RESUMEN
Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, increases worldwide and associates with type 2 diabetes and other cardiometabolic diseases. Here we demonstrate that Sema3a is elevated in liver sinusoidal endothelial cells of animal models for obesity, type 2 diabetes and MASLD. In primary human liver sinusoidal endothelial cells, saturated fatty acids induce expression of SEMA3A, and loss of a single allele is sufficient to reduce hepatic fat content in diet-induced obese mice. We show that semaphorin-3A regulates the number of fenestrae through a signaling cascade that involves neuropilin-1 and phosphorylation of cofilin-1 by LIM domain kinase 1. Finally, inducible vascular deletion of Sema3a in adult diet-induced obese mice reduces hepatic fat content and elevates very low-density lipoprotein secretion. Thus, we identified a molecular pathway linking hyperlipidemia to microvascular defenestration and early development of MASLD.
Asunto(s)
Células Endoteliales , Hígado , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico , Semaforina-3A , Transducción de Señal , Animales , Humanos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Hígado/metabolismo , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Enfermedad del Hígado Graso no Alcohólico/genética , Semaforina-3A/metabolismo , Semaforina-3A/genética , Neuropilina-1/metabolismo , Neuropilina-1/genética , Obesidad/metabolismo , Obesidad/patología , Obesidad/genética , Cofilina 1/metabolismo , Cofilina 1/genética , Modelos Animales de Enfermedad , Masculino , Fosforilación , Células Cultivadas , Ratones , Ratones Noqueados , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/genética , Dieta Alta en Grasa/efectos adversosRESUMEN
Recently, we have shown that after partial hepatectomy (PHx), an increased hepatic blood flow initiates liver growth in mice by vasodilation and mechanically-triggered release of angiocrine signals. Here, we use mass spectrometry to identify a mechanically-induced angiocrine signal in human hepatic endothelial cells, that is, myeloid-derived growth factor (MYDGF). We show that it induces proliferation and promotes survival of primary human hepatocytes derived from different donors in two-dimensional cell culture, via activation of mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3). MYDGF also enhances proliferation of human hepatocytes in three-dimensional organoids. In vivo, genetic deletion of MYDGF decreases hepatocyte proliferation in the regenerating mouse liver after PHx; conversely, adeno-associated viral delivery of MYDGF increases hepatocyte proliferation and MAPK signaling after PHx. We conclude that MYDGF represents a mechanically-induced angiocrine signal and that it triggers growth of, and provides protection to, primary mouse and human hepatocytes.
Asunto(s)
Células Endoteliales , Interleucinas , Regeneración Hepática , Animales , Humanos , Ratones , Proliferación Celular , Células Endoteliales/metabolismo , Hepatectomía , Hepatocitos/metabolismo , Hígado/metabolismo , Regeneración Hepática/fisiología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Interleucinas/metabolismoRESUMEN
The BiP co-chaperone DNAJC3 protects cells during ER stress. In mice, the deficiency of DNAJC3 leads to beta-cell apoptosis and the gradual onset of hyperglycemia. In humans, biallelic DNAJC3 variants cause a multisystem disease, including early-onset diabetes mellitus. Recently, hyperinsulinemic hypoglycemia (HH) has been recognized as part of this syndrome. This report presents a case study of an individual with HH caused by DNAJC3 variants and provides an overview of the metabolic phenotype of individuals with HH and DNAJC3 variants. The study demonstrates that HH may be a primary symptom of DNAJC3 deficiency and can persist until adolescence. Additionally, glycemia and insulin release were analyzed in young DNACJ3 knockout (K.O.) mice, which are equivalent to human infants. In the youngest experimentally accessible age group of 4-week-old mice, the in vivo glycemic phenotype was already dominated by a reduced total insulin secretion capacity. However, on a cellular level, the degree of insulin release of DNAJC3 K.O. islets was higher during periods of increased synthetic activity (high-glucose stimulation). We propose that calcium leakage from the ER into the cytosol, due to disrupted DNAJC3-controlled gating of the Sec61 channel, is the most likely mechanism for HH. This is the first genetic mechanism explaining HH solely by the disruption of intracellular calcium homeostasis. Clinicians should screen for HH in DNAJC3 deficiency and consider DNAJC3 variants in the differential diagnosis of congenital hyperinsulinism.
Asunto(s)
Hiperinsulinismo Congénito , Proteínas del Choque Térmico HSP40 , Adolescente , Animales , Humanos , Ratones , Calcio/metabolismo , Hiperinsulinismo Congénito/genética , Proteínas del Choque Térmico HSP40/genética , Proteínas del Choque Térmico HSP40/metabolismo , Insulina/metabolismo , Secreción de Insulina , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismoRESUMEN
For treatment of type 1 diabetes mellitus, a combination of immune-based interventions and medication to promote beta-cell survival and proliferation has been proposed. Dextromethorphan (DXM) is an N-methyl-D-aspartate receptor antagonist with a good safety profile, and to date, preclinical and clinical evidence for blood glucose-lowering and islet-cell-protective effects of DXM have only been provided for animals and individuals with type 2 diabetes mellitus. Here, we assessed the potential anti-diabetic effects of DXM in the non-obese diabetic mouse model of type 1 diabetes. More specifically, we showed that DXM treatment led to five-fold higher numbers of pancreatic islets and more than two-fold larger alpha- and beta-cell areas compared to untreated mice. Further, DXM treatment improved glucose homeostasis and reduced diabetes incidence by 50%. Our data highlight DXM as a novel candidate for adjunct treatment of preclinical or recent-onset type 1 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Islotes Pancreáticos , Ratones , Animales , Ratones Endogámicos NOD , Dextrometorfano/farmacología , Dextrometorfano/uso terapéutico , Receptores de N-Metil-D-Aspartato/uso terapéutico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Insulina , Glucemia , HomeostasisRESUMEN
Type 2 diabetes is characterized by insulin hypersecretion followed by reduced glucose-stimulated insulin secretion (GSIS). Here we show that acute stimulation of pancreatic islets with the insulin secretagogue dextrorphan (DXO) or glibenclamide enhances GSIS, whereas chronic treatment with high concentrations of these drugs reduce GSIS but protect islets from cell death. Bulk RNA sequencing of islets shows increased expression of genes for serine-linked mitochondrial one-carbon metabolism (OCM) after chronic, but not acute, stimulation. In chronically stimulated islets, more glucose is metabolized to serine than to citrate, and the mitochondrial ATP/ADP ratio decreases, whereas the NADPH/NADP+ ratio increases. Activating transcription factor-4 (Atf4) is required and sufficient to activate serine-linked mitochondrial OCM genes in islets, with gain- and loss-of-function experiments showing that Atf4 reduces GSIS and is required, but not sufficient, for full DXO-mediated islet protection. In sum, we identify a reversible metabolic pathway that provides islet protection at the expense of secretory function.
Asunto(s)
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Islotes Pancreáticos , Humanos , Diabetes Mellitus Tipo 2/metabolismo , Islotes Pancreáticos/metabolismo , Insulina/metabolismo , Glucosa/metabolismo , Carbono/metabolismo , Células Secretoras de Insulina/metabolismoRESUMEN
Dextromethorphan (DXM) acts as cough suppressant via its central action. Cell-protective effects of this drug have been reported in peripheral tissues, making DXM potentially useful for treatment of several common human diseases, such as type 2 diabetes mellitus (T2DM). Pancreatic islets are among the peripheral tissues that positively respond to DXM, and anti-diabetic effects of DXM were observed in two placebo-controlled, randomized clinical trials in humans with T2DM. Since these effects were associated with central side effects, we here developed chemical derivatives of DXM that pass the blood-brain barrier to a significantly lower extent than the original drug. We show that basic nitrogen-containing residues block central adverse events of DXM without reducing its anti-diabetic effects, including the protection of human pancreatic islets from cell death. These results show how to chemically modify DXM, and possibly other morphinans, as to exclude central side effects, while targeting peripheral tissues, such as pancreatic islets.
Asunto(s)
Glucemia/análisis , Dextrometorfano/farmacología , Hipoglucemiantes/farmacología , Islotes Pancreáticos/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Calcio/metabolismo , Dextrometorfano/análogos & derivados , Dextrometorfano/metabolismo , Dextrometorfano/uso terapéutico , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/patología , Diseño de Fármacos , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/metabolismo , Hipoglucemiantes/uso terapéutico , Insulina/sangre , Insulina/metabolismo , Islotes Pancreáticos/citología , Islotes Pancreáticos/metabolismo , Masculino , Potenciales de la Membrana/efectos de los fármacos , Ratones Endogámicos C57BLRESUMEN
As part of early drug development, preformulation studies are used to comprehensively explore the properties of new drugs. In particular, this includes the biopharmaceutical characterization and evaluation of impacting factors (e.g. excipients, microenvironmental conditions etc.) by permeation studies. To overcome the limitations of current studies, a novel standardized ex vivo procedure using esophageal mucosa as surrogate has been established successfully and applied to preformulation studies for oromucosal delivery of cyclobenzaprine hydrochloride, a tricyclic muscle relaxant with potential for psychopharmacotherapeutic use. By using the standardized ex vivo permeation process, a twofold enhancement of permeability (0.98 ± 0.16 to 1.96 ± 0.10 * 10-5 cm/s) was observed by adjustment and controlling of microenvironmental pH, empowering a targeted and effective development of sublingual formulations. Predictivity and suitability were superior compared to in vitro experiments using artificial biomimetic membranes, revealing a determination coefficient (R2) of 0.995 vs. 0.322 concerning pH-dependent permeability of cyclobenzaprine. In addition, diffusion properties were extensively examined (e.g. influence of mucosal thicknesses, tissue freezing etc.). The alignment of the study design regarding physiologically/clinically relevant conditions resulted in ex vivo data that allowed for the estimation of plasma AUC levels in the extend of reported in vivo ranges.
Asunto(s)
Excipientes , Preparaciones Farmacéuticas , Amitriptilina/análogos & derivados , PermeabilidadRESUMEN
An acute increase in blood flow triggers flow-mediated dilation (FMD), which is mainly mediated by endothelial nitric oxide synthase (eNOS). A long-term increase in blood flow chronically enlarges the arterial lumen, a process called arteriogenesis. In several common human diseases, these processes are disrupted for as yet unknown reasons. Here, we asked whether ß1 integrin, a mechanosensory protein in endothelial cells, is required for FMD and arteriogenesis in the ischemic hindlimb. Permanent ligation of the femoral artery in C57BL/6 J mice enlarged pre-existing collateral arteries and increased numbers of arterioles in the thigh. In the lower leg, the numbers of capillaries increased. Notably, injection of ß1 integrin-blocking antibody or tamoxifen-induced endothelial cell-specific deletion of the gene for ß1 integrin (Itgb1) inhibited both arteriogenesis and angiogenesis. Using high frequency ultrasound, we demonstrated that ß1 integrin-blocking antibody or endothelial cell-specific depletion of ß1 integrin attenuated FMD of the femoral artery, and blocking of ß1 integrin function did not further decrease FMD in eNOS-deficient mice. Our data suggest that endothelial ß1 integrin is required for both acute and chronic widening of the arterial lumen in response to hindlimb ischemia, potentially via functional interaction with eNOS.
Asunto(s)
Circulación Colateral/genética , Endotelio Vascular/metabolismo , Miembro Posterior/irrigación sanguínea , Integrina beta1/genética , Isquemia/etiología , Isquemia/metabolismo , Neovascularización Fisiológica/genética , Vasodilatación , Animales , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Técnicas de Inactivación de Genes , Miembro Posterior/metabolismo , Miembro Posterior/patología , Humanos , Integrina beta1/metabolismo , Isquemia/patología , Ratones , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo III/metabolismo , Unión ProteicaRESUMEN
[This corrects the article DOI: 10.1371/journal.pone.0013650.].
RESUMEN
Angiocrine signals derived from endothelial cells are an important component of intercellular communication and have a key role in organ growth, regeneration and disease1-4. These signals have been identified and studied in multiple organs, including the liver, pancreas, lung, heart, bone, bone marrow, central nervous system, retina and some cancers1-4. Here we use the developing liver as a model organ to study angiocrine signals5,6, and show that the growth rate of the liver correlates both spatially and temporally with blood perfusion to this organ. By manipulating blood flow through the liver vasculature, we demonstrate that vessel perfusion activates ß1 integrin and vascular endothelial growth factor receptor 3 (VEGFR3). Notably, both ß1 integrin and VEGFR3 are strictly required for normal production of hepatocyte growth factor, survival of hepatocytes and liver growth. Ex vivo perfusion of adult mouse liver and in vitro mechanical stretching of human hepatic endothelial cells illustrate that mechanotransduction alone is sufficient to turn on angiocrine signals. When the endothelial cells are mechanically stretched, angiocrine signals trigger in vitro proliferation and survival of primary human hepatocytes. Our findings uncover a signalling pathway in vascular endothelial cells that translates blood perfusion and mechanotransduction into organ growth and maintenance.
Asunto(s)
Comunicación Autocrina , Integrina beta1/metabolismo , Hígado/crecimiento & desarrollo , Hígado/fisiología , Mecanotransducción Celular/fisiología , Transducción de Señal , Animales , Células Cultivadas , Células Endoteliales/fisiología , Femenino , Factor de Crecimiento de Hepatocito/metabolismo , Hepatocitos/citología , Hepatocitos/fisiología , Humanos , Hígado/irrigación sanguínea , Hígado/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Receptor 3 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
AIMS/HYPOTHESIS: Angiopoietin-like 4 (ANGPTL4) is an important regulator of triacylglycerol metabolism, carrying out this role by inhibiting the enzymes lipoprotein lipase and pancreatic lipase. ANGPTL4 is a potential target for ameliorating cardiometabolic diseases. Although ANGPTL4 has been implicated in obesity, the study of the direct role of ANGPTL4 in diet-induced obesity and related metabolic dysfunction is hampered by the massive acute-phase response and development of lethal chylous ascites and peritonitis in Angptl4-/- mice fed a standard high-fat diet. The aim of this study was to better characterise the role of ANGPTL4 in glucose homeostasis and metabolic dysfunction during obesity. METHODS: We chronically fed wild-type (WT) and Angptl4-/- mice a diet rich in unsaturated fatty acids and cholesterol, combined with fructose in drinking water, and studied metabolic function. The role of the gut microbiota was investigated by orally administering a mixture of antibiotics (ampicillin, neomycin, metronidazole). Glucose homeostasis was assessed via i.p. glucose and insulin tolerance tests. RESULTS: Mice lacking ANGPTL4 displayed an increase in body weight gain, visceral adipose tissue mass, visceral adipose tissue lipoprotein lipase activity and visceral adipose tissue inflammation compared with WT mice. However, they also unexpectedly had markedly improved glucose tolerance, which was accompanied by elevated insulin levels. Loss of ANGPTL4 did not affect glucose-stimulated insulin secretion in isolated pancreatic islets. Since the gut microbiota have been suggested to influence insulin secretion, and because ANGPTL4 has been proposed to link the gut microbiota to host metabolism, we hypothesised a potential role of the gut microbiota. Gut microbiota composition was significantly different between Angptl4-/- mice and WT mice. Interestingly, suppression of the gut microbiota using antibiotics largely abolished the differences in glucose tolerance and insulin levels between WT and Angptl4-/- mice. CONCLUSIONS/INTERPRETATION: Despite increasing visceral fat mass, inactivation of ANGPTL4 improves glucose tolerance, at least partly via a gut microbiota-dependent mechanism.
Asunto(s)
Proteína 4 Similar a la Angiopoyetina/genética , Microbioma Gastrointestinal , Intolerancia a la Glucosa , Obesidad Abdominal/genética , Animales , Peso Corporal , Dieta Alta en Grasa , Ácidos Grasos/metabolismo , Fructosa/metabolismo , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Homeostasis , Insulina/metabolismo , Resistencia a la Insulina , Grasa Intraabdominal/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/metabolismo , Permeabilidad , Fenotipo , Aumento de PesoRESUMEN
OBJECTIVE: The aim was to investigate the influence of repetitive scuba diving in fresh water on the middle ear mucosa. The prevalence of middle ear barotrauma (MEB) and risk factors for MEB were evaluated. STUDY DESIGN: Prospective cohort study, Level of evidence 1b. METHODS: During three days, 23 divers made 144 repetitive dives in a freshwater lake. Participants underwent otoscopic examinations and were questioned about ENT-related complaints in the morning before the first dive, in between the dives and after the last dive. Otoscopic findings were documented and classified according to the TEED scale (0 = normal eardrum to 4 = perforation), for the right and the left ear separately. RESULTS: In total, 416 examinations were performed. ENT-related complaints during diving, mostly failed pressure equalization (74%), were reported after 10% of all dives. Most common pathology was MEB (TEED 1-3, 26%). Valsalva maneuver was possible during all exams. Significant increase of MEB (TEED⟩0) occurred with an increasing cumulative number of dives per day (P ⟨ .0001). Diving depth significantly influenced the MEB distribution (P = .035). MEB with higher TEED levels (2 and 3) was present only in the less experienced and intermediate divers. With increasing TEED level, more participants reported ENT-related problems (P ⟨ .0001). However, 74.4% of divers with MEB were still asymptomatic. CONCLUSION: During three days of diving, the MEB prevalence increased with a cumulative number of dives per day. The major risk factors were diving depth and diving experience. Higher TEED level correlated with an increasing number of subjective ENT-related disorders during diving.
Asunto(s)
Barotrauma/etiología , Buceo/efectos adversos , Oído Medio/lesiones , Adulto , Barotrauma/diagnóstico , Barotrauma/epidemiología , Estudios de Cohortes , Femenino , Agua Dulce , Alemania/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Otoscopía , Prevalencia , Estudios Prospectivos , Factores de Riesgo , Adulto JovenRESUMEN
Type 2 diabetes mellitus (T2DM) is a worldwide escalating health disorder resulting from insulin resistance and functional loss of insulin-producing beta cells that finally cause chronically elevated blood glucose concentrations. Here we review the role of ubiquitously expressed antioxidant protein DJ-1 in the pathogenesis of T2DM. In beta cells, DJ-1 protects against oxidative stress, endoplasmic reticulum stress, and streptozotocin- and cytokine-induced stress and preserves beta cell viability and insulin secretion. In skeletal muscle, DJ-1 controls energy metabolism and efficient fuel utilization, whereas in adipose tissue a role in adipogenesis and obesity-induced inflammation has been reported. This suggests that DJ-1 plays multiple roles in many cell types under metabolically challenging conditions as seen in obesity, insulin resistance, and T2DM.
Asunto(s)
Antioxidantes/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Resistencia a la Insulina , Proteína Desglicasa DJ-1/metabolismo , Tejido Adiposo/metabolismo , Animales , Metabolismo Energético , Humanos , Células Secretoras de Insulina/metabolismo , Músculo Esquelético/metabolismoRESUMEN
Diabetes mellitus is characterized by chronically elevated blood glucose levels accelerated by a progressive decline of insulin-producing ß-cells in the pancreatic islets. Although medications are available to transiently adjust blood glucose to normal levels, the effects of current drugs are limited when it comes to preservation of a critical mass of functional ß-cells to sustainably maintain normoglycemia. In this review, we recapitulate recent evidence on the role of pancreatic N-methyl-D-aspartate receptors (NMDARs) in ß-cell physiology, and summarize effects of morphinan-based NMDAR antagonists that are beneficial for insulin secretion, glucose tolerance and islet cell survival. We further discuss NMDAR-mediated molecular pathways relevant for neuronal cell survival, which may also be important for the preservation of ß-cell function and mass. Finally, we summarize the literature for evidence on the role of NMDARs in the development of diabetic long-term complications, and highlight beneficial pharmacologic aspects of NMDAR antagonists in diabetic nephropathy, retinopathy as well as neuropathy.
Asunto(s)
Complicaciones de la Diabetes/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Drogas en Investigación/uso terapéutico , Hiperglucemia/prevención & control , Hipoglucemiantes/uso terapéutico , Células Secretoras de Insulina/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/metabolismo , Nefropatías Diabéticas/prevención & control , Neuropatías Diabéticas/prevención & control , Retinopatía Diabética/prevención & control , Diseño de Fármacos , Resistencia a Múltiples Medicamentos , Drogas en Investigación/efectos adversos , Drogas en Investigación/química , Glucagón/metabolismo , Células Secretoras de Glucagón/efectos de los fármacos , Células Secretoras de Glucagón/metabolismo , Humanos , Hipoglucemia/inducido químicamente , Hipoglucemia/prevención & control , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/química , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Neuralgia/complicaciones , Neuralgia/prevención & control , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
An important question is how growing tissues establish a blood vessel network. Here we study vascular network formation in pancreatic islets, endocrine tissues derived from pancreatic epithelium. We find that depletion of integrin-linked kinase (ILK) in the pancreatic epithelial cells of mice results in glucose intolerance due to a loss of the intra-islet vasculature. In turn, blood vessels accumulate at the islet periphery. Neither alterations in endothelial cell proliferation, apoptosis, morphology, Vegfa expression and VEGF-A secretion nor 'empty sleeves' of vascular basement membrane are found. Instead, biophysical experiments reveal that the biomechanical properties of pancreatic islet cells, such as their actomyosin-mediated cortex tension and adhesive forces to endothelial cells, are significantly changed. These results suggest that a sorting event is driving the segregation of endothelial and epithelial cells and indicate that the epithelial biomechanical properties determine whether the blood vasculature invades or envelops a growing epithelial tissue.
Asunto(s)
Epitelio/irrigación sanguínea , Epitelio/fisiología , Islotes Pancreáticos/irrigación sanguínea , Proteínas Serina-Treonina Quinasas/fisiología , Actomiosina/fisiología , Animales , Membrana Basal/fisiología , Fenómenos Biomecánicos , Adhesión Celular/fisiología , Células Endoteliales/citología , Células Endoteliales/fisiología , Células Epiteliales/fisiología , Femenino , Intolerancia a la Glucosa/fisiopatología , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/citología , Islotes Pancreáticos/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neovascularización Fisiológica , Proteínas Serina-Treonina Quinasas/deficiencia , Proteínas Serina-Treonina Quinasas/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
INTRODUCTION: The aim was to investigate the prevalence of middle ear barotrauma (MEB) and to establish risk factors of MEB after repeated saltwater dives. METHODS: In this prospective observational cohort study 28 divers were examined over 6 consecutive days of diving in the Red Sea, Egypt. Participants underwent an otoscopic examination before the first dive, between each dive and after the last dive. In addition, they performed Valsalva maneuver (VM) and were questioned about dive-related complaints. Otoscopic findings were classified according to TEED classification for MEB (0â=ânormal otoscopy to 4â=âperforation) separately for each ear. First examination was conducted before the first dive. Final examination, including a questionnaire, was conducted at least 12âh after the last dive. RESULTS: In total, 436 dives were performed and 1161 otoscopic findings were analyzed. All participants showed a normal eardrum and a positive VM during initial exam. MEB prevalence (TEED >0) was 36.5% at final examination. Prevalence increased significantly with number of dives per day (pâ<â0.001) as with number of diving days (pâ=â0.032). Neither depth nor duration of dives significantly influenced MEB prevalence (all pâ>â0.05). More experienced divers (>200 dives lifetime) showed significantly less barotrauma (pâ<â0.0001). Despite the high prevalence of MEB, 81.7% (316 of 387) of all dives were reported asymptomatic. CONCLUSIONS: After 6 days of repetitive diving, MEB prevalence was high (36.5%). It was the most often cause of otalgia in divers. Cumulative pressure exposure during repetitive dives resulted in significant increase of MEB. Diving experience significantly reduced the MEB prevalence. Interestingly, the severity of MEB did not correlate with subjective complaints.
Asunto(s)
Barotrauma/epidemiología , Buceo/efectos adversos , Oído Medio/lesiones , Adulto , Estudios de Cohortes , Femenino , Humanos , Océano Índico , Masculino , Prevalencia , Estudios Prospectivos , Factores de RiesgoRESUMEN
A hallmark feature of type 1 and type 2 diabetes mellitus is the progressive dysfunction and loss of insulin-producing pancreatic beta cells, and inflammatory cytokines are known to trigger beta cell death. Here we asked whether the anti-oxidant protein DJ-1 encoded by the Parkinson's disease gene PARK7 protects islet cells from cytokine- and streptozotocin-mediated cell death. Wild type and DJ-1 knockout mice (KO) were treated with multiple low doses of streptozotocin (MLDS) to induce inflammatory beta cell stress and cell death. Subsequently, glucose tolerance tests were performed, and plasma insulin as well as fasting and random blood glucose concentrations were monitored. Mitochondrial morphology and number of insulin granules were quantified in beta cells. Moreover, islet cell damage was determined in vitro after streptozotocin and cytokine treatment of isolated wild type and DJ-1 KO islets using calcein AM/ethidium homodimer-1 staining and TUNEL staining. Compared to wild type mice, DJ-1 KO mice became diabetic following MLDS treatment. Insulin concentrations were substantially reduced, and fasting blood glucose concentrations were significantly higher in MLDS-treated DJ-1 KO mice compared to equally treated wild type mice. Rates of beta cell apoptosis upon MLDS treatment were twofold higher in DJ-1 KO mice compared to wild type mice, and in vitro inflammatory cytokines led to twice as much beta cell death in pancreatic islets from DJ-1 KO mice versus those of wild type mice. In conclusion, this study identified the anti-oxidant protein DJ-1 as being capable of protecting pancreatic islet cells from cell death induced by an inflammatory and cytotoxic setting.
Asunto(s)
Citocinas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Células Secretoras de Insulina/metabolismo , Mitocondrias/metabolismo , Proteínas Oncogénicas/metabolismo , Peroxirredoxinas/metabolismo , Animales , Muerte Celular , Citocinas/genética , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patología , Insulina/genética , Insulina/metabolismo , Células Secretoras de Insulina/patología , Ratones , Ratones Noqueados , Mitocondrias/genética , Mitocondrias/patología , Proteínas Oncogénicas/genética , Peroxirredoxinas/genética , Proteína Desglicasa DJ-1 , Vesículas Secretoras/genética , Vesículas Secretoras/metabolismoRESUMEN
In the nervous system, NMDA receptors (NMDARs) participate in neurotransmission and modulate the viability of neurons. In contrast, little is known about the role of NMDARs in pancreatic islets and the insulin-secreting beta cells whose functional impairment contributes to diabetes mellitus. Here we found that inhibition of NMDARs in mouse and human islets enhanced their glucose-stimulated insulin secretion (GSIS) and survival of islet cells. Further, NMDAR inhibition prolonged the amount of time that glucose-stimulated beta cells spent in a depolarized state with high cytosolic Ca(2+) concentrations. We also noticed that, in vivo, the NMDAR antagonist dextromethorphan (DXM) enhanced glucose tolerance in mice, and that in vitro dextrorphan, the main metabolite of DXM, amplified the stimulatory effect of exendin-4 on GSIS. In a mouse model of type 2 diabetes mellitus (T2DM), long-term treatment with DXM improved islet insulin content, islet cell mass and blood glucose control. Further, in a small clinical trial we found that individuals with T2DM treated with DXM showed enhanced serum insulin concentrations and glucose tolerance. Our data highlight the possibility that antagonists of NMDARs may provide a useful adjunct treatment for diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Páncreas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Adulto , Animales , Calcio/metabolismo , Línea Celular , Supervivencia Celular , Dextrometorfano/química , Modelos Animales de Enfermedad , Diseño de Fármacos , Exenatida , Femenino , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/citología , Islotes Pancreáticos/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Péptidos/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/genética , Ponzoñas/metabolismoRESUMEN
The metabolic syndrome is a worldwide problem mainly caused by obesity. FTO was found to be a obesity-risk gene in humans and FTO deficiency in mice led to reduction in adipose tissue. Thus, FTO is an important factor for the development of obesity. Leptin-deficient mice are a well characterized model for analysing the metabolic syndrome. To determine the relevance of FTO for the development of the metabolic syndrome we analysed different parameters in combined homozygous deficient mice (Lep(ob/ob);Fto(-/-)). Lep(ob/ob);Fto(-/-) mice showed an improvement in analysed hallmarks of the metabolic syndrome in comparison to leptin-deficient mice wild type or heterozygous for Fto. Lep(ob/ob);Fto(-/-) mice did not develop hyperglycaemia and showed an improved glucose tolerance. Furthermore, extension of beta-cell mass was prevented in Lep(ob/ob);Fto(-/-)mice and accumulation of ectopic fat in the liver was reduced. In conclusion this study demonstrates that FTO deficiency has a protective effect not only on the development of obesity but also on the metabolic syndrome. Thus, FTO plays an important role in the development of metabolic disorders and is an interesting target for therapeutic agents.