RESUMEN
The fat-derived factor, adiponectin, is considered a salutary circulating factor. We recently demonstrated that native adiponectin binds T-cadherin and promotes intracellular biogenesis and secretion of the exosome. Exosomes play important roles in various aspects of homeostasis, including glucose and energy metabolism. However, it remains unclear whether and how the promotion of exosome production by adiponectin in vivo is beneficial for glucose and lipid metabolism. In the present study, overexpression of human adiponectin in mice resulted in an increased number of circulating exosomes, but it did not significantly improve glucose metabolism, change body weights, or change triglyceride clearance under a high-fat diet. Multiple small doses of streptozotocin increased blood glucose and decreased triglyceride clearance similarly in both wild-type and transgenic mice. Thus, these results indicated that human adiponectin overexpression in mice increases plasma exosomes but does not significantly influence glucose and lipid metabolism.
Asunto(s)
Exosomas , Glucosa , Ratones , Animales , Humanos , Glucosa/metabolismo , Metabolismo de los Lípidos/genética , Adiponectina/genética , Exosomas/genética , Exosomas/metabolismo , Ratones Transgénicos , Triglicéridos/metabolismoRESUMEN
Previously, we have shown that the adipocyte-specific nuclear form of sterol regulatory element-binding protein-1c (nSREBP-1c) transgenic mice spontaneously developed hepatic lesions that are similar to those of human nonalcoholic steatohepatitis (NASH) with a concomitant elevation of plasma TNF-α. In this study, we analyzed the role of TNF-α in the progression of nonalcoholic fatty liver disease (NAFLD). We established a Tnf knockout nSREBP-1c transgenic mouse line. Glucose tolerance and liver histology were examined at the age of 20 weeks. The gene expression and protein levels were assessed by quantitative RT-PCR and Western blot, respectively. The Tnf knockout improved glucose tolerance and significantly reduced the prevalence of hepatic steatosis (20% vs. 100%, p<0.0001) and fibrosis (15% vs. 65%, p=0.0057). The expressions of Acaca, Scd1, Mcp1, Tgfb1, Col1a1, and Timp1 were increased in the liver from the original nSREBP-1c transgenic mice. However, gene upregulation was reduced in the livers from the Tnf(-/-) nSREBP-1c transgenic mice. Furthermore, the hepatic levels of TIMP1 protein were increased in the original nSREBP-1c transgenic mice but not in Tnf(-/-) nSREBP-1c transgenic mice. To assess the direct effect of TNF-α on the expression of the genes, we cultured primary hepatocytes in the presence of TNF-α and found that TNF-α increased the expression of Mcp1, Tgfb1, and Timp1 in hepatocytes. These observations indicate that TNF-α plays a pivotal role in the development of NAFLD and progression to NASH through upregulating key molecules associated with lipid metabolism, inflammatory cytokines, and fibrosis in the liver.
Asunto(s)
Progresión de la Enfermedad , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Prueba de Tolerancia a la Glucosa , Hepatocitos/metabolismo , Inflamación/genética , Metabolismo de los Lípidos/genética , Cirrosis Hepática/genética , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Fenotipo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Factor de Necrosis Tumoral alfa/deficienciaRESUMEN
Background We aimed to determine whether the discrepancy between haemoglobin A1c values determined by high-performance liquid chromatography and enzymatic haemoglobin A1c measurements in diabetic patients was clinically relevant. Methods We randomly recruited 1421 outpatients undergoing diabetic treatment and follow-up who underwent at least three haemoglobin A1c measurements between April 2014 and March 2015 at our clinic. In 6369 samples, haemoglobin A1c was simultaneously measured by HA-8160 and MetaboLead (enzymatic assay), and the values were compared. Results haemoglobin A1c measurements by high-performance liquid chromatography and enzymatic assay were strongly correlated (correlation coefficient: 0.9828, linear approximation curve y = 0.9986x - 0.2507). Mean haemoglobin A1c (6.8 ± 1.0%) measured by high-performance liquid chromatography was significantly higher than that measured by enzymatic assay (6.5 ± 1.0%, P < 0.0001). During the sample processing, four (0.3%) subjects presented consistently lower haemoglobin A1c values (<0.7%) by high-performance liquid chromatography than those from enzymatic assay. Of these, three had Hb Toranomon [ß112 (G14) CysâTrp]. The fourth had Hb Ube-2 [α68 (E17) AsnâAsp]. One other subject presented consistently higher haemoglobin A1c values (>1%) by high-performance liquid chromatography than those from enzymatic assay and was diagnosed with a -77 (T > C) mutation in the δ-globin gene. These unrelated asymptomatic subjects had normal erythrocyte profiles, without anaemia. Conclusions We showed that haemoglobin A1c values measured by high-performance liquid chromatography were significantly higher than those measured by enzymatic assay in diabetic subjects. However, when an oversized deviation (>0.7%) between glycaemic control status and haemoglobin A1c is apparent, clinicians should check the methods used to measure haemoglobin A1c and consider the possible presence of a haemoglobin variant.
Asunto(s)
Artefactos , Diabetes Mellitus/diagnóstico , Hemoglobina Glucada/genética , Hemoglobinas Anormales/genética , gamma-Globinas/genética , Adulto , Anciano , Cromatografía Líquida de Alta Presión/estadística & datos numéricos , Diabetes Mellitus/sangre , Pruebas de Enzimas/estadística & datos numéricos , Femenino , Expresión Génica , Hemoglobina Glucada/análisis , Hemoglobinas Anormales/análisis , Humanos , Masculino , Persona de Mediana Edad , Mutación , Pacientes Ambulatorios , Control de Calidad , Sensibilidad y Especificidad , gamma-Globinas/análisisRESUMEN
Adiponectin (Adipoq), a peptide hormone secreted from the white adipose tissue, may play a role in the anti-aging and/or anti-tumor effects of calorie restriction (CR). We analyzed metabolic traits in Adipoq gene-overexpressing mice fed ad libitum with a regular diet (RD) or a high-fat diet (HFD), or fed 30% CR of RD initiated at 12 weeks of age. Adipoq-RD and -HFD mice at 6 months of age showed reduced blood glucose and insulin concentrations, and thus increased insulin sensitivity, compared with WT mice fed a RD or a HFD. In the epididymal white adipose tissue in Adipoq mice, senescence-like changes such as upregulation of p53 protein and of biomarkers of inflammation, Cd68 and Ccl2 mRNA, were ameliorated compared with WT-RD and WT-HFD mouse tissues. Resistance to stress induced by lipopolysaccharide was also strengthened in Adipoq mice compared with WT mice. These metabolic changes and stress resistance were also noted in the WT-CR mice, suggesting that Adipoq plays a part in the effect of CR. In contrast, in an allograft tumor growth model, tumor growth was not inhibited in Adipoq mice. The present findings suggest that Adipoq plays a part in the anti-aging, but not in the anti-tumor, effects of CR.
Asunto(s)
Adiponectina/metabolismo , Tejido Adiposo Blanco/metabolismo , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Restricción Calórica , Quimiocina CCL2/metabolismo , Adiponectina/genética , Animales , Antígenos CD/genética , Antígenos de Diferenciación Mielomonocítica/genética , Biomarcadores , Quimiocina CCL2/genética , Dieta Alta en Grasa , Femenino , Expresión Génica , Insulina/sangre , Resistencia a la Insulina , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
BACKGROUND: Adiponectin-transgenic mice had many small adipocytes in both subcutaneous and visceral adipose tissues, and showed higher sensitivity to insulin, longer life span, and reduced chronic inflammation. We hypothesized that adiponectin regulates Wnt signaling in adipocytes and thereby modulates adipocyte proliferation and chronic inflammation in adipose tissue. MATERIALS AND METHODS: We examined the expression of all Wnt ligands and their receptors and the activity of Wnt signaling pathways in visceral adipose tissue from wild-type mice and two lines of adiponectin-transgenic mice. The effects of adiponectin were also investigated in cultured 3T3-L1 cells. RESULTS: The Wnt5b, Wnt6, Frizzled 6 (Fzd6), and Fzd9 genes were up-regulated in both lines of transgenic mice, whereas Wnt1, Wnt2, Wnt5a, Wnt9b, Wnt10b, Wnt11, Fzd1, Fzd2, Fzd4, Fzd7, and the Fzd coreceptor low-density-lipoprotein receptor-related protein 6 (Lrp6) were reduced. There was no difference in total ß-catenin levels in whole-cell extracts, non-phospho-ß-catenin levels in nuclear extracts, or mRNA levels of ß-catenin target genes, indicating that hyperadiponectinemia did not affect canonical Wnt signaling. In contrast, phosphorylated calcium/calmodulin-dependent kinase II (p-CaMKII) and phosphorylated Jun N-terminal kinase (p-JNK) were markedly reduced in adipose tissue from the transgenic mice. The adipose tissue of the transgenic mice consisted of many small cells and had increased expression of adiponectin, whereas cyclooxygenase-2 expression was reduced. Wnt5b expression was elevated in preadipocytes of the transgenic mice and decreased in diet-induced obese mice, suggesting a role in adipocyte differentiation. Some Wnt genes, Fzd genes, and p-CaMKII protein were down-regulated in 3T3-L1 cells cultured with a high concentration of adiponectin. CONCLUSION: Chronic hyperadiponectinemia selectively modulated the expression of Wnt ligands, Fzd receptors and LRP coreceptors accompanied by the inhibition of the Wnt/Ca(2+) and JNK signaling pathways, which may be involved in the altered adipocyte cellularity, endogenous adiponectin production, and anti-inflammatory action induced by hyperadiponectinemia.
Asunto(s)
Adiponectina/genética , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Receptores Frizzled/genética , Receptores de Lipoproteína/genética , Proteínas Wnt/genética , Células 3T3-L1 , Adiponectina/metabolismo , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Diferenciación Celular , Receptores Frizzled/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Ligandos , Masculino , Ratones , Ratones Transgénicos , Receptores de Lipoproteína/metabolismo , Transducción de Señal , Proteínas Wnt/metabolismoRESUMEN
To assess the effect of adiponectin on the circadian rhythm disturbances associated with metabolic syndrome, we generated a KK/Ta mouse line expressing the human adiponectin transgene in the liver. Locomotor activity of control C57BL/6 mice was highest during the beginning of the dark period and low during the light period. Under constant darkness, the length of locomotor activity rhythm of control mice was slightly shorter than 24 h. In KK/Ta mice the peak of locomotor activity was blunted and significant activity was observed during the light period. Furthermore, KK/Ta mice showed shorter average period length of free-running locomotor activity rhythm when compared with control mice. However, the transgenic expression of adiponectin in the liver significantly altered the circadian rhythm of locomotor activity and the length of free-running rhythm of KK/Ta mice towards those of C57BL/6 mice. In the liver and skeletal muscles from control mice, mRNA levels of Arntl and Cry1 were increased during the dark period, whereas those of Dbp, Cry2, Per1 and Per2 were elevated during the light period. KK/Ta mice exhibited phase advances in circadian rhythms of Arntl, Dbp, Cry2 and Per2 in both tissues. The phase shifts of the circadian clock gene expression in the liver were attenuated in adiponectin-transgenic mice. These results suggest that adiponectin is a peripheral regulator of the circadian clocks in the brain and peripheral organs, and may be a novel target for the treatment of obesity-associated disorders of circadian rhythms.
Asunto(s)
Adiponectina/metabolismo , Relojes Circadianos , Péptidos y Proteínas de Señalización del Ritmo Circadiano/metabolismo , Hígado/metabolismo , Síndrome Metabólico/metabolismo , Adiponectina/biosíntesis , Adiponectina/genética , Animales , Péptidos y Proteínas de Señalización del Ritmo Circadiano/biosíntesis , Péptidos y Proteínas de Señalización del Ritmo Circadiano/genética , Cruzamientos Genéticos , Regulación hacia Abajo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Transgénicos , Actividad Motora , Músculo Esquelético/metabolismo , ARN Mensajero/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND: There is growing evidence that adiponectin, a physiologically active polypeptide secreted by adipocytes, controls not only adipose tissue but also bone metabolism. However, a role for adiponectin in bone development remains controversial. METHODS: We therefore investigated the endocrine effects of adiponectin on bone metabolism using 12-week-old male transgenic (Ad-Tg) mice with significant hyperadiponectinemia overexpressing human full-length adiponectin in the liver. RESULTS: In Ad-Tg mice, the serum level of osteocalcin was significantly increased, but the levels of RANKL, osteoprotegerin, and TRAP5b were not. Bone mass was significantly greater in Ad-Tg mice with increased bone formation. In contrast, bone resorption parameters including the number of osteoclasts and eroded surface area did not differ between Ad-Tg and their littermates. CONCLUSIONS: These findings demonstrate that hyperadiponectinemia enhances bone formation in mice.
Asunto(s)
Desarrollo Óseo/fisiología , Huesos/metabolismo , Adiponectina/genética , Adiponectina/fisiología , Animales , Huesos/citología , Humanos , Masculino , Ratones , Ratones TransgénicosRESUMEN
In this study, we examined whether adiponectin suppresses endoplasmic reticulum (ER) stress in nonalcoholic steatohepatitis (NASH) using male transgenic mice expressing nSREBP-1c in adipose tissue, nSREBP-1c/adiponectin double-transgenic mice expressing human adiponectin in the liver, and wild-type male mice as the control. Histological findings similar to those observed in liver specimens from patients with NASH were observed in the livers from the nSREBP-1c transgenic mice at 30 weeks of age. By contrast, the NASH-like liver histology was markedly attenuated in age-matched nSREBP-1c/adiponectin double-transgenic mice. The nSREBP-1c/adiponectin double-transgenic mice showed human adiponectin production in the liver and a restored circulating human adiponectin level. Human adiponectin messenger ribonucleic acid (mRNA) expression in the liver was identified in the nSREBP-1c/adiponectin double-transgenic mice, but adiponectin receptor 1 and 2 mRNA expression in the liver was normal. TNFα mRNA was decreased in the liver of the nSREBP-1c/adiponectin double-transgenic mice compared with the nSREBP-1c transgenic mice. The protein expressions of X-box-binding protein-1, activating transcription factor 4, acetyl-CoA carboxylase, TNFα and NFκB were down-regulated in liver tissues from the nSREBP-1c/adiponectin double-transgenic mice. Mouse adiponectin and activating transcription factor 6 expressions were almost the same in the three groups. Post-load plasma glucose levels were significantly lower in the nSREBP-1c/adiponectin double-transgenic mice compared with the nSREBP-1c transgenic mice. These results indicate that adiponectin expressed in the liver suppresses ER stress and attenuates hepatic steatosis, inflammation and insulin resistance in NASH. Adiponectin may open the way to novel therapies for human NASH.
RESUMEN
The aim of the study is to identify the clinical characteristics of Japanese patients with young-onset type 2 diabetes (YT2D). Family history of diabetes and clinical data were collected for 30 unrelated males (from 11 to 20 years old at age of onset) and 20 females (from 10 to 20 years old at age of onset) with YT2D diagnosed at ≤ 20 years of age. Fasting C-peptide levels were measured in all, and glucagon stimulation tests were performed twice in six of them over several years. Moreover, 858 people with type 2 diabetes (T2D) diagnosed at >20 years of age were randomly recruited in order to compare the transmission pattern of them. Among the study subjects, 68% reported at least one parent with diabetes. Diabetes was more frequent among mothers than fathers of probands (P = 0.020), although this tendency was not observed in T2D diagnosed at >20 years of age. Fasting C-peptide levels of patients with diabetes duration of ≥ 10 years were significantly lower than for patients with diabetes duration of <10 years (0.61 ± 0.26 vs. 0.84 ± 0.43 nmol/l, P = 0.036). The fasting C-peptide levels among male patients with a family history of diabetes were also significantly lower than those without a family history (0.56 ± 0.25 vs. 0.83 ± 0.37 nmol/l, P = 0.034), while all female subjects had a family history of diabetes. Glucagon stimulation tests showed the following data; 0 min: 0.56 ± 0.31 vs. 0.39 ± 0.22 nmol/l, 3 min: 1.41 ± 0.77 vs. 0.87 ± 0.47 nmol/l, 6 min: 1.37 ± 0.80 vs. 0.79 ± 0.35 nmol/l, 10 min: 1.06 ± 0.60 vs. 0.81 ± 0.49 nmol/l, and 30 min: 0.58 ± 0.30 vs. 0.50 ± 0.19 nmol/l, respectively. These results demonstrated that YT2D among Japanese people occurring in excess with maternal transmission is associated with ß-cell dysfunction at the onset of diabetes and as the disease advances.
Asunto(s)
Diabetes Mellitus Tipo 2/epidemiología , Insulina/metabolismo , Intercambio Materno-Fetal , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Péptido C/sangre , Niño , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Humanos , Secreción de Insulina , Japón/epidemiología , Masculino , Persona de Mediana Edad , Madres , Embarazo , Factores Sexuales , Adulto JovenRESUMEN
We have previously reported that transgenic mice expressing nuclear sterol regulatory element-binding protein 1c (nSREBP-1c) in adipose tissue under the control of aP2 promoter, an inherited lipodystrophic model with insulin resistance and fatty liver, developed with age liver lesions similar to those of human nonalcoholic steatohepatitis (NASH). Because the spontaneous NASH model mice had marked hypoadiponectinemia, here we assessed the effect of adiponectin transgenically expressed in the liver of nSREBP-1c transgenic mice. The nSREBP-1c/adiponectin double-transgenic mice showed hepatic adiponectin production and restored circulating adiponectin levels. Both subtypes of adiponectin receptors proved to be expressed normally in the liver. Peroxisome proliferator-activated receptor-alpha was up-regulated in the double-transgenic mice. Histologic findings similar to those observed in the liver specimens of patients with NASH were observed in the livers from nSREBP-1c transgenic mice at the age of 30 weeks. In contrast, the NASH-like hepatic lesions were obviously attenuated in age-matched double-transgenic mice. Immunoreactivity of 8-hydroxy-2'-deoxyguanosine and proliferating cell nuclear antigen-positive cells were increased in nSREBP-1c transgenic mice, but not in the double-transgenic mice. Postload plasma glucose levels were significantly lower in the double-transgenic mice compared with nSREBP-1c transgenic mice, whereas serum leptin levels did not differ significantly in the 2 groups. These observations suggest that hypoadiponectinemia plays a key role in the pathogenesis of NASH associated with insulin resistance and may provide a clue to the novel therapy for human NASH.
Asunto(s)
Hígado Graso/metabolismo , 8-Hidroxi-2'-Desoxicoguanosina , Adiponectina/biosíntesis , Adiponectina/sangre , Adiponectina/genética , Adiponectina/metabolismo , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Northern Blotting , Western Blotting , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Modelos Animales de Enfermedad , Hígado Graso/genética , Hígado Graso/patología , Femenino , Prueba de Tolerancia a la Glucosa , Histocitoquímica , Leptina/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , PPAR alfa/genética , PPAR alfa/metabolismo , Antígeno Nuclear de Célula en Proliferación/metabolismo , ARN/química , ARN/genética , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismoRESUMEN
We aimed to define the detailed clinical features of Japanese childhood-onset Type 2 diabetes mellitus (T2DM) patients who were followed-up, and to determine whether discernable characteristics were dissimilar or not from those of adult- and childhood-onset T2DM in other countries. Subjects were 22 patients (10 males and 12 females) under treatment without HNF-1alpha or mitochondrial gene mutations, and who were apparently diagnosed as diabetic when less than 15 years of age. Body mass indexes at onset in boys and girls were 25.8 +/- 6.3 and 24.7 +/- 3.6, respectively, with mean ages 13.3 +/- 1.7 and 12.8 +/- 2.0 years, respectively. Most patients had a short diabetic duration that required insulin treatment. One or both parents of 18 of the 22 T2DM subjects were diabetic and 7 subjects had a history of diabetes in their family across three generations. We demonstrated that a relatively large number of Japanese childhood-onset T2DM cases have a strong genetic factor, and are not necessarily related to excessive obesity. Furthermore, most required insulin therapy in the initial stages because of insufficient pancreatic beta-cell reserves. This suggests that malfunction of pancreatic beta-cells triggers hyperglycemia resulting in the requirement for insulin in Japanese some childhood-onset T2DM patients.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/fisiopatología , Adolescente , Adulto , Edad de Inicio , Índice de Masa Corporal , Péptido C/sangre , Niño , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Familia , Femenino , Humanos , Insulina/uso terapéutico , Células Secretoras de Insulina/metabolismo , Japón , MasculinoRESUMEN
Adiponectin, a physiologically active polypeptide secreted by adipocytes, shows insulin-sensitizing, anti-inflammatory, and antiatherogenic properties in rodents and humans. To assess the effects of chronic hyperadiponectinemia on metabolic phenotypes, we established three lines of transgenic mice expressing human adiponectin in the liver. When maintained on a high-fat/high-sucrose diet, mice of two lines that had persistent hyperadiponectinemia exhibited significantly decreased weight gain associated with less fat accumulation and smaller adipocytes in both visceral and subcutaneous adipose tissues. Macrophage infiltration in adipose tissue was markedly suppressed in the transgenic mice. Expression levels of adiponectin receptors were not altered in skeletal muscle or liver. Circulating levels of endogenous adiponectin were elevated, whereas fasting glucose, insulin, and leptin levels were reduced compared with control mice. In the hyperadiponectinemic mice daily food intake was not altered, but oxygen consumption was significantly greater, suggesting increased energy expenditure. Moreover, high-calorie diet-induced premature death was almost completely prevented in the hyperadiponectinemic mice in association with attenuated oxidative DNA damage. The transgenic mice also showed longer life span on a conventional low-fat chow. In conclusion, transgenic expression of human adiponectin blocked the excessive fat accumulation and reduced the morbidity and mortality in mice fed a high-calorie diet. These observations may provide new insights into the prevention and therapy of metabolic syndrome in humans.
Asunto(s)
Tejido Adiposo/crecimiento & desarrollo , Muerte , Dieta Aterogénica , 8-Hidroxi-2'-Desoxicoguanosina , Adipocitos Blancos/citología , Adiponectina/sangre , Adiponectina/genética , Animales , Distribución de la Grasa Corporal , Peso Corporal , Quimiotaxis de Leucocito , Desoxiguanosina/análogos & derivados , Desoxiguanosina/orina , Ingestión de Alimentos/genética , Femenino , Regulación de la Expresión Génica , Humanos , Longevidad/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Tamaño de los Órganos/genética , Consumo de Oxígeno/genéticaRESUMEN
Nonalcoholic steatohepatitis (NASH) is one of the life-threatening hepatic diseases associated with insulin resistance. Here we report that nuclear sterol regulatory element-binding protein 1c (nSREBP-1c) transgenic mice, an inherited lipodystrophic model with severe insulin resistance, spontaneously develop steatohepatitis. The animal had marked fatty liver accompanied by hyperglycemia, hypoleptinemia, and hypoadiponectinemia. Liver histology similar to NASH, that is, mononuclear cell infiltration, pericellular fibrosis, ballooning degeneration, and Mallory hyaline body formation were seen in the livers from transgenic mice 20 weeks or older. In contrast, no liver histologic abnormalities were noted in wild-type mice aged 30 weeks. Immunoreactive 8-hydroxy-2'-deoxyguanosine was observed in the nuclei of livers from transgenic mice, suggesting that in addition to insulin resistance, oxidative stress may be involved in the development of the NASH-like lesion. Thus, the nSREBP-1c transgenic mouse may serve as a unique model of spontaneously occurring NASH.
Asunto(s)
Tejido Adiposo/metabolismo , Núcleo Celular/metabolismo , Hígado Graso/metabolismo , Hígado/patología , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Animales , Secuencia de Bases , Cartilla de ADN , Prueba de Tolerancia a la Glucosa , Resistencia a la Insulina , Ratones , Ratones TransgénicosRESUMEN
To assess the mechanism of beta-cell lipotoxicity in comparison with Fas-mediated cell death, we used a mouse beta-cell clone stably transfected with human Fas. Palmitate induced beta-cell death in correlation with medium glucose levels between 5 and 20 mmol/l, while Fas-mediated cytotoxicity was observed irrespective of glucose concentration. At the glucose level of 10 mmol/l, palmitate induced caspase-6 activity within 3 h, and caspase-3 activity after a lag period of 6 h. The activities of caspases were correlated with glucose concentration. A caspase-6 inhibitor attenuated caspase-3 activation and cell death induced by palmitate. Oxfenicine, an inhibitor of carnitine palmitoyltransferase-1, attenuated both palmitate-induced cytotoxicity and activation of caspases. Finally, beta-cell cytotoxicity caused by the combination of anti-Fas and palmitate at 25 mmol/l of glucose was greater than the sum of those induced by each. These observations suggest that palmitate induces sequential activation of caspase-6 and caspase-3 through a mitochondrial signal(s), and caspase-6 plays a primary role in the mechanism. Fas-mediated beta-cell death and lipotoxicity may share common mechanisms involving caspase activation, and thereby synergistically inducing beta-cell death, although upstream signaling pathways are distinct.
Asunto(s)
Anticuerpos/farmacología , Caspasas/metabolismo , Activación Enzimática/efectos de los fármacos , Células Secretoras de Insulina/efectos de los fármacos , Palmitatos/toxicidad , Receptor fas/inmunología , Animales , Carnitina O-Palmitoiltransferasa/metabolismo , Caspasa 3 , Caspasa 6 , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Glicina/análogos & derivados , Glicina/farmacología , Humanos , Ratones , Receptor Cross-Talk/efectos de los fármacosRESUMEN
Graves' disease (GD) is an autoimmune disorder with genetic predisposition. Interferon-gamma (IFN-gamma) is an important mediator of inflammatory and immune responses. The aim of the present study was to investigate whether the polymorphism of IFN-gamma gene is associated with the development of GD or with clinical course during the antithyroid drug therapy. We have studied the CA repeat polymorphisms in the first intron of IFN gamma gene in Japanese patients with GD (n = 162) and healthy control subjects without antithyroid autoantibodies or family history of autoimmune disorders (n = 133). There was no difference in allele frequency of IFN-gamma gene polymorphism between patients with GD and control subjects. However, the allele 4 (15 CA repeats) frequency was significantly greater in patients whose antithyrotropin receptor antibody (TRAb) became negative within 3 years by antithyroid drug treatment than those with consistently positive TRAb for more than 3 years (34.1% vs. 15.7%, chi2 = 8.545, p = 0.0035, pc = 0.049). The in vitro production of IFN-gamma by concanavalin A-stimulated peripheral blood mononuclear cells was significantly smaller in control subjects with the allele 4 compared to those with the other alleles. In conclusions, the CA repeat polymorphism of the IFN-gamma gene might be associated with the outcome of anti-thyroid drug treatment.
Asunto(s)
Antitiroideos/uso terapéutico , Pueblo Asiatico , Autoanticuerpos/sangre , Enfermedad de Graves/tratamiento farmacológico , Interferón gamma/genética , Polimorfismo Genético , Receptores de Tirotropina/inmunología , Adenina , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Citosina , Repeticiones de Dinucleótido , Femenino , Frecuencia de los Genes , Enfermedad de Graves/inmunología , Enfermedad de Graves/fisiopatología , Humanos , Interferón gamma/biosíntesis , Intrones/genética , Masculino , Persona de Mediana EdadRESUMEN
The genetic background that predisposes the Japanese population to type 2 diabetes is largely unknown. Therefore, we conducted a 10-cM genome-wide scan for type 2 diabetes traits in the 359 affected individuals from 159 families, yielding 224 affected sib-pairs of Japanese origin. Nonparametric multipoint linkage analyses performed in the whole population showed one suggestive linked region on 11p13-p12 (maximum logarithm of odds score [MLS] 3.08, near Pax6) and seven potentially linked regions (MLS >1.17) at 1p36-p32, 2q34, 3q26-q28, 6p23, 7p22-p21, 15q13-q21, and 20q12-q13 (near the gene for hepatocyte nuclear factor-4alpha [HNF-4alpha]). Subset analyses according to maximal BMI and early age at diagnosis added suggestive evidence of linkage with type 2 diabetes at 7p22-p21 (MLS 3.51), 15q13-q21 (MLS 3.91), and 20q12-q13 (MLS 2.32). These results support previous indication for linkage found on chromosome 3q, 15q, and 20q in other populations and identifies two new potential loci on 7p and 11p that may confer genetic risk for type 2 diabetes in the Japanese population.
Asunto(s)
Cromosomas Humanos Par 15 , Cromosomas Humanos Par 20 , Cromosomas Humanos Par 3 , Proteínas de Unión al ADN , Diabetes Mellitus Tipo 2/genética , Genoma Humano , Adulto , Edad de Inicio , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Mapeo Cromosómico , Cromosomas Humanos Par 1 , Cromosomas Humanos Par 7 , Diabetes Mellitus Tipo 2/clasificación , Ligamiento Genético , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Factor Nuclear 4 del Hepatocito , Humanos , Japón , Persona de Mediana Edad , Núcleo Familiar , Fosfoproteínas/genética , Factores de Transcripción/genéticaRESUMEN
An adipocyte-derived peptide, adiponectin (also known as GBP28), is decreased in subjects with type 2 diabetes. Recent genome-wide scans have mapped a diabetes susceptibility locus to chromosome 3q27, where the adiponectin gene (APM1) is located. Herein, we present evidence of an association between frequent single nucleotide polymorphisms at positions 45 and 276 in the adiponectin gene and type 2 diabetes (P = 0.003 and P = 0.002, respectively). Subjects with the G/G genotype at position 45 or the G/G genotype at position 276 had a significantly increased risk of type 2 diabetes (odds ratio 1.70 [95% CI 1.09-2.65] and 2.16 [1.22-3.95], respectively) compared with those having the T/T genotype at positions 45 and 276, respectively. In addition, the subjects with the G/G genotype at position 276 had a higher insulin resistance index than those with the T/T genotype (1.61 +/- 0.05 vs. 1.19 +/- 0.12, P = 0.001). The G allele at position 276 was linearly associated with lower plasma adiponectin levels (G/G: 10.4 +/- 0.85 microg/ml, G/T: 13.7 +/- 0.87 microg/ml, T/T: 16.6 +/- 2.24 microg/ml, P = 0.01) in subjects with higher BMIs. Based on these findings together with the observation that adiponectin improves insulin sensitivity in animal models, we conclude that the adiponectin gene may be a susceptibility gene for type 2 diabetes.