RESUMO
Despite numerous developed drugs based on glucose metabolism interventions for treatment of age-related diseases such as diabetes neuropathies (DNs), DNs are still increasing in patients with type 1 or type 2 diabetes (T1D, T2D). We aimed to identify novel candidates in adipose tissue (AT) and pancreas with T2D for targeting to develop new drugs for DNs therapy. AT-T2D displayed 15 (e.g. SYT4 up-regulated and VGF down-regulated) and pancreas-T2D showed 10 (e.g. BAG3 up-regulated, VAV3 and APOA1 down-regulated) highly differentially expressed genes with neuronal functions as compared to control tissues. ELISA was blindly performed to measure proteins of 5 most differentially expressed genes in 41 human subjects. SYT4 protein was upregulated, VAV3 and APOA1 were down-regulated, and BAG3 remained unchanged in 1- Obese and 2- Obese-T2D without insulin, VGF protein was higher in these two groups as well as in group 3- Obese-T2D receiving insulin than 4-lean subjects. Interaction networks analysis of these 5 genes showed several metabolic pathways (e.g. lipid metabolism and insulin signaling). Pancreas is a novel site for APOA1 synthesis. VGF is synthesized in AT and could be considered as good diagnostic, and even prognostic, marker for age-induced diseases obesity and T2D. This study provides new targets for rational drugs development for the therapy of age-related DNs.
Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Regulação da Expressão Gênica/genética , Neurônios/metabolismo , Obesidade/fisiopatologia , Proteínas Adaptadoras de Transdução de Sinal/sangue , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Tecido Adiposo/metabolismo , Adulto , Idoso , Análise de Variância , Apolipoproteína A-I/sangue , Apolipoproteína A-I/genética , Apolipoproteína A-I/metabolismo , Proteínas Reguladoras de Apoptose/sangue , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ensaio de Imunoadsorção Enzimática , Feminino , Perfilação da Expressão Gênica , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fatores de Crescimento Neural/sangue , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/metabolismo , Pâncreas/metabolismo , Proteínas Proto-Oncogênicas c-vav/sangue , Proteínas Proto-Oncogênicas c-vav/genética , Proteínas Proto-Oncogênicas c-vav/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sinaptotagminas/sangue , Sinaptotagminas/genética , Sinaptotagminas/metabolismoRESUMO
Lipid droplets (LDs) hypertrophy in adipocytes is the main cause of energy metabolic system dysfunction, obesity and its afflictions such as T2D. However, the role of adipocytes in linking energy metabolic disorders with insulin regulation is unknown in humans. Human adipocytes constitutively synthesize and secrete insulin, which is biologically functional. Insulin concentrations and release are fat mass- and LDs-dependent respectively. Fat reduction mediated by bariatric surgery repairs obesity-associated T2D. The expression of genes, like PCSK1 (proinsulin conversion enzyme), GCG (Glucagon), GPLD1, CD38 and NNAT, involved in insulin regulation/release were differentially expressed in pancreas and adipose tissue (AT). INS (insulin) and GCG expression reduced in human AT-T2D as compared to AT-control, but remained unchanged in pancreas in either state. Insulin levels (mRNA/protein) were higher in AT derived from prediabetes BB rats with destructed pancreatic ß-cells and controls than pancreas derived from the same rats respectively. Insulin expression in 10 human primary cell types including adipocytes and macrophages is an evidence for extrapancreatic insulin-producing cells. The data suggest a crosstalk between AT and pancreas to fine-tune energy metabolic system or may minimize the metabolic damage during diabetes. This study opens new avenues towards T2D therapy with a great impact on public health.
Assuntos
Adipócitos/metabolismo , Insulina/metabolismo , Gotículas Lipídicas/metabolismo , Adipócitos/citologia , Adipócitos/patologia , Animais , Biomarcadores , Diferenciação Celular/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Perfilação da Expressão Gênica , Humanos , Insulina/genética , Gotículas Lipídicas/patologia , Transporte Proteico , RNA Mensageiro/genética , RatosRESUMO
The coagulation/fibrinolysis system is essential for wound healing after vascular injury. According to the standard paradigm, the synthesis of most coagulation factors is restricted to liver, platelets and endothelium. We challenged this interpretation by measuring coagulation factors in nine human primary cell types. FX mRNA was expressed by fibroblasts, visceral preadipocytes/adipocytes and hepatocytes, but not in macrophages or other cells. All cells expressed FVIII except endothelial cells. Fibroblasts, endothelial cells and macrophages produced thrombomodulin but not FV. Interestingly, vascular-related cells (platelets/monocytes) that expressed FV did not express FX and vice versa. Monocytes expressed FV, FVIII and FXIIIA, which are positive regulators of clot formation, but these cells also contained thrombomodulin, a negative regulator of coagulation. Our data show that the expression of coagulation factors is much more complex than previously thought, and we speculate that this intricate regulation of coagulation factor expression is necessary for correct fine-tuning of fibrinogenesis versus fibrinolysis.