RESUMO
Insulin secretion is critical for glucose homeostasis, and increased levels of the precursor proinsulin relative to insulin indicate pancreatic islet beta-cell stress and insufficient insulin secretory capacity in the setting of insulin resistance. We conducted meta-analyses of genome-wide association results for fasting proinsulin from 16 European-ancestry studies in 45,861 individuals. We found 36 independent signals at 30 loci (p value < 5 × 10-8), which validated 12 previously reported loci for proinsulin and ten additional loci previously identified for another glycemic trait. Half of the alleles associated with higher proinsulin showed higher rather than lower effects on glucose levels, corresponding to different mechanisms. Proinsulin loci included genes that affect prohormone convertases, beta-cell dysfunction, vesicle trafficking, beta-cell transcriptional regulation, and lysosomes/autophagy processes. We colocalized 11 proinsulin signals with islet expression quantitative trait locus (eQTL) data, suggesting candidate genes, including ARSG, WIPI1, SLC7A14, and SIX3. The NKX6-3/ANK1 proinsulin signal colocalized with a T2D signal and an adipose ANK1 eQTL signal but not the islet NKX6-3 eQTL. Signals were enriched for islet enhancers, and we showed a plausible islet regulatory mechanism for the lead signal in the MADD locus. These results show how detailed genetic studies of an intermediate phenotype can elucidate mechanisms that may predispose one to disease.
Assuntos
Diabetes Mellitus Tipo 2 , Proinsulina , Humanos , Proinsulina/genética , Proinsulina/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Estudo de Associação Genômica Ampla/métodos , Insulina/genética , Insulina/metabolismo , Glucose , Fatores de Transcrição/genética , Proteínas de Homeodomínio/genéticaRESUMO
BACKGROUND: Despite mechanistic studies linking retinol and RBP4 (retinol binding protein 4) to the pathogenesis of cardiovascular diseases (CVD) and type 2 diabetes (T2D), epidemiological evidence is still conflicting. We investigated whether conflicting results of previous studies may be explained by differences in the association of retinol and RBP4 with cardiometabolic risk across subgroups with distinct sex, hypertension state, liver, or kidney function. METHODS: We used case-cohorts nested in the EPIC (European Prospective Investigation Into Cancer and Nutrition)-Potsdam cohort (N=27 548) comprising a random sample of participants (n=2500) and all physician-verified cases of incident CVD (n=508, median follow-up time 8.2 years) and T2D (n=820, median follow-up time 6.3 years). We estimated nonlinear and linear multivariable-adjusted associations between the biomarkers and cardiometabolic diseases by restricted cubic splines and Cox regression, respectively, testing potential interactions with hypertension, liver, and kidney function. Additionally, we performed 2-sample Mendelian Randomization analyses in publicly available data. RESULTS: The association of retinol with cardiometabolic risk was modified by hypertension state (P interaction CVD<0.001; P interaction T2D<0.001). Retinol was associated with lower cardiometabolic risk in participants with treated hypertension (hazard ratioper SD [95% CI]: CVD, 0.71 [0.56-0.90]; T2D, 0.81 [0.70-0.94]) but with higher cardiometabolic risk in normotensive participants (CVD, 1.32 [1.06-1.64]; T2D, 1.15 [0.98-1.36]). Our analyses also indicated a significant interaction between RBP4 and hypertension on CVD risk (P interaction=0.04). Regarding T2D risk, we observed a u-shaped association with RBP4 in women (P nonlinearity=0.01, P effect=0.02) and no statistically significant association in men. The biomarkers' interactions with liver or kidney function were not statistically significant. Hypertension state-specific associations for retinol concentrations with cardiovascular mortality risk were replicated in National Health and Nutrition Examination Survey III. CONCLUSIONS: Our findings suggest a hypertension-dependent relationship between plasma retinol and cardiometabolic risk and complex interactions of RBP4 with sex and hypertension on cardiometabolic risk.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Hipertensão , Biomarcadores , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Hipertensão/complicações , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Masculino , Inquéritos Nutricionais , Estudos Prospectivos , Proteínas Plasmáticas de Ligação ao Retinol , Fatores de Risco , Vitamina ARESUMO
AIM: To assess oxytocin's acute glucoregulatory impact in men with type 2 diabetes in the context of our previous findings that oxytocin improves ß-cell responsivity in healthy men. METHODS: In a double-blind, crossover comparison, intranasal oxytocin (24 IU) and placebo, respectively, were administered to 25 fasted men with non-insulin-treated type 2 diabetes (age ± standard error of the mean, 63.40 ± 1.36 years; body mass index, 27.77 ± 0.66 kg/m2; HbA1c, 6.86% ± 0.08%; Homeostatic Model Assessment of Insulin Resistance (HOMA-IR, 3.44 ± 0.39) 60 minutes before an oral glucose tolerance test (oGTT). Key outcomes were compared with previous results in men with normal weight or obesity. RESULTS: Oxytocin compared with placebo increased plasma oxytocin concentrations and reduced the heart rate, but did not alter glucose metabolism in the 3 hours after oGTT onset (area under the curve, glucose, 2240 ± 80.5 vs. 2190 ± 69.5 mmol/L × min; insulin, 45 663 ± 4538 vs. 44 343 ± 4269 pmol/L × min; C-peptide, 235 ± 5.1 vs. 231 ± 15.9 nmol/L × min). CONCLUSIONS: This outcome contrasts with the oxytocin-induced attenuation of early postprandial glucose excursions in normal-weight individuals, but is in line with the absence of respective effects in men with obesity. We conclude that insulin resistance in type 2 diabetes is associated with decreased sensitivity to the acute glucoregulatory effect of oxytocin in male individuals.
RESUMO
Reliability, robustness, and interlaboratory comparability of quantitative measurements is critical for clinical lipidomics studies. Lipids' different ex vivo stability in blood bears the risk of misinterpretation of data. Clear recommendations for the process of blood sample collection are required. We studied by UHPLC-high resolution mass spectrometry, as part of the "Preanalytics interest group" of the International Lipidomics Society, the stability of 417 lipid species in EDTA whole blood after exposure to either 4°C, 21°C, or 30°C at six different time points (0.5 h-24 h) to cover common daily routine conditions in clinical settings. In total, >800 samples were analyzed. 325 and 288 robust lipid species resisted 24 h exposure of EDTA whole blood to 21°C or 30°C, respectively. Most significant instabilities were detected for FA, LPE, and LPC. Based on our data, we recommend cooling whole blood at once and permanent. Plasma should be separated within 4 h, unless the focus is solely on robust lipids. Lists are provided to check the ex vivo (in)stability of distinct lipids and potential biomarkers of interest in whole blood. To conclude, our results contribute to the international efforts towards reliable and comparable clinical lipidomics data paving the way to the proper diagnostic application of distinct lipid patterns or lipid profiles in the future.
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Lipidômica , Lipídeos , Lipidômica/métodos , Lipídeos/química , Ácido Edético , Reprodutibilidade dos Testes , Espectrometria de Massas/métodosRESUMO
Ever since the brain was identified as an insulin-sensitive organ, evidence has rapidly accumulated that insulin action in the brain produces multiple behavioral and metabolic effects, influencing eating behavior, peripheral metabolism, and cognition. Disturbances in brain insulin action can be observed in obesity and type 2 diabetes (T2D), as well as in aging and dementia. Decreases in insulin sensitivity of central nervous pathways, i.e., brain insulin resistance, may therefore constitute a joint pathological feature of metabolic and cognitive dysfunctions. Modern neuroimaging methods have provided new means of probing brain insulin action, revealing the influence of insulin on both global and regional brain function. In this review, we highlight recent findings on brain insulin action in humans and its impact on metabolism and cognition. Furthermore, we elaborate on the most prominent factors associated with brain insulin resistance, i.e., obesity, T2D, genes, maternal metabolism, normal aging, inflammation, and dementia, and on their roles regarding causes and consequences of brain insulin resistance. We also describe the beneficial effects of enhanced brain insulin signaling on human eating behavior and cognition and discuss potential applications in the treatment of metabolic and cognitive disorders.
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Envelhecimento/metabolismo , Encéfalo/metabolismo , Transtornos Cognitivos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Resistência à Insulina/fisiologia , Obesidade/metabolismo , Humanos , Insulina/metabolismoRESUMO
BACKGROUND/OBJECTIVES: The orexigenic peptide hormone ghrelin has been implicated in the pathophysiology of obesity and type 2 diabetes mellitus through its effects on nutrient homeostasis. Ghrelin is subject to a unique post-translational acyl modification regulating its biochemical activity. SUBJECTS/METHODS: In this study we aimed to investigate the relation of acylated (AcG) as well as unacylated ghrelin (UnG) with body weight and insulin resistance in the fasting (n = 545) and post-oral glucose tolerance test (oGTT) state (n = 245) in a metabolically well characterized cohort covering a broad range of BMI (17.95 kg/m²-76.25 kg/m²). RESULTS: Fasting AcG (median 94.2 pg/ml) and UnG (median 175.3 pg/ml) were negatively and the AcG/UnG ratio was positively correlated with BMI (all p < 0.0001). Insulin sensitivity (ISI) correlated positively with AcG (p = 0.0014) and UnG (p = 0.0004) but not with the AcG/UnG ratio. In a multivariate analysis, including ISI and BMI, only BMI, but not ISI was independently associated with AcG and UnG concentrations. Significant changes of AcG and UnG concentrations were detectable after oGTT stimulation, with slight decreases after 30 min and increases after 90-120 min. Subject stratification into BMI-divergent groups revealed more pronounced AcG increases in the two groups with BMI < 40 kg/m². CONCLUSION: Our data demonstrate lower concentrations for both AcG and UnG with increasing BMI as well as an increased proportion of the biologically active, acylated form of ghrelin giving point to pharmacologic intervention in ghrelin acylation and/or increase in UnG for treatment of obesity despite decreased absolute AcG levels.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Humanos , Grelina/metabolismo , Teste de Tolerância a Glucose , Glicemia , Obesidade , Acilação , InsulinaRESUMO
BACKGROUND: Heterogeneous metabolic clusters have been identified in diabetic and prediabetic states. It is not known whether such pathophysiologic clusters impact survival in at-risk persons being evaluated for coronary heart disease. METHODS: The LURIC Study recruited patients referred for coronary angiography at a median age of 63 (IQR 56-70) with a follow-up of 16.1 (IQR 9.6, 17.7) years. Clustering of 1269 subjects without diabetes was performed with oGTT-derived glucose and insulin; fasting triglyceride, high-density lipoprotein, BMI, waist and hip circumference. Patients with T2D (n = 794) were clustered using age, BMI, glycemia, homeostasis model assessment, and islet autoantibodies. Associations of clusters with mortality were analysed using Cox regression. RESULTS: Individuals without diabetes were classified into six subphenotypes, with 884 assigned to subjects at low-risk (cluster 1,2,4) and 385 at high-risk (cluster 3,5,6) for diabetes. We found significantly increased mortality in clusters 3 (hazard ratio (HR)1.42), 5 (HR 1.43), and 6 (HR 1.46) after adjusting for age, BMI, HbA1c and sex. In the T2D group, 508 were assigned to mild age-related diabetes (MARD), 183 to severe insulin-resistant diabetes (SIRD), 84 to mild obesity-related diabetes (MOD), 19 to severe insulin-deficient diabetes (SIDD). Compared to the low-risk non-diabetes group, crude mortality was not different in MOD. Increased mortality was found for MARD (HR 2.2), SIRD (HR 2.2), and SIDD (HR 2.5). CONCLUSIONS: Metabolic clustering successfully stratifies survival even among persons undergoing invasive coronary diagnostics. Novel clustering approaches based on glucose metabolism can identify persons who require special attention as they are at risk of increased mortality.
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Diabetes Mellitus Tipo 2 , Estado Pré-Diabético , Humanos , Pessoa de Meia-Idade , Idoso , Estado Pré-Diabético/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Insulina , Autoanticorpos , Angiografia CoronáriaRESUMO
AIMS: Insulin action in the brain influences cognitive processes, peripheral metabolism and eating behaviour. However, the influence of age and peripheral insulin sensitivity on brain insulin action remains unclear. MATERIALS AND METHODS: We used intranasal administration of insulin and functional magnetic resonance imaging in a randomized, placebo-controlled within-subject design in 110 participants (54 women, body mass index 18-49 kg/m2 , age 21-74 years). Cerebral blood flow was measured before and after nasal spray application to assess brain insulin action. Peripheral insulin sensitivity was assessed by a five-point oral glucose tolerance test. Linear regressions were used to investigate associations between age and peripheral insulin sensitivity with brain insulin action in predefined region of interests (i.e. insulin-sensitive brain regions). RESULTS: We found significant negative associations between age and insulin action in the hippocampus (ß = -0.215; p = .017) and caudate nucleus (ß = -0.184; p = .047); and between peripheral insulin sensitivity and insulin action in the amygdala (ß = -0.190, p = .023). Insulin action in the insular cortex showed an interaction effect between age and peripheral insulin sensitivity (ß = -0.219 p = .005). Furthermore, women showed the strongest negative association between age and hippocampal insulin action, while men showed the strongest associations with peripheral insulin sensitivity and age in reward-related brain regions. CONCLUSION: We could show a region-specific relationship between brain insulin responsiveness, age and peripheral insulin sensitivity. Our findings underline the need to study brain insulin action in both men and women and further substantiate that brain insulin sensitivity is a possible link between systemic metabolism and neurocognitive functions.
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Resistência à Insulina , Insulina , Masculino , Humanos , Feminino , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Resistência à Insulina/fisiologia , Encéfalo/metabolismo , Insulina Regular Humana , Teste de Tolerância a GlucoseRESUMO
MicroRNAs (miRNAs) recently emerged as means of communication between insulin-sensitive tissues to mediate diabetes development and progression, and as such they present a valuable proxy for epigenetic alterations associated with type 2 diabetes. In order to identify miRNA markers for the precursor of diabetes called prediabetes, we applied a translational approach encompassing analysis of human plasma samples, mouse tissues and an in vitro validation system. MiR-652-3p, miR-877-5p, miR-93-5p, miR-130a-3p, miR-152-3p and let-7i-5p were increased in plasma of women with impaired fasting glucose levels (IFG) compared to those with normal fasting glucose and normal glucose tolerance (NGT). Among these, let-7i-5p and miR-93-5p correlated with fasting blood glucose levels. Human data were then compared to miRNome data obtained from islets of Langerhans and adipose tissue of 10-week-old female New Zealand Obese mice, which differ in their degree of hyperglycemia and liver fat content. Similar to human plasma, let-7i-5p was increased in adipose tissue and islets of Langerhans of diabetes-prone mice. As predicted by the in silico analysis, overexpression of let-7i-5p in the rat ß-cell line INS-1 832/12 resulted in downregulation of insulin signaling pathway components (Insr, Rictor, Prkcb, Clock, Sos1 and Kcnma1). Taken together, our integrated approach highlighted let-7i-5p as a potential regulator of whole-body insulin sensitivity and a novel marker of prediabetes in women.
Assuntos
Diabetes Mellitus Tipo 2 , Insulinas , MicroRNAs , Estado Pré-Diabético , Humanos , Feminino , Camundongos , Ratos , Animais , MicroRNAs/metabolismo , Estado Pré-Diabético/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Obesidade/complicações , Obesidade/genética , GlucoseRESUMO
Previously, we found that human pancreatic preadipocytes (PPAs) and islets influence each other and that the crosstalk with the fatty liver via the hepatokine fetuin-A/palmitate induces inflammatory responses. Here, we examined whether the mRNA-expression of pancreatic extracellular matrix (ECM)-forming and -degrading components differ in PPAs from individuals with normal glucose regulation (PPAs-NGR), prediabetes (PPAs-PD), and type 2 diabetes (PPAs-T2D), and whether fetuin-A/palmitate impacts ECM-formation/degradation and associated monocyte invasion. Human pancreatic resections were analyzed (immuno)histologically. PPAs were studied for mRNA expression by real-time PCR and protein secretion by Luminex analysis. Furthermore, co-cultures with human islets and monocyte migration assays in Transwell plates were conducted. We found that in comparison with NGR-PPAs, TIMP-2 mRNA levels were lower in PPAs-PD, and TGF-ß1 mRNA levels were higher in PPAs-T2D. Fetuin-A/palmitate reduced fibronectin, decorin, TIMP-1/-2 and TGF-ß1 mRNA levels. Only fibronectin was strongly downregulated by fetuin-A/palmitate independently of the glycemic status. Co-culturing of PPAs with islets increased TIMP-1 mRNA expression in islets. Fetuin-A/palmitate increased MMP-1, usherin and dermatopontin mRNA-levels in co-cultured islets. A transmigration assay showed increased monocyte migration towards PPAs, which was enhanced by fetuin-A/palmitate. This was more pronounced in PPAs-T2D. The expression of distinct ECM components differs in PPAs-PD and PPAs-T2D compared to PPAs-NGR, suggesting that ECM alterations can occur even in mild hyperglycemia. Fetuin-A/palmitate impacts on ECM formation/degradation in PPAs and co-cultured islets. Fetuin-A/palmitate also enhances monocyte migration, a process which might impact on matrix turnover.
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Diabetes Mellitus Tipo 2 , Estado Pré-Diabético , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Fibronectinas/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , alfa-2-Glicoproteína-HS/metabolismo , Matriz Extracelular/metabolismo , Hormônios Pancreáticos/metabolismo , Palmitatos/farmacologia , RNA Mensageiro/metabolismo , Adipócitos/metabolismo , Glucose/farmacologia , Glucose/metabolismoRESUMO
BACKGROUND/OBJECTIVES: Central insulin action influences cognitive processes, peripheral metabolism, and eating behavior. However, the contribution of obesity and sex on central insulin-mediated neural food cue processing still remains unclear. SUBJECTS/METHODS: In a randomized within-participant design, including two visits, 60 participants (30 women, BMI 18-32 kg/m2, age 21-69 years) underwent a functional MRI task measuring blood oxygen level-dependent (BOLD) signal in response to visual food cues after intranasal insulin or placebo spray administration. Central insulin action was defined as the neural BOLD response to food cues after insulin compared to placebo administration. Afterwards, participants were asked to rate the food cues for desire to eat (i.e., wanting rating). For statistical analyses, participants were grouped according to BMI and sex. RESULTS: Food cue reactivity in the amygdala showed higher BOLD activation in response to central insulin compared to placebo. Furthermore, women with overweight and obesity and men of normal weight showed higher BOLD neural food cue responsivity to central insulin compared to placebo. Higher central insulin action in the insular cortex was associated with better peripheral insulin sensitivity and higher cognitive control. Moreover, central insulin action in the dorsolateral prefrontal cortex (DLPFC) revealed significant sex differences. In response to central insulin compared to placebo, men showed lower DLPFC BOLD activity, whereas women showed higher DLPFC activity in response to highly desired food cues. On behavioral level, central insulin action significantly reduced hunger, whereas the desire to eat, especially for low caloric food cues was significantly higher with central insulin than with placebo. CONCLUSIONS: Obesity and sex influenced the central insulin-mediated neural BOLD activity to visual food cues in brain regions implicated in reward and cognitive control. These findings show that central insulin action regulates food response differentially in men and women, which may have consequences for metabolism and eating behavior.
Assuntos
Insulina , Sobrepeso , Adulto , Idoso , Encéfalo/fisiologia , Sinais (Psicologia) , Feminino , Alimentos , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Obesidade , Caracteres Sexuais , Adulto JovemRESUMO
AIMS: This study evaluated the effectiveness and safety of switching the basal insulin (BI) in a BI-supported oral therapy (BOT) to insulin glargine 300 U/ml (Gla-300) in adults with inadequately controlled type 2 diabetes (T2D). MATERIALS AND METHODS: This was a non-interventional, multicentre, prospective 12-month study, conducted in Germany, Austria and Switzerland. The study documented people with T2D with glycated haemoglobin (HbA1c) between 7.5% and 10.0%, currently treated by a non-Gla-300 BOT regimen, after the physician had decided to switch the BI to Gla-300. Primary endpoint was the proportion of patients achieving the fasting plasma glucose (FPG; ≤110 mg/dl) target. RESULTS: In total, 1194 participants comprised the full analysis set, of which 793 completed documentation of 12 months Gla-300 treatment (FAS-M12). The main previous BI was insulin glargine 100 U/ml (Gla-100; 47.2%). Twelve months after switching to Gla-300, 27.0% of FAS-M12 participants achieved the FPG target and 44.8% their individualized HbA1c target. The greatest FPG target achievements were seen in previous Gla-100 (29.3%), and greatest HbA1c target achievements in previous insulin detemir users (57.7%). The mean FPG decreased by -36.3 ± 51.2 mg/dl to 135.5 ± 36.9 mg/dl and mean HbA1c by -0.79 ± 1.01% to 7.45 ± 0.94%. Symptomatic and nocturnal hypoglycaemia incidence significantly decreased over 12 months of Gla-300 treatment. Body weight remained unchanged. CONCLUSIONS: Switching the BI to Gla-300 in a BOT regimen improved metabolic control and treatment satisfaction in a substantial proportion of patients with T2D and inadequate target achievement within 12 months in clinical practice with a decreased risk of symptomatic and nocturnal hypoglycaemia and without weight gain.
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Diabetes Mellitus Tipo 2 , Hipoglicemia , Adulto , Glicemia , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Hipoglicemia/prevenção & controle , Hipoglicemiantes/efeitos adversos , Insulina Glargina/efeitos adversos , Estudos ProspectivosRESUMO
AIM: To cluster adults with diabetes using variables from real-world clinical care at manifestation. MATERIALS AND METHODS: We applied hierarchical clustering using Ward's method to 56 869 adults documented in the prospective Diabetes Follow-up Registry (DPV). Clustering variables included age, sex, body mass index (BMI), HbA1c, diabetic ketoacidosis (DKA), components of the metabolic syndrome (hypertension/dyslipidaemia/hyperuricaemia) and beta-cell antibody status. Time until use of oral antidiabetic drugs (OADs), use of insulin, chronic kidney disease (CKD), cardiovascular disease (CVD), retinopathy or neuropathy were assessed using Kaplan-Meier analysis and Cox regression models. RESULTS: We identified eight clusters: four clusters comprised early diabetes onset (median age 40-50 years) but differed with regard to BMI, HbA1c, DKA and antibody positivity. Two clusters included adults with diabetes onset aged in their early 60s who met target HbA1c, but differed in BMI and sex distribution. Two clusters were characterized by late diabetes onset (median age 69 and 77 years) and comparatively low BMI, but differences in HbA1c. Earlier insulin use was observed in adults with high HbA1c, and earlier OAD use was observed in those with high BMI. Time until CKD or CVD was shorter in those with late onset, whereas retinopathy occurred earlier in adults with late onset and high HbA1c, and in adults with early onset, but high HbA1c and high percentage of antibody positivity. CONCLUSIONS: Adult diabetes is heterogeneous beyond classical type 1/type 2 diabetes, based on easily available variables in clinical practice using an automated clustering algorithm that allows both continuous and binary variables.
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Cetoacidose Diabética , Insuficiência Renal Crônica , Doenças Retinianas , Adulto , Idoso , Áustria/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Seguimentos , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemiantes , Insulina/uso terapêutico , Pessoa de Meia-Idade , Estudos Prospectivos , Sistema de RegistrosRESUMO
From microbes to human beings, nontargeted metabolic profiling by liquid chromatography (LC)-mass spectrometry (MS) has been commonly used to investigate metabolic alterations. Still, a major challenge is the annotation of metabolites from thousands of detected features. The aim of our research was to go beyond coverage of metabolite annotation in common nontargeted metabolomics studies by an integrated multistep strategy applying data-dependent acquisition (DDA)-based ultrahigh-performance liquid chromatography (UHPLC)-high-resolution mass spectrometry (HRMS) analysis followed by comprehensive neutral loss matches for characteristic metabolite modifications and database searches in a successive manner. Using pooled human urine as a model sample for method establishment, we found 22% of the detected compounds having modifying structures. Major types of metabolite modifications in urine were glucuronidation (33%), sulfation (20%), and acetylation (6%). Among the 383 annotated metabolites, 100 were confirmed by standard compounds and 50 modified metabolites not present in common databases such as human metabolite database (HMDB) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were structurally elucidated. Practicability was tested by the investigation of urines from pregnant women diagnosed with gestational diabetes mellitus vs healthy controls. Overall, 83 differential metabolites were annotated and 67% of them were modified metabolites including five previously unreported compounds. To conclude, the systematic modifying group-assisted strategy can be taken as a useful tool to extend the number of annotated metabolites in biological and biomedical nontargeted studies.
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Metabolômica , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Bases de Dados Factuais , Feminino , Humanos , Espectrometria de Massas , GravidezRESUMO
Forgetfulness is a common complaint of pregnant women, who also often report impaired nocturnal sleep. Considering sleep's well-known beneficial role in consolidating newly encoded memory content, we hypothesized that pregnant women would display detrimental changes in objective sleep measures and associated memory deficits. We compared the consolidation of declarative as well as procedural memory across sleep in 21 healthy, third-trimester pregnant women versus 20 matched non-pregnant controls. Subjects encoded and were tested on visuospatial and procedural memory tasks before and after, respectively, a night of sleep spent at home. The emergence of gist-based memories was tested with the Deese-Roediger-McDermott (DRM) paradigm. Sleep was polysomnographically recorded and subjective sleep quality was assessed with questionnaires. Although pregnant in comparison to non-pregnant women reported markedly impaired subjective sleep quality and efficiency, quantitative changes were limited to increases in wakefulness after sleep onset and reductions in rapid eye movement (REM) sleep. Retention of newly learned memory contents, which is believed to reflect sleep-associated memory consolidation, was comparable between groups, as was the formation of gist-based memories. The findings indicate that subjective deteriorations in sleep quality experienced by pregnant women are not necessarily linked to objective impairments. They raise the possibility that sufficient slow wave sleep towards the end of pregnancy allows for normal sleep-related memory consolidation. Although these results were obtained in a small number of pregnant women in very good health and should be corroborated in larger samples, they challenge the assumption of poor sleep and impaired memory as hallmarks of the "pregnancy brain".
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Transtornos da Memória/fisiopatologia , Sono/fisiologia , Adulto , Feminino , Humanos , Gravidez , GestantesRESUMO
BACKGROUND: Offspring of mothers with gestational diabetes mellitus (GDM) have an increased risk of neonatal complications like birth trauma due to macrosomia or postnatal hypoglycemia, as well as long-term metabolic sequelae. Neonatal body composition may be a sensitive marker of metabolic effects on the fetus caused by suboptimal glycemic control during pregnancy. OBJECTIVE: To determine body composition in offspring of mothers with GDM compared to a reference cohort of healthy term neonates and to assess whether increased body fat would be associated with postnatal hypoglycemia. METHODS: This prospective, observational, cross-sectional study included 311 full-term, singleton infants born between June 2014 and July 2015. Body composition was measured within 96 h of birth using air displacement plethysmography. Results are indicated as median (1st Quartile - 3rd Quartile). RESULTS: Of 311 infants, 40 (12.9%) were born to mothers with GDM. Birth weight standard deviation scores (SDS) (0.24 vs. - 0.07, p = 0.04), fat mass (370 g vs. 333 g, p = 0.02) as well as fat mass/total body mass (BF%; 11.4% vs. 10.8%, p = 0.03) were significantly higher in infants following maternal GDM than in controls. In GDM offspring, anthropometric parameters, fat mass or BF% did not differ between infants with or without postnatal hypoglycemia. In this cohort, SDS for birth weight, fat mass, fat free mass, BF% or postnatal hypoglycemia were not associated with maternal blood glucose levels measured at an oral glucose tolerance test. CONCLUSIONS: SDS for birth weight, neonatal fat mass, and BF% were significantly higher in newborns following maternal GDM. In these infants born to mothers with GDM, body composition did not differ between those with or without postnatal hypoglycemia.
Assuntos
Diabetes Gestacional , Hipoglicemia , Peso ao Nascer , Composição Corporal , Índice de Massa Corporal , Estudos Transversais , Feminino , Humanos , Hipoglicemia/diagnóstico , Hipoglicemia/etiologia , Lactente , Recém-Nascido , Gravidez , Estudos ProspectivosRESUMO
BACKGROUND: Increased portion size is an essential contributor to the current obesity epidemic. The decision of how much to eat before a meal begins (i.e. pre-meal planning), and the attention assigned to this task, plays a vital role in our portion control. OBJECTIVE: We investigated whether pre-meal planning can be influenced by a shift in mindset in individuals with overweight and obesity in order to influence portion size selection and brain activity. DESIGN: We investigated the neural underpinnings of pre-meal planning in 36 adults of different weight groups (BMI < 25 kg/m2 and BMI ≥ 25 kg/m2) by means of functional magnetic resonance imaging. To examine the important role of attentional focus, participants were instructed to focus their mindset on the health effects of food, expected pleasure, or their intention to stay full until dinnertime, while choosing their portion size for lunch. RESULTS: We observed that participants of all weight groups reduced their portion size when adopting a health mindset, which was accompanied by enhanced activation of the self-control network (i.e. left prefrontal cortex). Fullness and pleasure mindsets resulted in contrasting reward responses in individuals with overweight and obesity compared to normal-weight individuals. Under the pleasure mindset, persons with overweight and obesity showed heightened activity in parts of the taste cortex (i.e. right frontal operculum), while the fullness mindset caused reduced activation in the ventral striatum, an important component of the reward system. Moreover, participants with overweight and obesity did not modify their behaviour under the pleasure mindset and selected larger portions than the normal-weight group. CONCLUSIONS: We were able to identify specific brain response patterns as participants made a final choice of a portion size. The results demonstrate that different brain responses and behaviours during pre-meal planning can inform the development of effective strategies for healthy weight management.
Assuntos
Encéfalo/fisiologia , Obesidade/psicologia , Sobrepeso/psicologia , Prazer/fisiologia , Tamanho da Porção/psicologia , Adulto , Encéfalo/diagnóstico por imagem , Feminino , Comportamentos Relacionados com a Saúde/fisiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Recompensa , Autocontrole/psicologia , Adulto JovemRESUMO
The standard procedure for blood glucose measurements is enzymatic testing. This method is cheap, but requires small samples of open blood with direct contact to the test medium. In principle, NMR provides non-contact analysis of body fluids, but high-field spectrometers are expensive and cannot be easily utilized under clinical conditions. Low-field NMR systems with permanent magnets are becoming increasingly smaller and more affordable. The studies presented here aim at exploring the capabilities of low-field NMR for measuring glucose concentrations in whole blood. For this purpose, a modern 1 T benchtop NMR spectrometer was used. Challenges arise from broad spectral lines, the glucose peak locations close to the water signal, low SNR and the interference with signals from other blood components. Whole blood as a sample comprises even more boundary conditions: crucial for reliable results are avoiding the separation of plasma and cells by gravitation and reliable reference values. First, the accuracy of glucose levels measured by NMR was tested using aqueous glucose solutions and commercially available bovine plasma. Then, 117 blood samples from oral glucose tolerance testing were measured with minimal preparation by simple pulse-acquire NMR experiments. The analysis itself is the key to achieve high precision, so several approaches were investigated: peak integration, orthogonal projection to latent structure analysis and support vector machine regression. Correlations between results from the NMR spectra and the routine laboratory automated analyzer revealed an RMSE of 7.90 mg/dL for the best model. 91.5% of the model output lies within the limits of the German Medical Association guidelines, which require the glucose measurement to be within 11% of the reference method. It is concluded that spectral quantification of glucose in whole blood samples by high-quality NMR spectrometers operating at 1 T is feasible with sufficient accuracy.
Assuntos
Glicemia/análise , Espectroscopia de Ressonância Magnética , Animais , Bovinos , Estudos de Viabilidade , Teste de Tolerância a Glucose , Humanos , Análise dos Mínimos Quadrados , Sistemas Automatizados de Assistência Junto ao Leito , Valores de Referência , Processamento de Sinais Assistido por Computador , Soluções , Máquina de Vetores de SuporteRESUMO
BACKGROUND: Animal studies and initial correlative data in humans indicate that insulin action in the brain may affect pancreatic insulin secretion. An important brain region for this process is the hypothalamus, an area that can develop insulin resistance. METHODS: Fifteen young, healthy men (27 ± 3 years) with a wide BMI spectrum (20-30 kg/m2) underwent 2 hyperglycemic clamps (target blood glucose: 10 mmol/L). In this double-blind study, subjects received 160 U of insulin or placebo as a nasal spray on 2 days in randomized order. On another day, insulin sensitivity of the hypothalamus was determined by functional magnetic resonance imaging. RESULTS: Glucose levels were comparable on both study days. In the whole group, C-peptide levels were not significantly different between conditions. Though, there was a significant interaction between insulin sensitivity of the hypothalamus × nasal spray × time on C-peptide levels (p = 10-6). The group was therefore divided according to median hypothalamic insulin sensitivity. C-peptide concentrations were higher after intranasal insulin compared to placebo spray in the group with a strong hypothalamic insulin response (p < 0.0001, ß = 6.00 ± 1.24) and lower in the brain insulin-resistant group (p = 0.005, ß = -2.68 ± 0.95). Neither somatostatin nor glucagon kinetics was altered by the nasal spray. CONCLUSIONS: In participants with high hypothalamic insulin sensitivity, insulin action in the brain enhanced second-phase insulin secretion from pancreatic beta cells. This reaction could, for example, contribute to late postprandial glucose regulation by suppressing hepatic glucose production by portal venous insulin.
Assuntos
Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Resistência à Insulina , Secreção de Insulina/efeitos dos fármacos , Insulina/farmacologia , Administração Intranasal , Adulto , Índice de Massa Corporal , Método Duplo-Cego , Humanos , Insulina/administração & dosagem , Imageamento por Ressonância Magnética , Masculino , Adulto JovemRESUMO
AIM: To evaluate the effectiveness and safety of initiating basal insulin-supported oral therapy (BOT) with insulin glargine 300 U/mL (Gla-300) in patients with type 2 diabetes inadequately controlled on oral antidiabetic drugs (OADs). MATERIALS AND METHODS: This non-interventional, multi-centre, prospective 52-week study, conducted in Germany and Switzerland, documented patients with type 2 diabetes with an HbA1c of between 7.5% and 10.0%, currently treated with OADs, after the physician had decided to start a BOT regimen with Gla-300. The primary endpoint was the rate of achievement of the individualized predefined HbA1c target. RESULTS: Of 1748 patients included, 1153 comprised the full analysis set, of whom 721 completed documentation of 12 months of Gla-300 treatment. Twelve months after starting Gla-300, 49.9% achieved their individualized HbA1c target, and 61.1% achieved either their HbA1c target or a fasting plasma glucose (FPG) of ≤110 mg/dL. Mean HbA1c decreased by -1.22% ± 1.05% to 7.28% ± 0.92% and mean FPG by -51.5 (±48.63) mg/dl to 132.9 ± 33.0 mg/dL. Median duration of HbA1c target achievement was 341 days and probability to remain on target after 6 months was 81%. Hypoglycaemia incidence and rates remained low after 12 months of Gla-300 treatment; no severe or severe nocturnal hypoglycaemia was observed. Body weight remained unchanged. CONCLUSIONS: Starting a BOT regimen with Gla-300 allowed about 60% of 721 German and Swiss patients with inadequately controlled type 2 diabetes to achieve glycaemic control within 12 months in daily clinical practice. Glycaemic control was achieved without weight gain or increased risk of nocturnal or severe hypoglycaemia.