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Cell Rep ; 28(3): 759-772.e10, 2019 07 16.
Artículo en Inglés | MEDLINE | ID: mdl-31315053


Mechanisms coordinating pancreatic ß cell metabolism with insulin secretion are essential for glucose homeostasis. One key mechanism of ß cell nutrient sensing uses the mitochondrial GTP (mtGTP) cycle. In this cycle, mtGTP synthesized by succinyl-CoA synthetase (SCS) is hydrolyzed via mitochondrial PEPCK (PEPCK-M) to make phosphoenolpyruvate, a high-energy metabolite that integrates TCA cycling and anaplerosis with glucose-stimulated insulin secretion (GSIS). Several strategies, including xenotopic overexpression of yeast mitochondrial GTP/GDP exchanger (GGC1) and human ATP and GTP-specific SCS isoforms, demonstrated the importance of the mtGTP cycle. These studies confirmed that mtGTP triggers and amplifies normal GSIS and rescues defects in GSIS both in vitro and in vivo. Increased mtGTP synthesis enhanced calcium oscillations during GSIS. mtGTP also augmented mitochondrial mass, increased insulin granule number, and membrane proximity without triggering de-differentiation or metabolic fragility. These data highlight the importance of the mtGTP signal in nutrient sensing, insulin secretion, mitochondrial maintenance, and ß cell health.

Cell Host Microbe ; 25(1): 113-127.e6, 2019 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-30581114


Western lifestyle is linked to autoimmune and metabolic diseases, driven by changes in diet and gut microbiota composition. Using Toll-like receptor 7 (TLR7)-dependent mouse models of systemic lupus erythematosus (SLE), we dissect dietary effects on the gut microbiota and find that Lactobacillus reuteri can drive autoimmunity but is ameliorated by dietary resistant starch (RS). Culture of internal organs and 16S rDNA sequencing revealed TLR7-dependent translocation of L. reuteri in mice and fecal enrichment of Lactobacillus in a subset of SLE patients. L. reuteri colonization worsened autoimmune manifestations under specific-pathogen-free and gnotobiotic conditions, notably increasing plasmacytoid dendritic cells (pDCs) and interferon signaling. However, RS suppressed the abundance and translocation of L. reuteri via short-chain fatty acids, which inhibited its growth. Additionally, RS decreased pDCs, interferon pathways, organ involvement, and mortality. Thus, RS exerts beneficial effects in lupus-prone hosts through suppressing a pathobiont that promotes interferon pathways implicated in the pathogenesis of human autoimmunity.

Autoinmunidad , Dieta , Hipersensibilidad , Lactobacillus/patogenicidad , Lupus Eritematoso Sistémico/microbiología , Glicoproteínas de Membrana/metabolismo , Receptor Toll-Like 7/metabolismo , Animales , Clostridiaceae , ADN Ribosómico/genética , Células Dendríticas/metabolismo , Dietoterapia , Modelos Animales de Enfermedad , Ácidos Grasos Volátiles/antagonistas & inhibidores , Ácidos Grasos Volátiles/metabolismo , Heces/microbiología , Femenino , Microbioma Gastrointestinal , Vida Libre de Gérmenes , Glomerulonefritis/patología , Humanos , Interferón Tipo I/metabolismo , Riñón/patología , Lactobacillus/efectos de los fármacos , Lactobacillus/genética , Lactobacillus reuteri , Lupus Eritematoso Sistémico/mortalidad , Lupus Eritematoso Sistémico/patología , Ratones , Ratones Endogámicos C57BL , ARN Ribosómico 16S/genética , Almidón , Tasa de Supervivencia
J Clin Endocrinol Metab ; 100(10): 3625-32, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26176801


CONTEXT: Treatment of X-linked hypophosphatemia (XLH) with active vitamin D metabolites and phosphate can partially correct skeletal deformities. It is unclear whether therapy influences the occurrence of two major long-term morbidities in XLH: enthesopathy and dental disease. OBJECTIVE: The objective of the study was to investigate the relationship between treatment and enthesopathy and dental disease in adult XLH patients. DESIGN: The study was designed as observational and cross-sectional. SETTING: The study was conducted at an academic medical center's hospital research unit. PARTICIPANTS: Fifty-two XLH patients aged 18 years or older at the time of the study participated in the study. INTERVENTIONS: There were no interventions. MAIN OUTCOME MEASURES: The number of enthesopathy sites identified by radiographic skeletal survey and dental disease severity (more than five or five or fewer dental abscesses), identified historically, were measured. METHODS: Associations between proportion of adult life and total life with treatment and number of enthesopathy sites were assessed using multiple linear regression, whereas associations between these exposure variables and dental disease severity were assessed using multiple logistic regression. All models were adjusted for confounding factors. RESULTS: Neither proportion of adult nor total life with treatment was a significant predictor of extent of enthesopathy. In contrast, both of these treatment variables were significant predictors of dental disease severity (multivariate-adjusted global P = .0080 and P = .0010, respectively). Participants treated 0% of adulthood were more likely to have severe dental disease than those treated 100% of adulthood (adjusted odds ratio 25 [95% confidence interval 1.2-520]). As the proportion of adult life with treatment increased, the odds of having severe dental disease decreased (multivariate-adjusted P for trend = .015). CONCLUSIONS: Treatment in adulthood may not promote or prevent enthesopathy; however, it may be associated with a lower risk of experiencing severe dental disease.

Calcitriol/uso terapéutico , Raquitismo Hipofosfatémico Familiar/tratamiento farmacológico , Fosfatos/uso terapéutico , Enfermedades Reumáticas/tratamiento farmacológico , Enfermedades Estomatognáticas/tratamiento farmacológico , Adulto , Estudios Transversales , Raquitismo Hipofosfatémico Familiar/complicaciones , Raquitismo Hipofosfatémico Familiar/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad , Radiografía , Enfermedades Reumáticas/diagnóstico por imagen , Enfermedades Reumáticas/etiología , Índice de Severidad de la Enfermedad , Enfermedades Estomatognáticas/diagnóstico , Enfermedades Estomatognáticas/etiología , Resultado del Tratamiento , Adulto Joven
Endocrinology ; 156(8): 2762-73, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25961842


Lactation is associated with increased bone turnover and rapid bone loss, which liberates skeletal calcium used for milk production. Previous studies suggested that an increase in the skeletal expression of receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cells ligand (RANKL) coupled with a decrease in osteoprotegerin (OPG) levels likely triggered bone loss during lactation. In this study, we treated lactating mice with recombinant OPG to determine whether bone loss during lactation was dependent on RANKL signaling and whether resorption of the maternal skeleton was required to support milk production. OPG treatment lowered bone resorption rates and completely prevented bone loss during lactation but, surprisingly, did not decrease osteoclast numbers. In contrast, OPG was quite effective at lowering osteoblast numbers and inhibiting bone formation in lactating mice. Furthermore, treatment with OPG during lactation prevented the usual anabolic response associated with reversal of lactational bone loss after weaning. Preventing bone loss had no appreciable effect on milk production, milk calcium levels, or maternal calcium homeostasis when mice were on a standard diet. However, when dietary calcium was restricted, treatment with OPG caused maternal hypocalcemia, maternal death, and decreased milk production. These studies demonstrate that RANKL signaling is a requirement for bone loss during lactation, and suggest that osteoclast activity may be required to increase osteoblast numbers during lactation in preparation for the recovery of bone mass after weaning. These data also demonstrate that maternal bone loss is not absolutely required to supply calcium for milk production unless dietary calcium intake is inadequate.

Resorción Ósea/prevención & control , Calcio/metabolismo , Lactancia/efectos de los fármacos , Leche/efectos de los fármacos , Leche/metabolismo , Osteoprotegerina/uso terapéutico , Animales , Animales Lactantes , Densidad Ósea/efectos de los fármacos , Calcio en la Dieta/farmacología , Femenino , Lactancia/fisiología , Ratones , Madres , Osteoprotegerina/farmacología , Destete
J Clin Endocrinol Metab ; 90(2): 1012-20, 2005 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-15562028


Oncogenic osteomalacia (OO), a tumor-associated phosphate-wasting syndrome, provides an opportunity to identify regulators of renal phosphate homeostasis. We established cultures from OO-associated tumors. Conditioned medium from these cultures inhibited phosphate uptake in renal tubular epithelial cells. We then compared RNA from tumor-derived cultures expressing inhibitory activity with RNA from tumor-derived cultures in which inhibitory activity was not evident and identified candidate mRNAs specifically expressed by cultures inhibiting renal phosphate transport. Testing of identified candidates revealed that one protein, fibroblast growth factor 7 (FGF7), was a potent and direct inhibitor of phosphate uptake in vitro. A neutralizing monoclonal antibody to FGF7 reversed FGF7-dependent phosphate transport inhibition and inhibitory activity in conditioned medium from tumor cell cultures. Immunoassay revealed abundant FGF7 in inhibitory conditioned medium and minimal amounts in nonconditioned medium or conditioned medium with no phosphate transport inhibitory activity. Furthermore, only small amounts of FGF23 were present in inhibitory conditioned medium, comparable to concentrations found in conditioned medium with no phosphate transport inhibitory activity. Thus, FGF7 was specifically identified when selecting for in vitro phosphate transport inhibitory activity of tumor-derived cultures and was confirmed as a potent inhibitor of phosphate transport. Finally, FGF7 message was confirmed in PCR products of mRNA extracted from fragments of each tumor. Members of the FGF family (other than FGF23) are expressed by OO-associated tumors and may play a role in mediating this syndrome.

Neoplasias Óseas/fisiopatología , Factores de Crecimiento de Fibroblastos/fisiología , Osteomalacia/fisiopatología , Proteínas de Transporte de Fosfato/antagonistas & inhibidores , Adulto , Antígenos CD4/genética , Línea Celular Tumoral , Niño , Medios de Cultivo Condicionados , Factor 7 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos/genética , Regulación de la Expresión Génica , Humanos , Proteína 4 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Cinética , Masculino , Persona de Mediana Edad
Biochem Biophys Res Commun ; 315(4): 872-6, 2004 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-14985093


The impact of muscarinic type 3 receptor knockout (M3KO) on the cholinergic regulation of insulin secretion and phospholipase C (PLC) activation was determined. Islets isolated from control, wild-type mice or heterozygotes responded with comparable insulin secretory responses to 15 mM glucose. This response was markedly amplified by the inclusion of 10 microM carbachol. While 15 mM glucose-induced release remained similar to wild-type and heterozygote responses in M3KO mice, the stimulatory impact of carbachol was abolished. Stimulation with 15 mM glucose plus 50 microM carbachol increased fractional efflux rates of myo-[2-3H]inositol from control wild-type and heterozygote islets but not from M3KO islets. Fed plasma insulin levels of M3KO mice were reduced 68% when compared to values obtained from combined wild-type and heterozygote animals. These studies support the conclusion that the M3 receptor in islets is coupled to PLC activation and insulin secretion and that cholinergic stimulation of the islets may play an important role in the regulation of plasma insulin levels.

Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Receptor Muscarínico M3/deficiencia , Animales , Carbacol/metabolismo , Carbacol/farmacología , Activación Enzimática/efectos de los fármacos , Femenino , Glucosa/metabolismo , Glucosa/farmacología , Heterocigoto , Inositol/análogos & derivados , Inositol/metabolismo , Insulina/sangre , Secreción de Insulina , Islotes Pancreáticos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptor Muscarínico M3/genética , Fosfolipasas de Tipo C/metabolismo