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1.
Front Neurol ; 12: 543866, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33889121

RESUMEN

Lobar cerebral microbleeds (CMBs) in Alzheimer's disease (AD) are associated with cerebral amyloid angiopathy (CAA) due to vascular amyloid beta (Aß) deposits. However, the relationship between lobar CMBs and clinical subtypes of AD remains unknown. Here, we enrolled patients with early- and late-onset amnestic dominant AD, logopenic variant of primary progressive aphasia (lvPPA) and posterior cortical atrophy (PCA) who were compatible with the AD criteria. We then examined the levels of cerebrospinal fluid (CSF) biomarkers [Aß1-42, Aß1-40, Aß1-38, phosphorylated tau 181 (P-Tau), total tau (T-Tau), neurofilament light chain (NFL), and chitinase 3-like 1 protein (YKL-40)], analyzed the number and localization of CMBs, and measured the cerebral blood flow (CBF) volume by 99mTc-ethyl cysteinate dimer single photon emission computerized tomography (99mTc ECD-SPECT), as well as the mean cortical standard uptake value ratio by 11C-labeled Pittsburgh Compound B-positron emission tomography (11C PiB-PET). Lobar CMBs in lvPPA were distributed in the temporal, frontal, and parietal lobes with the left side predominance, while the CBF volume in lvPPA significantly decreased in the left temporal area, where the number of lobar CMBs and the CBF volumes showed a significant inversely correlation. The CSF levels of NFL in lvPPA were significantly higher compared to the other AD subtypes and non-demented subjects. The numbers of lobar CMBs significantly increased the CSF levels of NFL in the total AD patients, additionally, among AD subtypes, the CSF levels of NFL in lvPPA predominantly were higher by increasing number of lobar CMBs. On the other hand, the CSF levels of Aß1-38, Aß1-40, Aß1-42, P-Tau, and T-Tau were lower by increasing number of lobar CMBs in the total AD patients. These findings may suggest that aberrant brain hypoperfusion in lvPPA was derived from the brain atrophy due to neurodegeneration, and possibly may involve the aberrant microcirculation causing by lobar CMBs and cerebrovascular injuries, with the left side dominance, consequently leading to a clinical phenotype of logopenic variant.

2.
J Alzheimers Dis ; 68(2): 797-808, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30775989

RESUMEN

Neuroimages of cerebral amyloid-ß (Aß) accumulation and small vessel disease (SVD) were examined in patients with various types of cognitive disorders using 11C-labeled Pittsburgh Compound B-positron emission tomography (PiB-PET) and magnetic resonance imaging (MRI). The mean cortical standardized uptake value ratio (mcSUVR) was applied for a quantitative analysis of PiB-PET data. The severity of white matter lesions (WML) and enlarged perivascular spaces (EPVS) on MRI were assessed to evaluate complicating cerebral SVD using semiquantitative scales. In homozygous apolipoprotein E ɛ3/ɛ3 carriers, the incidence of more severe WML and EPVS was higher in PiB-positive than PiB-negative patients, indicating that WML and EPVS might be associated with enhanced Aß accumulation. An association study between PiB-PET and MRI findings revealed that higher WML grades significantly correlate with lower mcSUVRs, especially in the frontal area, indicating that more severe ischemic MRI findings are associated with milder Aß accumulation among patients with Alzheimer's disease. In these patients SVD may accelerate the occurrence of cognitive decline and facilitate early recognition of dementia.


Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Demencia/diagnóstico por imagen , Demencia/metabolismo , Diagnóstico Precoz , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones/métodos
3.
Intern Med ; 56(11): 1345-1349, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28566596

RESUMEN

Paraneoplastic syndromes are generally defined as clinical disorders associated with malignant diseases, and hypocalcemia associated with cancer is a rare condition. A woman in her 60s was referred to our hospital for the further examination of massive ascites due to carcinoma of unknown primary origin. She complained of numbness around her lips, and marked hypocalcemia of 5.0 mg/dL was noted. After two courses of chemotherapy, computed tomography showed a decrease in the ascites, and her serum calcium level increased. Although hypocalcemia is a very rare condition in patients with gastric cancer, serum calcium values should be evaluated when neurological symptoms are observed.


Asunto(s)
Hipocalcemia/tratamiento farmacológico , Hipocalcemia/etiología , Síndromes Paraneoplásicos/tratamiento farmacológico , Síndromes Paraneoplásicos/etiología , Neoplasias Gástricas/complicaciones , Neoplasias Gástricas/fisiopatología , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia/fisiopatología , Osteoblastos/patología , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Adulto Joven
4.
Digestion ; 95(3): 242-251, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28384634

RESUMEN

BACKGROUND AND AIM: Although des-gamma-carboxy prothrombin (DCP) is a well-known tumor marker for hepatocellular carcinoma (HCC), the mechanism of DCP production is unclear. This study aimed to investigate the mechanism how DCP is produced in HCC cells. METHODS: Levels of mRNA and DCP were analyzed by real-time polymerase chain reaction and electro-chemiluminescence immunoassay respectively. Secreted alkaline phosphatase (SEAP) expression vectors including deletion mutants of the prothrombin gene promoter were constructed for reporter gene assay. The transcription factors bound to DNA fragments were analyzed by mass spectrometry. An electrophoretic mobility shift assay (EMSA) was performed using a biotin end-labeled DNA. RESULTS: The prothrombin mRNA levels in all 5 DCP producing cell lines were appreciably high. However, those in 2 DCP non-producing cell lines were below detectable levels. A SEAP vector with -2985 to +27 showed a very high transcription activity in DCP-producing Huh-1 cells. However, transcription abruptly decreased when the vector with -2955 to +27 was transfected, and then remained at the similar levels with larger deletion mutants, indicating the existence of a cis-element at -2985 to -2955 (31-bp). Mass spectrometry analysis identified the protein that bound to the 31-bp DNA as poly-(ADP-ribose) polymerase-1 (PARP-1). Knockdown of the PARP-1 gene by small interfering RNA in Huh-1 cells induced marked inhibition of prothrombin gene transcription. The EMSA clearly showed that PARP-1 specifically binds to the 31-bp DNA fragment in the prothrombin gene promoter. CONCLUSIONS: Our data suggest that PARP-1 activates prothrombin gene transcription and that the excessive prothrombin gene transcription induces DCP production in DCP-producing HCC cells.


Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/genética , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Precursores de Proteínas/genética , Protrombina/genética , Fosfatasa Alcalina/metabolismo , Biomarcadores/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Supervivencia Celular , Ensayo de Cambio de Movilidad Electroforética , Técnicas de Silenciamiento del Gen , Genes Reporteros , Humanos , Técnicas para Inmunoenzimas , Neoplasias Hepáticas/patología , Espectrometría de Masas , Poli(ADP-Ribosa) Polimerasa-1/genética , Precursores de Proteínas/metabolismo , Protrombina/metabolismo , Interferencia de ARN , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Transcripción Genética
5.
Clin J Gastroenterol ; 9(3): 109-13, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-27170299

RESUMEN

A 73-year-old man was referred to our hospital for further examination of a depressed lesion in the stomach found by cancer screening gastroscopy. A barium upper gastrointestinal series showed an area of irregular mucosa measuring 15 mm on the anterior wall of the gastric body. Esophagogastroduodenoscopy revealed a 15 mm depressed lesion on the anterior wall of the lower gastric body. We suspected an undifferentiated adenocarcinoma from the appearance and took some biopsies. However, histology of the specimens revealed amyloidal deposits in the submucosal layer without malignant findings. Congo red staining was positive for amyloidal protein and green birefringence was observed under polarized light microscopy. Congo red staining with prior potassium permanganate incubation confirmed the light chain (AL) amyloid type. There were no amyloid deposits in the colon or duodenum. Computed tomography of the chest, abdomen, and pelvis showed no remarkable findings. Thus, this case was diagnosed as a localized gastric amyloidosis characterized by AL type amyloid deposition in the mucosal or submucosal layer. As the clinical outcome of gastric AL amyloidosis seems favorable, this case is scheduled for periodic examination to recognize potential disease progression and has been stable for 2 years.


Asunto(s)
Amiloidosis/diagnóstico , Neoplasias Gástricas/diagnóstico , Anciano , Amiloidosis/patología , Biopsia , Diagnóstico Diferencial , Gastroscopía , Humanos , Masculino , Estómago/patología , Gastropatías/diagnóstico , Gastropatías/patología
6.
J Med Invest ; 62(3-4): 251-7, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26399359

RESUMEN

Gastric neuroendocrine tumor (NET) is sometimes found as a submucosal tumor on upper gastrointestinal endoscopy. Gastric NET with malignant profile and neuroendocrine carcinoma (NEC) show various forms which are difficult to distinguish from gastric cancer and other disease. We report a case of a cauliflower-shaped NET of the stomach. A 61-year-old man was referred to our hospital with a complaint of abdominal fullness. Upper gastrointestinal endoscopic examination revealed an unusual, whitish cauliflower-shaped tumor that belongs to Borrmann type I on the lesser curvature of the gastric antrum. Histological examination of the biopsy specimen revealed NET G2, because the tumor cells were CD56- and synaptophysin-positive by immunohistochemical analysis. A distal gastrectomy with D2 lymphadenectomy was performed. A recurrence in the liver was revealed by follow up computed tomography after 11 months from operation. Combined chemotherapy with irinotecan (CPT-11) plus cisplatin (CDDP) was treated. The patient achieved a partial response, but he died after 31 months from gastrectomy. There is no independent, large-scaled prospective study and no standard treatment for gastric NETs with distant metastases. Our case is reported with a literature review of the treatment of metastatic gastric NET G2.


Asunto(s)
Endoscopía Gastrointestinal , Tumores Neuroendocrinos/patología , Neoplasias Gástricas/patología , Humanos , Masculino , Persona de Mediana Edad
8.
Artículo en Inglés | MEDLINE | ID: mdl-25679630

RESUMEN

Pattern formation of a step on a growing crystal surface induced by a straight line source of atoms, which is escaping from the step at a velocity V(p), is studied with the use of a phase field model. From a straight step, fluctuations of the most unstable wavelength λ(max) grow. Competition of intrusions leads to coarsening of the pattern, and survived intrusions grow exponentially. With sufficient strength of the crystal anisotropy, a regular comblike pattern appears. This peculiar step pattern is similar to that observed on a Ga-deposited Si(111) surface. The final period of the intrusions, Λ, is determined when the exponential growth ends. The period depends on the strength F(u) of a current noise in diffusion as Λ∼λ(max)|lnF(u)|: such a logarithmic dependence is confirmed for the first time. A nonmonotonic V(p) dependence of Λ indicates that the comblike pattern with a small V(p) is related to an unstable growth mode of the free needle growth in a channel. The pattern is stabilized by the guiding linear source.

9.
Dig Endosc ; 24(3): 139-49, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22507086

RESUMEN

AIM: In Japan, endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) have been widely accepted and standardized for the treatment of gastrointestinal superficial neoplasia. METHODS: In contrast, mucosal ablation techniques are more common in Western countries and a variety of endoscopic ablation modalities, including argon plasma coagulation (APC), photodynamic therapy (PDT) and lasers, are used. RESULTS: Recently developed modalities such as radiofrequency ablation (RFA) and cryotherapy are also available for the treatment of superficial lesions such as dysplasia of Barrett's esophagus. CONCLUSION: Although we should understand that the completeness of destruction of neoplastic tissue can only be judged at follow up, endoscopic ablation is a viable alternative to endoscopic resection for dysplasia and early-stage malignancies, especially for poor candidates of surgery or endoscopic resection.


Asunto(s)
Adenoma/cirugía , Carcinoma de Células Escamosas/cirugía , Endoscopía Gastrointestinal/métodos , Neoplasias Gastrointestinales/cirugía , Lesiones Precancerosas/cirugía , Adenoma/epidemiología , Coagulación con Plasma de Argón/métodos , Carcinoma de Células Escamosas/epidemiología , Ablación por Catéter/métodos , Crioterapia/métodos , Predicción , Neoplasias Gastrointestinales/epidemiología , Humanos , Japón , Terapia por Láser/métodos , Fotoquimioterapia/métodos , Lesiones Precancerosas/epidemiología
10.
Mol Cell Biol ; 29(11): 3134-50, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19307309

RESUMEN

Polo-like kinase 1 (Plk1) functions as a key regulator of mitotic events by phosphorylating substrate proteins on centrosomes, kinetochores, the mitotic spindle, and the midbody. Through mechanisms that are incompletely understood, Plk1 is released from and relocalizes to different mitotic structures as cells proceed through mitosis. We used fluorescence recovery after photobleaching to examine the kinetics of this process in more detail. We observed that Plk1 displayed a range of different recovery rates that differ at each mitotic substructure and depend on both the Polo-box domain and a functional kinase domain. Upon mitotic entry, centrosomal Plk1 becomes more dynamic, a process that is directly enhanced by Plk1 kinase activity. In contrast, Plk1 displays little dynamic exchange at the midbody, a process that again is modulated by the kinase activity of Plk1. Our findings suggest that the intrinsic kinase activity of Plk1 triggers its release from early mitotic structures and its relocalization to late mitotic structures. To assess the importance of Plk1 dynamic relocalization, Plk1 was persistently tethered to the centrosome. This resulted in a G(2) delay, followed by a prominent prometaphase arrest, as a consequence of defective spindle formation and activation of the spindle checkpoint. The dynamic release of Plk1 from early mitotic structures is thus crucial for mid- to late-stage mitotic events and demonstrates the importance of a fully dynamic Plk1 at the centrosome for proper cell cycle progression. This dependence on dynamic Plk1 was further observed during the mitotic reentry of cells after a DNA damage G(2) checkpoint, as this process was significantly delayed upon centrosomal tethering of Plk1. These results indicate that mitotic progression and control of mitotic reentry after DNA damage resides, at least in part, on the dynamic behavior of Plk1.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Centrosoma/enzimología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas de Anclaje a la Quinasa A/metabolismo , Línea Celular Tumoral , Supervivencia Celular , Daño del ADN , Recuperación de Fluorescencia tras Fotoblanqueo , Fase G2 , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Cinetocoros/enzimología , Metafase , Modelos Biológicos , Transporte de Proteínas , Proteínas Recombinantes de Fusión/metabolismo , Huso Acromático/enzimología , Fracciones Subcelulares/enzimología , Quinasa Tipo Polo 1
11.
Endocr J ; 56(3): 345-59, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19139597

RESUMEN

Akt substrate of 160kDa (AS160) is a Rab GTPase activating protein (GAP) and was recently identified as a component of the insulin signaling pathway of glucose transporter type 4 (GLUT4) translocation. We and others, previously reported that the activation of Galphaq protein-coupled receptors (GalphaqPCRs) also stimulated GLUT4 translocation and glucose uptake in several cell lines. Here, we report that the activation of GalphaqPCRs also promoted phosphorylation of AS160 by the 5'-AMP activated protein kinase (AMPK). The suppression of AS160 phosphorylation by the siRNA mediated AMPKalpha1 subunit knockdown promoted GLUT4 vesicle retention in intracellular compartments. This suppression did not affect the ratio of non-induced cell surface GLUT4 to Galphaq-induced it. Rat 3Y1 cells lacking AS160 did not show insulin-induced GLUT4 translocation. The cells stably expressing GLUT4 revealed GLUT4 vesicles that were mainly localized in the perinuclear region and less frequently on the cell surface. After expression of exogenous AS160, GLUT4 on the cell surface decreased and GLUT4 vesicles were redistributed throughout the cytoplasm. Although PMA-induced or sodium fluoride-induced GLUT4 translocation was significantly increased in these cells, insulin did not affect GLUT4 translocation. These results suggest that AS160 is a common regulator of insulin- and GalphaqPCR activation-mediated GLUT4 distribution in the cells.


Asunto(s)
Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Proteínas Activadoras de GTPasa/metabolismo , Transportador de Glucosa de Tipo 4/metabolismo , Células 3T3-L1/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Células CHO , Cricetinae , Cricetulus , Proteínas Activadoras de GTPasa/fisiología , Humanos , Insulina/fisiología , Ratones , Ratas
12.
EMBO J ; 26(9): 2262-73, 2007 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-17446864

RESUMEN

Polo-like kinase-1 (Plk1) phosphorylates a number of mitotic substrates, but the diversity of Plk1-dependent processes suggests the existence of additional targets. Plk1 contains a specialized phosphoserine-threonine binding domain, the Polo-box domain (PBD), postulated to target the kinase to its substrates. Using the specialized PBD of Plk1 as an affinity capture agent, we performed a screen to define the mitotic Plk1-PBD interactome by mass spectrometry. We identified 622 proteins that showed phosphorylation-dependent mitosis-specific interactions, including proteins involved in well-established Plk1-regulated processes, and in processes not previously linked to Plk1 such as translational control, RNA processing, and vesicle transport. Many proteins identified in our screen play important roles in cytokinesis, where, in mammalian cells, the detailed mechanistic role of Plk1 remains poorly defined. We go on to characterize the mitosis-specific interaction of the Plk1-PBD with the cytokinesis effector kinase Rho-associated coiled-coil domain-containing protein kinase 2 (Rock2), demonstrate that Rock2 is a Plk1 substrate, and show that Rock2 colocalizes with Plk1 during cytokinesis. Finally, we show that Plk1 and RhoA function together to maximally enhance Rock2 kinase activity in vitro and within cells, and implicate Plk1 as a central regulator of multiple pathways that synergistically converge to regulate actomyosin ring contraction during cleavage furrow ingression.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteoma/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteína de Unión al GTP rhoA/metabolismo , Actomiosina/metabolismo , Línea Celular Tumoral , Biología Computacional , Citocinesis , Activación Enzimática , Humanos , Fosforilación , Unión Proteica , Mapeo de Interacción de Proteínas , Estructura Terciaria de Proteína , Proteínas Recombinantes/metabolismo , Espectrometría de Masas en Tándem , Quinasas Asociadas a rho , Quinasa Tipo Polo 1
13.
J Med Invest ; 54(1-2): 19-27, 2007 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-17380010

RESUMEN

There is crosstalk in intracellular signaling between Angiotensin II (Ang II) and insulin. We hypothesized that the underlying mechanism might be related to changes in cytoskeleton. In the presence of 100 nM of Ang II, insulin-induced glucose uptake was decreased and insulin-induced actin filament organization was inhibited. PKC inhibitors, including GF109203x and p38MAPK inhibitor (SB203580) neither improved insulin-induced actin reorganization nor glucose uptake. In contrast, the Ang II-induced inhibition of glucose uptake and actin filament disorganization was reversed by 10 micromol ERK 1/2 MAPK inhibitor (PD98059). Pretreatment of Ang II increased ERK1/2 phosphorylation and inhibited insulin-induced Akt phosphorylation. The effect of Ang II on ERK1/2 phosphorylation was blocked by Ang II type 1 receptor antagonists, RNH6270 and PD98059 but not by SB203580 or Guanosine-5'-O-(2-ThioDiphosphate), a G-protein inhibitor. We next tested the effect of broad-spectrum matrix metalloproteinase (MMP) inhibitor (GM6001) on Ang II-inhibition of insulin signaling pathway. GM6001 did not improve Ang II-induced actin filament disorganization and did not inhibit ERK1/2 phosphorylation. From these data in L6 myotube, we conclude that Ang II negatively regulates the insulin signal not through MMP signaling pathway but specifically through MMP-independent ERK1/2 activation pathway, providing an alternative molecular mechanism for angiotensin-induced insulin resistance.


Asunto(s)
Angiotensina II/farmacología , Glucosa/metabolismo , Insulina/farmacología , Proteína Quinasa 1 Activada por Mitógenos/fisiología , Proteína Quinasa 3 Activada por Mitógenos/fisiología , Fibras de Estrés/efectos de los fármacos , Línea Celular , Humanos , Sistema de Señalización de MAP Quinasas , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor de Angiotensina Tipo 1/fisiología , Fibras de Estrés/fisiología
14.
Endocr J ; 54(1): 77-88, 2007 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-17102568

RESUMEN

APS, a tyrosine kinase adaptor protein with pleckstrin homology and Src homology 2 domains, is rapidly and strongly tyrosine-phosphorylated by insulin receptor kinase upon insulin stimulation. We have previously shown that APS knockout mice have increased insulin sensitivity, and that this enhancement is possibly due to increased insulin-response on adipose tissues. However, the function of APS in insulin signaling has so far been controversial. Here, we report that APS enhanced ligand-dependent multi-ubiquitination of the insulin receptor (IR) in CHO cells overexpressing the IR. APS-mediated ubiquitination of the IR induced enhancement of the IR internalization, but did not affect the IR degradation. This finding shows one of the pleiotropic functions of APS in insulin signaling.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/fisiología , Procesamiento Proteico-Postraduccional , Receptor de Insulina/metabolismo , Ubiquitina/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Células CHO , Cricetinae , Cricetulus , Humanos , Insulina/metabolismo , Ratones , Transporte de Proteínas , Receptor de Insulina/genética , Transducción de Señal/genética , Transfección
15.
Diabetes ; 53(11): 2776-86, 2004 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-15504957

RESUMEN

Insulin stimulates the disposal of blood glucose into skeletal muscle and adipose tissues by the translocation of GLUT4 from intracellular pools to the plasma membrane, and consequently the concentration of blood glucose levels decreases rapidly in vivo. Phosphatidylinositol (PI) 3-kinase and Akt play a pivotal role in the stimulation of glucose transport by insulin, but detailed mechanisms are unknown. We and others reported that not only insulin but also platelet-derived growth factor (PDGF) and epidermal growth factor facilitate glucose uptake through GLUT4 translocation by activation of PI 3-kinase and Akt in cultured cells. However, opposite results were also reported. We generated transgenic mice that specifically express the PDGF receptor in skeletal muscle. In these mice, PDGF stimulated glucose transport into skeletal muscle in vitro and in vivo. Thus, PDGF apparently shares with insulin some of the signaling molecules needed for the stimulation of glucose transport. The degree of glucose uptake in vivo reached approximately 60% of that by insulin injection in skeletal muscle, but blood glucose levels were not decreased by PDGF in these mice. Therefore, PDGF-induced disposal of blood glucose into skeletal muscle is insufficient for rapid decrease of blood glucose levels.


Asunto(s)
Glucemia/metabolismo , Glucosa/metabolismo , Factor de Crecimiento Derivado de Plaquetas/farmacología , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/fisiología , Animales , Transporte Biológico/efectos de los fármacos , Glucemia/efectos de los fármacos , Corazón/fisiología , Insulina/farmacología , Ratones , Ratones Transgénicos , Músculo Esquelético/fisiología , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/efectos de los fármacos , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Proteínas Recombinantes/farmacología , Transducción de Señal
16.
Endocr J ; 51(2): 133-44, 2004 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-15118262

RESUMEN

Impaired insulin secretion and insulin resistance are thought to be two major causes of type 2 diabetes mellitus. There are two kinds of diabetic model mice: one is a K(ATP) channel knockout (Kir6.2KO) mouse which is defective in glucose-induced insulin secretion, and the other is a transgenic mouse expressing the tyrosine kinase-deficient (dominant-negative form of) human insulin receptor (hIR(KM)TG), and which has insulin resistance in muscle and fat. However, all of these mice have no evidence of overt diabetes. To determine if the double mutant Kir6.2KO/hIR(KM)TG mice would have diabetes, we generated mutant mice by crossbreeding, which would show both impaired glucose-induced insulin secretion and insulin resistance in muscle and fat. We report here that: 1) blood glucose levels of randomly fed and 6 h fasted double mutant (Kir6.2KO/hIR(KM)TG) mice were comparable with those of wild type mice; 2) in intraperitoneal glucose tolerance test (ipGTT), Kir6.2KO/hIR(KM)TG mice had an impaired glucose tolerance; and 3) during ipGTT, insulin secretion was not induced in either Kir6.2KO/hIR(KM)TG or Kir6.2KO mice, while the hIR(KM)TG mice showed a more prolonged insulin secretion than did wild type mice; 4) hyperinsulinemic euglycemic clamp test revealed that Kir6.2KO, Kir6.2KO/hIR(KM)TG and hIR(KM)TG mice, showed decreased whole-body glucose disposal compared with wild type mice; 5) Kir6.2KO, but not Kir6.2KO/hIR(KM)TG mice had some obesity and hyperleptinemia compared with wild type mice. Thus, the defects in glucose-induced insulin secretion (Kir6.2KO) and an insulin resistance in muscle and fat (hIR(KM)TG) were not sufficient to lead to overt diabetes.


Asunto(s)
Genes Dominantes , Intolerancia a la Glucosa/metabolismo , Canales de Potasio de Rectificación Interna/deficiencia , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Tejido Adiposo/patología , Animales , Glucemia/metabolismo , Activación Enzimática , Epidídimo/patología , Ayuno/sangre , Genotipo , Glucosa/farmacocinética , Técnica de Clampeo de la Glucosa , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/metabolismo , Insulina/farmacología , Secreción de Insulina , Leptina/sangre , Hígado/enzimología , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Tamaño de los Órganos , Periodo Posprandial , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt
17.
Diabetes ; 52(11): 2657-65, 2003 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-14578283

RESUMEN

A tyrosine kinase adaptor protein containing pleckstrin homology and SH2 domains (APS) is rapidly and strongly tyrosine phosphorylated by insulin receptor kinase upon insulin stimulation. The function of APS in insulin signaling has heretofore remained unknown. APS-deficient (APS(-/-)) mice were used to investigate its function in vivo. The blood glucose-lowering effect of insulin, as assessed by the intraperitoneal insulin tolerance test, was increased in APS(-/-) mice. Plasma insulin levels during fasting and in the intraperitoneal glucose tolerance test were lower in APS(-/-) mice. APS(-/-) mice showed an increase in the whole-body glucose infusion rate as assessed by the hyperinsulinemic-euglycemic clamp test. These findings indicated that APS(-/-) mice exhibited increased sensitivity to insulin. However, overexpression of wild-type or dominant-negative APS in 3T3L1 adipocytes did not affect insulin receptor numbers, phosphorylations of insulin receptor, insulin receptor substrate-1, or Akt and mitogen-activated protein kinase. The glucose uptake and GLUT4 translocation were not affected by insulin stimulation in these cells. Nevertheless, the insulin-stimulated glucose transport in isolated adipocytes of APS(-/-) mice was increased over that of APS(+/+) mice. APS(-/-) mice also showed increased serum levels of leptin and adiponectin, which might explain the increased insulin sensitivity of adipocytes.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Proteínas Adaptadoras del Transporte Vesicular/fisiología , Glucemia/metabolismo , Insulina/deficiencia , Insulina/farmacología , Péptidos y Proteínas de Señalización Intercelular , Células 3T3 , Proteínas Adaptadoras del Transporte Vesicular/deficiencia , Proteínas Adaptadoras del Transporte Vesicular/genética , Adipocitos/metabolismo , Adiponectina , Animales , Peso Corporal , Ingestión de Energía , Glucagón/sangre , Glucosa/metabolismo , Técnica de Clampeo de la Glucosa , Hiperinsulinismo/sangre , Insulina/sangre , Leptina/sangre , Ratones , Ratones Noqueados , Proteínas/metabolismo , Receptor de Insulina/metabolismo , Triglicéridos/sangre
18.
J Biol Chem ; 278(30): 28312-23, 2003 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-12734182

RESUMEN

Insulin plays a central role in the regulation of glucose homeostasis in part by stimulating glucose uptake and glycogen synthesis. The serine/threonine protein kinase Akt has been proposed to mediate insulin signaling in several processes. However, it is unclear whether Akt is involved in insulin-stimulated glucose uptake and which isoforms of Akt are responsible for each insulin action. We confirmed that expression of a constitutively active Akt, using an adenoviral expression vector, promoted translocation of glucose transporter 4 (GLUT4) to plasma membrane, 2-deoxyglucose (2-DG) uptake, and glycogen synthesis in both Chinese hamster ovary cells and 3T3-L1 adipocytes. Inhibition of Akt either by adenoviral expression of a dominant negative Akt or by the introduction of synthetic 21-mer short interference RNA against Akt markedly reduced insulin-stimulated GLUT4 translocation, 2-DG uptake, and glycogen synthesis. Experiments with isoform-specific short interference RNA revealed that Akt2, and Akt1 to a lesser extent, has an essential role in insulin-stimulated GLUT4 translocation and 2-DG uptake in both cell lines, whereas Akt1 and Akt2 contribute equally to insulin-stimulated glycogen synthesis. These data suggest a prerequisite role of Akt in insulin-stimulated glucose uptake and distinct functions among Akt isoforms.


Asunto(s)
Adenoviridae/genética , Silenciador del Gen , Técnicas Genéticas , Insulina/metabolismo , Proteínas Musculares , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas/química , Interferencia de ARN , Células 3T3 , Animales , Secuencia de Bases , Encéfalo/metabolismo , Células CHO , Células COS , Cricetinae , Desoxiglucosa/farmacocinética , Relación Dosis-Respuesta a Droga , Biblioteca de Genes , Transportador de Glucosa de Tipo 4 , Glucógeno/metabolismo , Immunoblotting , Luciferasas/metabolismo , Ratones , Datos de Secuencia Molecular , Proteínas de Transporte de Monosacáridos/metabolismo , Plásmidos/metabolismo , Pruebas de Precipitina , Isoformas de Proteínas , Transporte de Proteínas , Proteínas Proto-Oncogénicas c-akt , Ratas , Factores de Tiempo
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