Effect of sustained decreases in sedentary time and increases in physical activity on liver enzymes and indices in type 2 diabetes.

Background: Current guidelines for nonalcoholic fatty liver disease (NAFLD) recommend high volumes and/or intensities of physical activity (PA), the achievement of which generally requires participation in supervised exercise training programs that however are difficult to implement in routine clinical practice. Conversely, counselling interventions may be more suitable, but result in only modest increases in moderate-to-vigorous-intensity PA (MVPA). This study assessed whether a counseling intervention for increasing PA and decreasing sedentary time (SED-time) is effective in improving NAFLD markers in people with type 2 diabetes. Methods: Three-hundred physically inactive and sedentary patients were randomized 1:1 to receive one-month theoretical and practical counseling once-a-year (intervention group) or standard care (control group) for 3 years. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltranspeptidase (γGT) levels were measured and fatty liver index (FLI), hepatic steatosis index (HSI), and visceral adiposity index (VAI) were calculated. Total PA volume, light-intensity PA (LPA), moderate-to-vigorous-intensity PA (MVPA), and SED-time were objectively measured by an accelerometer. Results: Throughout the 3-year period, NAFLD markers did not change in the control group, whereas ALT, γGT, FLI, and HSI decreased in the intervention group, with significant between-group differences, despite modest MVPA increases, which however were associated with larger decrements in SED-time and reciprocal increments in LPA. Mean changes in NAFLD markers varied according to quartiles of (and correlated with) changes in MVPA (all markers) and SED-time, LPA, and PA volume (ALT, γGT, and HSI). Mean changes in MVPA or PA volume were independent predictors of changes in NAFLD markers. When included in the models, change in cardiorespiratory fitness and lower body muscle strength were independently associated with some NAFLD markers. Conclusion: A behavior change involving all domains of PA lifestyle, even if insufficient to achieve the recommended MVPA target, may provide beneficial effects on NAFLD markers in people with type 2 diabetes.

Impaired Remodeling of White Adipose Tissue in Obesity and Aging: From Defective Adipogenesis to Adipose Organ Dysfunction.

The adipose organ adapts and responds to internal and environmental stimuli by remodeling both its cellular and extracellular components. Under conditions of energy surplus, the subcutaneous white adipose tissue (WAT) is capable of expanding through the enlargement of existing adipocytes (hypertrophy), followed by de novo adipogenesis (hyperplasia), which is impaired in hypertrophic obesity. However, an impaired hyperplastic response may result from various defects in adipogenesis, leading to different WAT features and metabolic consequences, as discussed here by reviewing the results of the studies in animal models with either overexpression or knockdown of the main molecular regulators of the two steps of the adipogenesis process. Moreover, impaired WAT remodeling with aging has been associated with various age-related conditions and reduced lifespan expectancy. Here, we delve into the latest advancements in comprehending the molecular and cellular processes underlying age-related changes in WAT function, their involvement in common aging pathologies, and their potential as therapeutic targets to influence both the health of elderly people and longevity. Overall, this review aims to encourage research on the mechanisms of WAT maladaptation common to conditions of both excessive and insufficient fat tissue. The goal is to devise adipocyte-targeted therapies that are effective against both obesity- and age-related disorders.

Renal Expression and Localization of the Receptor for (Pro)renin and Its Ligands in Rodent Models of Diabetes, Metabolic Syndrome, and Age-Dependent Focal and Segmental Glomerulosclerosis.

The (pro)renin receptor ((P)RR), a versatile protein found in various organs, including the kidney, is implicated in cardiometabolic conditions like diabetes, hypertension, and dyslipidemia, potentially contributing to organ damage. Importantly, changes in (pro)renin/(P)RR system localization during renal injury, a critical information base, remain unexplored. This study investigates the expression and topographic localization of the full length (FL)-(P)RR, its ligands (renin and prorenin), and its target cyclooxygenase-2 and found that they are upregulated in three distinct animal models of renal injury. The protein expression of these targets, initially confined to specific tubular renal cell types in control animals, increases in renal injury models, extending to glomerular cells. (P)RR gene expression correlates with protein changes in a genetic model of focal and segmental glomerulosclerosis. However, in diabetic and high-fat-fed mice, (P)RR mRNA levels contradict FL-(P)RR immunoreactivity. Research on diabetic mice kidneys and human podocytes exposed to diabetic glucose levels suggests that this inconsistency may result from disrupted intracellular (P)RR processing, likely due to increased Munc18-1 interacting protein 3. It follows that changes in FL-(P)RR cellular content mechanisms are specific to renal disease etiology, emphasizing the need for consideration in future studies exploring this receptor's involvement in renal damage of different origins.

Muscular Adaptations to Concurrent Resistance Training and High-Intensity Interval Training in Adults with Type 2 Diabetes: A Pilot Study.

This pilot study aimed to compare the effects of eight weeks of concurrent resistance training (RT) and high-intensity interval training (HIIT) vs. RT alone on muscle performance, mass and quality in adults with type 2 diabetes (T2DM). Twelve T2DM adults were randomly allocated to the RT + HIIT (n = 5) or RT (n = 7) group. Before and after training, maximal oxygen uptake (VO2max), muscle strength and power were evaluated by calorimetry, dynamometry and one-repetition maximum (1RM) test. Quadriceps muscle volume was determined by MRI, and muscle quality was estimated. After RT, VO2max (+12%), knee muscle power (+20%), quadriceps muscle volume (+5.9%) and quality (leg extension, +65.4%; leg step-up, +223%) and 1RM at leg extension (+66.4%), leg step-up (+267%), lat pulldown (+60.9%) and chest press (+61.2%) significantly increased. The RT + HIIT group improved on VO2max (+27%), muscle volume (+6%), muscle power (+9%) and 1RM at lat pulldown (+47%). No other differences were detected. Among groups, changes in muscle quality at leg step-up and leg extension and VO2max were significantly different. The combination of RT and HIIT effectively improves muscle function and size and increases cardiorespiratory fitness in adults with T2DM. However, HIIT combined with RT may interfere with the development of muscle quality.

Sustained increase in physical fitness independently predicts improvements in cardiometabolic risk profile in type 2 diabetes.

AIMS: To investigate the relationship between changes in physical fitness and cardiovascular risk factors and scores in patients with type 2 diabetes receiving either a behavioural counselling intervention to increase moderate-to-vigorous-intensity physical activity (MVPA) and decrease sedentary-time (SED-time) or standard care. MATERIALS AND METHODS: This is a pre-specified ancillary analysis of the Italian Diabetes and Exercise Study_2, a 3-year randomized clinical trial in which 300 physically inactive and sedentary patients were randomized 1:1 to receive either a one-month theoretical and practical counselling each year or standard care. Mean changes from baseline throughout the 3-year period in MVPA, SED-time, cardiorespiratory fitness (VO2max ), muscle strength, flexibility, cardiovascular risk factors and scores were calculated for study completers (n = 267) and considered irrespective of study arm. RESULTS: Haemoglobin (Hb) A1c and coronary heart disease (CHD) risk scores decreased with quartiles of VO2max and lower body muscle strength changes. Multivariable linear regression analysis showed that increases in VO2max independently predicted decreases in HbA1c , blood glucose, diastolic blood pressure (BP), CHD and total stroke 10-year risk and increases in HDL cholesterol, whereas increases in lower body muscle strength independently predicted decreases in body mass index (BMI), waist circumference, triglycerides, systolic BP, CHD and fatal stroke 10-year risk. These associations remained after including changes in BMI, waist circumference, fat mass and fat-free mass, or MVPA and SED-time as covariates. CONCLUSIONS: Improvement in physical fitness predicts favourable changes in cardiometabolic risk profile, independent of changes not only in (central) adiposity or body composition but also in MVPA and SED-time. TRIAL REGISTRATION: ClinicalTrials.gov; NCT01600937; URL https://clinicaltrials.gov/ct2/show/NCT01600937.

Body mass index versus surrogate measures of central adiposity as independent predictors of mortality in type 2 diabetes.

BACKGROUND: An "obesity paradox" for mortality has been shown in chronic disorders such as diabetes, and attributed to methodological bias, including the use of body mass index (BMI) for obesity definition. This analysis investigated the independent association of BMI versus surrogate measures of central adiposity with all-cause mortality in individuals with type 2 diabetes. METHODS: The Renal Insufficiency And Cardiovascular Events Italian Multicentre Study is a prospective cohort study that enrolled 15,773 patients in 19 Italian centres in 2006-2008. Exposures were BMI and the surrogate measures of central adiposity waist circumference (WC), waist-to-height ratio (WHtR), and A Body Shape Index (ABSI). Vital status was retrieved on 31 October 2015 for 15,656 patients (99.3%), RESULTS: Age- and sex-adjusted hazard ratios and 95% confidence intervals were significantly higher in BMI-based underweight (1.729 [1.193-2.505), P = 0.004), moderately obese (1.214 [1.058-1.392), P = 0.006) and severely obese (1.703 [1.402-2.068), P < 0.0001), lower in overweight (0.842 [0.775-0.915), P < 0.0001) and similar in mildly obese (0.950 [0.864-1.045), P = 0.292), compared to normal-weight individuals. When further adjusting for smoking, physical activity (PA), and comorbidities, risk was lower also in mildly obese versus normal-weight patients. The BMI-mortality relationship did not change after sequentially excluding ever smokers, individuals with comorbidities, and those died within two years from enrollment and when analyzing separately participants below and above the median age. Conversely, a paradox relationship was observed among inactive/moderately inactive, but not moderately/highly active patients. Mortality risk adjusted for age, gender, smoking, PA and comorbidities was significantly higher in the highest tertile of WC (1.279 [1.089-1.501], P = 0.003), WHtR (1.372 [1.165-1.615], P < 0.0001), and ABSI (1.263 [1.067-1.495], P = 0.007) versus the lowest tertile. However, risk was lower in the intermediate versus lowest tertile for WC (0.823 [0.693-0.979], P = 0.028), similar for WHtR, and higher, though not significantly, for ABSI. CONCLUSIONS: An "overweight paradox" remained after controlling for age, smoking, and comorbidities, arguing against a collider bias or reverse causation. However, it could be partly explained by confounding from PA level, possibly through its impact on lean mass and cardiorespiratory fitness. No obesity paradox was observed with WHtR and especially ABSI, which predicted mortality risk associated with central adiposity better than WC. Trial registration ClinicalTrials.gov, NCT00715481, 15 July, 2008.

Sustained decreases in sedentary time and increases in physical activity are associated with preservation of estimated ß-cell function in individuals with type 2 diabetes.

AIMS: In the Italian Diabetes and Exercise Study_2, a counselling intervention produced modest but sustained increments in moderate-to vigorous-intensity physical activity (MVPA), with reallocation of sedentary-time (SED-time) to light-intensity physical activity (LPA). This post hoc analysis evaluated the impact of intervention on estimated ß-cell function and insulin sensitivity. METHODS: Patients with type 2 diabetes were randomized to one-month counselling once-a-year or standard care for 3 years. The HOmeostatic Model Assessment-2 (HOMA-2) method was used for estimating indices of ß-cell function (HOMA-B%), insulin sensitivity (HOMA-S%), and insulin resistance (HOMA-IR); the disposition index (DI) was estimated as HOMA-ß%/HOMA-IR; MVPA, LPA, and SED-time were objectively measured by accelerometer. RESULTS: HOMA-B% and DI decreased in control group, whereas HOMA-B% remained stable and DI increased in intervention group. Between-group differences were significant for almost all insulin secretion and sensitivity indices. Changes in HOMA-B% and DI correlated with SED-time, MVPA and LPA. Changes in HOMA-B%, DI, and all indices were independently predicted by changes in SED-time (or LPA), MVPA, and BMI (or waist circumference), respectively. CONCLUSIONS: In individuals with type 2 diabetes, increasing MVPA, even without achieving the recommended target, is effective in maintaining estimated ß-cell function if sufficient amounts of SED-time are reallocated to LPA.

Mutual Regulation between Redox and Hypoxia-Inducible Factors in Cardiovascular and Renal Complications of Diabetes.

Oxidative stress and hypoxia-inducible factors (HIFs) have been implicated in the pathogenesis of diabetic cardiovascular and renal diseases. Reactive oxygen species (ROS) mediate physiological and pathophysiological processes, being involved in the modulation of cell signaling, differentiation, and survival, but also in cyto- and genotoxic damage. As master regulators of glycolytic metabolism and oxygen homeostasis, HIFs have been largely studied for their role in cell survival in hypoxic conditions. However, in addition to hypoxia, other stimuli can regulate HIFs stability and transcriptional activity, even in normoxic conditions. Among these, a regulatory role of ROS and their byproducts on HIFs, particularly the HIF-1α isoform, has received growing attention in recent years. On the other hand, HIF-1α and HIF-2α exert mutually antagonistic effects on oxidative damage. In diabetes, redox-mediated HIF-1α deregulation contributes to the onset and progression of cardiovascular and renal complications, and recent findings suggest that deranged HIF signaling induced by hyperglycemia and other cellular stressors associated with metabolic disorders may cause mitochondrial dysfunction, oxidative stress, and inflammation. Understanding the mechanisms of mutual regulation between HIFs and redox factors and the specific contribution of the two main isoforms of HIF-α is fundamental to identify new therapeutic targets for vascular complications of diabetes.

Food-Related Carbonyl Stress in Cardiometabolic and Cancer Risk Linked to Unhealthy Modern Diet.

Carbonyl stress is a condition characterized by an increase in the steady-state levels of reactive carbonyl species (RCS) that leads to accumulation of their irreversible covalent adducts with biological molecules. RCS are generated by the oxidative cleavage and cellular metabolism of lipids and sugars. In addition to causing damage directly, the RCS adducts, advanced glycation end-products (AGEs) and advanced lipoxidation end-products (ALEs), cause additional harm by eliciting chronic inflammation through receptor-mediated mechanisms. Hyperglycemia- and dyslipidemia-induced carbonyl stress plays a role in diabetic cardiovascular complications and diabetes-related cancer risk. Moreover, the increased dietary exposure to AGEs/ALEs could mediate the impact of the modern, highly processed diet on cardiometabolic and cancer risk. Finally, the transient carbonyl stress resulting from supraphysiological postprandial spikes in blood glucose and lipid levels may play a role in acute proinflammatory and proatherogenic changes occurring after a calorie dense meal. These findings underline the potential importance of carbonyl stress as a mediator of the cardiometabolic and cancer risk linked to today's unhealthy diet. In this review, current knowledge in this field is discussed along with future research courses to offer new insights and open new avenues for therapeutic interventions to prevent diet-associated cardiometabolic disorders and cancer.

Effect of a Behavioural Intervention for Adoption and Maintenance of a Physically Active Lifestyle on Psychological Well-Being and Quality of Life in Patients with Type 2 Diabetes: The IDES_2 Randomized Clinical Trial.

BACKGROUND: Psychological well-being and quality of life (QoL) are important outcomes of lifestyle interventions, as a positive impact may favour long-term maintenance of behaviour change. OBJECTIVE: This study investigated the effect of a behavioural intervention for adopting and maintaining an active lifestyle on psychological well-being and health-related QoL in individuals with type 2 diabetes. METHODS: Three hundred physically inactive and sedentary patients were randomized 1:1 to receive 1 month's theoretical and practical counselling once a year (intervention group, INT) or standard care (control group, CON) for 3 years. Psychological well-being and QoL, assessed using the World Health Organization (WHO)-5 and the 36-Item Short Form (SF-36) questionnaire, respectively, were pre-specified secondary endpoints. The primary endpoint was sustained behaviour change, as assessed by accelerometer-based measurement of physical activity (PA) and sedentary time. RESULTS: WHO-5 and SF-36 physical and mental component summary (PCS and MCS) scores increased progressively in the INT group and decreased in the CON group, resulting in significant between-group differences (WHO-5: mean difference 7.35 (95% confidence interval (CI) 3.15-11.55), P = 0.0007; PCS 4.20 (95% CI 2.25-6.15), P < 0.0001; MCS 3.04 (95% CI 1.09-4.99), P = 0.0025). Percentage of participants with likely depression decreased in the INT group and increased in the CON group. PA volume changes were independently associated with WHO-5 changes, which were significantly higher in participants who accumulated > 150 min·wk-1 of moderate-to-vigorous intensity PA versus those who did not (13.06 (95% CI 7.51-18.61), P < 0.0001), whereas no relationship was detected for QoL. CONCLUSION: A counselling intervention that was effective in promoting a sustained change in PA and sedentary behaviour significantly improved psychological well-being and QoL. TRIAL REGISTRATION: ClinicalTrials.gov; NCT01600937; 10 October 2012.

Relationships of Changes in Physical Activity and Sedentary Behavior With Changes in Physical Fitness and Cardiometabolic Risk Profile in Individuals With Type 2 Diabetes: The Italian Diabetes and Exercise Study 2 (IDES_2).

OBJECTIVE: In the Italian Diabetes and Exercise Study_2 (IDES_2), behavioral counseling promoted a sustained increase in physical activity (PA) volume (+3.3 MET h ⋅ week-1), moderate- to vigorous-intensity PA (MVPA) (+6.4 min ⋅ day-1), and light-intensity PA (LPA) (+0.8 h ⋅ day-1) and decrease in sedentary time (SED-time) (-0.8 h ⋅ day-1). Here, we investigated the relationships of changes in PA/SED-time with changes in physical fitness and cardiometabolic risk profile in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: In this 3-year randomized clinical trial, 300 physically inactive and sedentary patients were randomized 1:1 to receive 1-month theoretical and practical counseling once a year or standard care. Changes in physical fitness and cardiovascular risk factors/scores according to quartiles of accelerometer-measured changes in PA/SED-time were assessed, together with univariate and multivariable associations between these parameters, in the whole cohort and by study arm. RESULTS: Physical fitness increased and HbA1c and coronary heart disease 10-year risk scores decreased with quartiles of MVPA and SED-time change. In quartile IV of MVPA increase and SED-time decrease, cardiorespiratory fitness increased by 5.23 and 4.49 mL ⋅ min-1 ⋅ kg-1 and HbA1c decreased by 0.73 and 0.85%, respectively. Univariate correlations confirmed these relationships, and mean changes in both MPVA and SED-time predicted changes in physical fitness and cardiovascular risk factors/scores independently of one another and of other confounders. Similar findings were observed with LPA and PA volume and in each group separately. CONCLUSIONS: Even modest increments in MVPA may have a clinically meaningful impact, and reallocating SED-time to LPA may also contribute to improved outcomes, possibly by increasing total energy expenditure.

Sedentary behaviour is an independent predictor of diabetic foot ulcer development: An 8-year prospective study.

AIMS: To prospectively explore the association between sedentary time (SED-time) and the development of diabetic foot ulcer (DFU) in people with diabetic peripheral neuropathy (DPN). METHODS: 175 DPN individuals who attended the annual evaluation for the SAMBA Study (2012-2019) were included. Main outcome measure was the first diagnosis of DFU. SED-time was measured by the PAS 2.1 questionnaire. Nerve function was evaluated by nerve conduction studies. Vascular function was assessed by Ankle-brachial index (ABI) and pedal pulses. Foot deformity and skin dryness were examined by visual inspection. RESULTS: 62 participants (35.5%) developed a DFU during the study. SED-time was significantly higher in people who developed DFUs (12.8 ± 3.0 vs 9.4 ± 3.1 h/day). Logistic regression showed that among several nervous (motor amplitude, OR 0.33, 95% CI, 0.18-0.60; sensory amplitude, 0.85, 0.77-0.94) and vascular parameters (ABI, 0.23, 0.1-0.61; pedal pulses, 2.81, 0.12-0.63) and foot characteristics (deformity, 2.63, 1.30-5.32; skin dryness, 2.04, 0.95-4.37), SED-time was one of the strongest variables contributing to the development of DFUs (2.95, 1.45-6.44). CONCLUSIONS: SED-time is an independent predictor of the risk of DFU in people with DPN. The monitoring of SED-time with strategies aimed at reducing it should be included in the standard care of diabetic patients.

Effects of exercise before and/or after a mixed lunch on postprandial metabolic responses in healthy male individuals.

PURPOSE: Exercise plays an important role in preventing and treating postprandial dysmetabolism. We investigated the postprandial metabolic responses to a standard lunch when a session of aerobic exercise is performed in the early postprandial phase or divided between the pre- and postprandial period. METHODS: Nine healthy volunteers consumed a standardised mixed lunch and rested for the following 3 h (Con) or performed 40 min of cycling at 65% V̇O2max after lunch (CPPEx), or two 20-min sessions, one before (SplitEx1) and the other after lunch (SplitEx2), at the same intensity. RESULTS: At 1-h post-lunch, a significant reduction (P < 0.001) in glycaemia was observed for CPPEx (- 25 ± 10%) and SplitEx (- 34 ± 7%) compared to Con. Yet, a post-exercise rebound lessened the exercise effect on the glycaemic area under the curve (AUC) at 2 and 3 h. At 1 h, a significant reduction (P < 0.009) in plasma insulin (SplitEx - 53 ± 31%; CCPEx - 48 ± 20%) and C-peptide (SplitEx - 57 ± 20%; CCPEx - 47 ± 24%) was observed compared to Con. Glucose-dependent insulinotropic polypeptide (GIP) increased after the meal, without differences between conditions. Compared with SplitEx1, cortisol response was attenuated during SplitEx2 and CPPEx. At 3 hours, triglyceride AUC was significantly higher (P = 0.039) in SplitEx compared to Con (+ 19 ± 8%). CONCLUSION: Forty minutes of postprandial exercise or 20 min of pre- and postprandial exercise are both effective at attenuating the glycaemic and insulinaemic response to a mixed lunch, while a higher lipaemia was found in the pre- and postprandrial exercise condition.

Rationale for the use of metformin and exercise to counteract statin-associated side effects.

INTRODUCTION: Statins are the most widely prescribed drugs for lowering low-density lipoprotein cholesterol (LDL-C) and reducing cardiovascular morbidity and mortality. They are usually well-tolerated, but have two main safety concerns: statin-associated muscle symptoms (SAMS) and new-onset type 2 diabetes (NOD). METHODS: A PubMed search was carried out using the following key words were used: statins, statin-associated muscle symptoms, statin myalgia, statin-associated diabetes, metformin and statins, exercise and statins. RESULTS: Mitochondrial damage and muscle atrophy are likely the central mechanisms producing SAMS, whereas decreased glucose transport, fatty acid oxidation and insulin secretion are likely involved in the development of NOD. Metformin and exercise training share many pathways that could potentially contrast SAMS and NOD. Clinical evidence also supports the combination of statins with metformin and exercise. CONCLUSION: This combination appears attractive both from a clinical and an economical viewpoint, since all three therapies are highly cost-effective and their combination could result in diabetes and cardiovascular disease prevention.

Renal protection with glucagon-like peptide-1 receptor agonists.

There is an unmet need for renoprotective drugs for more pronounced reduction of albuminuria beyond that provided by renin-angiotensin system (RAS) blockers and for effective slowdown of eGFR decline independent of albuminuria. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have proven effective in reducing prespecified secondary composite kidney outcomes in cardiovascular outcome trials. However, GLP-1 RAs showed a prevailing anti-albuminuric effect, additional to that of RAS blockers, and a non-significant risk reduction in worsening of kidney function, at variance with sodium-glucose cotransporter 2 inhibitors. Mechanisms underlying renal protection with GLP-1 RAs are porly understood. Though treatment with GLP-1 RAs resulted in better glycaemic, blood pressure and body weight control versus placebo, correction for on-trial changes in these parameters did not significantly affect results. Anti-inflammatory/anti-oxidant effects via intracellular signalling through protein kinase A, natriuretic effect via inhibition of sodium-hydrogen exchanger 3 and reduction of hyperfiltration have been proposed as direct renoprotective effects.

Sedentariness and Urinary Metabolite Profile in Type 2 Diabetic Patients, a Cross-Sectional Study.

Recent findings indicate a significant association between sedentary (SED)-time and type 2 diabetes mellitus(T2DM). The aim of this study was to investigate whether different levels of SED-time could impact on biochemical and physiological processes occurring in sedentary and physically inactive T2DM patients. In particular, patients from the "Italian Diabetes and Exercise Study (IDES)_2 trial belonging to the first and fourth quartile of SED-time were compared. Urine samples were analyzed by comprehensive two-dimensional gas chromatography(GC×GC) with parallel detection by mass spectrometry and flame ionization detection(GC×2GC-MS/FID). This platform enables accurate profiling and fingerprinting of urinary metabolites while maximizing the overall information capacity, quantitation reliability, and response linearity. Moreover, using advanced pattern recognition, the fingerprinting process was extended to untargeted and targeted features, revealing diagnostic urinary fingerprints between groups. Quantitative metabolomics was then applied to analytes of relevance for robust comparisons. Increased levels of glycine, L-valine,L-threonine, L-phenylalanine, L-leucine, L-alanine, succinic acid, 2-ketoglutaric acid, xylitol, and ribitol were revealed in samples from less sedentary women. In conclusion, SED-time is associated with changes in urine metabolome signatures. These preliminary results suggest that reducing SED-time could be a strategy to improve the health status of a large proportion of diabetic patients.

Coronary artery disease with normal lipids and low coronary artery calcium in two women with high lipoprotein(a).

We present 2 patients with elevated levels of lipoprotein (a) and significant coronary artery disease despite having little coronary artery calcification. Clinicians should be aware that patients with elevated lipoprotein (a) may have important coronary artery disease with low coronary artery calcification scores.

Muscle fatigability in patients with type 2 diabetes: relation with long-term complications.

AIMS: It is unclear whether long-term complications play a role in muscle fatigue characteristic of patients with type 2 diabetes mellitus (T2DM). The purpose of this study was to investigate the association between muscle fatigability and microvascular and macrovascular complications in patients with T2DM. METHODS: One-hundred forty-six patients with T2DM (80 males, 66 females, aged 66.9 ± 7.9 years) were recruited. Maximal voluntary contraction (MCV) and endurance time (ET, 50% of the MVC) were assessed at the knee extensor muscles with an isometric dynamometer. Univariate and multivariate correlations of ET values with diabetic complications, a wide range of surrogate measures of these sequelae, and cardiovascular risk factors were examined. RESULTS: A higher muscle fatigability was detected in patients with diabetic peripheral neuropathy (DPN, ET: -32.4%), cardiovascular disease (CVD, ET: -32.1%), retinopathy (ET: -35.8%), and nephropathy (ET: -30.4%). At univariate analysis, muscle fatigability was associated with age, physical activity level, diabetes duration, HbA1c , systolic blood pressure, albuminuria, eGFR, and several parameters of nervous and vascular function. Multivariate analysis showed that, after adjusting for covariates, ET was independently associated with sensory nerve conduction velocity, vibration perception threshold at malleolus, and ankle-brachial index. In addition, ET values were independently associated with the presence of DPN, CVD, and retinopathy. CONCLUSIONS: In T2DM, muscle fatigability is associated with presence of DPN, CVD, and retinopathy. Such defect appears to be mediated predominantly by sensory nerve and peripheral vascular dysfunction.

Study to Weigh the Effect of Exercise Training on BONE quality and strength (SWEET BONE) in type 2 diabetes: study protocol for a randomised clinical trial.

INTRODUCTION: Type 2 diabetes (T2D) is associated with an increased fracture risk despite normal-to-increased bone mineral density, suggesting reduced bone quality. Exercise may be effective in reducing fracture risk by ameliorating muscle dysfunction and reducing risk of fall, though it is unclear whether it can improve bone quality. METHODS AND ANALYSIS: The 'Study to Weigh the Effect of Exercise Training on BONE quality and strength (SWEET BONE) in T2D' is an open-label, assessor-blinded, randomised clinical trial comparing an exercise training programme of 2-year duration, specifically designed for improving bone quality and strength, with standard care in T2D individuals. Two hundred T2D patients aged 65-75 years will be randomised 1:1 to supervised exercise training or standard care, stratified by gender, age ≤ or >70 years and non-insulin or insulin treatment. The intervention consists of two weekly supervised sessions, each starting with 5 min of warm-up, followed by 20 min of aerobic training, 30 min of resistance training and 20 min of core stability, balance and flexibility training. Participants will wear weighted vests during aerobic and resistance training. The primary endpoint is baseline to end-of-study change in trabecular bone score, a parameter of bone quality consistently shown to be reduced in T2D. Secondary endpoints include changes in other potential measures of bone quality, as assessed by quantitative ultrasound and peripheral quantitative CT; bone mass; markers of bone turnover; muscle strength, mass and power; balance and gait. Falls and asymptomatic and symptomatic fractures will be evaluated over 7 years, including a 5-year post-trial follow-up. The superiority of the intervention will be assessed by comparing between-groups baseline to end-of-study changes. ETHICS AND DISSEMINATION: This study was approved by the institutional ethics committee. Written informed consent will be obtained from all participants. The study results will be submitted for peer-reviewed publication. TRIAL REGISTRATION NUMBER: NCT02421393; Pre-results.