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1.
Diabetes ; 69(8): 1692-1707, 2020 08.
Article in English | MEDLINE | ID: mdl-32381645

ABSTRACT

A failure in self-tolerance leads to autoimmune destruction of pancreatic ß-cells and type 1 diabetes (T1D). Low-molecular-weight dextran sulfate (DS) is a sulfated semisynthetic polysaccharide with demonstrated cytoprotective and immunomodulatory properties in vitro. However, whether DS can protect pancreatic ß-cells, reduce autoimmunity, and ameliorate T1D is unknown. In this study, we report that DS, but not dextran, protects human ß-cells against cytokine-mediated cytotoxicity in vitro. DS also protects mitochondrial function and glucose-stimulated insulin secretion and reduces chemokine expression in human islets in a proinflammatory environment. Interestingly, daily treatment with DS significantly reduces diabetes incidence in prediabetic NOD mice and, most importantly, reverses diabetes in early-onset diabetic NOD mice. DS decreases ß-cell death, enhances islet heparan sulfate (HS)/HS proteoglycan expression, and preserves ß-cell mass and plasma insulin in these mice. DS administration also increases the expression of the inhibitory costimulatory molecule programmed death-1 (PD-1) in T cells, reduces interferon-γ+CD4+ and CD8+ T cells, and enhances the number of FoxP3+ cells. Collectively, these studies demonstrate that the action of one single molecule, DS, on ß-cell protection, extracellular matrix preservation, and immunomodulation can reverse diabetes in NOD mice, highlighting its therapeutic potential for the treatment of T1D.


Subject(s)
Autoimmunity/drug effects , Dextran Sulfate/therapeutic use , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/metabolism , Insulin-Secreting Cells/drug effects , Animals , Blotting, Western , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , Chemokines/metabolism , Flow Cytometry , Forkhead Transcription Factors/metabolism , Glutathione/metabolism , Glutathione Disulfide/metabolism , Heparan Sulfate Proteoglycans/metabolism , Humans , Immunohistochemistry , Insulin-Secreting Cells/metabolism , Mice , Nitrogen Oxides/metabolism , Reactive Oxygen Species/metabolism , Real-Time Polymerase Chain Reaction , T-Lymphocytes/metabolism
2.
J Med Chem ; 63(6): 2986-3003, 2020 03 26.
Article in English | MEDLINE | ID: mdl-32003560

ABSTRACT

Recently, our group identified that harmine is able to induce ß-cell proliferation both in vitro and in vivo, mediated via the DYRK1A-NFAT pathway. Since, harmine suffers from a lack of selectivity, both against other kinases and CNS off-targets, we therefore sought to expand structure-activity relationships for harmine's DYRK1A activity, to enhance selectivity for off-targets while retaining human ß-cell proliferation activity. We carried out optimization of the 9-N-position of harmine to synthesize 29 harmine-based analogs. Several novel inhibitors showed excellent DYRK1A inhibition and human ß-cell proliferation capability. An optimized DYRK1A inhibitor, 2-2c, was identified as a novel, efficacious in vivo lead candidate. 2-2c also demonstrates improved selectivity for kinases and CNS off-targets, as well as in vivo efficacy for ß-cell proliferation and regeneration at lower doses than harmine. Collectively, these findings demonstrate that 2-2c is a much improved in vivo lead candidate as compared to harmine for the treatment of diabetes.


Subject(s)
Harmine/analogs & derivatives , Harmine/pharmacology , Insulin-Secreting Cells/drug effects , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Cell Proliferation/drug effects , Cells, Cultured , Harmine/chemical synthesis , Humans , Insulin-Secreting Cells/cytology , Insulin-Secreting Cells/metabolism , Male , Mice, Inbred C57BL , Molecular Docking Simulation , Nervous System/drug effects , Nervous System/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/metabolism , Rats, Wistar , Dyrk Kinases
3.
Sci Transl Med ; 12(530)2020 02 12.
Article in English | MEDLINE | ID: mdl-32051230

ABSTRACT

Glucagon-like peptide-1 receptor (GLP1R) agonists and dipeptidyl peptidase 4 inhibitors are widely prescribed diabetes drugs due to their ability to stimulate insulin secretion from remaining ß cells and to reduce caloric intake. Unfortunately, they fail to increase human ß cell proliferation. Small-molecule inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) are able to induce adult human ß cell proliferation, but rates are modest (~2%), and their specificity to ß cells is limited. Here, we provide evidence that combining any member of the GLP1R agonist class with any member of the DYRK1A inhibitor class induces a synergistic increase in human ß cell replication (5 to 6%) accompanied by an actual increase in numbers of human ß cells. GLP1R agonist-DYRK1A inhibitor synergy required combined inhibition of DYRK1A and an increase in cAMP and did not lead to ß cell dedifferentiation. These beneficial effects on proliferation were seen in both normal human ß cells and ß cells derived from individuals with type 2 diabetes. The ability of the GLP1R agonist-DYRK1A inhibitor combination to enhance human ß cell proliferation, human insulin secretion, and blood glucose control extended in vivo to studies of human islets transplanted into euglycemic and streptozotocin-diabetic immunodeficient mice. No adverse events were observed in the mouse studies during a 1-week period. Because of the relative ß cell specificity of GLP1R agonists, the combination provides an improved, although not complete, degree of human ß cell specificity.


Subject(s)
Diabetes Mellitus, Type 2 , Glucagon-Like Peptide-1 Receptor/agonists , Insulin-Secreting Cells , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Adult , Animals , Humans , Mice , Regeneration , Dyrk Kinases
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