Randomized Crossover Clinical Trial of Nicotinamide Riboside and Coenzyme Q10 on Metabolic Health and Mitochondrial Bioenergetics in CKD.

Background: Mitochondria-driven oxidative/redox stress and inflammation play a major role in chronic kidney disease (CKD) pathophysiology. Compounds targeting mitochondrial metabolism may improve mitochondrial function, inflammation, and redox stress; however, there is limited evidence of their efficacy in CKD. Methods: We conducted a randomized, double-blind, placebo-controlled crossover trial comparing the effects of 1200 mg/day of coenzyme Q10 (CoQ10) or 1000 mg/day of nicotinamide riboside (NR) supplementation to placebo in 25 people with moderate-to-severe CKD (eGFR <60mL/min/1.73 m2). We assessed changes in the blood transcriptome using 3'-Tag-Seq gene expression profiling and changes in pre-specified secondary outcomes of inflammatory and oxidative stress biomarkers. For a subsample of participants (n=14), we assessed lymphocyte and monocyte bioenergetics using an extracellular flux analyzer. Results: The (mean±SD) age, eGFR, and BMI of the participants were 61±11 years, 37±9 mL/min/1.73m2, and 28±5 kg/m2 respectively. Of the participants, 16% had diabetes and 40% were female. Compared to placebo, NR-mediated transcriptomic changes were enriched in gene ontology (GO) terms associated with carbohydrate/lipid metabolism and immune signaling while, CoQ10 changes were enriched in immune/stress response and lipid metabolism GO terms. NR increased plasma IL-2 (estimated difference, 0.32, 95% CI of 0.14 to 0.49 pg/mL), and CoQ10 decreased both IL-13 (estimated difference, -0.12, 95% CI of -0.24 to -0.01 pg/mL) and CRP (estimated difference, -0.11, 95% CI of -0.22 to 0.00 mg/dL) compared to placebo. Both NR and CoQ10 reduced 5 series F2-Isoprostanes (estimated difference, -0.16 and -0.11 pg/mL, respectively; P<0.05 for both). NR, but not CoQ10, increased the bioenergetic health index (BHI) (estimated difference, 0.29, 95% CI of 0.06 to 0.53) and spare respiratory capacity (estimated difference, 3.52, 95% CI of 0.04 to 7 pmol/min/10,000 cells) in monocytes. Conclusion: Six weeks of NR and CoQ10 improved in oxidative stress, inflammation, and cell bioenergetics in persons with moderate to severe CKD.

Short, frequent, light-intensity walking activity improves postprandial vascular-inflammatory biomarkers in people with type 1 diabetes: The SIT-LESS randomized controlled trial.

AIM: To examine the effect of interrupting prolonged sitting with short, frequent, light-intensity activity on postprandial cardiovascular markers in people with type 1 diabetes (T1D). MATERIALS AND METHODS: In a randomized crossover trial, 32 adults with T1D (mean ± SD age 28 ± 5 years, glycated haemoglobin 67.9 ± 12.6 mmol/mol, 17 women) completed two 7-h laboratory visits separated by >7 days. Participants either remained seated for 7 h (SIT) or interrupted sitting with 3-min bouts of self-paced walking at 30-min intervals commencing 1 h after each meal (SIT-LESS). Physical activity, insulin regimen, experimental start times, and meal consumption were standardized during each arm. Plasma levels of interleukin (IL)-1ß, tumour necrosis factor (TNF)-α, plasminogen activator inhibitor (PAI)-1 and fibrinogen were sampled at baseline, 3.5 and 7 h, and assessed for within- and between-group effects using a repeated measures ANOVA. The estimated glucose disposal rate was used to determine the insulin resistance status. RESULTS: Vascular-inflammatory parameters were comparable between SIT and SIT-LESS at baseline (p > .05). TNF-α, IL-1ß, PAI-1 and fibrinogen increased over time under SIT, whereas these rises were attenuated under SIT-LESS (p < .001). Specifically, over the 7 h under SIT, postprandial increases were detected in TNF-α, IL-1ß, PAI-1 and fibrinogen (+67%, +49%, +49% and +62%, respectively; p < .001 for all). Conversely, the SIT-LESS group showed no change in IL-1ß (-9%; p > .50), whereas reductions were observed in TNF-α, PAI-1 and fibrinogen (-22%, -42% and -44%, respectively; p < .001 for all). The intervention showed enhanced effects in insulin-resistant individuals with T1D. CONCLUSIONS: Interrupting prolonged sitting with light-intensity activity ameliorates postprandial increases in vascular-inflammatory markers in T1D. TRIAL REGISTRATION: The trial was prospectively registered (ISRCTN13641847).

Reduced morbidity with early surgical ligation of patent ductus arteriosus in extremely low birth weight infants: a retrospective single-centre study.

INTRODUCTION: Failure of the patent ductus arteriosus to close is common among extremely low birth weight neonates and has been associated with increased morbidities. The objective of this study was to compare outcomes between early and late surgical ligation in extremely low birth weight patients. METHODS: This was a single-centre retrospective cohort study of infants who required surgical closure of patent ductus arteriosus between January 2017 and August 2022. RESULTS: A total of 43 neonates were identified with birth weight less than 1 kg that underwent surgical patent ductus arteriosus ligation. Compared to the late ligation group, the early ligation group experienced fewer total days of mechanical ventilation (43.9 days vs. 97.2 days, p < 0.05) and a shorter length of hospital stay (114.2 days vs. 169.0 days, p < 0.05). CONCLUSION: Early surgical ligation of haemodynamically significant patent ductus arteriosus in extremely low birth weight neonates may improve hospital morbidity, including improved ventilatory outcomes and a shorter length of stay.

Plasma levels of mannan-binding lectin-associated serine proteases are increased in type 1 diabetes patients with insulin resistance.

Activation of the lectin pathway of the complement system, as demonstrated by elevated levels of mannan-binding lectin proteins (MBL), contributes to vascular pathology in type 1 diabetes (T1D). Vascular complications are greatest in T1D individuals with concomitant insulin resistance (IR), however, whether IR amplifies activiation of the lectin pathway in T1D is unknown. We pooled pretreatment data from two RCTs and performed a cross-sectional analysis on 46 T1D individuals. We employed estimated glucose disposal rate (eGDR), a validated IR surrogate with cut-points of: <5.1, 5.1-8.7, and > 8.7 mg/kg/min to determine IR status, with lower eGDR values conferring higher degrees of IR. Plasma levels of MBL-associated proteases (MASP-1, MASP-2, and MASP-3) and their regulatory protein MAp44 were compared among eGDR classifications. In a subset of 14 individuals, we assessed change in MASPs and MAp44 following improvement in IR. We found that MASP-1, MASP-2, MASP-3, and MAp44 levels increased in a stepwise fashion across eGDR thresholds with elevated MASPs and MAp44 levels conferring greater degrees of IR. In a subset of 14 patients, improvement in IR was associated with significant reductions in MASPs, but not MAp44, levels. In conclusion, IR in T1D amplifies levels of MASP-1/2/3 and their regulator MAp44, and improvement of IR normalizes MASP-1/2/3 levels. Given that elevated levels of these proteins contribute to vascular pathology, amplification of the lectin pathway of the complement system may offer mechanistic insight into the relationship between IR and vascular complications in T1D.

Age-related changes of skeletal muscle metabolic response to contraction are also sex-dependent.

Mitochondria adapt to increased energy demands during muscle contraction by acutely altering metabolite fluxes and substrate oxidation. With age, an impaired mitochondrial metabolic response may contribute to reduced exercise tolerance and decreased skeletal muscle mass, specific force, increased overall fatty depositions in the skeletal muscle, frailty and depressed energy maintenance. We hypothesized that elevated energy stress in mitochondria with age alters the capacity of mitochondria to utilize different substrates following muscle contraction. To test this hypothesis, we used in vivo electrical stimulation to simulate high-intensity intervals (HII) or low intensity steady-state (LISS) exercise in young (5-7 months) and aged (27-29 months) male and female mice to characterize effects of age and sex on mitochondrial substrate utilization in skeletal muscle following contraction. Mitochondrial respiration using glutamate decreased in aged males following HII and glutamate oxidation was inhibited following HII in both the contracted and non-stimulated muscle of aged female muscle. Analyses of the muscle metabolome of female mice indicated that changes in metabolic pathways induced by HII and LISS contractions in young muscle are absent in aged muscle. To test improved mitochondrial function on substrate utilization following HII, we treated aged females with elamipretide (ELAM), a mitochondrially-targeted peptide shown to improve mitochondrial bioenergetics and restore redox status in aged muscle. ELAM removed inhibition of glutamate oxidation and showed increased metabolic pathway changes following HII, suggesting rescuing redox status and improving bioenergetic function in mitochondria from aged muscle increases glutamate utilization and enhances the metabolic response to muscle contraction in aged muscle. KEY POINTS: Acute local contraction of gastrocnemius can systemically alter mitochondrial respiration in non-stimulated muscle. Age-related changes in mitochondrial respiration using glutamate or palmitoyl carnitine following contraction are sex-dependent. Respiration using glutamate after high-intensity contraction is inhibited in aged female muscle. Metabolite level and pathway changes following muscle contraction decrease with age in female mice. Treatment with the mitochondrially-targeted peptide elamipretide can partially rescue metabolite response to muscle contraction.

Interrupting prolonged sitting with frequent short bouts of light-intensity activity in people with type 1 diabetes improves glycaemic control without increasing hypoglycaemia: The SIT-LESS randomised controlled trial.

AIM: To examine the impact of interrupting prolonged sitting with frequent short bouts of light-intensity activity on glycaemic control in people with type 1 diabetes (T1D). MATERIALS AND METHODS: In total, 32 inactive adults with T1D [aged 27.9 ± 4.7 years, 15 men, diabetes duration 16.0 ± 6.9 years and glycated haemoglobin 8.4 ± 1.4% (68 ± 2.3 mmol/mol)] underwent two 7-h experimental conditions in a randomised crossover fashion with >7-day washout consisting of: uninterrupted sitting (SIT), or, interrupted sitting with 3-min bouts of self-paced walking at 30-min intervals (SIT-LESS). Standardised mixed-macronutrient meals were administered 3.5 h apart during each condition. Blinded continuous glucose monitoring captured interstitial glucose responses during the 7-h experimental period and for a further 48-h under free-living conditions. RESULTS: SIT-LESS reduced total mean glucose (SIT 8.2 ± 2.6 vs. SIT-LESS 6.9 ± 1.7 mmol/L, p = .001) and increased time in range (3.9-10.0 mmol/L) by 13.7% (SIT 71.5 ± 9.5 vs. SIT-LESS 85.1 ± 7.1%, p = .002). Hyperglycaemia (>10.0 mmol/L) was reduced by 15.0% under SIT-LESS (SIT 24.2 ± 10.8 vs. SIT-LESS 9.2 ± 6.4%, p = .002), whereas hypoglycaemia exposure (<3.9 mmol/L) (SIT 4.6 ± 3.0 vs. SIT-LESS 6.0 ± 6.0%, p = .583) was comparable across conditions. SIT-LESS reduced glycaemic variability (coefficient of variation %) by 7.8% across the observation window (p = .021). These findings were consistent when assessing discrete time periods, with SIT-LESS improving experimental and free-living postprandial, whole-day and night-time glycaemic outcomes (p < .05). CONCLUSIONS: Interrupting prolonged sitting with frequent short bouts of light-intensity activity improves acute postprandial and 48-h glycaemia in adults with T1D. This pragmatic strategy is an efficacious approach to reducing sedentariness and increasing physical activity levels without increasing risk of hypoglycaemia in T1D.

The mitochondrially targeted peptide elamipretide (SS-31) improves ADP sensitivity in aged mitochondria by increasing uptake through the adenine nucleotide translocator (ANT).

Aging muscle experiences functional decline in part mediated by impaired mitochondrial ADP sensitivity. Elamipretide (ELAM) rapidly improves physiological and mitochondrial function in aging and binds directly to the mitochondrial ADP transporter ANT. We hypothesized that ELAM improves ADP sensitivity in aging leading to rescued physiological function. We measured the response to ADP stimulation in young and old muscle mitochondria with ELAM treatment, in vivo heart and muscle function, and compared protein abundance, phosphorylation, and S-glutathionylation of ADP/ATP pathway proteins. ELAM treatment increased ADP sensitivity in old muscle mitochondria by increasing uptake of ADP through the ANT and rescued muscle force and heart systolic function. Protein abundance in the ADP/ATP transport and synthesis pathway was unchanged, but ELAM treatment decreased protein s-glutathionylation incuding of ANT. Mitochondrial ADP sensitivity is rapidly modifiable. This research supports the hypothesis that ELAM improves ANT function in aging and links mitochondrial ADP sensitivity to physiological function. ELAM binds directly to ANT and ATP synthase and ELAM treatment improves ADP sensitivity, increases ATP production, and improves physiological function in old muscles. ADP (adenosine diphosphate), ATP (adenosine triphosphate), VDAC (voltage-dependent anion channel), ANT (adenine nucleotide translocator), H+ (proton), ROS (reactive oxygen species), NADH (nicotinamide adenine dinucleotide), FADH2 (flavin adenine dinucleotide), O2 (oxygen), ELAM (elamipretide), -SH (free thiol), -SSG (glutathionylated protein).

Age and sex dependent effects of metabolic response to muscle contraction.

Sarcopenia, the age-related loss of muscle mass and function, contributes to decreased quality of life in the elderly and increased healthcare costs. Decreased skeletal muscle mass, specific force, increased overall fatty depositions in the skeletal muscle, frailty and depressed energy maintenance are all associated with increased oxidative stress and the decline in mitochondrial function with age. We hypothesized that elevated mitochondrial stress with age alters the capacity of mitochondria to utilize different substrates following muscle contraction. To test this hypothesis, we designed two in vivo muscle-stimulation protocols to simulate high-intensity intervals (HII) or low intensity steady-state (LISS) exercise to characterize the effect of age and sex on mitochondrial substrate utilization in skeletal muscle following muscle contraction. Following HII stimulation, mitochondria from young skeletal muscle increased fatty acid oxidation compared to non-stimulated control muscle; however, mitochondria from aged muscle decreased fatty acid oxidation. In contrast, following LISS, mitochondrial from young skeletal muscle decreased fatty acid oxidation, whereas aged mitochondria increased fatty acid oxidation. We also found that HII can inhibit mitochondrial oxidation of glutamate in both stimulated and non-stimulated aged muscle, suggesting HII initiates circulation of an exerkine capable of altering whole-body metabolism. Analyses of the muscle metabolome indicates that changes in metabolic pathways induced by HII and LISS contractions in young muscle are absent in aged muscle. Treatment with elamipretide, a mitochondrially targeted peptide, restored glutamate oxidation and metabolic pathway changes following HII suggesting rescuing redox status and improving mitochondrial function in aged muscle enhances the metabolic response to muscle contraction.

Barriers to Exercise in Adults With Type 1 Diabetes and Insulin Resistance.

OBJECTIVE: Our aim in this study was to assess attitudes toward exercise and quality of life (QoL) in adults with type 1 diabetes (T1D) with and without insulin resistance (IR). METHODS: We pooled baseline pretreatment data from a subset of individuals with T1D from 2 randomized controlled trials. Estimated glucose disposal rate (eGDR), a validated surrogate marker of IR, was calculated using an established formula to classify individuals according to IR status with a cutpoint of <6 mg/kg/min for the determination of IR. Self-reported barriers to exercise were obtained using a validated questionnaire, the Barriers to Physical Activity in T1D (BAPAD-1). In addition, QoL was determined using the 36-item Short Form (SF-36) questionnaire. Differences between dichotomized variables were assessed using the independent t test, Mann-Whitney U test, or Fisher exact test. Linear regression was employed to explore the association of eGDR with BAPAD-1 and QoL scores, with sequential adjustment for potential confounders. RESULTS: Of the 85 individuals included in our study, 39 were classified as having IR. The mean BAPAD-1 total score was higher for individuals with IR (IR: 3.87±0.61; non-IR: 2.83±0.55; p<0.001). The highest exercise barrier scores for individuals with IR were risk of hypoglycemia (5.67±1.26) and risk of hyperglycemia (5.23±1.20), whereas the highest scoring exercise barrier scores for non-IR individuals were not diabetes-related, with low level of fitness (3.91±1.26) and physical health status, excluding diabetes (3.67±1.48), ranked highest. QoL scores were comparable between groups (p>0.05). CONCLUSIONS: Risk of hypoglycemia was the greatest barrier to exercise in individuals with T1D with IR, whereas non-diabetes-related barriers to exercise were more salient in individuals with T1D without IR.

Skeletal muscle mitochondrial interactome remodeling is linked to functional decline in aged female mice.

Genomic, transcriptomic and proteomic approaches have been used to gain insight into molecular underpinnings of aging in laboratory animals and in humans. However, protein function in biological systems is under complex regulation and includes factors besides abundance levels, such as modifications, localization, conformation and protein-protein interactions. By making use of quantitative chemical cross-linking technologies, we show that changes in the muscle mitochondrial interactome contribute to mitochondrial functional decline in aging in female mice. Specifically, we identify age-related changes in protein cross-links relating to assembly of electron transport system complexes I and IV, activity of glutamate dehydrogenase, and coenzyme-A binding in fatty acid ß-oxidation and tricarboxylic acid cycle enzymes. These changes show a remarkable correlation with complex I respiration differences within the same young-old animal pairs. Each observed cross-link can serve as a protein conformational or protein-protein interaction probe in future studies, which will provide further molecular insights into commonly observed age-related phenotypic differences. Therefore, this data set could become a valuable resource for additional in-depth molecular studies that are needed to better understand complex age-related molecular changes.

Reducing Sitting Time in Type 1 Diabetes: Considerations and Implications.

Sedentary behaviours are ubiquitous in modern society, with Western populations spending approximately 50% of their waking hours in low levels of energy expenditure. This behaviour is associated with cardiometabolic derangements and increased morbidity and mortality. In individuals living with or at risk of developing type 2 diabetes (T2D), "breaking up" sedentariness by interrupting prolonged periods of sitting has been shown to acutely improve glucose management and cardiometabolic risk factors related to diabetes complications. As such, current guidelines recommend interrupting prolonged periods of sitting with short, frequent activity breaks. However, the evidence underpinning these recommendations remains preliminary and is focussed on those with or at risk of developing T2D, with little information regarding whether and how reducing sedentariness may be effective and safe in those living with type 1 diabetes (T1D). In this review, we discuss the potential application of interventions that target prolonged sitting time in T2D within the context of T1D.

Effects of exercise training on metabolic syndrome risk factors in post-menopausal women - A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND & AIMS: Alterations in the hormonal profiles as women transition to the menopause predisposes individuals to the metabolic syndrome (MetS). In post-menopausal women, this can be exacerbated by sedentary behaviour and physical inactivity. Physical activity can convey many health benefits including improvement in MetS risk factors. However, it remains to be elucidated how differing exercise intensities and its mode of delivery can ameliorate MetS risk factors and resultant progression amongst post-menopausal women. The purpose of this systematic review and meta-analysis was to investigate the effects and efficacy of exercise training on MetS risk factors in post-menopausal women. METHODS: Database searches using PubMed, Scopus, Web of Science and the Cochrane Central Register of Controlled Trials were conducted from inception to December 2021 for randomised controlled studies (RCTs) investigating exercise training (>8 weeks) in at least one of the MetS risk factors in post-menopausal women. Utilising the random-effects model, appropriate standardised mean differences (SMD) or mean differences (MD) with 95% confidence interval (CI) for each MetS risk factor were used to calculate the overall effect size between the exercise and control groups. Sub-group analyses were performed for exercise intensity, modality, and duration for each risk factor. Meta-regression was performed for categorical (health status) and continuous (body mass index) covariates. RESULTS: 39 RCTs (40 studies) involving 2132 participants were identified as eligible. Overall, the meta-analysis shows that exercise training significantly improved all MetS risk factors: waist circumference (WC) [MD: -2.61 cm; 95% CI: -3.39 to -1.86 cm; p < 0.001; 21 studies]; triglycerides (TG) [SMD: -0.40 mmol/L; 95% CI: -0.71 to -0.09 mmol/L; p = 0.01; 25 studies]; high-density lipoprotein (HDL) [SMD: 0.84 mmol/L (95% CI: 0.41-1.27 mmol/L; p < 0.001; 26 studies]; fasting glucose (BG) [SMD: -0.38 mmol/L (95% CI: -0.60 to -0.16 mmol/L; p < 0.001; 20 studies]; systolic blood pressure (SBP) [MD: -5.95 mmHg (95% CI: -7.98 to -3.92 mmHg; p < 0.001; 23 studies]; and diastolic blood pressure (DBP) [MD: -4.14 mmHg (95% CI: -6.19 to -2.08 mmHg; p < 0.001; 23 studies]. Furthermore, sub-group analyses identified that moderate intensity and combined exercise training significantly improved MetS risk factors (p < 0.05) except for HDL, with combined exercise being the most effective. Long duration (≥12 weeks) training also significantly improved MetS risk factors except for TG. Meta-regression revealed no moderating effects on any MetS risk variables. CONCLUSION: This study reinforces the importance of regular physical activity as a non-pharmacological tool in the reduction of MetS risk in post-menopausal women, with significant metabolic improvements seen in interventions spanning 8-10 weeks. Moderate intensity and combined training significantly benefitted abdominal obesity, dyslipidaemia, dysglycaemia and hypertension in post-menopausal women. Improvements in at least one MetS risk were also seen with other exercise modalities and intensities.

Elamipretide Improves ADP Sensitivity in Aged Mitochondria by Increasing Uptake through the Adenine Nucleotide Translocator (ANT).

Aging muscle experiences functional decline in part mediated by impaired mitochondrial ADP sensitivity. Elamipretide (ELAM) rapidly improves physiological and mitochondrial function in aging and binds directly to the mitochondrial ADP transporter ANT. We hypothesized that ELAM improves ADP sensitivity in aging leading to rescued physiological function. We measured the response to ADP stimulation in young and old muscle mitochondria with ELAM treatment, in vivo heart and muscle function, and compared protein abundance, phosphorylation, and S-glutathionylation of ADP/ATP pathway proteins. ELAM treatment increased ADP sensitivity in old muscle mitochondria by increasing uptake of ADP through the ANT and rescued muscle force and heart systolic function. Protein abundance in the ADP/ATP transport and synthesis pathway was unchanged, but ELAM treatment decreased protein s-glutathionylation incuding of ANT. Mitochondrial ADP sensitivity is rapidly modifiable. This research supports the hypothesis that ELAM improves ANT function in aging and links mitochondrial ADP sensitivity to physiological function.

Intermittent treatment with elamipretide preserves exercise tolerance in aged female mice.

The pathology of aging impacts multiple organ systems, including the kidney and skeletal and cardiac muscles. Long-term treatment with the mitochondrial-targeted peptide elamipretide has previously been shown to improve in vivo mitochondrial function in aged mice, which is associated with increased fatigue resistance and treadmill performance, improved cardiovascular diastolic function, and glomerular architecture of the kidney. However, elamipretide is a short tetrameric peptide that is not orally bioavailable, limiting its routes of administration. This study tested whether twice weekly intermittent injections of elamipretide could recapitulate the same functional improvements as continuous long-term infusion. We found that intermittent treatment with elamipretide for 8 months preserved exercise tolerance and left ventricular mass in mice with modest protection of diastolic function and skeletal muscle force production but did not affect kidney function as previously reported using continuous treatment.

Observational assessments of the relationship of dietary and pharmacological treatment on continuous measures of dysglycemia over 24 hours in women with gestational diabetes.

Objectives: Studies that use continuous glucose monitoring (CGM) to monitor women with gestational diabetes (GDM), highlight the importance of managing dysglycemia over a 24-hour period. However, the effect of current treatment methods on dysglycemia over 24-hrs are currently unknown. This study aimed to characterise CGM metrics over 24-hrs in women with GDM and the moderating effect of treatment strategy. Methods: Retrospective analysis of CGM data from 128 women with GDM in antenatal diabetes clinics. CGM was measured for 7-days between 30-32 weeks gestation. Non-parametric tests were used to evaluate differences of CGM between periods of day (morning, afternoon, evening, and overnight) and between treatment methods (i.e., diet alone or diet+metformin). Exploratory analysis in a subgroup of 34 of participants was performed to investigate the association between self-reported macronutrient intake and glycaemic control. Results: Glucose levels significantly differed during the day (i.e., morning to evening; P<0.001) and were significantly higher (i.e., mean blood glucose and area under the curve [AUC]) and more variable (i.e., SD and CV) than overnight glucose levels. Morning showed the highest amount of variability (CV; 8.4% vs 6.5%, P<0.001 and SD; 0.49 mmol/L vs 0.38 mmol/L, P<0.001). When comparing treatment methods, mean glucose (6.09 vs 5.65 mmol/L; P<0.001) and AUC (8760.8 vs 8115.1 mmol/L.hr; P<0.001) were significantly higher in diet+metformin compared to diet alone. Finally, the exploratory analysis revealed a favourable association between higher protein intake (+1SD or +92 kcal/day) and lower mean glucose (-0.91 mmol/L p, P=0.02) and total AUC (1209.6 mmol/L.h, P=0.021). Conclusions: Glycemia varies considerably across a day, with morning glycemia demonstrating greatest variability. Additionally, our work supports that individuals assigned to diet+metformin have greater difficulty managing glycemia and results suggest that increased dietary protein may assist with management of dysglycemia. Future work is needed to investigate the benefit of increased protein intake on management of dysglycemia.

The multi-tissue landscape of somatic mtDNA mutations indicates tissue-specific accumulation and removal in aging.

Accumulation of somatic mutations in the mitochondrial genome (mtDNA) has long been proposed as a possible mechanism of mitochondrial and tissue dysfunction that occurs during aging. A thorough characterization of age-associated mtDNA somatic mutations has been hampered by the limited ability to detect low-frequency mutations. Here, we used Duplex Sequencing on eight tissues of an aged mouse cohort to detect >89,000 independent somatic mtDNA mutations and show significant tissue-specific increases during aging across all tissues examined which did not correlate with mitochondrial content and tissue function. G→A/C→T substitutions, indicative of replication errors and/or cytidine deamination, were the predominant mutation type across all tissues and increased with age, whereas G→T/C→A substitutions, indicative of oxidative damage, were the second most common mutation type, but did not increase with age regardless of tissue. We also show that clonal expansions of mtDNA mutations with age is tissue- and mutation type-dependent. Unexpectedly, mutations associated with oxidative damage rarely formed clones in any tissue and were significantly reduced in the hearts and kidneys of aged mice treated at late age with elamipretide or nicotinamide mononucleotide. Thus, the lack of accumulation of oxidative damage-linked mutations with age suggests a life-long dynamic clearance of either the oxidative lesions or mtDNA genomes harboring oxidative damage.

Nutritional and Exercise-Focused Lifestyle Interventions and Glycemic Control in Women with Diabetes in Pregnancy: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

Diabetes disrupts one in six pregnancies, bestowing immediate and long-term health risks to mother and child. Diet and exercise are commonly prescribed to control dysglycemia, but their effectiveness across sub-populations and types of diabetes (type-1; type-2; or gestational diabetes mellitus, GDM) is uncertain. Therefore, a systematic review and meta-analysis on the effect of diet and/or exercise on glycemia in pregnant women with diabetes was conducted. Random effects models were used to evaluate effect sizes across studies and anticipated confounders (e.g., age, ethnicity, BMI). Of the 4845 records retrieved, 26 studies (8 nutritional supplements, 12 dietary, and 6 exercise interventions) were included. All studies were conducted in patients with GDM. Overall, supplement- and exercise-based interventions reduced fasting glucose (−0.30 mmol/L; 95% CI = −0.55, −0.06; p = 0.02; and 0.10 mmol/L; 95% CI = −0.20, −0.01; p = 0.04); and supplement- and diet-based interventions reduced HOMA-IR (−0.40; 95% CI = −0.58, −0.22; p < 0.001; and −1.15; 95% CI = −2.12, −0.17; p = 0.02). Subgroup analysis by confounders only confirmed marginal changed effect sizes. Our results suggest a favorable role of certain nutritional supplements, diet, and exercise practices on glycemia in women with GDM and underline a lack of evidence in ~20% of other diabetes-related pregnancies (i.e., women with pre-existing diabetes).

Dietary fat intake is associated with insulin resistance and an adverse vascular profile in patients with T1D: a pooled analysis.

BACKGROUND: Insulin resistance (IR) increases vascular risk in individuals with Type 1 Diabetes (T1D). We aimed to investigate the relationship between dietary intake and IR, as well as vascular biomarkers in T1D. METHODS: Baseline data from three randomised controlled trials were pooled. Estimated glucose disposal rate (eGDR) was used as an IR marker. Employing multivariate nutrient density substitution models, we examined the association between macronutrient composition and IR/vascular biomarkers (tumour necrosis factor-α, fibrinogen, tissue factor activity, and plasminogen activator inhibitor-1). RESULTS: Of the 107 patients, 50.5% were male with mean age of 29 ± 6 years. Those with lower eGDR were older with a longer diabetes duration, higher insulin requirements, and an adverse vascular profile (p < 0.05). Patients with higher degrees of IR had higher total energy intake (3192 ± 566 vs. 2772 ± 268 vs. 2626 ± 395 kcal/d for eGDR < 5.1 vs. 5.1-8.6 vs. ≥ 8.7 mg/kg/min, p < 0.001) and consumed a higher absolute and proportional amount of fat (47.6 ± 18.6 vs. 30.4 ± 8.1 vs. 25.8 ± 10.4%, p < 0.001). After adjusting for total energy intake, age, sex, and diabetes duration, increased carbohydrate intake offset by an isoenergetic decrease in fat was associated with higher eGDR (ß = 0.103, 95% CI 0.044-0.163). In contrast, increased dietary fat at the expense of dietary protein intake was associated with lower eGDR (ß = - 0.119, 95% CI - 0.199 to - 0.040). Replacing fat with 5% isoenergetic amount of carbohydrate resulted in decreased vascular biomarkers (p < 0.05). CONCLUSION: Higher fat, but not carbohydrate, intake is associated with increased IR and an adverse vascular profile in patients with T1D.

Kounis syndrome following allergy injection in a paediatric patient.

Kounis syndrome is the concurrence of acute coronary syndrome or coronary vasospasm with conditions associated with the release of inflammatory cytokines through mast cell activation in the setting of allergic or anaphylactic reactions. Many identified triggers have been identified in paediatric patients including exposures, drugs, and immunisations; however, to our knowledge this is the first case report of Kounis syndrome linked to immunotherapy. We present a case of a 9-year-old with seasonal allergies presenting with clinical symptoms of Kounis syndrome following her weekly subcutaneous injection of allergens. Clinicians need a high index of suspicion for Kounis syndrome in patients who develop systemic signs of anaphylaxis with clinical, laboratory, electrocardiographic, and echocardiographic findings of acute coronary syndrome to help direct therapy and improve outcomes.