RESUMO
Type 1 diabetes mellitus (T1D) is a chronic disease with potentially severe complications, and ß-cell deficiency underlies this disease. Despite active research, no therapy to date has been able to induce ß-cell regeneration in humans. Here, we discover the ß-cell regenerative effects of glucagon receptor antibody (anti-GcgR). Treatment with anti-GcgR in mouse models of ß-cell deficiency leads to reversal of hyperglycemia, increase in plasma insulin levels, and restoration of ß-cell mass. We demonstrate that both ß-cell proliferation and α- to ß-cell transdifferentiation contribute to anti-GcgR-induced ß-cell regeneration. Interestingly, anti-GcgR-induced α-cell hyperplasia can be uncoupled from ß-cell regeneration after antibody clearance from the body. Importantly, we are able to show that anti-GcgR-induced ß-cell regeneration is also observed in non-human primates. Furthermore, anti-GcgR and anti-CD3 combination therapy reverses diabetes and increases ß-cell mass in a mouse model of autoimmune diabetes.
Assuntos
Diabetes Mellitus Tipo 1 , Células Secretoras de Glucagon , Hiperglicemia , Células Secretoras de Insulina , Animais , Modelos Animais de Doenças , Glucagon , Hiperglicemia/tratamento farmacológico , Camundongos , Receptores de GlucagonRESUMO
A Correction to this paper has been published: https://doi.org/10.1038/s42255-021-00397-5.
RESUMO
Colchicine has served as a traditional medicine for millennia and remains widely used to treat inflammatory and other disorders. Colchicine binds tubulin and depolymerizes microtubules, but it remains unclear how this mechanism blocks myeloid cell recruitment to inflamed tissues. Here we show that colchicine inhibits myeloid cell activation via an indirect mechanism involving the release of hepatokines. We find that a safe dose of colchicine depolymerizes microtubules selectively in hepatocytes but not in circulating myeloid cells. Mechanistically, colchicine triggers Nrf2 activation in hepatocytes, leading to secretion of anti-inflammatory hepatokines, including growth differentiation factor 15 (GDF15). Nrf2 and GDF15 are required for the anti-inflammatory action of colchicine in vivo. Plasma from colchicine-treated mice inhibits inflammatory signalling in myeloid cells in a GDF15-dependent manner, by positive regulation of SHP-1 (PTPN6) phosphatase, although the precise molecular identities of colchicine-induced GDF15 and its receptor require further characterization. Our work shows that the efficacy and safety of colchicine depend on its selective action on hepatocytes, and reveals a new axis of liver-myeloid cell communication. Plasma GDF15 levels and myeloid cell SHP-1 activity may be useful pharmacodynamic biomarkers of colchicine action.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Colchicina/farmacologia , Citocinas/fisiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Células Mieloides/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacocinética , Antioxidantes/farmacologia , Colchicina/farmacocinética , Simulação por Computador , Citocinas/biossíntese , Fator 15 de Diferenciação de Crescimento/genética , Hepatócitos/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Peritonite/induzido quimicamente , Peritonite/prevenção & controle , Proteína Tirosina Fosfatase não Receptora Tipo 6/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
A series of substituted benzofuropyrimidinones with pan-PIM activities and excellent selectivity against a panel of diverse kinases is described. Initial exploration identified aryl benzofuropyrimidinones that were potent, but had cell permeability limitation. Using X-ray crystal structures of the bound PIM-1 complexes with 3, 5m, and 6d, we were able to guide the SAR and identify the alkyl benzofuropyrimidinone (6l) with good PIM potencies, permeability, and oral exposure.