producing capacity, but that potential is masked by two factors. The first and most important is the anti-beta cell specific autoimmune response that first lead to T1DM, and strong evidence exists to suggest that the anti-beta cell specific autoimmunity persists throughout that individual's life. The second factor is the abnormal metabolic melieu (hyperglycemia, hyperlipidemia, etc) characteristic of T1DM. Much data exists to suggest the hypothesis has validity, including much published work suggesting that patients with long-standing T1DM have both persistent pancreatic beta cell function and persistent anti-beta cell specific autoimmune responses: ? ? (1) Most studies evaluating patients with long-standing T1DM find a substantial proportion continue to have measureable circulating C-peptide,? (2) Autopsy series report that pancreatic beta cells can be found in most individuals with long-standing T1DM,? (2) Investigators have reported a high frequency of anti-insulin specific T cells in the pancreatic draining lymph nodes from patients dying years after their T1DM was diagnosed,? (3) Most patients with long-standing T1DM have persistent anti-beta cell specific autoantibodies while in other autoimmune states, such tissue specific antibodies normally disappear when the inciting autoantigenic tissue is destroyed.? ? Other small series or case reports have suggested that tight glycemia control and a modified immune response (e.g. that associated with pregnancy or post-transplantation) can lead to improved native pancreatic insulin producing capacity or increased numbers of pancreatic cells immunostaining for insulin.? ? In previous years, we evaluated the hypothesis by evaluating three NIH islet transplant recipients in detail. Each had enjoyed insulin independent euglycemia for at least 1 year following their islet transplant allowing us to ask whether the immunosuppression required to maintain their islet allograft coupled with the improved metabolic parameters promoted by the transplanted islets, had promoted their native pancreatic insulin producing capacity. And since the transplanted islets were placed in the subject's liver, we were able to differentiate native pancreatic from transplanted islet insulin production by placing one cannula just downstream from the native pancreas, and others just downstream from the liver. Two of the three subjects displayed clear evidence of native pancreatic insulin production, but the amount of native pancreatic insulin production was quite small.? ? During this past year, we asked whether longer duration immunosuppression and normalized metabolism might promote ever-improving native pancreatic insulin production. For this study, we enrolled 4 subjects with a history of long-standing T1DM but who had enjoyed several years of insulin independent euglycemia following a successful pancreas transplant. We again were able to diffentiate the source of any circulating insulin by strategically placing cannulas downstream from both the native pancreas, and the pancreas allograft. Consistent with our earlier experience from the islet allograft recipients, each subject displayed clear evidence of minimal native pancreatic insulin production. However, despite years of immunosuppression and transplant-associated euglycemia, native pancreatic insulin production remained clinically insignificant. The results of these studies are being submitted for publication.
| Ren, Jiaqiang; Jin, Ping; Wang, Ena et al. (2007) Pancreatic islet cell therapy for type I diabetes: understanding the effects of glucose stimulation on islets in order to produce better islets for transplantation. J Transl Med 5:1 |
| Liu, Eric H; Siegel, Richard M; Harlan, David M et al. (2007) T cell-directed therapies: lessons learned and future prospects. Nat Immunol 8:25-30 |
| Dy, Emily C; Harlan, David M; Rother, Kristina I (2006) Assessment of islet function following islet and pancreas transplantation. Curr Diab Rep 6:316-22 |
| Neeman, Ziv; Hirshberg, Boaz; Harlan, David et al. (2006) Radiologic aspects of islet cell transplantation. Curr Diab Rep 6:310-5 |
