RESUMO
BACKGROUND: Proliferative diabetic retinopathy (PDR), a sight-threatening retinopathy, is the leading cause of irreversible blindness in adults. Despite strict control of systemic risk factors, a fraction of patients with diabetes develop PDR, suggesting the existence of other potential pathogenic factors underlying PDR. This study aimed to investigate the plasma metabotype of patients with PDR and to identify novel metabolite markers for PDR. Biomarkers identified from this study will provide scientific insight and new strategies for the early diagnosis and intervention of diabetic retinopathy. METHODS: A total of 1024 patients with type 2 diabetes were screened. To match clinical parameters between case and control subjects, patients with PDR (PDR, n = 21) or those with a duration of diabetes of ≥10 years but without diabetic retinopathy (NDR, n = 21) were assigned to the present case-control study. Distinct metabolite profiles of serum were examined using liquid chromatography-mass spectrometry (LC-MS). RESULTS: The distinct metabolites between PDR and NDR groups were significantly enriched in 9 KEGG pathways (P < 0.05, impact > 0.1), namely, alanine, aspartate and glutamate metabolism, caffeine metabolism, beta-alanine metabolism, purine metabolism, cysteine and methionine metabolism, sulfur metabolism, sphingosine metabolism, and arginine and proline metabolism. A total of 63 altered metabolites played important roles in these pathways. Finally, 4 metabolites were selected as candidate biomarkers for PDR, namely, fumaric acid, uridine, acetic acid, and cytidine. The area under the curve for these biomarkers were 0.96, 0.95, 1.0, and 0.95, respectively. CONCLUSIONS: This study suggested that impairment in the metabolism of pyrimidines, arginine and proline were identified as metabolic dysregulation associated with PDR. And fumaric acid, uridine, acetic acid, and cytidine might be potential biomarkers for PDR. Fumaric acid was firstly reported as a novel metabolite marker with no prior reports of association with diabetes or diabetic retinopathy, which might provide insights into potential new pathogenic pathways for diabetic retinopathy.
RESUMO
Glucose-stimulated insulin secretion from islet ß cells is mediated by KATP channels. However, the role of non-KATP K+ channels in insulin secretion is largely unknown. Here, we show that a non-KATP K+ channel, KCNH6, plays a key role in insulin secretion and glucose hemostasis in humans and mice. KCNH6 p.P235L heterozygous mutation co-separated with diabetes in a four-generation pedigree. Kcnh6 knockout (KO) or Kcnh6 p.P235L knockin (KI) mice had a phenotype characterized by changing from hypoglycemia with hyperinsulinemia to hyperglycemia with insulin deficiency. Islets from the young KO mice had increased intracellular calcium concentration and increased insulin secretion. However, islets from the adult KO mice not only had increased intracellular calcium levels but also had remarkable ER stress and apoptosis, associated with loss of ß cell mass and decreased insulin secretion. Therefore, dysfunction of KCNH6 causes overstimulation of insulin secretion in the short term and ß cell failure in the long term.
Assuntos
Diabetes Mellitus/patologia , Canais de Potássio Éter-A-Go-Go/metabolismo , Hiperinsulinismo/patologia , Secreção de Insulina , Potenciais de Ação , Adolescente , Adulto , Animais , Sequência de Bases , Diabetes Mellitus/genética , Canais de Potássio Éter-A-Go-Go/genética , Feminino , Genes Dominantes , Células HEK293 , Humanos , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Ativação do Canal Iônico , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/genética , Linhagem , Adulto JovemRESUMO
Heme oxygenase (HO) represents an intrinsic antiinflammatory system based on its ability to inhibit expression of proinflammatory cytokines. The constitutive isoform heme oxygenase-2 (HO-2) has high expression and activity in cerebral microvascular endothelial cells (CMVEC). This study was undertaken to evaluate the role of HO-2 in regulation of TLR4/MyD88-dependent signaling and to study the effect of HO-2 on the expression and secretion of the proinflammatory cytokines tumor necrosis factor α (TNF-α) and Interleukin-6 (IL6) in CMVEC. HO-2 short hairpin RNA (shRNA) and HO-2 overexpression plasmids were used to observe the effect of HO-2 on proinflammatory cytokines in CMVEC in vitro, and the results showed that the messenger RNA (mRNA) and protein levels of TNF-α and IL6 were increased and decreased, respectively, compared with control groups. LPS-stimulated TNF-α and IL6 mRNA and protein were also reduced in CMVEC treated with an inhibitor of TLR4 signaling, CLI-095, or HO-2 overexpression. CLI-095 and HO-2 overexpression both reduced TLR4 expression in CMVEC, and HO-2 shRNA blocked these effects of CLI-095. CLI-095 and HO-2 overexpression potently suppressed TLR4/MyD88-dependent proinflammatory cytokine expression in CMVEC. These results suggest that HO-2 plays an important role in protecting CMVEC against cytokine-mediated inflammation.
Assuntos
Células Endoteliais/metabolismo , Endotélio Vascular/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Interleucina-6/metabolismo , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/genética , Interleucina-6/genética , Lipopolissacarídeos/farmacologia , Camundongos , RNA Interferente Pequeno , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Fator de Necrose Tumoral alfa/genéticaRESUMO
Overexpression of calbindin-D(28k) (CaBP-28 k) induces neurite outgrowth in dopaminergic neuronal cells and could provide some protection to dopaminergic neurons against the pathological process in Parkinson's disease. Transgenic mice CaBP-28 k overexpression and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse models were generated, and the effect of midbrain dopamine neurons in ethology was also assessed. Tyrosine hydroxylase (TH)-immunoreactive neurons were counted, and the concentration of total protein and dopamine (DA) of striatum corpora was measured in four animal models. Results showed that the positive TH cells, content of DA, and ability of ethology in MPTP-induced transgenic mice were significantly higher than that in MPTP-induced wild-type mice. The findings demonstrate that overexpression of CaBP-28 k could provide protection for DA neurons from neurodegeneration. It would provide a potential strategy in the treatment of Parkinson's diseases.
Assuntos
Fármacos Neuroprotetores/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Proteína G de Ligação ao Cálcio S100/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Comportamento Animal , Western Blotting , Calbindinas , Caspase 3/metabolismo , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Doença de Parkinson/enzimologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Substância Negra/enzimologia , Substância Negra/metabolismo , Substância Negra/patologia , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
OBJECTIVE: To investigate the changes of bone mineral density(BMD) and the relationship of BMD to serum Insulin-like growth factor-1 concentrations, body mass index (BMI), waist hip ratio (WHR), estradiol (E2), testosterone (T), biochemical markers of bone turnover as well as other factors in the elderly individuals with Type 2 diabetes mellitus (T2DM). METHODS: BMDs of spine were measured by quantitative CT for patients with T2DM (n=53) and health controls (n=40). The relationships of BMD related to serum Insulin-like growth factor-1 concentrations, BMI, WHR, E2, T, bone Gla'protein, bone alkaline phosphatase, tartrate resistant acid phosphatase 5b levels were also analyzed. RESULTS: The spine BMD values for the T2DM patients were significantly reduced when compared with controls [(74.75 +/- 22.70) mg/cc vs. (88.04 +/- 28.29) mg/cc, P < 0.05], and the concentration of serum Insulin-like growth factor-1 in T2DM group was significantly lower than that in control [(27.63 +/- 5.74) ng/mL vs. (32.51 +/- 9.68) ng/mL, P < 0.05]. The level of serum Insulin-like growth factor-1 was positive correlation to bone-specific alkaline phosphatase (B-ALP) in the T2DM patients (r = 0.46, P < 0.01). CONCLUSION: The spine BMD in elderly T2DM patients is lower than that in control group. The circulating serum Insulin-like growth factor-1 does not have a significant influence on bone mass in elderly T2DM patients.