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Pancreatic islet transplantation: toward definitive treatment for diabetes mellitus.

ABSTRACT: Since the late 20th century, advances in pancreatic islet transplantation have targeted improved glycemic control and fewer hypoglycemic events in patients with type 1 diabetes, and some important milestones have been reached. Following the Edmonton group's success in achieving insulin independence in all transplanted patients with type 1 diabetes, clinical islet transplantation is now performed worldwide. ? cell replacement therapy for type 1 diabetes was established based on the favorable outcomes of a phase 3, prospective, open-label, single-arm, clinical study conducted at 8 centers in North America, in which 42 of 48 patients who underwent islet transplantation from 2008 to 2011 achieved HbA1c < 7.0% (53 mmol/mol) at day 365, which was maintained at 2 years in 34 patients. In Japan, a phase 2 multicenter clinical trial of islet transplantation for type 1 diabetes patients is currently ongoing and will end soon, but the interim results have already led to positive changes, with allogeneic islet transplantation being covered by the national health insurance system since April 2020. Current efforts are being made to solve the problem of donor shortage by studying alternative donor sources, such as porcine islets and pancreatic progenitor cells derived from pluripotent stem cells. The results of clinical trials in this area are eagerly awaited. It is hoped that they will contribute to establishing alternative sources for insulin-producing ? cells in the near future.

SUBMITTER: Takaki T

PROVIDER: S-EPMC7731068 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Pancreatic islet transplantation: toward definitive treatment for diabetes mellitus.

Takaki Tadashi T Shimoda Masayuki M

Global health & medicine 20200801 4

Since the late 20th century, advances in pancreatic islet transplantation have targeted improved glycemic control and fewer hypoglycemic events in patients with type 1 diabetes, and some important milestones have been reached. Following the Edmonton group's success in achieving insulin independence in all transplanted patients with type 1 diabetes, clinical islet transplantation is now performed worldwide. β cell replacement therapy for type 1 diabetes was established based on the favorable outc ...[more]

PMID: 33330809

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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.

Project description:BackgroundType 1 diabetes mellitus (T1D) is characterized by the autoimmune destruction of the pancreatic β cells. The transplantation of mesenchymal stromal/stem cells (MSC) was reported to rescue the damaged pancreatic niche. However, there is an ongoing discussion on whether direct physical contact between MSC and pancreatic islets results in a superior outcome as opposed to indirect effects of soluble factors released from the MSC entrapped in the lung microvasculature after systemic administration. Hence, MSC were studied in direct contact (DC) and indirect contact (IDC) with murine pancreatic β cell line MIN6-cells damaged by nitrosourea derivative streptozotocin (STZ) in vitro. Further, the protective and antidiabetic outcome of MSC transplantation was evaluated through the intrapancreatic route (IPR) and intravenous route (IVR) in STZ-induced diabetic NMRI nude mice.MethodsMSC were investigated in culture with STZ-damaged MIN6-cells, either under direct contact (DC) or separated through a semi-permeable membrane (IDC). Moreover, multiple low doses of STZ were administered to NMRI nude mice for the induction of hyperglycemia. 0.5 × 106 adipose-derived mesenchymal stem cells (ADMSC) were transferred through direct injection into the pancreas (IPR) or the tail vein (IVR), respectively. Bromodeoxyuridine (BrdU) was injected for the detection of proliferating islet cells in vivo, and real-time polymerase chain reaction (RT-PCR) was employed for the measurement of the expression of growth factor and immunomodulatory genes in the murine pancreas and human MSC. Phosphorylation of AKT and ERK was analyzed with Western blotting.ResultsThe administration of MSC through IPR ameliorated hyperglycemia in contrast to IVR, STZ, and non-diabetic control in a 30-day window. IPR resulted in a higher number of replicating islet cells, number of islets, islet area, growth factor (EGF), and balancing of the Th1/Th2 response in vivo. Physical contact also provided a superior protection to MIN6-cells from STZ through the AKT and ERK pathway in vitro in comparison with IDC.ConclusionOur study suggests that the physical contact between MSC and pancreatic islet cells is required to fully unfold their protective potential.

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Pancreatic islet transplantation: toward definitive treatment for diabetes mellitus.

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Pancreatic islet transplantation: toward definitive treatment for diabetes mellitus.

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