Abstract
While exogenous insulin therapy remains the most common and effective standard for day-to-day control of Type 1 Diabetes (T1D), recurring incidences of hypoglycemic episodes and long-term complications such as retinopathy, neuropathy, nephropathy, and cerebrovascular/cardiovascular diseases necessitate transplantation of either whole pancreas or pancreatic islets as a more effective treatment in a high percentage of patients [1-6]. Of the two, clinical islet transplantation is less invasive, being associated with a 20% lower morbidity risk compared to whole pancreas transplantation. At the same time, it offers substantial benefits in terms of lowering daily insulin requirement, improving levels of glycated hemoglobin (HbA1c), reducing incidences of debilitating hypoglycemic episodes and unawareness, and affording potential insulin independence. However, widespread applicability of the procedure is mainly hindered by an inadequate supply of donor pancreata, graft rejection, recurrence of autoimmunity, deleterious side-effects associated with chronic immune-suppression, and last but not least, financial considerations [1].
Highlights
While exogenous insulin therapy remains the most common and effective standard for day-to-day control of Type 1 Diabetes (T1D), recurring incidences of hypoglycemic episodes and long-term complications such as retinopathy, neuropathy, nephropathy, and cerebrovascular/cardiovascular diseases necessitate transplantation of either whole pancreas or pancreatic islets as a more effective treatment in a high percentage of patients [1,2,3,4,5,6]
Clinical islet transplantation is less invasive, being associated with a 20% lower morbidity risk compared to whole pancreas transplantation
Our studies conducted in both the murine sub-kidney capsule as well as the clinically-relevant hepatic intra-portal islet transplantation models indicate that infusion of A2AR agonist ATL146e and ATL313 in diabetic recipient mice during the peritransplant period resulted in reduction of both, inflammation-mediated early loss of a minimal dose islet graft as well as in the time taken to achieve sustained normoglycemia [7]
Summary
While exogenous insulin therapy remains the most common and effective standard for day-to-day control of Type 1 Diabetes (T1D), recurring incidences of hypoglycemic episodes and long-term complications such as retinopathy, neuropathy, nephropathy, and cerebrovascular/cardiovascular diseases necessitate transplantation of either whole pancreas or pancreatic islets as a more effective treatment in a high percentage of patients [1,2,3,4,5,6]. Factors contributing to the eventual decline in graft function and survival include, amongst others, a) innate non-specific inflammatory reactions in the microenvironment of the graft during the peritransplant period that mediate early loss of nearly 50% of the transplanted islets; b) ischemiareperfusion injury (IRI) following transplantation; c) relative hypoxia and poor vascularization of islets resulting in inefficient engraftment and primary dysfunction of islets, d) progressive destruction of the graft by innate and adaptive immune mechanisms and the recurrence of autoimmunity; e) metabolic distress from exhaustion of a marginal β-cell mass and f) drug toxicity associated with immunosuppressive regimens [1,7].
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