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Islet transplantation in the subcutaneous space achieves long-term euglycaemia in preclinical models of type 1 diabetes.

ABSTRACT: The intrahepatic milieu is inhospitable to intraportal islet allografts^1-3, limiting their applicability for the treatment of type?1 diabetes. Although the subcutaneous space represents an alternate, safe and easily accessible site for pancreatic islet transplantation, lack of neovascularization and the resulting hypoxic cell death have largely limited the longevity of graft survival and function and pose a barrier to the widespread adoption of islet transplantation in the clinic. Here we report the successful subcutaneous transplantation of pancreatic islets admixed with a device-free islet viability matrix, resulting in long-term euglycaemia in diverse immune-competent and immuno-incompetent animal models. We validate sustained normoglycaemia afforded by our transplantation methodology using murine, porcine and human pancreatic islets, and also demonstrate its efficacy in a non-human primate model of syngeneic islet transplantation. Transplantation of the islet-islet viability matrix mixture in the subcutaneous space represents a simple, safe and reproducible method, paving the way for a new therapeutic paradigm for type?1 diabetes.

SUBMITTER: Yu M

PROVIDER: S-EPMC7572844 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Islet transplantation in the subcutaneous space achieves long-term euglycaemia in preclinical models of type 1 diabetes.

Yu Ming M Agarwal Divyansh D Korutla Laxminarayana L May Catherine L CL Wang Wei W Griffith Negin Noorchashm NN Hering Bernhard J BJ Kaestner Klaus H KH Velazquez Omaida C OC Markmann James F JF Vallabhajosyula Prashanth P Liu Chengyang C Naji Ali A

Nature metabolism 20200907 10

The intrahepatic milieu is inhospitable to intraportal islet allografts<sup>1-3</sup>, limiting their applicability for the treatment of type 1 diabetes. Although the subcutaneous space represents an alternate, safe and easily accessible site for pancreatic islet transplantation, lack of neovascularization and the resulting hypoxic cell death have largely limited the longevity of graft survival and function and pose a barrier to the widespread adoption of islet transplantation in the clinic. Her ...[more]

PMID: 32895576

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Project description:AIMS/INTRODUCTION:To investigate the long-term efficacy and safety of islet transplantation (ITx) compared with multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII). MATERIALS AND METHODS:Among 619 patients diagnosed as insulin-dependent diabetes mellitus or type 1 diabetes at Kyoto University, Kyoto, Japan, seven patients were selected as the ITx group and 26 age-matched patients with no endogenous insulin secretion were selected as the MDI/CSII group. Hemoglobin A1c, aspartate aminotransferase/alanine aminotransferase (AST/ALT) and creatinine were assessed retrospectively at 1, 2, 5 and 10 years for both groups; serum C-peptide immunoreactivity was assessed for the ITx group. Major clinical events were also assessed. RESULTS:Hemoglobin A1c improvement in ITx was significant at 1 year (8.4% [7.8-9.9%] at baseline to 7.1% [6.3-7.4%] in ITx vs 8.2% [7.4-9.8%] at baseline to 8.1% [7.3-9.5%] in MDI/CSII, P < 0.01 between groups), and was maintained at 2 years (7.4% [6.3-8.2%] vs 8.4% [7.4-9.6%], P = 0.11). The increase of stimulated C-peptide immunoreactivity was significant at 1 year (0.57 ng/mL [0.26-0.99 ng/mL], P < 0.05 from baseline) and 2 years (0.43 ng/mL [0.19-0.67 ng/mL], P < 0.05), although it became insignificant thereafter. There was no significant difference in AST/ALT or creatinine at 10 years, although a transient AST/ALT elevation was observed in ITx. In regard to clinical events, the occurrence of severe hypoglycemia was 14% vs 31% (relative risk 0.46, P = 0.64), that of infectious disease was 43% vs 12% (relative risk 3.71, P = 0.09) and digestive symptoms was 43% vs 7.7% (relative risk 5.57, P = 0.05) in ITx vs MDI/CSII, respectively. No patient died in either group. CONCLUSIONS:The present findings showed that ITx was considered to contribute to the reduction of hypoglycemia and better glycemic control with tolerable, but attention-requiring, risks over a period of 10 years compared with MDI/CSII.

Dataset Information

Islet transplantation in the subcutaneous space achieves long-term euglycaemia in preclinical models of type 1 diabetes.

Publications

Islet transplantation in the subcutaneous space achieves long-term euglycaemia in preclinical models of type 1 diabetes.

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