RESUMEN
BACKGROUND: This study aimed to examine the effect of metabolic surgery on pre-existing and future microvascular complications in patients with type 2 diabetes mellitus (T2DM) in comparison with medical treatment. Although metabolic surgery is the most effective treatment for obese patients with T2DM regarding glycaemic control, it is unclear whether the incidence or severity of microvascular complications is reduced. METHODS: A systematic literature search was performed in MEDLINE, Embase, Web of Science and the Cochrane Central Register of Controlled Trials (CENTRAL) with no language restrictions, looking for RCTs, case-control trials and cohort studies that assessed the effect of metabolic surgery on the incidence of microvascular diabetic complications compared with medical treatment as control. The study was registered in the International prospective register of systematic reviews (CRD42016042994). RESULTS: The literature search yielded 1559 articles. Ten studies (3 RCTs, 7 controlled clinical trials) investigating 17 532 patients were included. Metabolic surgery reduced the incidence of microvascular complications (odds ratio 0·26, 95 per cent c.i. 0·16 to 0·42; P < 0·001) compared with medical treatment. Pre-existing diabetic nephropathy was strongly improved by metabolic surgery versus medical treatment (odds ratio 15·41, 1·28 to 185·46; P = 0·03). CONCLUSION: In patients with T2DM, metabolic surgery prevented the development of microvascular complications better than medical treatment . Metabolic surgery improved pre-existing diabetic nephropathy compared with medical treatment.
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Cirugía Bariátrica , Diabetes Mellitus Tipo 2/complicaciones , Angiopatías Diabéticas/prevención & control , Hipoglucemiantes/uso terapéutico , Diabetes Mellitus Tipo 2/terapia , Angiopatías Diabéticas/epidemiología , Angiopatías Diabéticas/etiología , Humanos , Incidencia , Microvasos , Oportunidad Relativa , Resultado del TratamientoRESUMEN
A 62-year-old diabetologist diagnosed himself to have diabetes type-2, with an HbA1c of 9.5. Five months after lifestyle intervention and a multi-drug approach, HbA1c was 6.3, systolic blood pressure was below 135mmHg and BMI reduced to 27. But he suffered from severe painful diabetic neuropathy. Therefore he decided to visit his friend, a famous neuroscientist at an even more famous university. He asked him several plain questions: 1. What is the natural course of painful diabetic neuropathy? 2. Why do I have, despite almost normalizing HbA1c, more problems than before? 3. Are you sure my problems are due to diabetes or should we do a nerve biopsy? 4. Are there imaging techniques helpful for the diagnosis of this diabetic complication, starting in the distal nerve endings of the foot and slowly moving ahead? 5. Can you suggest any drug, specific and effective, for relieving painful diabetic neuropathy? This review will use the experts' answers to the questions of the diabetologist, not only to give a summary of the current knowledge, but even more to highlight areas of research needed for improving the fate of patients with painful diabetic neuropathy. Based on the unknowns, which exceed the knowns in diabetic neuropathy, a quest for more public support of research is made.
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Investigación Biomédica , Neuropatías Diabéticas/complicaciones , Dolor/complicaciones , Animales , Neuropatías Diabéticas/diagnóstico , Neuropatías Diabéticas/tratamiento farmacológico , Progresión de la Enfermedad , HumanosRESUMEN
Renal sinus fat (RSF) is a perivascular fat compartment located around renal arteries. In this in vitro and in vivo study we hypothesized that the hepatokine fetuin-A may impair renal function in non alcoholic fatty liver disease (NAFLD) by altering inflammatory signalling in RSF. To study effects of the crosstalk between fetuin-A, RSF and kidney, human renal sinus fat cells (RSFC) were isolated and cocultured with human endothelial cells (EC) or podocytes (PO). RSFC caused downregulation of proinflammatory and upregulation of regenerative factors in cocultured EC and PO, indicating a protective influence of RFSC. However, fetuin-A inverted these benign effects of RSFC from an anti- to a proinflammatory status. RSF was quantified by magnetic resonance imaging and liver fat content by 1H-MR spectroscopy in 449 individuals at risk for type 2 diabetes. Impaired renal function was determined via urinary albumin/creatinine-ratio (uACR). RSF did not correlate with uACR in subjects without NAFLD (n = 212, p = 0.94), but correlated positively in subjects with NAFLD (n = 105, p = 0.0005). Estimated glomerular filtration rate (eGRF) was inversely correlated with RSF, suggesting lower eGFR for subjects with higher RSF (r = 0.24, p < 0.0001). In conclusion, our data suggest that in the presence of NAFLD elevated fetuin-A levels may impair renal function by RSF-induced proinflammatory signalling in glomerular cells.
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Grasa Intraabdominal/fisiología , Glomérulos Renales/citología , Glomérulos Renales/metabolismo , Riñón/anatomía & histología , Riñón/fisiología , Arteria Renal/anatomía & histología , alfa-2-Glicoproteína-HS/metabolismo , Adipocitos/metabolismo , Adulto , Células Cultivadas , Técnicas de Cocultivo , Citocinas/metabolismo , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Mediadores de Inflamación/metabolismo , Grasa Intraabdominal/diagnóstico por imagen , Riñón/diagnóstico por imagen , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , Arteria Renal/diagnóstico por imagenRESUMEN
Essentials The role of protein C (PC) activation in experimental autoimmune encephalitis (EAE) is unknown. PC activation is required for mitochondrial function in the central nervous system. Impaired PC activation aggravates EAE, which can be compensated for by soluble thrombomodulin. Protection of myelin by activated PC or solulin is partially independent of immune-modulation. SUMMARY: Background Studies with human samples and in rodents established a function of coagulation proteases in neuro-inflammatory demyelinating diseases (e.g. in multiple sclerosis [MS] and experimental autoimmune encephalitis [EAE]). Surprisingly, approaches to increase activated protein C (aPC) plasma levels as well as antibody-mediated inhibition of PC/aPC ameliorated EAE in mice. Hence, the role of aPC generation in demyelinating diseases and potential mechanisms involved remain controversial. Furthermore, it is not known whether loss of aPC has pathological consequences at baseline (e.g. in the absence of disease). Objective To explore the role of thrombomodulin (TM)-dependent aPC generation at baseline and in immunological and non-immunological demyelinating disease models. Methods Myelination and reactive oxygen species (ROS) generation were evaluated in mice with genetically reduced TM-mediated protein C activation (TMPro/Pro ) and in wild-type (WT) mice under control conditions or following induction of EAE. Non-immunological demyelination was analyzed in the cuprizone-diet model. Results Impaired TM-dependent aPC generation already disturbs myelination and mitochondrial function at baseline. This basal phenotype is linked with increased mitochondrial ROS and aggravates EAE. Reducing mitochondrial ROS (p66Shc deficiency), restoring aPC plasma levels or injecting soluble TM (solulin) ameliorates EAE in TMPro/Pro mice. Soluble TM additionally conveyed protection in WT-EAE mice. Furthermore, soluble TM dampened demyelination in the cuprizone-diet model, demonstrating that its myelin-protective effect is partially independent of an immune-driven process. Conclusion These results uncover a novel physiological function of TM-dependent aPC generation within the CNS. Loss of TM-dependent aPC generation causes a neurological defect in healthy mice and aggravates EAE, which can be therapeutically corrected.
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Sistema Nervioso Central/metabolismo , Mitocondrias/metabolismo , Vaina de Mielina/química , Proteína C/metabolismo , Trombomodulina/sangre , Animales , Encéfalo/metabolismo , Cardiolipinas/química , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Humanos , Sistema Inmunológico , Ratones , Ratones Endogámicos C57BL , Mutación , Neuronas , Estrés Oxidativo , Células PC12 , Fenotipo , Ratas , Especies Reactivas de Oxígeno/metabolismo , Solubilidad , Trombomodulina/químicaRESUMEN
AIMS: The glycolysis-derived metabolite methylglyoxal has been linked to clinical microvascular complications, including diabetic nephropathy. We aimed to further investigate the hypothesis that methylglyoxal is involved in decline in renal function by assessing the associations between measures of renal function during a 6-year follow-up in 1481 people with screen-detected Type 2 diabetes, as part of the Danish arm of the ADDITION-Europe trial (ADDITION-DK). METHODS: Biobank serum samples collected at ADDITION-DK baseline (2001-2006) and follow-up (2009-2010) were used in the current analysis of methylglyoxal. We assessed cross-sectional baseline and longitudinal associations between methylglyoxal and urinary albumin-to-creatinine ratio (ACR) or estimated GFR (eGFR), and between methylglyoxal and categories of albuminuria or reduced eGFR. RESULTS: Baseline methylglyoxal was positively associated with ACR at baseline (12% higher ACR per doubling in methylglyoxal levels), and change in methylglyoxal during 6 years of follow-up was inversely associated with change in eGFR (-1.6 ml/min/1.73 m2 per doubling in methylglyoxal change), in models adjusted for age, sex, HbA1c , systolic blood pressure, anti-hypertensive treatment, LDL-cholesterol, lipid-lowering treatment, C-reactive protein and smoking. CONCLUSIONS: In a population of people with screen-detected Type 2 diabetes, we observed associations between methylglyoxal and markers of renal function: 6-year change in methylglyoxal was inversely associated with 6-year change in eGFR. Also, methylglyoxal at baseline was positively associated with ACR at baseline. Our study lends further support to a role for methylglyoxal in the pathogenesis of diabetic nephropathy.
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Diabetes Mellitus Tipo 2/fisiopatología , Nefropatías Diabéticas/fisiopatología , Piruvaldehído/metabolismo , Insuficiencia Renal Crónica/fisiopatología , Adulto , Anciano , Albuminuria/fisiopatología , Creatinina/orina , Estudios Transversales , Femenino , Tasa de Filtración Glomerular/fisiología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Predicting an individual's success in a non-surgical weight loss approach is a demanding need since obesity is becoming an epidemic burden. A possible predictive marker is myostatin, a member of the transforming growth factor b superfamily, which has been shown to be an important regulator of muscle homeostasis. METHODS: In the present study, we analyzed myostatin as a marker to predict weight loss of patients that participated in a 2 phased weight reduction program, comprising a weight loss period of 12 weeks and a weight stabilization period of 40 weeks. Therefore, 62 obese individuals with a mean BMI of 40.6 kg/m(2) were included. Plasma myostatin was measured with ELISA at the beginning (T0), after weight loss (T1) and at the end of the program (T2). RESULTS: Although significant weight loss of -23.9±14.9 kg was achieved, myostatin did not change significantly during the program (T0>T1: p=0.46; T1>T2: p=0.70; T0>T2: p=0.57). Myostatin at baseline did neither negatively correlate with the achieved weight loss in the weight reduction phase (T0>T1: r=0.27, p=0.16) nor with weight loss during the whole program (T0>T2: r=0.20, p=0.29). Only a minor correlation with myostatin levels after weight loss with weight regain during maintenance period was detected. (T1>T2: r=-0.37, p=0.05). CONCLUSION: Plasma myostatin might be suitable in predicting weight regain after marked weight loss, but no association with weight loss was observed in patients undergoing a non-surgical weight loss program. Therefore, myostatin does not seem to be a predictor for success in non-surgical weight loss approaches.
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Miostatina/sangre , Obesidad/sangre , Obesidad/terapia , Pérdida de Peso , Adulto , Anciano , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Comprehensive diabetes treatment has been shown to reduce quality of life in diabetic patients. However, there is evidence to suggest that group singing can have positive effects on quality of life in various clinical settings. In this randomized controlled pilot study, the effect of singing as a therapy to reduce stress and improve quality of life was investigated in insulin-dependent diabetic patients, undergoing a lifestyle intervention program. Patients from the singing group felt less discontented following treatment. This effect, however, was lost after 3 months. No effect on serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels could be seen when comparing the singing group with the control group, although reduced levels of ACTH and cortisol 3 days after treatment could be found and were still present after 3 months within the group of patients who undertook singing as a therapy. Singing led to an increase in bodyweight, which interestingly had no effect on glucose control or methylglyoxal levels. Therefore, singing during a lifestyle intervention program for insulin-dependent diabetic patients had a short lasting and weak effect on patients' mood without affecting glucose control, but no significant effect on stress related hormones.
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Diabetes Mellitus Tipo 1/terapia , Canto , Estrés Psicológico/terapia , Adulto , Anciano , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estrés Psicológico/sangre , Estrés Psicológico/fisiopatología , Factores de TiempoRESUMEN
Current guidelines for the treatment of type 2 diabetes focus on pharmacological treatment of glucose and cardio-vascular risk factors. The aim of this prospective randomized controlled intervention study was to examine the effects of a psychosocial intervention on clinical endpoints and risk factors in patients with type 2 diabetes and early diabetic kidney disease.110 patients were randomized to receive an 8-week mindfulness-based stress reduction (MBSR) training (n = 53) compared to standard care (n = 57). The study was carried out open-labelled and randomization was performed computer-generated in a 1:1 ratio. Primary outcome of the study was the change in urinary albumin excretion (albumin-creatinine-ratio, ACR); secondary outcomes were metabolic parameters, intima media thickness (IMT), psychosocial parameters and cardiovascular events.89 patients (42 in control group and 47 in intervention group) were analysed after 3 years of follow-up. After 1 year, the intervention group showed a reduction of ACR from 44 [16/80] to 39 [20/71] mg/g, while controls increased from 47 [16/120] to 59 [19/128] mg/g (p = 0.05). Parallel to the reduction of stress levels after 1 year, the intervention-group additionally showed reduced catecholamine levels (p < 0.05), improved 24 h-mean arterial (p < 0.05) and maximum systolic blood pressure (p < 0.01), as well as a reduction in IMT (p < 0.01). However, these effects were lost after 2 and 3 years of follow-up.This is the first study to show that a psychosocial intervention improves cardiovascular risk factors in high risk type 2 diabetes patients. Trial-Registration: NCT00263419 http://clinicaltrials.gov/ct2/show/NCT00263419 TRIAL REGISTRATION: clinicaltrials.gov-Identifier: NCT00263419.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Estrés Psicológico , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/psicología , Diabetes Mellitus Tipo 2/psicología , Diabetes Mellitus Tipo 2/terapia , Nefropatías Diabéticas/psicología , Nefropatías Diabéticas/terapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Estrés Psicológico/psicología , Estrés Psicológico/terapiaRESUMEN
The effect of metformin on methylglyoxal (MG) metabolism was studied in a prospective non-randomized 24 weeks trial in patients with type 2 diabetes.Metformin treatment, in addition to life style intervention, significantly reduced morning glucose and HbA1c whilst body weight and BMI were only marginally reduced during the 24 week trial. Treatment significantly reduced both plasma MG and carboxymethyl-lysine (CML), a marker of oxidative stress. The reduction in MG was paralleled by a significant increase in the activity of Glyoxalase 1 (Glo1), the major route of MG detoxification, in peripheral blood mononuclear cells and red blood cells. Multivariate analysis showed that the changes in MG were dependent upon the metformin treatment.This study supports previous findings that metformin can reduce plasma MG in type 2 diabetic patients. However, given the observed increase in Glo1 activity, this reduction is due not only to the scavenging properties of metformin, but the restoration of Glo1 activity.
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Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Metformina/análogos & derivados , Piruvaldehído/sangre , Adulto , Femenino , Humanos , Lactoilglutatión Liasa/metabolismo , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
The clinical symptoms of diabetic neuropathy (DN) manifest in a time dependent manner as a positive symptoms (i. e. pain, hypersensitivity, tingling, cramps, cold feet etc.) during its early stages and by a loss of function (i. e. loss of sensory perception, delayed wound healing etc.) predominating in the later stages. Elevated blood glucose alone cannot explain the development and progression of DN and the lowering of blood glucose is insufficient in preventing and/or reversing neuropathy in patients with type 2 diabetes. Recently it has been shown that the endogenous reactive metabolite methylglyoxal (MG) can contribute to the gain of function via post-translational modification in DN of neuronal ion channels involved in chemosensing and action potential generation in nociceptive nerve endings. Dicarbonyls, such as MG, that are elevated in diabetic patients, modify DNA as well as extra- and intracellular proteins, leading to the formation of advanced glycation endproducts (AGEs). Increased formation of AGEs leads to increased cellular stress, dysfunction and ultimately cell death. The interaction of AGE-modified proteins through cell surface receptors, such as RAGE, can lead to increased cellular activation and sustained inflammatory responses, which are the molecular hallmarks of the later, degenerative, stages of DN. The direct and indirect effects of dicarbonyls on nerves or neuronal microvascular network provides a unifying mechanism for the development and progression of DN. Targeting the accumulation of MG and/or prevention of RAGE interactions may therefore provide new, more effective, therapeutic approaches for the treatment of DN.
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Diabetes Mellitus Tipo 2/metabolismo , Neuropatías Diabéticas/metabolismo , Neuropatías Diabéticas/terapia , Animales , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/terapia , Neuropatías Diabéticas/sangre , Productos Finales de Glicación Avanzada/sangre , Productos Finales de Glicación Avanzada/metabolismo , Glioxal/sangre , Glioxal/metabolismo , Humanos , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/sangre , Receptores Inmunológicos/metabolismoRESUMEN
BACKGROUND: Prospective, placebo-controlled, double-blind, randomized studies on osteoporosis treatment with bisphosphonates in men are rare. This review focuses on a recent trial and compares the results with other studies. METHODS: This review provides a summary of recent literature on fracture risk in men following treatment with zoledronic acid. According to a recent clinical study with 1,199 men, zoledronic acid was linked to a lower risk of vertebral fractures. In this manuscript, a re-analysis of the presented statistical data will be demonstrated by performing a Bonferroni-correction to adjust for type 1 error accumulation in multiple statistical tests. RESULTS: It will be shown that the provided evidence linking zoledronic acid to a lower fracture risk in male osteoporosis is true, but less pronounced than originally assumed. CONCLUSION: Comparative clinical studies are recommended, where the benefits of different bisphosphonates are compared to each other under the same experimental conditions.
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Conservadores de la Densidad Ósea/uso terapéutico , Difosfonatos/uso terapéutico , Fracturas Óseas/prevención & control , Imidazoles/uso terapéutico , Osteoporosis/tratamiento farmacológico , Humanos , Masculino , Medición de Riesgo , Ácido ZoledrónicoRESUMEN
The established marker for tubular damage, urinary n-acetyl-beta-d-glucosaminidase is significantly increased in type 1 and 2 diabetes patients and is related to albuminuria and other diabetic complications. In this cross sectional study of type 2 diabetes patients with a history of albuminuria, we studied the relationship between excretion of n-acetyl-beta-d-glucosaminidase in urine and diabetic neuropathy.160 type 2 diabetes patients were screened for diabetic peripheral neuropathy and cardiovascular autonomic neuropathy. N-acetyl-beta-d-glucosaminidase excretion was detected in 24 h urine samples.Urinary excretion of n-acetyl-beta-d-glucosaminidase correlated significantly with -glucose control (fasting glucose r=0.18; p=0.04; HbA1c r=0.20; p=0.02) and urine albumin excretion (r=0.22; p=0.01). Binary regression analyses showed that increased urinary n-acetyl-beta-d-glucosaminidase concentration is an independent predictor for presence of clinical symptoms of peripheral neuropathy (OR 1.8 [95%CI 1.2-2.74] and vibration deficiency [OR 1.7; 95% CI 1.2-2.66]. There was also a significant negative association between urinary n-acetyl-beta-d-glucosaminidase and E/I-Ratio (r=-0.21, p<0.02) as well as the 30:15-Ratio (r=-0.24; p<0.01) of heart rate variability. Furthermore, increased n-acetyl-beta-d-glucosaminidase excretion independently predicted cardiovascular autonomic diabetic neuropathy with an OR for decreased E/I-Ratio of 1.7 [95%CI 1.1-2.75]; (p<0.02) and 30:15-Ratio:OR 2.4 [95% CI 1.26-4.45]; (p<0.01).Urinary n-acetyl-beta-d-glucosami-nidase excretion is an independent marker for diabetic peripheral and cardiovascular autonomic neuropathy in type 2 diabetic patients.
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Acetilglucosaminidasa/orina , Diabetes Mellitus Tipo 2/orina , Neuropatías Diabéticas/orina , Anciano , Albuminuria/orina , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
AIMS/INTRODUCTION: Glyoxalase 1 catalyses the detoxification of methylglyoxal, a major precursor of advanced glycation end products associated with aging, neurodegenerative diseases, and microvascular complications of diabetes. Here, we examine a possible association of a single nucleotide polymorphism of glyoxalase 1 gene (Glo1 A332C, rs4746 or rs2736654) with the prevalence of microvascular diabetic complications in patients with type 1 and type 2 diabetes. MATERIALS AND METHODS: Genotyping was performed in 209 patients with type 1 and 524 patients with type 2 diabetes using polymerase chain reaction and subsequent cleavage by restriction endonuclease Bsa I. RESULTS: Frequencies of the glyoxalase 1 genotypes were different with respect to diabetes type with a significantly higher prevalence of A332A-genotype in type 1 diabetes (35.9% vs. 27.3%; p=0.03). In type 1 diabetes, there was no correlation of any genotype with diabetic retinopathy, nephropathy or neuropathy. In contrast, type 2 diabetic patients homozygous for the C332C allele showed a significantly increased prevalence of diabetic neuropathy (p=0.03; OR=1.49 [95%-CI: 1.04; 2.11]), while no association with diabetic nephropathy or retinopathy was found. However, the significance of this association was lost after correction for multiple testing. CONCLUSIONS: Our data suggest a possible association of C332C-genotype of the glyoxalase 1 gene with diabetic neuropathy in type 2 diabetes, supporting the hypothesis that methylglyoxal might be an important mediator of diabetic neuropathy in type 2 diabetes.
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Complicaciones de la Diabetes/genética , Diabetes Mellitus Tipo 2/genética , Genotipo , Lactoilglutatión Liasa/genética , Polimorfismo de Nucleótido Simple , Adulto , Estudios Transversales , Complicaciones de la Diabetes/enzimología , Diabetes Mellitus Tipo 1/enzimología , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/enzimología , Femenino , Humanos , Lactoilglutatión Liasa/metabolismo , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: The A-allele of the fat mass and obesity-associated (FTO) gene variant rs9939609 has been associated with increased body weight, whereas no effect on weight loss during weight reduction programs has been observed. We questioned whether the AA-genotype interferes with weight stabilization after weight loss. DESIGN: We conducted a monocentric, longitudinal study involving obese individuals. The FTO gene variant rs9939609 was genotyped in participants attending a weight reduction program that was divided into two phases: a weight reduction period with formula diet (12 weeks) and a weight maintenance phase (40 weeks). Body weight, body mass index (BMI), blood pressure and concentrations of blood glucose, total cholesterol, low-density lipoprotein, high-density lipoprotein and triglycerides were determined in week 0 (T(0)), after 12 weeks (T(1)) and at the end in week 52 (T(2)). SUBJECTS: A total of 193 obese subjects aged between 18 and 72 years (129 female, 64 male; initial body weight: 122.4±22.3 kg, initial BMI: 41.8±6.7 kg m(-2)) were included. RESULTS: Genotyping revealed 32.1% TT-, 39.4% AT- and 28.5% AA-genotype carriers. At T (0), carriers of the AA-genotype had significantly higher body weight (P=0.04) and BMI (P=0.005) than carriers of the TT-genotype. Of the 193 participants, 68 discontinued and 125 completed the program. Dropout rate was not influenced by genotype (P=0.33). Completers with AA-genotype showed significantly lower additional weight loss during the weight maintenance phase than TT-genotype carriers (P=0.02). Furthermore, among participants facing weight regain during weight maintenance (n=52), more subjects were carrying the AA-genotype (P=0.006). No influence of genotype on weight reduction under formula diet was observed (P=0.32). CONCLUSION: In this program, the AA-genotype of rs9939609 was associated with a higher initial body weight and did influence success of weight stabilization. Thus, emphasizing the maintenance phase during a weight reduction program might result in better success for AA-genotype carriers.
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Peso Corporal/genética , Obesidad/genética , Proteínas/genética , Aumento de Peso/genética , Pérdida de Peso/genética , Adolescente , Adulto , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Glucemia/metabolismo , Índice de Masa Corporal , Estudios Transversales , Femenino , Predisposición Genética a la Enfermedad , Variación Genética , Genotipo , Alemania/epidemiología , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Obesidad/sangre , Obesidad/epidemiología , Proyectos Piloto , Triglicéridos/sangreRESUMEN
The receptor for advanced glycation endproduct (RAGE) is involved in diabetic complications and chronic inflammation, conditions known to affect the sensitivity towards apoptosis. Here, we studied the effect of genetically depleting RAGE on the susceptibility towards apoptosis. In murine osteoblastic cells, RAGE knockout increased both spontaneous and induced apoptosis. Decreased levels of B-cell lymphoma 2 protein and increased intrinsic apoptosis were observed in Rage(-/-) cells. Furthermore, loss of RAGE increased expression of the death receptor CD95 (Fas, Apo-1), CD95-dependent caspase activation and extrinsic apoptosis, whereas NF-kB-p65 nuclear translocation was diminished. Importantly, depletion of RAGE reduced the ubiquitination and degradation of p53 and p73 and increased their nuclear translocation. The increase of p53 and p73 transactivational activity was essential for the RAGE-dependent regulation of apoptosis, because knockdown of p53 and p73 significantly decreased apoptosis in RAGE-deficient but not in RAGE-expressing cells. Thus, the RAGE-mediated posttranslational regulation of p53 and p73 orchestrates a sequence of events culminating in control of intrinsic and extrinsic apoptosis signaling pathways.
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Apoptosis/genética , Proteínas de Unión al ADN/metabolismo , Proteínas Nucleares/metabolismo , Procesamiento Proteico-Postraduccional/genética , Receptores Inmunológicos/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Apoptosis/efectos de los fármacos , Células Cultivadas , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Eliminación de Gen , Ratones , Ratones Noqueados , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Nucleares/genética , Procesamiento Proteico-Postraduccional/fisiología , Proteolisis , ARN Interferente Pequeño/farmacología , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/fisiología , Proteína Tumoral p73 , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/genética , Proteínas Supresoras de Tumor/antagonistas & inhibidores , Proteínas Supresoras de Tumor/genética , Ubiquitinación/genética , Ubiquitinación/fisiologíaAsunto(s)
Investigación Biomédica , Diabetes Mellitus , Femenino , Historia del Siglo XX , Historia del Siglo XXI , HumanosRESUMEN
A number of studies have addressed diabetic neuropathy (DN) in transgenic and knock out mouse models to unravel the molecular mechanisms underlying metabolic pain and loss of pain perception. However, it is difficult to compare these studies with each other or even with human DN due to experimental differences including the type of diabetes, the background strain of the respective mouse model, the methods of diabetes induction and the duration of diabetes, animal age and gender. To receive useful information for DN from genetically modified mice, it is therefore mandatory to first define the appropriate model and - if necessary - to backcross transgenic strains into the respective background to allow a reliable (and at least in part translatable to human DN) interpretation of the results.
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Agnosia/etiología , Neuropatías Diabéticas/complicaciones , Modelos Animales de Enfermedad , Ratones , Percepción del Dolor/fisiología , Dolor/etiología , Agnosia/genética , Animales , Neuropatías Diabéticas/etiología , Neuropatías Diabéticas/genética , Neuropatías Diabéticas/patología , Estudios de Evaluación como Asunto , Humanos , Ratones/genética , Ratones/metabolismo , Ratones/fisiología , Ratones Transgénicos , Dolor/genética , Dolor/patologíaRESUMEN
During long-term peritoneal dialysis (PD) the peritoneal membrane underlies processes of structural and functional reorganization mediated by high glucose and reactive glucose metabolites that are contained in PD solutions; this process is accompanied by increasing fibrosis. Mechanistically, the peritoneal damage is triggered by the interaction of advanced glycation end-products with their receptor; this is true for rodents as well as for humans. With this knowledge interventional strategies can be tested in rodent models, among them are the lipid soluble vitamin B1 analogue benfotiamine (BF) or detoxifying enzymes such as glyoxalase. Of additional interest is the finding that PD fluids do not only cause local but also systemic damage, in particular renal and cardiovascular. In the case of kidney damage, the intervention with BF was also successful. Taken together, PD can be regarded as a local model for long-term diabetes together with systemic aspects of damage.
Asunto(s)
Glucosa/farmacología , Modelos Animales , Peritoneo/efectos de los fármacos , Roedores/fisiología , Animales , Productos Finales de Glicación Avanzada/metabolismo , Productos Finales de Glicación Avanzada/farmacología , Humanos , Aprendizaje , Ratones , Peritoneo/metabolismo , Peritoneo/fisiología , Ratas , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/metabolismo , Receptores Inmunológicos/fisiologíaRESUMEN
Pathogenesis of late diabetic complications is influenced by a complex interplay of multiple exogenous and intrinsic factors. The well characterised nematode Caenorhabditis elegans is an ideal model to study causes of diabetic polyneuropathy because of its easily accessible nervous system. A repertoire of methods allows the assessment of both morphological and functional glucotoxic damages as well as reduction of lifespan, thereby helping to examine the influence of different pathways and mechanisms on neurodegeneration. Its insulin signalling system allows to directly visualize effects of insulin on high glucose induced neuronal damage, leading to a better understanding of diabetic polyneuropathy.
Asunto(s)
Caenorhabditis elegans/fisiología , Neuropatías Diabéticas/etiología , Neuropatías Diabéticas/fisiopatología , Modelos Animales de Enfermedad , Longevidad/fisiología , Animales , Animales Modificados Genéticamente , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Comprensión/fisiología , Neuropatías Diabéticas/genética , Neuropatías Diabéticas/patología , Humanos , Longevidad/genéticaRESUMEN
AIMS/HYPOTHESIS: We hypothesised that diabetic patients would differ from those without diabetes in regard to the handling of glucose-derived reactive metabolites, evidenced by triosephosphate intermediates (TP(INT)) and methylglyoxal (MG), irrespective of the type of diabetes, plasma glucose level or HbA(1c) value. METHODS: To test this hypothesis, erythrocytes were isolated from patients with type 1 (n = 12) and type 2 (n = 12) diabetes with varying blood glucose and HbA(1c) levels. These were then compared with erythrocytes isolated from individuals without diabetes (n = 10), with respect to MG, as determined by HPLC, and TP(INT), as determined by endpoint enzymatic assays. RESULTS: The concentrations of intracellular TP(INT) and MG were significantly elevated in erythrocytes from diabetic patients. Normalisation of either TP(INT) or MG to intracellular glucose concentration (nmol glucose/mgHb) confirmed that erythrocytes from diabetic patients accumulated more reactive metabolites than did those from healthy controls. CONCLUSIONS/INTERPRETATION: Diabetic patients can be characterised by an increased formation of TP(INT) and MG. The 25-fold increase of MG in type 1 and the 15-fold increase in type 2 diabetes, together with a several-fold increase in TP(INT) and decreased glyceraldehyde-3-phosphate dehydrogenase activity even under normal glucose conditions, imply that normalising glucose level cannot completely prevent late diabetic complications until this acquired error of metabolism has been restored.