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The hypothalamic neuropeptide oxytocin not only modulates psychosocial function, but also contributes to metabolic regulation. We have recently shown that intranasal oxytocin acutely improves beta-cell responsivity and glucose tolerance in normal-weight men. In the present experiment, we investigated the acute glucoregulatory impact of oxytocin in obese men with impaired insulin sensitivity. Fifteen obese healthy men with an average body mass index of 35 kg/m2 and an average body fat content of 33% received a single intranasal dose (24 IU) of oxytocin before undergoing an oral glucose tolerance test. Results were analysed according to the oral minimal model and compared with our findings in normal-weight participants. In contrast to the results in normal-weight subjects, oxytocin did not blunt postprandial glucose and insulin excursions in obese men, and moreover failed to enhance beta-cell responsivity and glucose tolerance. These results indicate that pronounced obesity may be associated with a certain degree of resistance to the glucoregulatory impact of exogenous oxytocin, and underlines the need for further investigations into the potential of oxytocin to improve glucose homeostasis in the clinical context.
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Glucemia/efectos de los fármacos , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Oxitocina/administración & dosificación , Administración Intranasal , Adolescente , Adulto , Glucemia/metabolismo , Índice de Masa Corporal , Estudios Cruzados , Método Doble Ciego , Intolerancia a la Glucosa/tratamiento farmacológico , Intolerancia a la Glucosa/metabolismo , Intolerancia a la Glucosa/patología , Prueba de Tolerancia a la Glucosa , Humanos , Resistencia a la Insulina , Masculino , Obesidad/patología , Oxitocina/farmacocinética , Insuficiencia del Tratamiento , Adulto JovenRESUMEN
The abundance of highly palatable food items in our environment represents a possible cause of overconsumption. Neuroimaging studies in humans have demonstrated that watching pictures of food increases activation in brain areas involved in homeostatic and hedonic food cue processing. Nevertheless, the impact of food cues on actual food intake and metabolic parameters has not been systematically investigated. We tested the hypothesis that watching high-calorie food cues increases food intake and modifies anticipatory blood parameters in lean and especially in obese men. In 20 normal-weight and 20 obese healthy fasted men, we assessed the effects of watching pictures of high-calorie food items versus neutral contents on food intake measured during a standardized test buffet and subsequent snacking as well as on glucose homeostasis and endocrine parameters. Compared to neutral pictures, viewing food pictures reduced postprandial blood glucose concentrations in lean (p = 0.016) and obese (p = 0.044) subjects, without any differences in insulin or C-peptide concentrations (all p > 0.4). Viewing food pictures did not affect total calorie intake during the buffet (all p > 0.5) and snack consumption (all p > 0.4). Concentrations of ghrelin, adrenocorticotropic hormone (ACTH), cortisol, and glucagon also remained unaffected (all p > 0.08). These data indicate that preprandial processing of food cues curbs postprandial blood glucose excursions, without immediately affecting eating behavior in normal-weight and obese men. Findings indicate that exposure to food cues does not acutely trigger calorie overconsumption but rather improves the glucoregulatory response to food intake.
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Anticipación Psicológica , Regulación del Apetito , Ingestión de Energía , Preferencias Alimentarias , Hiperglucemia/prevención & control , Modelos Psicológicos , Obesidad/dietoterapia , Adulto , Glucemia/análisis , Índice de Masa Corporal , Señales (Psicología) , Dieta Reductora/psicología , Preferencias Alimentarias/psicología , Alemania , Humanos , Conducta Impulsiva , Almuerzo , Masculino , Obesidad/sangre , Obesidad/psicología , Cooperación del Paciente , Fotograbar , Periodo Posprandial , Bocadillos , Adulto JovenRESUMEN
Background: Transcatheter aortic valve replacement (TAVR) has evolved as first-line therapy for severe aortic valve stenosis (AS), with pre-procedural computed tomography (CT) providing critical anatomical information. While primarily used for anatomical planning, TAVR-CT also offers an opportunity to assess low bone mineral density (BMD), a known indicator of frailty. Despite this, the prognostic role of BMD in TAVR patients remains unknown. This study aimed to evaluate BMD on routine TAVR-CT and its impact on long-term survival. Methods: In this retrospective study, 770 consecutive TAVR patients (mean age 80.7 ± 6.7 years, 54.0% males) between November 2015 and March 2022 were included. BMD was measured from a single axial image at the thoracic vertebral level on unenhanced CT scans. Cox regression models assessed the impact of BMD on mortality, and Restricted Cubic Spline models identified potential mortality thresholds. Results: The mean BMD value, as measured on non-contrast CT, was 147.5 ± 5.4 Hounsfield units, demonstrating a noteworthy association with mortality (adjusted hazard ratio per 100 HU decrease: 1.27 [95%CI: 1.01-1.59], p = 0.041). Restricted cubic spline analysis indicated that BMD below 200 HU was linked to a substantial increase in mortality risk. Upon crude Cox regression analysis, every 100 HU decrease was associated with a 32% increase in risk for death (HR 1.32 [95%CI: 1.068-1.65)], p = 0.010). Conclusions: In conclusion, low BMD on TAVR-CT is independently associated with reduced survival, suggesting its potential as a tool for comprehensive frailty assessment and improved risk prediction in TAVR patients.
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Previous experiments of our group have demonstrated that preprandial processing of food cues attenuates postprandial blood glucose excursions. Here we systematically re-evaluated the glucose-lowering effect of visual food cues by submitting 40 healthy fasted men (20 normal-weight men, mean age 24.8 ± 3.7 years, BMI 21.9 ± 0.3 kg/m2; 20 obese men, 26.8 ± 4.2 years, 34.3 ± 1.3 kg/m2) to an oral glucose tolerance test (OGTT) following exposure to pictures of high-calorie food items versus neutral items. OGTT-related changes in blood concentrations of glucose and relevant glucoregulatory hormones including GLP-1 were assessed and analyzed according to the oral minimal model. Independent of body weight, food-cue compared to neutral stimulus presentation reduced postprandial concentrations of glucose (p = 0.041), insulin (p = 0.026) and C-peptide (p = 0.007); accordingly, oral minimal model analyses yielded a food-cue induced decrease of dynamic-phase insulin secretion (p = 0.036). We also observed a trend towards lower GLP-1 levels directly after food cue stimulation in both body weight groups (p = 0.057), as well as a trend towards decreased heart rate (p = 0.093) and significantly decreased diastolic blood pressure (p = 0.019). While we did not detect indicators of an early rise in insulin levels in terms of a 'cephalic phase insulin response', our findings support the assumption that preprandial processing of food cues exerts marked effect on postprandial glucose regulation, with possible contributions of changes in GLP-1. The mechanisms linking food cue exposure and glucoregulatory improvements should be investigated in greater detail, to potentially open new treatment options for metabolic dysfunctions.
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Glucemia , Señales (Psicología) , Obesidad , Adulto , Prueba de Tolerancia a la Glucosa , Humanos , Insulina , Masculino , Adulto JovenRESUMEN
BACKGROUND: Delay discounting as a measure of impulsivity has been shown to be higher in obesity with an association of increased food intake. Moreover, obese humans showed a higher wanting for high-calorie food than lean men when blood glucose concentrations were low. First studies linking blood glucose levels to delay discounting yielded mixed results. We hypothesized that obese people - in comparison to lean men - have a relative lack of energy, especially when blood glucose levels are low, that results in higher levels of delay discounting, food intake and hormonal counterregulation. METHODS: We investigated 20 lean and 20 obese healthy young men in a single-blind balanced cross-over design. With a standardized glucose clamp technique, subjects underwent a hypoglycemic state in one condition and a euglycemic state in the control condition. Regularly, blood was sampled for assessment of hormonal status, and questionnaires were filled out to assess delay discounting and symptom awareness. After normalizing blood glucose concentrations, subjects were free to eat from a standardized test buffet, followed by a snack test. RESULTS: Delay discounting was higher in obese than in lean men throughout experiments (pâ¯<â¯0.03). However, we did not observe significant discounting differences between glucose conditions (pâ¯>â¯0.1). Furthermore, the discounting performance did not correlate with food intake from the test buffet or snack test (pâ¯>â¯0.3). As a response to hypoglycemia, hormonal counterregulation was pronounced in both weight groups (pâ¯<â¯0.03), but responses of ACTH, norepinephrine and glucagon were stronger in obese compared to lean men (pâ¯<â¯0.03). Also, intake from the high-calorie buffet after hypoglycemia compared to euglycemia was higher in obese subjects (pâ¯<â¯0.02) but comparable in lean men (pâ¯>â¯0.5). CONCLUSIONS: Our data suggest that augmented delay discounting is a robust feature in obesity that is not linked to glucose levels or actual food intake. With our systematically controlled approach, combining performance in delay discounting with regard to distinct blood glucose levels, different weight groups, counterregulatory behavior and food intake, our results imply that delay discounting is not susceptible to fluctuations of blood glucose and do not support the assumption that a low body's energy content leads to increased impulsivity. Further replications including women and larger sample sizes are needed to corroborate our data.
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Glucemia/fisiología , Descuento por Demora/fisiología , Conducta Impulsiva/fisiología , Adulto , Índice de Masa Corporal , Peso Corporal , Estudios Cruzados , Ingestión de Alimentos/fisiología , Ingestión de Energía/fisiología , Humanos , Insulina/sangre , Masculino , Obesidad/sangre , Método Simple CiegoRESUMEN
In addition to its pivotal role in psychosocial behavior, the hypothalamic neuropeptide oxytocin contributes to metabolic control by suppressing eating behavior. Its involvement in glucose homeostasis is less clear, although pilot experiments suggest that oxytocin improves glucose homeostasis. We assessed the effect of intranasal oxytocin (24 IU) administered to 29 healthy, fasted male subjects on glucose homeostasis measured by means of an oral glucose tolerance test. Parameters of glucose metabolism were analyzed according to the oral minimal model. Oxytocin attenuated the peak excursion of plasma glucose and augmented the early increases in insulin and C-peptide concentrations in response to the glucose challenge, while slightly blunting insulin and C-peptide peaks. Oral minimal model analyses revealed that oxytocin compared with placebo induced a pronounced increase in ß-cell responsivity (PHItotal) that was largely due to an enhanced dynamic response (PHId), and a more than twofold improvement in glucose tolerance (disposition index). Adrenocorticotropic hormone (ACTH), cortisol, glucagon, and nonesterified fatty acid (NEFA) concentrations were not or were only marginally affected. These results indicate that oxytocin plays a significant role in the acute regulation of glucose metabolism in healthy humans and render the oxytocin system a potential target of antidiabetic treatment.
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Glucemia/efectos de los fármacos , Células Secretoras de Insulina/efectos de los fármacos , Oxitócicos/farmacología , Oxitocina/farmacología , Hormona Adrenocorticotrópica/efectos de los fármacos , Hormona Adrenocorticotrópica/metabolismo , Adulto , Glucemia/metabolismo , Péptido C/efectos de los fármacos , Péptido C/metabolismo , Ácidos Grasos no Esterificados/metabolismo , Glucagón/efectos de los fármacos , Glucagón/metabolismo , Prueba de Tolerancia a la Glucosa , Voluntarios Sanos , Humanos , Hidrocortisona/metabolismo , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Masculino , Adulto JovenRESUMEN
The term metabolic syndrome (MeS) refers to a cluster of associated symptoms composed of impaired fasting glucose, abdominal obesity, hypertension, and dyslipidemia. MeS is associated with an increased risk of cardiovascular and diabetes-associated morbidity and mortality. The increased amount of visceral fat together with a chronic inflammatory state predisposes to the development of arteriosclerosis. Furthermore, insulin resistance (IR) and dyslipidemia are associated with fatty liver disease. In addition, MeS is linked to non-cardiovascular diseases such as cancer as well as psychiatric or endocrine disorders. Here, we discuss the clinical impact of MeS in cardiovascular and non-cardiovascular diseases to highlight the importance of prevention, early diagnosis, and multifactorial treatment of high-risk individuals.
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OBJECTIVE: One of the major side effects of glucocorticoid (GC) treatment is lean tissue wasting, indicating a prominent role in systemic amino acid metabolism. In order to uncover a novel aspect of GCs and their intracellular-receptor, the glucocorticoid receptor (GR), on metabolic control, we conducted amino acid and acylcarnitine profiling in human and mouse models of GC/GR gain- and loss-of-function. METHODS: Blood serum and tissue metabolite levels were determined in Human Addison's disease (AD) patients as well as in mouse models of systemic and liver-specific GR loss-of-function (AAV-miR-GR) with or without dexamethasone (DEX) treatments. Body composition and neuromuscular and metabolic function tests were conducted in vivo and ex vivo, the latter using precision cut liver slices. RESULTS: A serum metabolite signature of impaired urea cycle function (i.e. higher [ARG]:[ORN + CIT]) was observed in human (CTRL: 0.45 ± 0.03, AD: 1.29 ± 0.04; p < 0.001) and mouse (AAV-miR-NC: 0.97 ± 0.13, AAV-miR-GR: 2.20 ± 0.19; p < 0.001) GC/GR loss-of-function, with similar patterns also observed in liver. Serum urea levels were consistently affected by GC/GR gain- (â¼+32%) and loss (â¼-30%) -of-function. Combined liver-specific GR loss-of-function with DEX treatment revealed a tissue-autonomous role for the GR to coordinate an upregulation of liver urea production rate in vivo and ex vivo, and prevent hyperammonaemia and associated neuromuscular dysfunction in vivo. Liver mRNA expression profiling and GR-cistrome mining identified Arginase I (ARG1) a urea cycle gene targeted by the liver GR. CONCLUSIONS: The liver GR controls systemic and liver urea cycle function by transcriptional regulation of ARG1 expression.
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OBJECTIVE: It is known that exogenous lactate given as an i.v. energy infusion is able to counteract a neuroglycopenic state that developed during psychosocial stress. It is unknown, however, whether the brain under stressful conditions can induce a rise in plasma lactate to satisfy its increased needs during stress. Since lactate is i) an alternative cerebral energy substrate to glucose and ii) its plasmatic concentration is influenced by the sympathetic nervous system, the present study aimed at investigating whether plasma lactate concentrations increase with psychosocial stress in humans. METHODS: 30 healthy young men participated in two sessions (stress induced by the Trier Social Stress Test and a non-stress control session). Blood samples were frequently taken to assess plasma lactate concentrations and stress hormone profiles. RESULTS: Plasma lactate increased 47% during psychosocial stress (from 0.9 ± 0.05 to 1.4 ± 0.1 mmol/l; interaction time × stress intervention: F = 19.7, p < 0.001). This increase in lactate concentrations during stress was associated with an increase in epinephrine (R(2) = 0.221, p = 0.02) and ACTH concentrations (R(2) = 0.460, p < 0.001). CONCLUSION: Plasma lactate concentrations increase during acute psychosocial stress in humans. This finding suggests the existence of a demand mechanism that functions to allocate an additional source of energy from the body towards the brain, which we refer to as 'cerebral lactate demand'.
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Hormona Adrenocorticotrópica/sangre , Encéfalo/metabolismo , Metabolismo Energético , Epinefrina/sangre , Ácido Láctico/sangre , Estrés Psicológico/sangre , Sistema Nervioso Simpático , Adolescente , Adulto , Humanos , Masculino , Adulto JovenRESUMEN
Systemic bile acid (BA) homeostasis is a critical determinant of dietary fat digestion, enterohepatic function, and postprandial thermogenesis. However, major checkpoints for the dynamics and the molecular regulation of BA homeostasis remain unknown. Here we show that hypothalamic-pituitary-adrenal (HPA) axis impairment in humans and liver-specific deficiency of the glucocorticoid receptor (GR) in mice disrupts the normal changes in systemic BA distribution during the fasted-to-fed transition. Fasted mice with hepatocyte-specific GR knockdown had smaller gallbladder BA content and were more susceptible to developing cholesterol gallstones when fed a cholesterol-rich diet. Hepatic GR deficiency impaired liver BA uptake/transport via lower expression of the major hepatocyte basolateral BA transporter, Na(+)-taurocholate transport protein (Ntcp/Slc10a1), which affected dietary fat absorption and brown adipose tissue activation. Our results demonstrate a role of the HPA axis in the endocrine regulation of BA homeostasis through the liver GR control of enterohepatic BA recycling.
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Ácidos y Sales Biliares/metabolismo , Hígado/metabolismo , Receptores de Glucocorticoides/metabolismo , Animales , Ácidos y Sales Biliares/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Transportadores de Anión Orgánico Sodio-Dependiente/antagonistas & inhibidores , Transportadores de Anión Orgánico Sodio-Dependiente/genética , Transportadores de Anión Orgánico Sodio-Dependiente/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Receptores de Glucocorticoides/antagonistas & inhibidores , Receptores de Glucocorticoides/genética , Simportadores/antagonistas & inhibidores , Simportadores/genética , Simportadores/metabolismoRESUMEN
BACKGROUND: This is the first study to experimentally explore the direct relationship between circulating VEGF levels and body mass index (BMI) as well as to unravel the role of insulin sensitivity in this context under standardized glucose clamp conditions as the methodical gold-standard. In order to control for known influencing factors such as gender, medication, and arterial hypertension, we examined a highly homogeneous group of young male subjects. Moreover, to encompass also subjects beyond the normal BMI range, low weight and obese participants were additionally included and stress hormones as a main regulator of VEGF were assessed. METHODOLOGY/PRINCIPAL FINDINGS: Under euglycemic clamp conditions, VEGF was measured in 15 normal weight (BMI 20-25 kg/m(2)), 15 low weight (BMI<20 kg/m(2)), and 15 obese (BMI>30 kg/m(2)) male subjects aged 18-30 years and the insulin sensitivity index (ISI) was calculated. Since stress axis activation promotes VEGF secretion, concentrations of ACTH, cortisol, and catecholamines were monitored. Despite of comparable ACTH (Pâ=â0.145), cortisol (Pâ=â0.840), and norepinephrine (Pâ=â0.065) levels, VEGF concentrations differed significantly between BMI-groups (Pâ=â0.008) with higher concentrations in obese subjects as compared to normal weight (Pâ=â0.061) and low weight subjects (Pâ=â0.002). Pearson's correlation analysis revealed a positive relationship between BMI and VEGF levels (râ=â0.407; Pâ=â0.010) but no correlation of VEGF with ISI (râ=â0.224; Pâ=â0.175). CONCLUSIONS/SIGNIFICANCE: Our data demonstrate a positive correlation between concentrations of circulating VEGF levels and BMI in healthy male subjects under highly controlled conditions. This relationship which is apparently disconnected from insulin sensitivity may be part of some pathogenetic mechanisms underlying obesity and type 2 diabetes.
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Índice de Masa Corporal , Insulina/metabolismo , Factor A de Crecimiento Endotelial Vascular/sangre , Adolescente , Adulto , Peso Corporal , Catecolaminas/sangre , Técnica de Clampeo de la Glucosa , Estado de Salud , Humanos , Hidrocortisona/sangre , Masculino , Adulto JovenRESUMEN
CONTEXT/OBJECTIVE: Patients with Addison's disease often suffer from fatigue, faintness, lack of concentration, and memory deficits, i.e. symptoms reminiscent of those of neuroglycopenia. Suspecting that a lack of central nervous glucose contributes to these symptoms, we examined whether they can be attenuated by the intake of palatable food rich in glucose ("comfort food") in these patients and, furthermore, whether comfort food reduces hypothalamus-pituitary-adrenal axis activity as observed in animal studies. Design/Setting/Patients/Outcome: Ten Addison patients with primary adrenal insufficiency and acutely discontinued cortisol substitution and 10 matched healthy controls each participated in two experimental sessions in which they were offered a free-choice high-calorie buffet (comfort food) and green salad, respectively, after a mental stress test. Neuroglycopenic and autonomic symptoms, cognitive function (short-term memory, attention), and hormones of the sympathoadrenal system (ACTH, cortisol, catecholamines) were assessed throughout the sessions. RESULTS: Scores of neuroglycopenic symptoms were persistently higher in Addison patients than in controls and were improved by comfort food in comparison to salad (P < 0.04), whereas control subjects did not show such changes. Attention was generally reduced in patients as compared to controls (P < 0.05) and was slightly improved by comfort food, as was memory (each P < 0.07). Sympathoadrenal hormone concentrations remained unaltered. CONCLUSIONS: High-calorie comfort food reduces symptoms of neuroglycopenia in Addison patients, suggesting that Addison's disease is associated with a deficit in cerebral energy supply that can partly be alleviated by intake of palatable food. It will be important to investigate whether additional oral glucose supply may be helpful in improving patients' well-being.
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Enfermedad de Addison/dietoterapia , Ingestión de Energía , Glucosa/administración & dosificación , Enfermedad de Addison/psicología , Hormona Adrenocorticotrópica/sangre , Adulto , Glucemia/análisis , Cognición , Femenino , Humanos , Hidrocortisona/sangre , Sistema Hipotálamo-Hipofisario/fisiología , Insulina/sangre , Masculino , Persona de Mediana Edad , Sistema Hipófiso-Suprarrenal/fisiologíaRESUMEN
Sucrose intake has been shown to suppress increased adrenocorticotropic hormone (ACTH) levels in adrenalectomized rats, suggesting that increased cerebral energy supply can compensate for the loss of glucocorticoid feedback inhibition of the hypothalamo-pituitary-adrenal axis. We hypothesized that glucose infusion might acutely down-regulate increased ACTH secretion in patients with Addison disease. We studied 8 patients with primary adrenal insufficiency (Addison group) with short-term discontinuation of hydrocortisone substitution and 8 matched healthy controls in 2 randomized conditions. Subjects received either intravenous glucose infusion (0.75 g glucose per kilogram body weight for 2.5 hours) or placebo. Concentrations of ACTH, cortisol, catecholamines, growth hormone, glucagon, and insulin were measured; and cognitive functions as well as neuroglycopenic and autonomic symptoms were assessed. The ACTH concentrations were not affected by glucose infusion either in the Addison or in the control group. Likewise, concentrations of cortisol, epinephrine, norepinephrine, growth hormone, and glucagon remained unchanged in both groups. Neurocognitive performance and symptom scores were likewise not affected. Independent of glucose infusion, attention of the Addison patients was impaired in comparison with the control group. Our study in patients with Addison disease was not able to support the assumption of a compensatory effect of intravenous glucose infusion on hormonal parameters and neurocognitive symptoms in states of chronic cortisol deficiency. Further studies should examine whether different regimens of glucose administration are more effective.