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Islet transplantation is a promising therapy for diabetes, yet the limited survival and functionality of transplanted islet grafts hinder optimal outcomes. Glucagon-like peptide-1 (GLP-1), an endogenous hormone, has shown potential to enhance islet survival and function; however, its systemic administration can result in poor localization and undesirable side effects. To address these challenges, we developed a novel peptide-based nanofiber hydrogel incorporating GLP-1 functionality for localized delivery. By conjugating the FFG tripeptide (a self-assembling motif derived from phenylalanine-phenylalanine-glycine) to the C-terminus of native GLP-1, we engineered GLP-1-FFG, a self-assembling peptide that forms a robust nanofiber structure resistant to enzymatic degradation. When GLP-1-FFG co-assembles with the biotin-DFYIGSRGD peptide (referred to as SupraGel), a self-assembling supramolecular polypeptide hydrogel we previously identified containing motifs derived from extracellular matrix components, the resulting hydrogel (SupraGel + GLP-1-FFG) creates a stable nanofibrous network with excellent rheological properties. In vitro, this nanofiber hydrogel significantly improves islet function and survival. Bulk RNA sequencing results demonstrate that the hydrogel suppresses the expression of hypoxia-related genes, downregulates pro-inflammatory genes, and upregulates genes associated with islet function. Further analysis reveals that these effects are related to the activation of the AKT signaling pathway. In a syngeneic mouse islet transplantation model, the localized application of SupraGel + GLP-1-FFG at the renal subcapsular islet transplant site significantly enhanced the efficacy of marginal-dose islet transplantation, as shown by improved glycemic control, faster and higher rates of diabetes reversal, better glucose tolerance, and greater islet graft survival in diabetic recipient mice. This innovative nanotechnology-based hydrogel offers a promising strategy for enhancing the efficacy of islet grafts in transplantation therapy. [ABSTRACT FROM AUTHOR]

Background: Diabetes is a widespread disease with increasing prevalence. Transplantation of islets of Langerhans is a viable treatment for a selected group of patients with repeated hypoglycemic episodes in type 1 diabetes. The countries where islet transplantation has not been explored suffer from insufficient knowledge concerning key elements of the isolation process. Donor and organ procurement parameters impact human islet yield, although for research purposes, islet yield may be secondary in importance to islet function. This paper will analyze the feasibility of research--only human islet isolation and signify parameters underlying a successful yield in the Indian population. This eventually can make islet transplantation a clinical reality in India. Method: After receiving the consent for procuring brain-dead pancreas from the first-degree of relatives, samples were collected and transported in a transportation buffer at 4 °C. The procedure consists of a mechanically enhanced enzymatic digestion of the pancreas, after which it was taken for purification using Ficoll method, followed by islet quality testing. Results: Through 15 isolations done over a span of approximately 2 years during the COVID pandemic in India,we confirm that ischemic time and glycated hemoglobin, each have a negative impact on isolation purity and yield. Notably, extending cold ischemic tim beyond the typical clinical isolation cutoff of 12 hours (to ≥ 18 h) had a huge impact on islet function and yield. Age had a negative correlation with islet yield; however other biological parameters (specifically body mass index) and isolation variables appear to make a significant contribution to the heterogeneity of human islet yield. Our current work demonstrates the feasibility of extending acceptable cold ischemic time for research-focused human islet isolation and highlights the biological variation in isolation of human islets from donors with and without diabetes. Conclusion: India requires establishment of an islet transplant program using the current standard methods of"islet isolation" and donor program and process. Research should focus on improving standards in the islet preparation process to increase the number of successful preparations, shorten the isolation time, and increase patient safety so that the theoretical risk involved can become a practical reality. [ABSTRACT FROM AUTHOR]

Islet transplantation is a treatment for selected adults with type 1 diabetes and severe hypoglycemia. Islets from two or more donor pancreases, a scarce resource, are usually required to impact glycemic control, but the treatment falls short of a cure. Islets are avascular when transplanted into the hypoxic liver environment and subjected to inflammatory insults, immune attack, and toxicity from systemic immunosuppression. The Collaborative Islet Transplant Registry, with outcome data on over 1,000 islet transplant recipients, has demonstrated that larger islet numbers transplanted and older age of recipients are associated with better outcomes. Induction with T-cell depleting agents and the TNF-α inhibitor etanercept and maintenance systemic immunosuppression with mTOR inhibitors in combination with calcineurin inhibitors also appear advantageous, but concerns remain over immunosuppressive toxicity. We discuss strategies and therapeutics that address specific challenges of islet transplantation, many of which are at the preclinical stage of development. On the horizon are adjuvant cell therapies with mesenchymal stromal cells and regulatory T cells that have been used in preclinical models and in humans in other contexts; such a strategy may enable reductions in immunosuppression in the early peri-transplant period when the islets are vulnerable to apoptosis. Human embryonic stem cell-derived islets are in early-phase clinical trials and hold the promise of an inexhaustible supply of insulinproducing cells; effective encapsulation of such cells or, silencing of the human leukocyte antigen (HLA) complex would eliminate the need for immunosuppression, enabling this therapy to be used in all those with type 1 diabetes. [ABSTRACT FROM AUTHOR]