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Background: The benefit of Glucagon-like Peptide-1 (GLP-1) receptor agonists (RAs) in weight reduction against potential harms remains unclear. This study aimed at evaluating the benefit-harm balance of initiating GLP-1 RAs versus placebo for weight loss in people living with overweight and obesity but without diabetes. Methods: We performed benefit-harm balance modelling, which will be updated as new evidence emerges. We searched for randomised controlled trials (RCTs) in PubMed, controlled trials registry, drug approval and regulatory documents, and outcome preference weights as of April 10, 2024. We synthesize data using pairwise meta-analysis to estimate the effect of GLP-1 RAs to inform the benefit-harm balance modelling. We predicted the absolute effects of the positive and negative outcomes over 1 and 2 years of treatment using exponential models. We applied preference weights to the outcomes, ranging from 0 for least concerning to 1.0 for most concerning. We then calculated whether the benefit of achieving 5% and 10% weight loss outweighed the harms on a common scale. The analyses accounted for the statistical uncertainties of treatment effects, preference weights, and outcome risks. Findings: We included 8 RCTs involving 8847 participants. The pooled average age was 46.7 years, with the majority being women (74%) and people living with obesity (96%). Of 1000 persons treated with GLP-1 RAs for 2 years, 375 (95% confidence interval 352 to 399) achieved a 10% weight loss, and 318 (296 to 339) achieved a 5% weight loss compared to those treated with placebo. Several harm outcomes were more frequent in the GLP-1 RA group, including 41 abdominal pain events per 1000 persons over 2 years (19 to 69), cholelithiasis (8, 1 to 21), constipation (118, 78 to 164), diarrhoea (100, 42 to 173), alopecia (57, 10 to 176), hypoglycaemia (17, 1 to 68), injection site reactions (4, -3 to 19), and vomiting (110, 80 to 145) among others. Achieving a 10% weight loss with GLP-1 RA therapy outweighed the cumulative harms, with a net benefit probability of 0.97 at year 1 and 0.91 at year 2. The absolute net benefit was equivalent to 104 (100 to 112) per 1000 persons achieving a 10% weight loss over 2 years without experiencing any worrisome harm. A 5% weight loss did not show a net benefit, with probabilities of 0.13 and 0.01 at year 1 and year 2, respectively. However, these benefits were sensitive to preference weights, suggesting that even a 5% weight loss could be net beneficial for individuals with less concern about harm outcomes. The net benefit for a 10% weight loss was highest for semaglutide, followed by liraglutide and tirzepatide, with 2-year probabilities of 0.96, 0.72, and 0.60, respectively. Interpretation: The benefit of GLP-1 RAs exceeded the harms for weight loss in the first 2 years of treatment, yet the net benefit was dependent on individual' treatment goals (10% or 5% weight loss) and willingness to accept harms in pursuit of weight loss. This implies that treatment decisions have to be personalized to individuals to optimize benefits and reduce harms and overuse of treatments. Due to varying evidence, especially regarding harm outcomes across studies, it is necessary to continuously update and monitor the benefit-harm balance of GLP-1 RAs. Funding: SNSF and LOOP Zurich.
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BACKGROUND: Obesity and type 2 diabetes (T2D) are major risk factors for cardiovascular diseases (CVD). Dysregulated pro-apoptotic ceramide synthesis reduces ß-cell insulin secretion, thereby promoting hyperglycemic states which may manifest as T2D. Pro-apoptotic ceramides modulate insulin sensitivity and glucose tolerance while being linked to poor cardiovascular outcomes. Sirtuin-1 (SIRT1) is a NAD + - dependent deacetylase that protects against pancreatic ß-cell dysfunction; however, systemic levels are decreased in obese T2D mice and may promote pro-apoptotic ceramide synthesis and hyperglycemia. Herein, we aimed to assess the effects of restoring circulating SIRT1 levels to prevent metabolic imbalance in obese and diabetic mice. METHODS AND RESULTS: Circulating SIRT1 levels were reduced in obese diabetic mice (db/db) as compared to age-matched non-diabetic db/+ controls. Restoration of SIRT1 plasma levels with recombinant murine SIRT1 for 4-weeks prevented body weight gain, improved glucose tolerance, insulin sensitivity and vascular function in mice models of obesity and T2D. Untargeted lipidomics revealed that SIRT1 restored insulin-secretory function of ß-cells by reducing synthesis and accumulation of pro-apoptotic ceramides. Molecular mechanisms involved direct binding to and deacetylation of Toll-like receptor 4 (TLR4) by SIRT1 in ß-cells thereby decreasing the rate limiting enzymes of sphingolipid synthesis SPTLC1/2 via AKT/NF-κB. Among T2D patients, those with high baseline plasma levels of SIRT1 prior to metabolic surgery displayed restored ß-cell function (HOMA2- ß) and were more likely to have T2D remission during follow-up. CONCLUSION: Acetylation of TLR4 promotes ß-cell dysfunction via ceramide synthesis in T2D, which is blunted by systemic SIRT1 replenishment. Hence, restoration of systemic SIRT1 may provide a novel therapeutic strategy to counteract toxic ceramide synthesis and mitigate cardiovascular complications of T2D.
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AIM: To assess weight loss associated with liraglutide 3.0 mg treatment in individuals with obesity (body mass index [BMI] ≥30 kg/m2 ) or overweight (BMI > 27 to <30 kg/m2 ) in a reimbursed, real-world setting in Switzerland. MATERIALS AND METHODS: ADDRESS was a non-comparative, multicentre, retrospective exposure cohort study in Switzerland, examining weight loss in individuals with obesity or overweight whose treatment was reimbursed (divided into BMI subgroups) or non-reimbursed. The primary outcomes were proportions of participants in the reimbursed cohort achieving predefined weight loss targets with liraglutide 3.0 mg at Week 16 (≥5% and ≥7% for the lower BMI [28 to <35 kg/m2 with weight-related comorbidities] and higher BMI [≥35 kg/m2 ] subgroups, respectively) and Month 10 (additional ≥5% from Week 16; per Swiss reimbursement criteria). RESULTS: The full analysis set comprised 258 individuals (195 reimbursed; 63 non-reimbursed). In the reimbursed cohort, 139 individuals (71.3%) achieved their weight loss targets at Week 16. Of individuals who met the Week-16 criteria, 43.2% attained an additional 5% weight loss at Month 10. In 162 individuals for whom data were recorded at Month 10, the mean (standard deviation) relative weight loss from baseline to Month 10 was -12.4% (6.4%). CONCLUSIONS: Although reimbursement criteria may be difficult to achieve, particularly the additional weight loss of 5% from Week 16 to Month 10, a clinically relevant overall weight loss from baseline to Month 10 was shown in most individuals with obesity or overweight who received liraglutide 3.0 mg.
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Liraglutida , Sobrepeso , Adulto , Humanos , Liraglutida/uso terapêutico , Sobrepeso/complicações , Sobrepeso/tratamento farmacológico , Sobrepeso/epidemiologia , Suíça/epidemiologia , Estudos Retrospectivos , Estudos de Coortes , Obesidade/tratamento farmacológico , Obesidade/epidemiologia , Redução de PesoRESUMO
Accurate dietary assessment is crucial for nutrition and health research. Traditional methods, such as food records, food frequency questionnaires, and 24-hour dietary recalls (24HR), have limitations, such as the need for trained interviewers, time-consuming procedures, and inaccuracies in estimations. Novel technologies, such as image-based dietary assessment apps, have been developed to overcome these limitations. SNAQ is a novel image-based food-recognition app which, based on computer vision, assesses food type and volume, and provides nutritional information about dietary intake. This cross-sectional observational study aimed to investigate the validity of SNAQ as a dietary assessment tool for measuring energy and macronutrient intake in adult women with normal body weight (n = 30), compared to doubly labeled water (DLW), a reference method for total daily energy expenditure (TDEE). Energy intake was also estimated using a one-day 24HR for direct comparison. Bland-Altman plots, paired difference tests, and Pearson's correlation coefficient were used to assess agreement and relationships between the methods. SNAQ showed a slightly higher agreement (bias = -329.6 kcal/day) with DLW for total daily energy intake (TDEI) compared to 24HR (bias = -543.0 kcal/day). While both SNAQ and 24HR tended to underestimate TDEI, only 24HR significantly differed from DLW in this regard (p < 0.001). There was no significant relationship between estimated TDEI and TDEE using SNAQ (R2 = 27%, p = 0.50) or 24HR (R2 = 34%, p = 0.20) and there were no significant differences in energy and macronutrient intake estimates between SNAQ and 24HR (Δ = 213.4 kcal/day). In conclusion, these results indicate that SNAQ provides a closer representation of energy intake in adult women with normal body weight than 24HR when compared to DLW, but no relationship was found between the energy estimates of DLW and of the two dietary assessment tools. Further research is needed to determine the clinical relevance and support the implementation of SNAQ in research and clinical settings. Clinical trial registration: This study is registered on ClinicalTrials.gov with the unique identifier NCT04600596 (https://clinicaltrials.gov/ct2/show/NCT04600596).
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INTRODUCTION: Endocrinological or metabolic disorders often affect a wide variety of functions of the organism. This can also include an impairment of respiratory function. Diabetic ketoacidosis as a result of insulin deficiency is a typical metabolic acidosis, which the body tries to compensate by an increased exhalation of carbon dioxide. This leads to the classic picture of "Kussmaul" breathing. Due to the increased use of SGLT2 inhibitors, which can reduce the otherwise typical hyperglycemia and thus complicate diagnosis, the occurrence of diabetic ketoacidosis has remained an important differential diagnosis in recent years. Pathologies of the thyroid gland can lead to dyspnea not only by morphological changes, for example in the case of goiter (compression). Functional disorders must also be considered here. Both hypo- and hyperthyroidism affect the cardiovascular system in different ways and may ultimately lead to the clinical picture of dyspnea. If the corresponding entities are thought of, the laboratory diagnosis of the aforementioned metabolic/endocrinological disorders is then basically straightforward. Accordingly, knowledge of these disorders as a differential diagnosis of tachy- and dyspnea is important.
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Acidose , Cetoacidose Diabética , Hiperglicemia , Humanos , Cetoacidose Diabética/diagnóstico , Cetoacidose Diabética/terapia , Cetoacidose Diabética/complicações , Acidose/complicações , Acidose/diagnóstico , Hiperglicemia/complicações , Insulina , Dispneia/diagnóstico , Dispneia/etiologiaRESUMO
Non-invasive breath analysis with mobile health devices bears tremendous potential to guide therapeutic treatment and personalize lifestyle changes. Of particular interest is the breath volatile acetone, a biomarker for fat burning, that could help in understanding and treating metabolic diseases. Here, we report a hand-held (6 × 10 × 19.5 cm3), light-weight (490 g), and simple device for rapid acetone detection in breath. It comprises a tailor-made end-tidal breath sampling unit, connected to a sensor and a pump for on-demand breath sampling, all operated using a Raspberry Pi microcontroller connected with a HDMI touchscreen. Accurate acetone detection is enabled by introducing a catalytic filter and a separation column, which remove and separate undesired interferents from acetone upstream of the sensor. This way, acetone is detected selectively even in complex gas mixtures containing highly concentrated interferents. This device accurately tracks breath acetone concentrations in the exhaled breath of five volunteers during a ketogenic diet, being as high as 26.3 ppm. Most importantly, it can differentiate small acetone changes during a baseline visit as well as before and after an exercise stimulus, being as low as 0.5 ppm. It is stable for at least four months (122 days), and features excellent bias and precision of 0.03 and 0.6 ppm at concentrations below 5 ppm, as validated by proton-transfer-reaction time-of-flight mass spectrometry (PTR-ToF-MS). Hence, this detector is highly promising for simple-in-use, non-invasive, and routine monitoring of acetone to guide therapeutic treatment and track lifestyle changes.
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Viruses have been present during all evolutionary steps on earth and have had a major effect on human history. Viral infections are still among the leading causes of death. Another public health concern is the increase of non-communicable metabolic diseases in the last four decades. In this Review, we revisit the scientific evidence supporting the presence of a strong bidirectional feedback loop between several viral infections and metabolic diseases. We discuss how viruses might lead to the development or progression of metabolic diseases and conversely, how metabolic diseases might increase the severity of a viral infection. Furthermore, we discuss the clinical relevance of the current evidence on the relationship between viral infections and metabolic disease and the present and future challenges that should be addressed by the scientific community and health authorities.
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Doenças Metabólicas , Viroses , Humanos , Relevância Clínica , Viroses/complicações , Doenças Metabólicas/epidemiologia , Saúde PúblicaRESUMO
Aims: To investigate the effect of empagliflozin on glucose dynamics in individuals suffering from postbariatric hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB). Methods: Twenty-two adults with PBH after RYGB were randomized to empagliflozin 25 mg or placebo once daily over 20 days in a randomized, double-blind, placebo-controlled, crossover trial. The primary efficacy outcome was the amplitude of plasma glucose excursion (peak to nadir) during a mixed-meal tolerance test (MMTT). Outcomes of the outpatient period were assessed using continuous glucose monitoring (CGM) and an event-tracking app. Results: The amplitude of glucose excursion during the MMTT was 8.1 ± 2.4 mmol/L with empagliflozin versus 8.1 ± 2.6 mmol/L with placebo (mean ± standard deviation, P = 0.807). CGM-based mean amplitude of glucose excursion during the 20-day period was lower with empagliflozin than placebo (4.8 ± 1.3 vs. 5.2 ± 1.6. P = 0.028). Empagliflozin reduced the time spent with CGM values >10.0 mmol/L (3.8 ± 3.5% vs. 4.7 ± 3.8%, P = 0.009), but not the time spent with CGM values <3.0 mmol/L (1.7 ± 1.6% vs. 1.5 ± 1.5%, P = 0.457). No significant difference was observed in the quantity and quality of recorded symptoms. Eleven adverse events occurred with empagliflozin (three drug-related) and six with placebo. Conclusions: Empagliflozin 25 mg reduces glucose excursions but not hypoglycemia in individuals with PBH. Clinical Trial Registration: Clinicaltrials.gov: NCT05057819.
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Derivação Gástrica , Hipoglicemia , Adulto , Humanos , Derivação Gástrica/efeitos adversos , Glicemia , Automonitorização da Glicemia , Estudos Cross-Over , Hipoglicemia/tratamento farmacológico , Hipoglicemia/etiologia , Hipoglicemia/prevenção & controle , Glucose , Método Duplo-CegoRESUMO
INTRODUCTION: Weight bias refers to negative attitudes toward individuals because of their weight. Evidence-based strategies to successfully reduce weight bias in medical students are lacking. The purpose of this study was to investigate the impact of a multifaceted intervention on medical students' attitudes toward patients with obesity. METHODS: Third and fourth year medical students (n = 79), who enrolled in an 8-week graduate course focusing on the various epidemiologic, physiological, and clinical aspects of obesity, including a gamification task with bariatric weight suits (BWSs), were asked to complete the Nutrition, Exercise and Weight Management (NEW) Attitudes Scale questionnaire pre- and post-course. The inclusion period was between September 2018 and June 2021 and covered 4 consecutive groups of students. RESULTS: The overall NEW Attitudes Scale scores did not change significantly pre- versus post-intervention (pre-course: 19.59, post-course: 24.21, p value = 0.24). However, the subgroup of 4th year medical students showed a significant improvement in their attitudes (pre-course: 16.4, post-course: 26.16, p value = 0.02). The Thurstone rating of 9 out of 31 individual survey items changed significantly from pre- to post-course with a moderate strength (Cramer's V >0.2), including 5 items showing weight bias reduction. The disagreement with the statement "overweight/obese individuals lack willpower" increased from 37 to 68%. CONCLUSION: These findings suggest that in medical students with a low level of weight bias at baseline, a semester course on obesity combined with BWS use affects only a limited number of items of the NEW Attitudes Scale questionnaire. The sensitization of medical students to weight stigma has the potential to improve quality of healthcare for patients with obesity.
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Bariatria , Estudantes de Medicina , Preconceito de Peso , Humanos , Atitude do Pessoal de Saúde , Obesidade/terapia , Inquéritos e QuestionáriosRESUMO
Despite the existence of numerous studies supporting a pathological link between fructose consumption and the development of the metabolic syndrome and its sequelae, such as non-alcoholic fatty liver disease (NAFLD), this link remains a contentious issue. With this article, we shed a light on the impact of sugar/fructose intake on hepatic de novo lipogenesis (DNL), an outcome parameter known to be dysregulated in subjects with type 2 diabetes and/or NAFLD. In this review, we present findings from human intervention studies using physiological doses of sugar as well as mechanistic animal studies. There is evidence from both human and animal studies that fructose is a more potent inducer of hepatic lipogenesis than glucose. This is most likely due to the liver's prominent physiological role in fructose metabolism, which may be disrupted under pathological conditions by increased hepatic expression of fructolytic and lipogenic enzymes. Increased DNL may not only contribute to ectopic fat deposition (i.e. in the liver), but it may also impair several metabolic processes through DNL-related fatty acids (e.g. beta-cell function, insulin secretion, or insulin sensitivity).
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Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Animais , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Frutose/efeitos adversos , Lipogênese/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Fígado/metabolismoRESUMO
Previous data from short term studies have shown an efficacy of the duodenal-jejunal bypass liner (DJBL) for weight loss. However, less data is available regarding weight change after device removal and possible predictors for weight loss. This is a retrospective chart review of all patients who had DJBL inserted at the University Hospital Zurich between December 2012 and June 2015. A total of 27 patients had DJBL insertion. The median BMI at baseline was 38.5 (34.0-42.2) kg/m2 . In the 24 patients with DJBL treatment >3 months (failed implantation or early removal due to side effects in 3 patients), the mean duration of implantation was 42.9 ± 13.1 weeks. During the treatment, the mean total body weight loss (%TBWL) was 15.0 ± 8.3%. Fifteen patients had long-term follow-up data available (mean duration of follow-up 4.0 ± 0.9 years). The mean weight change was 12.7 ± 12.8 kg, corresponding with a mean % weight regain of 13.3 ± 13.3%. Five patients (33.3%) subsequently underwent bariatric surgery. In patients with class I obesity (BMI <35 kg/m2 at baseline), 4 out of 6 (66.7%) had a stable weight or only a weight regain <7%. In contrast, no patient with BMI >35 kg/m2 at baseline was able to keep weight regain below 7%. DJBL is an effective treatment for obesity, but substantial weight regain occurs during long-term follow up after the device removal, in particular in patients with BMI > 35 kg/m2 .
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Cirurgia Bariátrica , Diabetes Mellitus Tipo 2 , Obesidade Mórbida , Humanos , Duodeno/cirurgia , Jejuno/cirurgia , Índice de Massa Corporal , Estudos Retrospectivos , Seguimentos , Obesidade Mórbida/cirurgia , Diabetes Mellitus Tipo 2/cirurgia , Estudos Prospectivos , Obesidade/etiologia , Resultado do Tratamento , Cirurgia Bariátrica/efeitos adversos , Redução de Peso , Aumento de PesoRESUMO
BACKGROUND & AIMS: Advances in technology enable patients on home parenteral nutrition (HPN) to manage their treatment more independently and safely. eHealth is a promising application of electronic means in healthcare, aimed at improving and simplifying processes and connecting the different parties involved. A thorough understanding of the attitudes and expectations of patients on HPN towards eHealth is a prerequisite for a successful implementation. However, to the best of our knowledge, such a survey preceding the implementation of HPN specific eHealth care has never been conducted. The objective of this preliminary survey is the acquisition of insights on the attitudes and expectations of patients on HPN towards eHealth. Resulting findings then serve as the basis for the design of an eHealth platform to facilitate communication among those involved in HPN care, improve the HPN management, and safeguard and monitor the treatment. METHODS: We conducted a survey on the attitudes and expectations of patients towards an envisioned eHealth platform for HPN. Patients were recruited from large Swiss hospitals by their treating physician or directly by the research team. The surveys were conducted between September 2020 and October 2021 by structured personal interviews based on a questionnaire. RESULTS: We included 35 patients on HPN (21 [60%] females) treated in ambulant care of 4 hospitals. They had a median (interquartile range) age of 55 (18) years and a median (interquartile range) duration of parenteral nutrition of 1.3 (3.1) years. Most patients (n = 30, 86%) were equipped with a smartphone, tablet, or computer and 22 (63%) used apps and rated themselves as proficient with the corresponding digital device. A majority of patients rated the following aspects and features of the platform as important: Data collection and storage (n = 29, 83%), checklists for PN, catheter, and infusion pump handling (n = 28, 80%), video instructions (n = 27, 77%), and videoconferencing with physicians (n = 25, 71%). Most patients (n = 26, 74%) were willing to enter data into the platform themselves. The type of data to be entered should be defined on an individual basis. CONCLUSIONS: Patients on HPN are open to videoconference consultations and using an eHealth platform. Two-thirds have the necessary technical skills including suitable digital devices for an eHealth care. We identified key features of an eHealth platform to improve HPN management.
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Nutrição Parenteral no Domicílio , Telemedicina , Feminino , Humanos , Lactente , Masculino , Atitude , Motivação , Inquéritos e QuestionáriosRESUMO
Human fibroblast growth factor 21 (FGF21) is a multifaceted metabolic regulator considered to control sugar intake and to exert beneficial effects on glucose and lipid metabolism. Elevated serum FGF21 levels are associated with metabolic syndrome, suggesting a state of FGF21 resistance. Further, given the evidence of a hepatic ChREBP and FGF21 signaling axis, it can be assumed that SSBs containing fructose would possibly increase FGF21 concentrations. We investigated the effects of sugar-sweetened beverage (SSB) consumption on fasting FGF21 levels in healthy, lean men, discriminating the effects of glucose, fructose, and their disaccharide sucrose by secondary data analysis from a randomized controlled trial. Seven weeks of daily SSB consumption resulted in increased fasting FGF21 in healthy, lean men, irrespective of the sugar type. Medians of ΔFGF21 between post-SSB intervention values (week 7) and no-intervention period values (IQR) in pg/mL were: glucose 17.4 (0.4-45.8), fructose 22.9 (-8.6-35.1), and sucrose 13.7 (2.2-46.1). In contrast, this change in FGF21 concentration was only 6.3 (-20.1-26.9) pg/mL in the control group. The lack of a fructose-specific effect on FGF21 concentrations is contrary to our assumption. It is concluded that SSB intake may impact FGF21 concentrations and could contribute to the increased FGF21 concentrations observed in subjects suffering from metabolic syndrome that is possibly associated with decreased FGF21 responsiveness.
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Síndrome Metabólica , Bebidas Adoçadas com Açúcar , Bebidas , Jejum , Fatores de Crescimento de Fibroblastos , Frutose/efeitos adversos , Glucose/metabolismo , Humanos , Masculino , Síndrome Metabólica/etiologia , Sacarose/efeitos adversos , Bebidas Adoçadas com Açúcar/efeitos adversos , AçúcaresRESUMO
Coronavirus disease 2019 (COVID-19) is characterized by a wide clinical spectrum that includes abnormalities in liver function indicative of liver damage. Conversely, people with liver diseases are at higher risk of severe COVID-19. In the current review, we summarize first the epidemiologic evidence describing the bidirectional relationship between COVID-19 and liver function/liver diseases. Additionally, we present the most frequent histologic findings as well as the most important direct and indirect mechanisms supporting a COVID-19 mediated liver injury. Furthermore, we focus on the most frequent liver disease in the general population, non-alcoholic or metabolic-associated fatty liver disease (NAFLD/MAFLD), and describe how COVID-19 may affect NAFLD/MAFLD development and progression and conversely how NAFLD/MAFLD may further aggravate a COVID-19 infection. Finally, we present the long-term consequences of the pandemic on the development and management of NAFLD.
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COVID-19 , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Pandemias , Fatores de RiscoRESUMO
Pancreatic ß-cells depend on the well-balanced regulation of cytosolic zinc concentrations, providing sufficient zinc ions for the processing and storage of insulin, but avoiding toxic effects. The zinc transporter ZnT8, encoded by SLC30A8,is a key player regarding islet cell zinc homeostasis, and polymorphisms in this gene are associated with altered type 2 diabetes susceptibility in man. The objective of this study was to investigate the role of ZnT8 and zinc in situations of cellular stress as hypoxia or inflammation. Isolated islets of WT and global ZnT8-/- mice were exposed to hypoxia or cytokines and cell death was measured. To explore the role of changing intracellular Zn2+ concentrations, WT islets were exposed to different zinc concentrations using zinc chloride or the zinc chelator N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN). Hypoxia or cytokine (TNF-α, IFN-γ, IL1-ß) treatment induced islet cell death, but to a lesser extent in islets from ZnT8-/- mice, which were shown to have a reduced zinc content. Similarly, chelation of zinc with TPEN reduced cell death in WT islets treated with hypoxia or cytokines, whereas increased zinc concentrations aggravated the effects of these stressors. This study demonstrates a reduced rate of cell death in islets from ZnT8-/- mice as compared to WT islets when exposed to two distinct cellular stressors, hypoxia or cytotoxic cytokines. This protection from cell death is, in part, mediated by a reduced zinc content in islet cells of ZnT8-/- mice. These findings may be relevant for altered diabetes burden in carriers of risk SLC30A8 alleles in man.
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Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Ilhotas Pancreáticas/metabolismo , Transportador 8 de Zinco/genética , Animais , Apoptose/genética , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Hipóxia Celular , Linhagem Celular , Proliferação de Células/genética , Células Cultivadas , Citocinas/farmacologia , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Zinco/metabolismo , Zinco/farmacologia , Transportador 8 de Zinco/metabolismoRESUMO
BACKGROUND & AIMS: Excessive fructose intake is associated with increased de novo lipogenesis, blood triglycerides, and hepatic insulin resistance. We aimed to determine whether fructose elicits specific effects on lipid metabolism independently of excessive caloric intake. METHODS: A total of 94 healthy men were studied in this double-blind, randomized trial. They were assigned to daily consumption of sugar-sweetened beverages (SSBs) containing moderate amounts of fructose, sucrose (fructose-glucose disaccharide) or glucose (80 g/day) in addition to their usual diet or SSB abstinence (control group) for 7 weeks. De novo fatty acid (FA) and triglyceride synthesis, lipolysis and plasma free FA (FFA) oxidation were assessed by tracer methodology. RESULTS: Daily intake of beverages sweetened with free fructose and fructose combined with glucose (sucrose) led to a 2-fold increase in basal hepatic fractional secretion rates (FSR) compared to control (median FSR %/day: sucrose 20.8 (p = 0.0015); fructose 19.7 (p = 0.013); control 9.1). Conversely, the same amounts of glucose did not change FSR (median of FSR %/day 11.0 (n.s.)). Fructose intake did not change basal secretion of newly synthesized VLDL-triglyceride, nor did it alter rates of peripheral lipolysis, nor total FA and plasma FFA oxidation. Total energy intake was similar across groups. CONCLUSIONS: Regular consumption of both fructose- and sucrose-sweetened beverages in moderate doses - associated with stable caloric intake - increases hepatic FA synthesis even in a basal state; this effect is not observed after glucose consumption. These findings provide evidence of an adaptative response to regular fructose exposure in the liver. LAY SUMMARY: This study investigated the metabolic effects of daily sugar-sweetened beverage consumption for several weeks in healthy lean men. It revealed that beverages sweetened with the sugars fructose and sucrose (glucose and fructose combined), but not glucose, increase the ability of the liver to produce lipids. This change may pave the way for further unfavorable effects on metabolic health. CLINICAL TRIAL REGISTRATION NUMBER: NCT01733563.
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Ácidos Graxos/biossíntese , Frutose , Glucose , Lipogênese , Lipoproteínas VLDL/biossíntese , Fígado , Sacarose , Triglicerídeos/biossíntese , Adulto , Método Duplo-Cego , Ingestão de Energia , Frutose/administração & dosagem , Frutose/efeitos adversos , Frutose/metabolismo , Glucose/administração & dosagem , Glucose/metabolismo , Voluntários Saudáveis , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/fisiologia , Lipogênese/efeitos dos fármacos , Lipogênese/fisiologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Sacarose/administração & dosagem , Sacarose/efeitos adversos , Sacarose/metabolismo , Bebidas Adoçadas com Açúcar , Edulcorantes/farmacologiaRESUMO
Methanol poisoning outbreaks after consumption of adulterated alcohol frequently overwhelm health care facilities in developing countries. Here, we present how a recently developed low-cost and handheld breath detector can serve as a noninvasive and rapid diagnostic tool for methanol poisoning. The detector combines a separation column and a micromachined chemoresistive gas sensor fully integrated into a device that communicates wirelessly with a smartphone. The performance of the detector is validated with methanol-spiked breath of 20 volunteers (105 breath samples) after consumption of alcoholic beverages. Breath methanol concentrations were quantified accurately within 2 min in the full breath-relevant range (10-1000 ppm) in excellent agreement (R2 = 0.966) with benchtop mass spectrometry. Bland-Altman analysis revealed sufficient limits of agreement (95% confidence intervals), promising to indicate reliably the clinical need for antidote and hemodialysis treatment. This simple-in-use detector features high diagnostic capability for accurate measurement of methanol in spiked breath, promising for rapid screening of methanol poisoning and assessment of severity. It can be applied readily by first responders to distinguish methanol from ethanol poisoning and monitor in real time the subsequent hospital treatment.
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Testes Respiratórios , Metanol/análise , Humanos , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
BACKGROUND: Obesity adversely affects wait-listing and precludes patients with concomitant end-stage renal disease and type 1 diabetes mellitus from getting a simultaneous pancreas and kidney transplantation (SPK). OBJECTIVE: To analyze safety and efficacy of laparoscopic sleeve gastrectomy (LSG) before SPK in severely obese type I diabetics. METHODS: We assessed weight curve, complications, and graft function of three patients who underwent LSG before SPK. RESULTS: LSG was uneventful in all patients. Body mass index dropped from 38.4 (range 35.7 - 39.9) before LSG to 28.5 (26.8 - 30.9) until SPK, with a mean loss of 25.8% (22.4 - 32.3). Interval between LSG and SPK was 364.3 (173 - 587) days. Pancreas and kidney graft function was excellent, with 100% insulin-free and dialysis-free survival over a mean follow-up of 3.6 (2.9 - 4.5) years. A1C dropped from 7% (6.3 - 8.2) before LSG to 4.9% (4.7 - 5.3) and 4.8% (4.5 - 5.1) 1 and 2 years after SPK, respectively. CONCLUSION: LSG before SPK is safe and effective to enable severely obese type I diabetics to receive a lifesaving transplant. This is the first study analyzing the role of bariatric surgery before simultaneous pancreas and kidney transplantation.
Assuntos
Transplante de Rim , Laparoscopia , Obesidade Mórbida , Transplante de Pâncreas , Gastrectomia , Sobrevivência de Enxerto , Humanos , Obesidade , Obesidade Mórbida/complicações , Obesidade Mórbida/cirurgia , Pâncreas , Estudos Retrospectivos , Resultado do Tratamento , Redução de PesoRESUMO
Exhaled breath acetone (BrAce) was investigated during and after submaximal aerobic exercise as a volatile biomarker for metabolic responsiveness in high and lower-fit individuals in a prospective cohort pilot-study. Twenty healthy adults (19-39 years) with different levels of cardiorespiratory fitness (VO2peak), determined by spiroergometry, were recruited. BrAce was repeatedly measured by proton-transfer-reaction time-of-flight mass spectrometry (PTR-TOF-MS) during 40-55 min submaximal cycling exercise and a post-exercise period of 180 min. Activity of ketone and fat metabolism during and after exercise were assessed by indirect calorimetric calculation of fat oxidation rate and by measurement of venous ß-hydroxybutyrate (ßHB). Maximum BrAce ratios were significantly higher during exercise in the high-fit individuals compared to the lower-fit group (t-test; p= 0.03). Multivariate regression showed 0.4% (95%-CI = -0.2%-0.9%, p= 0.155) higher BrAce change during exercise for every ml kg-1 min-1 higher VO2peak. Differences of BrAce ratios during exercise were similar to fat oxidation rate changes, but without association to respiratory minute volume. Furthermore, the high-fit group showed higher maximum BrAce increase rates (46% h-1) in the late post-exercise phase compared to the lower-fit group (29% h-1). As a result, high-fit young, healthy individuals have a higher increase in BrAce concentrations related to submaximal exercise than lower-fit subjects, indicating a stronger exercise-related activation of fat metabolism.