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Dynamic pathology of islet endocrine cells in type 2 diabetes: β-Cell growth, death, regeneration and their clinical implications.

ABSTRACT: Diabetes is defined as a disease of hyperglycemic metabolic disorder caused by impaired insulin action or low insulin secretion, resulting in the occurrence of vascular complications. Based on this definition, diabetes therapy has long been oriented to correct hyperglycemia against the specific complications of diabetes. This definition has posed some difficulties, however, in understanding of the pathophysiology of this complicated disease and as such in the establishment of an effective treatment. With continuing efforts to explore the structural basis for diabetes onset and methodological development of immunohistochemistry, progressive decline of β-cells is now established as a salient feature of type 2 diabetes. Accordingly, diabetes therapy has now turned out to protect β-cells concurrently with the correction of hyperglycemia. Together with this effort, exploration of the means to regenerate β-cells or to supply new β-cells by, for example, induced pluripotential stem cells, are vigorously made with the search for the mechanism of β-cell decline in diabetes. In the present review, we describe the advances in the islet pathology in type 2 diabetes with special reference to the dynamic alterations of islet endocrine cells in the milieu of maturation, obesity, aging and ethnic differences. The effect of amyloid deposition is also discussed. We hope it will help with understanding the pathophysiology of diabetes, and suggest the future direction of diabetes treatment.

SUBMITTER: Yagihashi S

PROVIDER: S-EPMC4773678 | biostudies-other | 2016 Mar

REPOSITORIES: biostudies-other

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Project description:BackgroundInability to control autoimmunity is the primary barrier to developing a cure for type 1 diabetes (T1D). Evidence that human cord blood-derived multipotent stem cells (CB-SCs) can control autoimmune responses by altering regulatory T cells (Tregs) and human islet β cell-specific T cell clones offers promise for a new approach to overcome the autoimmunity underlying T1D.MethodsWe developed a procedure for Stem Cell Educator therapy in which a patient's blood is circulated through a closed-loop system that separates lymphocytes from the whole blood and briefly co-cultures them with adherent CB-SCs before returning them to the patient's circulation. In an open-label, phase1/phase 2 study, patients (n=15) with T1D received one treatment with the Stem Cell Educator. Median age was 29 years (range: 15 to 41), and median diabetic history was 8 years (range: 1 to 21).ResultsStem Cell Educator therapy was well tolerated in all participants with minimal pain from two venipunctures and no adverse events. Stem Cell Educator therapy can markedly improve C-peptide levels, reduce the median glycated hemoglobin A1C (HbA1C) values, and decrease the median daily dose of insulin in patients with some residual β cell function (n=6) and patients with no residual pancreatic islet β cell function (n=6). Treatment also produced an increase in basal and glucose-stimulated C-peptide levels through 40 weeks. However, participants in the Control Group (n=3) did not exhibit significant change at any follow-up. Individuals who received Stem Cell Educator therapy exhibited increased expression of co-stimulating molecules (specifically, CD28 and ICOS), increases in the number of CD4+CD25+Foxp3+ Tregs, and restoration of Th1/Th2/Th3 cytokine balance.ConclusionsStem Cell Educator therapy is safe, and in individuals with moderate or severe T1D, a single treatment produces lasting improvement in metabolic control. Initial results indicate Stem Cell Educator therapy reverses autoimmunity and promotes regeneration of islet β cells. Successful immune modulation by CB-SCs and the resulting clinical improvement in patient status may have important implications for other autoimmune and inflammation-related diseases without the safety and ethical concerns associated with conventional stem cell-based approaches.Trial registrationClinicalTrials.gov number, NCT01350219.

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Dynamic pathology of islet endocrine cells in type 2 diabetes: β-Cell growth, death, regeneration and their clinical implications.

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