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BACKGROUND: Physical activity (PA) measured by accelerometry is proposed as a novel trial endpoint for heart failure (HF). However, standardised methods and associations with established markers are lacking. This study aimed to examine PA measurements and accelerometer repeatability in patients with HF and age- and sex-matched controls, and study correlations with established prognostic HF markers, body composition, and quality of life (QoL). METHODS: Accelerometry was performed in 105 patients with HF with left ventricular ejection fraction (LVEF) ≤ 40% and in 46 controls. Participants also underwent dual X-ray absorptiometry, cardiopulmonary exercise testing, a six-minute walking test (6MWT), echocardiography, and NT-proBNP measurement, and completed a QoL questionnaire. RESULTS: Average acceleration was markedly reduced in patients with HF compared with healthy controls (16.1 ± 4.8 mg vs 27.2 ± 8.5 mg, p < 0.001). Healthy controls spent a median daily 56 min (IQR 41-96 min) in moderate-to-vigorous PA (MVPA), whereas HF patients spent only 12 min (IQR 6-24) in MVPA. In HF patients, average acceleration correlated moderately with 6MWT (R = 0.41, p < 0.001) and maximal oxygen uptake (peak VO2) (R = 0.36, p < 0.001) but not with NT-proBNP, LVEF, or QoL. Patients in NYHA class II showed a higher average acceleration than patients in NYHA III (16.6 ± 4.9 mg vs 14.0 ± 3.6 mg, p = 0.01). CONCLUSIONS: Daily PA was severely reduced in patients with HF compared with healthy controls. In HF patients, we found moderate correlations of accelerometer measurements with markers of physical capacity but not with LVEF or NT-proBNP. TRIAL REGISTRATION: NCT05063955. Registered 01 June 2021-retrospectively registered.
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INTRODUCTION: Children and adolescents with recent-onset type 1 diabetes (T1D) commonly maintain a certain level of insulin production during the remission phase, which can last months to years. Preserving ß-cell function can reduce T1D complications and improve glycaemic control. Influenza vaccination has pleiotropic effects and administration of the vaccine during the early phases of T1D may offer ß-cell protection. This study aims to assess the effect of influenza vaccination on preserving ß-cell function in children and adolescents with recent-onset T1D. METHODS AND ANALYSIS: The INfluenza VaccInation To mitigate typE 1 Diabetes trial is a randomised, double-blind, placebo-controlled, multicentre trial in paediatric patients with recent-onset T1D aged 7-17 years. 100 participants will be randomised in a 1:1 ratio to receive either a standard inactivated quadrivalent influenza vaccine or a placebo within 14 days of diagnosis. The primary outcome is a difference in mean change (from baseline to 12 months) in C-peptide level between groups during a 2-hour mixed-meal tolerance test. Secondary outcomes include mean change (from baseline to 6 months) in C-peptide levels, haemoglobin A1c, ambulatory glucose profiles and insulin requirements. Exploratory outcomes are diabetes-related autoantibodies, inflammatory markers and serum haemagglutinin inhibition antibody titres against the influenza viruses. The current treatment for T1D is largely symptomatic, relying on insulin administration. There is a pressing need for novel pharmacological approaches aimed at modulating the immune system to preserve residual ß-cell function. Existing immunotherapies are cost-prohibitive and associated with multiple side effects, whereas influenza vaccination is inexpensive and generally well tolerated. A positive outcome of this study holds potential for immediate implementation into standard care for children and adolescents with recent-onset T1D and may guide future research on immune modulation in T1D. ETHICS AND DISSEMINATION: Ethical approval was obtained from Danish Health Authorities prior to participant enrollment. The trial results will be submitted to a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT05585983 and EudraCT Number 2022-500906-17-01.
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Diabète de type 1 , Vaccins antigrippaux , Humains , Diabète de type 1/immunologie , Diabète de type 1/thérapie , Adolescent , Enfant , Vaccins antigrippaux/administration et posologie , Méthode en double aveugle , Femelle , Mâle , Grippe humaine/prévention et contrôle , Hémoglobine glyquée/métabolisme , Peptide C/sang , Essais contrôlés randomisés comme sujet , Glycémie/métabolisme , Insuline , Vaccination , Cellules à insuline/immunologieRÉSUMÉ
To tackle the burden of obesity-induced cardiometabolic disease, the scientific community relies on accurate and reproducible adiposity measurements in the clinic. These measurements guide our understanding of underlying biological mechanisms and clinical outcomes of human trials. However, measuring adiposity and adipose tissue distribution in a clinical setting can be challenging, and different measurement methods pose important limitations. BMI is a simple and high-throughput measurement, but it is associated relatively poorly with clinical outcomes when compared with waist-to-hip and sagittal abdominal diameter measurements. Body composition measurements by dual energy X-ray absorptiometry or MRI scans would be ideal due to their high accuracy, but are not high-throughput. Another important consideration is that adiposity measurements vary between men and women, between adults and children, and between people of different ethnic backgrounds. In this Perspective article, we discuss how these critical challenges can affect our interpretation of research data in the field of obesity and the design and implementation of clinical guidelines.
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CONTEXT: Cardiorespiratory fitness, commonly assessed as maximal volume of oxygen consumption (VO2max), has emerged as an important predictor of morbidity and mortality. OBJECTIVE: We investigated the causality and directionality of the associations of VO2max with body composition, physical activity, diabetes, performance enhancers, and longevity. METHODS: Using publicly available summary statistics from the largest genome-wide association studies publicly available, we conducted a bidirectional two-sample Mendelian randomization (MR) study. Bidirectional MR tested directionality, and estimated the total causal effects, whereas multivariable MR (MVMR) estimated independent causal effects. Cardiorespiratory fitness (VO2max) was estimated from a submaximal cycle ramp test (N≈90,000) and scaled to total body weight, and in additional analyses to fat-free mass (mL/min/kg). RESULTS: Genetically predicted higher (per one standard deviation increase) body fat percentage was associated with lower VO2max (ß=-0.36 [95% CI: -0.40, -0.32], p=6E-77). Meanwhile, genetically predicted higher appendicular lean mass (0.10 [0.08,0.13] p=3E-16), physical activity (0.29 [0.07,0.52]), and performance enhancers (fasting insulin, hematocrit, and free testosterone in men) were all positively associated with VO2max (p<0.01). Genetic predisposition to diabetes had no effect on VO2max. MVMR showed independent causal effects of body fat percentage, appendicular lean mass, physical activity, and hematocrit on VO2max, as well as of body fat percentage and type 2 diabetes (T2D) on longevity. Genetically predicted VO2max showed no associations. CONCLUSION: Cardiorespiratory fitness can be improved by favorable body composition, physical activity, and performance enhancers. Despite being a strong predictor of mortality, VO2max is not causally associated with T2D or longevity.
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AIMS/HYPOTHESIS: Low birthweight is a risk factor for type 2 diabetes and CVD. This prospective cohort study investigated whether lower birthweight increases CVD risk after diagnosis of type 2 diabetes. METHODS: Original midwife records were evaluated for 8417 participants recently diagnosed with type 2 diabetes in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort. Patients were followed for the first occurrence of a composite CVD endpoint (myocardial infarction, coronary revascularisation, peripheral arterial disease, stroke, unstable angina, heart failure or CVD death), a three-component endpoint comprising major adverse cardiovascular events (MACE), and all-cause mortality. Ten-year risks were estimated using the Aalen-Johansen estimator considering non-CVD death as a competing risk. HRs were determined by Cox regression. Models were controlled for sex, age, calendar year at birth, family history of diabetes and born-at-term status. RESULTS: A total of 1187 composite CVD endpoints, 931 MACE, and 1094 deaths occurred during a median follow-up period of 8.5 years. The 10-year standardised composite CVD risk was 19.8% in participants with a birthweight <3000 g compared with 16.9% in participants with a birthweight of 3000-3700 g, yielding a risk difference (RD) of 2.9% (95% CI 0.4, 5.4) and an adjusted HR of 1.20 (95% CI 1.03, 1.40). The 10-year MACE risk for birthweight <3000 g was similarly elevated (RD 2.4%; 95% CI 0.1, 4.7; HR 1.22; 95% CI 1.01, 1.46). The elevated CVD risk was primarily driven by stroke, peripheral arterial disease and CVD death. All-cause mortality showed no substantial difference. CONCLUSIONS/INTERPRETATION: Having a birthweight <3000 g is associated with higher CVD risk among patients with type 2 diabetes, driven primarily by risk of stroke and CVD death.
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Maladies cardiovasculaires , Diabète de type 2 , Humains , Diabète de type 2/complications , Diabète de type 2/mortalité , Diabète de type 2/épidémiologie , Femelle , Mâle , Maladies cardiovasculaires/mortalité , Maladies cardiovasculaires/épidémiologie , Adulte d'âge moyen , Études prospectives , Facteurs de risque , Nourrisson à faible poids de naissance , Sujet âgé , Poids de naissance , Adulte , Danemark/épidémiologie , Nouveau-néRÉSUMÉ
BACKGROUND: Skeletal muscle wasting is critical in patients with heart failure (HF). Whereas prior studies have employed appendicular lean mass (ALM) normalized by height squared to identify low skeletal muscle mass, the potential of ALM normalized to body mass index (ALM/BMI) remains unexplored in patients with HF. In this study, we compared the use of 2 skeletal muscle mass indices in patients with HF to examine their sex-specific correlations with measures of physical capacity, quality of life, and daily physical activity. METHODS AND RESULTS: A total of 111 patients with HF underwent dual x-ray absorptiometry, physical capacity tests, and accelerometry and answered a quality-of-life questionnaire. ALM normalized by height squared and ALM/BMI indices disagreed in classifying low muscle mass (Cohen's κ, -0.008 [95% CI, -0.094 to 0.177]; P=0.93). ALM/BMI correlated well with 6-minute walking distance in women and men (R=0.67 and 0.49; P<0.001), with maximal oxygen uptake in women and men (R=0.41 and 0.48; P<0.05), and with maximal muscle strength in women and men (R=0.54 and 0.43; P<0.01). Inversely, ALM normalized by height squared did not correlate significantly with 6-minute walking distance or maximal oxygen uptake and correlated with maximal muscle strength only in men (R=0.43; P<0.001). Only ALM/BMI allowed for identification of a low-muscle-mass group characterized by poor quality of life (Minnesota Living With Heart Failure Questionnaire score of 33±21 versus 25±16; P=0.027) and less daily time spent in moderate to vigorous physical activity (8 [3-17] versus 15 [9-37] minutes; P<0.001). CONCLUSIONS: ALM/BMI was superior for identifying clinically significant muscle dysfunction in both female and male patients with HF.
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Absorptiométrie photonique , Indice de masse corporelle , Défaillance cardiaque , Muscles squelettiques , Qualité de vie , Humains , Défaillance cardiaque/physiopathologie , Défaillance cardiaque/diagnostic , Défaillance cardiaque/complications , Mâle , Femelle , Muscles squelettiques/physiopathologie , Adulte d'âge moyen , Sujet âgé , Tolérance à l'effort/physiologie , Test de marche , Composition corporelle , Facteurs sexuels , Force musculaire , Enquêtes et questionnaires , Accélérométrie , Exercice physique/physiologie , Sarcopénie/physiopathologie , Sarcopénie/diagnosticRÉSUMÉ
AIMS: To determine the magnitude of the association between abdominal adiposity and low-grade inflammation in persons with recently diagnosed type 2 diabetes (T2D) and to determine to what extent this association is mediated by low physical activity level, hyperinsulinaemia, hyperglycaemia, dyslipidaemia, hypertension, and comorbidities. MATERIALS AND METHODS: We measured waist circumference, clinical characteristics, and inflammatory markers i.e. tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hsCRP), in >9000 persons with recently diagnosed T2D. We applied multiple mediation analysis using structural equation modelling, with adjustment for age and sex. RESULTS: Waist circumference as a proxy for abdominal adiposity was positively associated with all inflammatory markers. Hence, a one-standard deviation (SD) increase in waist circumference (SD = 15 cm) was associated with a 22%, 35%, and 46% SD increase in TNF-α (SD = 1.5 pg/mL), IL-6 (SD = 4.4 pg/mL), and hsCRP (SD = 6.9 mg/L), respectively. The level of hyperinsulinaemia assessed by fasting C-peptide was quantitatively the most important mediator, accounting for 9%-25% of the association between abdominal adiposity and low-grade inflammation, followed by low physical activity (5%-7%) and high triglyceride levels (2%-6%). Although mediation of adiposity-induced inflammation by greater comorbidity and higher glycated haemoglobin levels reached statistical significance, their impact was minor (1%-2%). CONCLUSIONS: In persons with recently diagnosed T2D, there was a clear association between abdominal adiposity and low-grade inflammation. A considerable part (20%-40%) of this association was mediated by other factors, with hyperinsulinaemia as a potentially important driver of adiposity-induced inflammation in T2D.
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Protéine C-réactive , Diabète de type 2 , Inflammation , Interleukine-6 , Obésité abdominale , Facteur de nécrose tumorale alpha , Tour de taille , Humains , Diabète de type 2/complications , Diabète de type 2/sang , Diabète de type 2/épidémiologie , Femelle , Mâle , Adulte d'âge moyen , Inflammation/sang , Inflammation/complications , Obésité abdominale/complications , Obésité abdominale/épidémiologie , Facteur de nécrose tumorale alpha/sang , Interleukine-6/sang , Protéine C-réactive/analyse , Protéine C-réactive/métabolisme , Hyperinsulinisme/complications , Hyperinsulinisme/épidémiologie , Hyperinsulinisme/sang , Sujet âgé , Adiposité , Médiateurs de l'inflammation/sang , Médiateurs de l'inflammation/métabolisme , Marqueurs biologiques/sang , Dyslipidémies/épidémiologie , Dyslipidémies/sang , Hypertension artérielle/complications , Hypertension artérielle/épidémiologie , Hyperglycémie/épidémiologie , AdulteRÉSUMÉ
Diabetes represents a major public health concern with a considerable impact on human life and healthcare expenditures. It is now well established that diabetes is characterized by a severe skeletal muscle pathology that limits functional capacity and quality of life. Increasing evidence indicates that diabetes is also one of the most prevalent disorders characterized by impaired skeletal muscle regeneration, yet underlying mechanisms and therapeutic treatments remain poorly established. In this review, we describe the cellular and molecular alterations currently known to occur during skeletal muscle regeneration in people with diabetes and animal models of diabetes, including its associated comorbidities, e.g., obesity, hyperinsulinemia, and insulin resistance. We describe the role of myogenic and non-myogenic cell types on muscle regeneration in conditions with or without diabetes. Therapies for skeletal muscle regeneration and gaps in our knowledge are also discussed, while proposing future directions for the field.
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Diabète , Muscles squelettiques , Régénération , Humains , Muscles squelettiques/métabolisme , Muscles squelettiques/anatomopathologie , Animaux , Diabète/thérapie , Diabète/métabolisme , Développement musculaire , InsulinorésistanceRÉSUMÉ
AIMS: Sodium glucose co-transporter-2 (SGLT2) inhibition lowers glucose levels independently of insulin, leading to reduced insulin secretion and increased lipolysis, resulting in elevated circulating free fatty acids (FFAs). While SGLT2 inhibition improves tissue insulin sensitivity, the increase in circulating FFAs could reduce insulin sensitivity in skeletal muscle and the liver. We aimed to investigate the effects of SGLT2 inhibition on substrate utilization in skeletal muscle and the liver and to measure beta-cell function and glucose tolerance. METHODS: Thirteen metformin-treated individuals with type 2 diabetes were randomized to once-daily empagliflozin 25 mg or placebo for 4 weeks in a crossover design. Skeletal muscle glucose and FFA uptake together with hepatic tissue FFA uptake were measured using [18F]FDG positron emission tomography/computed tomography (PET/CT) and [11C]palmitate PET/CT. Insulin secretion and action were estimated using the oral minimal model. RESULTS: Empagliflozin did not affect glucose (0.73 ± 0.30 vs. 1.16 ± 0.64, µmol/g/min p = 0.11) or FFA (0.60 ± 0.30 vs. 0.56 ± 0.3, µmol/g/min p = 0.54) uptake in skeletal muscle. FFA uptake in the liver (21.2 ± 10.1 vs. 19 ± 8.8, µmol/100 ml/min p = 0.32) was unaffected. Empagliflozin increased total beta-cell responsivity (20 ± 8 vs. 14 ± 9, 10-9 min-1, p < 0.01) and glucose effectiveness (2.6 × 10-2 ± 0.3 × 10-2 vs. 2.4 × 10-2 ± 0.3 × 10-2, dL/kg/min, p = 0.02). CONCLUSIONS: Despite improved beta-cell function and glucose tolerance, empagliflozin does not appear to affect skeletal muscle FFA or glucose uptake.
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Composés benzhydryliques , Diabète de type 2 , Glucosides , Insulinorésistance , Humains , Acide gras libre , Diabète de type 2/traitement médicamenteux , Diabète de type 2/métabolisme , Transporteur-2 sodium-glucose/métabolisme , Tomographie par émission de positons couplée à la tomodensitométrie , Glucose/métabolisme , Insuline/métabolisme , Muscles squelettiquesRÉSUMÉ
CONTEXT: Fibroblast growth factor (FGF) 21 acts as a metabolic regulator and its therapeutic use is under investigation. FGF21 signaling requires binding to surface receptors, FGFR1c and ß-klotho. FGF21 resistance is observed in metabolic diseases and FGF21 signaling is regulated by fibroblast activation protein (FAP). Metformin is reported to influence expression and secretion of FGF21 in preclinical models, but the effect of metformin on FGF21 in a clinical trial remains unknown. OBJECTIVE: To investigate how 12 weeks of treatment with metformin affects the FGF21 signaling pathway in patients with type 2 diabetes (T2D). METHODS: Randomized, placebo-controlled study in patients with T2D (n = 24) receiving either metformin (1000 mg twice daily) or placebo. A control group of body mass index- and age-matched healthy individuals (n = 12) received a similar dose of metformin. Blood samples and muscle and fat biopsies were collected at study entry and after 12 weeks. METHODS: Plasma levels of FGF21 (total and intact) and FAP (total and activity) were measured. Muscle and fat biopsies were analyzed for mRNA and protein expression of targets relevant for activation of the FGF21 signaling pathway. RESULTS: Circulating FAP activity decreased after metformin treatment compared with placebo (P = .006), whereas FGF21 levels were unchanged. Metformin treatment increased gene and protein expression of ß-klotho, FGFR1c, and pFGFR1c in adipose tissue. FGF21 mRNA expression increased in muscle tissue after metformin and the FGF21 protein, but not mRNA levels, were observed in adipose tissue. CONCLUSION: Our findings suggest that metformin suppresses the circulating FAP activity and upregulates the expression of FGFR1c and ß-klotho for increased FGF21 signaling in adipose tissue, thus improving peripheral FGF21 sensitivity.
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Diabète de type 2 , Metformine , Humains , Metformine/pharmacologie , Metformine/usage thérapeutique , Diabète de type 2/traitement médicamenteux , Facteurs de croissance fibroblastique , Transduction du signal , Protéines membranaires/génétique , Protéines membranaires/métabolisme , ARN messagerRÉSUMÉ
BACKGROUND: The appetite-suppressing potential of liver-expressed antimicrobial peptide 2 (LEAP2), and its antagonistic effects on the hunger-inducing hormone ghrelin have attracted scientific interest. It is unclear how LEAP2 is influenced by fasting and how it responds to specific nutrients. OBJECTIVES: The purpose of this investigation was to assess whether LEAP2 concentration 1) decreases after fasting, 2) increases postprandially, and 3) is regulated by nutrient sensing in the splanchnic bed. METHODS: Plasma LEAP2 concentration was measured in blood samples from 5 clinical cross-over trials, following 1) 36 h of fasting (n = 8), 2) 10 h of fasting (n = 37, baseline data pooled from 4 of the clinical trials), 3) Oral and intravenous glucose administration (n = 11), 4) Oral and intravenous Na-lactate administration (n = 10), and 5) Oral and intravenous Na-ß-hydroxybutyrate (BHB) administration (n = 8). All 5 trials included healthy males. RESULTS: Compared with a 10-h fasting period, the median LEAP2 concentration was 38% lower following 36 h of fasting (P < 0.001). Oral administration of glucose elevated, whereas intravenous glucose administration lowered LEAP2 concentration (intervention x time, P = 0.001), resulting in a mean difference of 9 ng/mL (95% confidence interval [CI]: 1, 17) after 120 min. Oral lactate increased, and intravenous lactate decreased LEAP2 (intervention x time, P = 0.007), with a mean difference between interventions of 10 ng/mL (95% CI: 6, 15) after 120 min. In contrast, oral and intravenous administration of BHB reduced the LEAP2 concentration (main effect of time, P < 0.001). CONCLUSIONS: Our investigations show that LEAP2 concentration was lower after a 36-h fast than an overnight fast and that oral delivery of glucose and lactate elevated LEAP2 concentration compared with intravenous administration, whereas LEAP2 concentrations decreased with both oral and intravenous BHB. This indicates that the LEAP2 concentration is sensitive to intestinal exposure to specific substrates, highlighting the need for future studies exploring the relationship between nutrients and LEAP2. This trial was registered at clinicaltrials.gov as NCT01840098, NCT03204877, NCT04299815, NCT03935841, and NCT01705782.
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Glucose , Acide lactique , Humains , Mâle , Acide 3-hydroxy-butyrique , Jeûne , Ghréline , FaimRÉSUMÉ
BACKGROUND AND AIMS: During diabetic ketoacidosis (DKA), muscle tissue develops a profound insulin resistance that complicates reversal of this potentially lethal condition. We have investigated mediators of insulin action in human skeletal muscle during total insulin withdrawal in patients with type 1 diabetes, under the hypothesis that initial phases of DKA are associated with impaired postreceptor signaling. MATERIALS AND METHODS: Muscle biopsies were obtained during a randomized, controlled, crossover trial involving 9 patients with type 1 diabetes. The subjects were investigated during a high-dose insulin clamp preceded by either: (1) insulin-controlled euglycemia (control) or (2) total insulin withdrawal for 14 hours. Insulin action in skeletal muscle and whole-body substrate metabolism were investigated using western blot analysis and indirect calorimetry respectively. RESULTS: During insulin withdrawal, insulin-stimulated dephosphorylation of glycogen synthase decreased by â¼30% (P < .05) compared with the control situation. This was associated with a decrease in glucose oxidation by â¼30% (P < .05). Despite alterations in glucose metabolism, insulin transduction to glucose transport and protein synthesis (Akt, AS160, mammalian target of rapamycin, and eukaryotic translation initiation factor 4E binding protein) was intact, and glucose transporter (GLUT4) and mitochondrial proteins (succinate dehydrogenase complex, subunit A and prohibitin 1) protein expression were unaffected by the intervention. CONCLUSION: DKA impairs insulin-stimulated activation of glycogen synthase, whereas insulin signal transduction to glucose transport and protein synthesis remains intact. Reversal of insulin resistance during treatment of DKA should target postreceptor mediators of glucose uptake. CLINICAL TRIAL REGISTRATION NUMBER: NCT02077348.
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Diabète de type 1 , Acidocétose diabétique , Insulinorésistance , Humains , Diabète de type 1/traitement médicamenteux , Acidocétose diabétique/métabolisme , Glucose/métabolisme , Glycogen synthase/métabolisme , Insuline/métabolisme , Insulinorésistance/physiologie , Muscles squelettiques/métabolisme , Transduction du signal , Études croiséesRÉSUMÉ
OBJECTIVE: Metabolic syndrome components may cumulatively increase the risk of diabetic polyneuropathy (DPN) in type 2 diabetes mellitus (T2DM) patients, driven by insulin resistance and hyperinsulinemia. We investigated the prevalence of DPN in three T2DM subgroups based on indices of ß-cell function and insulin sensitivity. RESEARCH DESIGN AND METHODS: We estimated ß-cell function (HOMA2-B) and insulin sensitivity (HOMA2-S) in 4,388 Danish patients with newly diagnosed T2DM. Patients were categorized into subgroups of hyperinsulinemic (high HOMA2-B, low HOMA2-S), classical (low HOMA2-B, low HOMA2-S), and insulinopenic (low HOMA2-B, high HOMA2-S) T2DM. After a median follow-up of 3 years, patients filled the Michigan Neuropathy Screening Instrument questionnaire (MNSIq) to identify DPN (score ≥ 4). We used Poisson regression to calculate adjusted prevalence ratios (PRs) for DPN, and spline models to examine the association with HOMA2-B and HOMA2-S. RESULTS: A total of 3,397 (77%) patients filled in the MNSIq. The prevalence of DPN was 23% among hyperinsulinemic, 16% among classical, and 14% among insulinopenic patients. After adjusting for demographics, diabetes duration and therapy, lifestyle behaviors, and metabolic syndrome components (waist circumference, triglycerides, HDL cholesterol, hypertension, and HbA1c), the PR of DPN was 1.35 (95% CI 1.15-1.57) for the hyperinsulinemic compared with the classical patients. In spline analyses, we observed a linear relation of higher DPN prevalence with increasing HOMA2-B, independent of both metabolic syndrome components and HOMA2-S. CONCLUSIONS: Hyperinsulinemia marked by high HOMA2-B is likely an important risk factor for DPN beyond metabolic syndrome components and insulin resistance. This should be considered when developing interventions to prevent DPN.
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Diabète de type 2 , Neuropathies diabétiques , Insulinorésistance , Syndrome métabolique X , Polyneuropathies , Humains , Diabète de type 2/complications , Diabète de type 2/épidémiologie , Diabète de type 2/diagnostic , Syndrome métabolique X/épidémiologie , Syndrome métabolique X/complications , Prévalence , Neuropathies diabétiques/épidémiologie , Neuropathies diabétiques/complicationsRÉSUMÉ
AIMS/HYPOTHESIS: Low birthweight is a risk factor for type 2 diabetes but it is unknown whether low birthweight is associated with distinct clinical characteristics at disease onset. We examined whether a lower or higher birthweight in type 2 diabetes is associated with clinically relevant characteristics at disease onset. METHODS: Midwife records were traced for 6866 individuals with type 2 diabetes in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort. Using a cross-sectional design, we assessed age at diagnosis, anthropomorphic measures, comorbidities, medications, metabolic variables and family history of type 2 diabetes in individuals with the lowest 25% of birthweight (<3000 g) and highest 25% of birthweight (>3700 g), compared with a birthweight of 3000-3700 g as reference, using log-binomial and Poisson regression. Continuous relationships across the entire birthweight spectrum were assessed with linear and restricted cubic spline regression. Weighted polygenic scores (PS) for type 2 diabetes and birthweight were calculated to assess the impact of genetic predispositions. RESULTS: Each 1000 g decrease in birthweight was associated with a 3.3 year (95% CI 2.9, 3.8) younger age of diabetes onset, 1.5 kg/m2 (95% CI 1.2, 1.7) lower BMI and 3.9 cm (95% CI 3.3, 4.5) smaller waist circumference. Compared with the reference birthweight, a birthweight of <3000 g was associated with more overall comorbidity (prevalence ratio [PR] for Charlson Comorbidity Index Score ≥3 was 1.36 [95% CI 1.07, 1.73]), having a systolic BP ≥155 mmHg (PR 1.26 [95% CI 0.99, 1.59]), lower prevalence of diabetes-associated neurological disease, less likelihood of family history of type 2 diabetes, use of three or more glucose-lowering drugs (PR 1.33 [95% CI 1.06, 1.65]) and use of three or more antihypertensive drugs (PR 1.09 [95% CI 0.99, 1.20]). Clinically defined low birthweight (<2500 g) yielded stronger associations. Most associations between birthweight and clinical characteristics appeared linear, and a higher birthweight was associated with characteristics mirroring lower birthweight in opposite directions. Results were robust to adjustments for PS representing weighted genetic predisposition for type 2 diabetes and birthweight. CONCLUSION/INTERPRETATION: Despite younger age at diagnosis, and fewer individuals with obesity and family history of type 2 diabetes, a birthweight <3000 g was associated with more comorbidities, including a higher systolic BP, as well as with greater use of glucose-lowering and antihypertensive medications, in individuals with recently diagnosed type 2 diabetes.
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Diabète de type 2 , Humains , Diabète de type 2/épidémiologie , Poids de naissance/génétique , Études transversales , Facteurs de risque , Prédisposition génétique à une maladie , GlucoseRÉSUMÉ
BACKGROUND: Active acromegaly is characterized by increased lean body mass, but the mechanisms underlying the protein anabolic effect are unclear. AIM: To study if active acromegaly induces reversible changes in whole-body and skeletal muscle protein kinetics. PATIENTS AND METHODS: Eighteen patients with acromegaly were investigated before and 47 ± 10 weeks after disease control by surgery (n = 8) and/or medical treatment (n = 10). Labeled phenylalanine and tyrosine tracers were employed to assess whole-body and regional forearm muscle protein kinetics. Intramyocellular protein signaling was assessed in skeletal muscle biopsies, and whole-body dual-energy X-ray absorptiometry scan and indirect calorimetry assessed lean body mass (LBM) and resting energy expenditure, respectively. RESULTS: Disease control induced a 7% decrease in lean body mass (P < .000) and a 14% decrease in LBM-adjusted energy expenditure. Whole-body phenylalanine breakdown decreased after disease control (P = .005) accompanied by a decrease in the degradation of phenylalanine to tyrosine (P = .005) and a decrease in whole-body phenylalanine synthesis (P = .030). Skeletal muscle protein synthesis tended to decrease after disease control (P = .122), whereas the muscle protein breakdown (P = .437) and muscle protein loss were unaltered (P = .371). Unc-51 like autophagy activating kinase 1 phosphorylation, an activator of protein breakdown, increased after disease control (P = .042). CONCLUSIONS: Active acromegaly represents a reversible high flux state in which both whole-body protein breakdown and synthesis are increased, whereas forearm muscle protein kinetics are unaltered. Future studies are needed to decipher the link between protein kinetics and the structure and function of the associated growth hormone-induced increase in lean body mass.
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Acromégalie , Humains , Acromégalie/thérapie , Acromégalie/métabolisme , Avant-bras , Tyrosine , Phénylalanine , Protéines du muscle/métabolisme , Composition corporelle/physiologie , Métabolisme énergétique/physiologie , Muscles squelettiques/métabolismeRÉSUMÉ
The gut microbiota impacts systemic levels of multiple metabolites including NAD+ precursors through diverse pathways. Nicotinamide riboside (NR) is an NAD+ precursor capable of regulating mammalian cellular metabolism. Some bacterial families express the NR-specific transporter, PnuC. We hypothesized that dietary NR supplementation would modify the gut microbiota across intestinal sections. We determined the effects of 12 weeks of NR supplementation on the microbiota composition of intestinal segments of high-fat diet-fed (HFD) rats. We also explored the effects of 12 weeks of NR supplementation on the gut microbiota in humans and mice. In rats, NR reduced fat mass and tended to decrease body weight. Interestingly, NR increased fat and energy absorption but only in HFD-fed rats. Moreover, 16S rRNA gene sequencing analysis of intestinal and fecal samples revealed an increased abundance of species within Erysipelotrichaceae and Ruminococcaceae families in response to NR. PnuC-positive bacterial strains within these families showed an increased growth rate when supplemented with NR. The abundance of species within the Lachnospiraceae family decreased in response to HFD irrespective of NR. Alpha and beta diversity and bacterial composition of the human fecal microbiota were unaltered by NR, but in mice, the fecal abundance of species within Lachnospiraceae increased while abundances of Parasutterella and Bacteroides dorei species decreased in response to NR. In conclusion, oral NR altered the gut microbiota in rats and mice, but not in humans. In addition, NR attenuated body fat mass gain in rats, and increased fat and energy absorption in the HFD context.
RÉSUMÉ
The ability of stem cells to activate and differentiate is critical for maintaining the regenerative capacity of skeletal muscle. Here, we detail steps for specific quantification and isolation of primary human fibro-adipogenic progenitors and skeletal muscle stem cells using fluorescence-activated cell sorting. We describe important phenotypic traits such as time to enter the cell cycle and assessment of cell differentiation for the isolated cell populations. The technique has been applied on tissue obtained from surgery and needle biopsies. For complete details on the use and execution of this protocol, please refer to Farup et al. (2021).1.
Sujet(s)
Adipogenèse , Cellules souches , Humains , Cytométrie en flux/méthodes , Différenciation cellulaire/physiologie , Muscles squelettiquesRÉSUMÉ
CONTEXT: Exogenous ketone body administration lowers circulating glucose levels but the underlying mechanisms are uncertain. OBJECTIVE: We tested the hypothesis that administration of the ketone body ß-hydroxybutyrate (ßOHB) acutely increases insulin sensitivity via feedback suppression of circulating free fatty acid (FFA) levels. METHODS: In a randomized, single-blinded crossover design, 8 healthy men were studied twice with a growth hormone (GH) infusion to induce lipolysis in combination with infusion of either ßOHB or saline. Each study day comprised a basal period and a hyperinsulinemic-euglycemic clamp combined with a glucose tracer and adipose tissue and skeletal muscle biopsies. RESULTS: ßOHB administration profoundly suppressed FFA levels concomitantly with a significant increase in glucose disposal and energy expenditure. This was accompanied by a many-fold increase in skeletal muscle content of both ßOHB and its derivative acetoacetate. CONCLUSION: Our data unravel an insulin-sensitizing effect of ßOHB, which we suggest is mediated by concomitant suppression of lipolysis.