A cross-sectional study observing the association of psychosocial stress and dietary intake with gut microbiota genera and alpha diversity among a young adult cohort of black and white women in Birmingham, Alabama.

BACKGROUND: The relationships between psychosocial stress and diet with gut microbiota composition and diversity deserve ongoing investigation. The primary aim of this study was to examine the associations of psychosocial stress measures and dietary variables with gut microbiota genera abundance and alpha diversity among young adult, black and white females. The secondary aim was to explore mediators of psychosocial stress and gut microbiota diversity and abundance. METHODS: Data on 60 females who self-identified as African American (AA; n = 29) or European American (EA; n = 31) aged 21-45 years were included. Cortisol was measured in hair and saliva, and 16S analysis of stool samples were conducted. Discrimination experiences (recent and lifetime), perceived stress, and depression were evaluated based on validated instruments. Spearman correlations were performed to evaluate the influence of psychosocial stressors, cortisol measures, and dietary variables on gut microbiota genus abundance and alpha diversity measured by amplicon sequence variant (ASV) count. Mediation analyses assessed the role of select dietary variables and cortisol measures on the associations between psychosocial stress, Alistipes and Blautia abundance, and ASV count. RESULTS: AA females were found to have significantly lower ASV count and Blautia abundance. Results for the spearman correlations assessing the influence of psychosocial stress and dietary variables on gut microbiota abundance and ASV count were varied. Finally, diet nor cortisol was found to partially or fully mediate the associations between subjective stress measures, ASV count, and Alistipes and Blautia abundance. CONCLUSION: In this cross-sectional study, AA females had lower alpha diversity and Blautia abundance compared to EA females. Some psychosocial stressors and dietary variables were found to be correlated with ASV count and few gut microbiota genera. Larger scale studies are needed to explore the relationships among psychosocial stress, diet and the gut microbiome.

Association between skeletal muscle mitochondrial dysfunction and insulin resistance in patients with rheumatoid arthritis: a case-control study.

BACKGROUND: Insulin resistance affects a substantial proportion of patients with rheumatoid arthritis (RA). Skeletal muscle mitochondrial dysfunction results in the accumulation of lipid intermediates that interfere with insulin signaling. We therefore sought to determine if lower oxidative phosphorylation and muscle mitochondrial content are associated with insulin resistance in patients with RA. METHODS: This was a cross-sectional prospective study of RA patients. Matsuda index from the glucose tolerance test was used to estimate insulin sensitivity. Mitochondrial content was measured by citrate synthase (CS) activity in snap-frozen muscle samples. Mitochondrial function was measured by using high-resolution respirometry of permeabilized muscle fibers and electron transport chain complex IV enzyme kinetics in isolated mitochondrial subpopulations. RESULTS: RA participants demonstrated lower insulin sensitivity as measured by the Matsuda index compared to controls [median 3.95 IQR (2.33, 5.64) vs. 7.17 (5.83, 7.75), p = 0.02]. There was lower muscle mitochondrial content among RA vs. controls [median 60 mU/mg IQR (45, 80) vs. 79 mU/mg (65, 97), p = 0.03]. Notably, OxPhos normalized to mitochondrial content was higher among RA vs. controls [mean difference (95% CI) = 0.14 (0.02, 0.26), p = 0.03], indicating a possible compensatory mechanism for lower mitochondrial content or lipid overload. Among RA participants, the activity of muscle CS activity was not correlated with the Matsuda index (ρ = - 0.05, p = 0.84), but it was positively correlated with self-reported (IPAQ) total MET-minutes/week (ρ = 0.44, p = 0.03) and Actigraph-measured time on physical activity (MET rate) (ρ = 0.47, p = 0.03). CONCLUSIONS: Mitochondrial content and function were not associated with insulin sensitivity among participants with RA. However, our study demonstrates a significant association between muscle mitochondrial content and physical activity level, highlighting the potential for future exercise interventions that enhance mitochondrial efficiency in RA patients.

Body fat percentage assessment using skinfold thickness agrees with measures obtained by DXA scan in African American and Caucasian American women.

Dual-energy x-ray absorptiometry (DXA) is considered to have high accuracy in estimating fat mass; however, DXA is not always available. We hypothesized that the equations most commonly used for predicting body fat percentage (BF%) using skinfold thickness agree with direct measures of BF% obtained by DXA scan in African American (AA) and Caucasian American (CA) women. Data from 42 women from Alabama who were 21 to 45 years of age, who self-identify as AA (n = 20) or CA (n = 22) were included. BF% was estimated using DXA scan and through 6 different skinfold thickness equations. Agreement between DXA-BF% and BF% based on the skinfold thickness equations was assessed following the Bland-Altman method (bias and agreement limits). Agreement analysis showed in both AA and CA women that the BF%-Siri equation reflects better agreement and lower mean differences (bias) with BF%-DXA than the BF%-Brozek equation after applying 4 body density (BD) equations. Limits showed that BF%-Siri and BF%-Brozek predictive equations overestimate BF% compared with DXA-BF% in both AA and CA women. In AAs, equations that overestimated less were Wilmore and Behnke-Siri (by 1.81%) and Durnin and Womersley-Siri (by 2.5%) equations. Regarding CAs, equations that overestimated less were Durnin and Womersley-Siri (by 2.74%) and Wilmore and Behnke-Siri (by 3.11%) equations. The results of this study show that the BF%-Siri equation is a more accurate alternative than the BF%-Brozek equation for the calculation of BF%. In the calculation of BD, the Wilmore and Behnke equation in AA women and Durnin and Womersley in CA women were those that overestimated BF% to a lesser degree.

Hydrogen sulfide stimulates Mycobacterium tuberculosis respiration, growth and pathogenesis.

Hydrogen sulfide (H2S) is involved in numerous pathophysiological processes and shares overlapping functions with CO and •NO. However, the importance of host-derived H2S in microbial pathogenesis is unknown. Here we show that Mtb-infected mice deficient in the H2S-producing enzyme cystathionine ß-synthase (CBS) survive longer with reduced organ burden, and that pharmacological inhibition of CBS reduces Mtb bacillary load in mice. High-resolution respirometry, transcriptomics and mass spectrometry establish that H2S stimulates Mtb respiration and bioenergetics predominantly via cytochrome bd oxidase, and that H2S reverses •NO-mediated inhibition of Mtb respiration. Further, exposure of Mtb to H2S regulates genes involved in sulfur and copper metabolism and the Dos regulon. Our results indicate that Mtb exploits host-derived H2S to promote growth and disease, and suggest that host-directed therapies targeting H2S production may be potentially useful for the management of tuberculosis and other microbial infections.

Physiological Significance of Discrimination on Stress Markers, Obesity, and LDL Oxidation among a European American and African American Cohort of Females.

BACKGROUND: Factors underlying physiological reactions from perceived discrimination and its relation to adverse health outcomes are not completely understood. The main purpose of this study was to test the hypothesis that experiences of discrimination (recent and lifetime) correlate with biomarkers of stress, oxidative stress, and obesity among adult females. METHOD: Data on 62 females who self-identify as African American (AA; n = 31) or European American (EA; n = 31) aged 21-45 years were included. Discrimination experiences (recent and lifetime) were evaluated based on a validated instrument. Stress was assessed based on hair cortisol (HC) and salivary cortisol (SC), hsC-reactive protein (hsCRP), cardiovascular markers, and LDL-cholesterol oxidation. Obesity was measured based on BMI, waist circumference, and body fat percent. Multiple linear regression analyses were performed to evaluate the influence of experiences of discrimination. RESULTS: Significant differences in experiences of discrimination were observed by race (p < 0.05) and were higher in AA females. Results for the multiple regression models assessing the contribution of discrimination indicate that hsCRP and pulse were significantly associated with recent experiences of discrimination, and SC, HC, hsCRP, diastolic blood pressure (DBP), and pulse were significantly associated with lifetime experiences of discrimination when adjusted for BMI and race (p < 0.05). Finally, oxidation of LDL-cholesterol was significantly associated with salivary cortisol (p = 0.0420) when adjusted by lifetime experiences of discrimination (p = 0.0366) but not for BMI (p = 0.6252). CONCLUSION: In this cross-sectional study, AA females experienced more discrimination compared to EA females. Levels of recent and lifetime experiences of discrimination were associated with some stress biomarkers. Salivary cortisol was associated with oxidation of LDL-cholesterol with shorter lag times and increased risk for cardiovascular disease.

Exercise Effects on Mitochondrial Function and Lipid Metabolism during Energy Balance.

INTRODUCTION/PURPOSE: Aerobic exercise training (AET) has been shown to improve mitochondrial bioenergetics and upregulate proteins related to lipid metabolism. However, it remains to be determined if these alterations associated with AET persist when measured in energy balance (EB) in the days after the last bout of training. The purpose of the study was to test the hypothesis that improvements in skeletal muscle mitochondrial function induced by AET observed in previous literature would persist when measured after restoring EB conditions 72 h removed from the last exercise bout. METHODS: Participants were 14 premenopausal women (age = 31.2 ± 6.7 yr, BMI = 26.6 ± 5.1 kg·m). The AET program required three monitored training sessions per week for 8-16 wk. Skeletal muscle biopsies were obtained at baseline and after 8-16 wk of AET (≥72 h after the last exercise bout). All food was provided for 72 h before biopsies, and EB was managed 24 h before testing within ±100 kcal of measured energy requirements using a whole-room calorimeter. Mitochondrial oxidative capacity was quantified in permeabilized muscle fibers from the vastus lateralis. RESULTS: We found that AET increased coupled respiration (154%) and uncoupled respiration (90%) rates using a fatty acid substrate (palmitoyl carnitine) (P < 0.05). However, when rates were normalized to complex IV activity (a marker of mitochondrial content), no significant differences were observed. In addition, there were no changes in proteins known to mediate mitochondrial biogenesis or lipid transport and metabolism after AET. CONCLUSION: Eight to 16 wk of AET improved mitochondrial capacity under fatty acid substrate when assessed in EB, which appears to be due to mitochondrial biogenesis.

Relationship between V̇o2peak, cycle economy, and mitochondrial respiration in untrained/trained.

Aerobic capacity is negatively related to locomotion economy. The purpose of this paper is to determine what effect aerobic exercise training has on the relationship between net cycling oxygen uptake (inverse of economy) and aerobic capacity [peak oxygen uptake (V̇o2peak)], as well as what role mitochondrial coupled and uncoupled respiration may play in whole body aerobic capacity and cycling economy. Cycling net oxygen uptake and V̇o2peak were evaluated on 31 premenopausal women before exercise training (baseline) and after 8-16 wk of aerobic training. Muscle tissue was collected from 15 subjects at baseline and post-training. Mitochondrial respiration assays were performed using high-resolution respirometry. Pre- (r = 0.46, P < 0.01) and postexercise training (r = 0.62, P < 0.01) V̇o2peak and cycling net oxygen uptake were related. In addition, uncoupled and coupled fat respiration were related both at baseline (r = 0.62, P < 0.01) and post-training (r = 0.89, P < 01). Post-training coupled (r = 0.74, P < 0.01) and uncoupled carbohydrate respiration (r = 0.52, P < 05) were related to cycle net oxygen uptake. In addition, correlations between V̇o2peak and cycle net oxygen uptake persist both at baseline and after training, even after adjusting for submaximal cycle respiratory quotient (an index of fat oxidation). These results suggest that the negative relationship between locomotion economy and aerobic capacity is increased following exercise training. In addition, it is proposed that at least one of the primary factors influencing this relationship has its foundation within the mitochondria. Strong relationships between coupled and uncoupled respiration appear to be contributing factors for this relationship.NEW & NOTEWORTHY The negative relationship between cycle economy and aerobic capacity is increased following exercise training. The strong relationship between coupled and uncoupled respiration, especially after training, appears to be contributing to this negative relationship between aerobic capacity and cycling economy, suggesting that mitochondrial economy is not increased following aerobic exercise training. These results are suggestive that training programs designed to improve locomotion economy should focus on changing biomechanics.

Central IGF-1 protects against features of cognitive and sensorimotor decline with aging in male mice.

Disruptions in growth hormone/insulin-like growth factor-1 (GH/IGF-1) signaling have been linked to improved longevity in mice and humans. Nevertheless, while IGF-1 levels are associated with increased cancer risk, they have been paradoxically implicated with protection from other age-related conditions, particularly in the brain, suggesting that strategies aimed at selectively increasing central IGF-1 action may have favorable effects on aging. To test this hypothesis, we generated inducible, brain-specific (TRE-IGF-1 × Camk2a-tTA) IGF-1 (bIGF-1) overexpression mice and studied effects on healthspan. Doxycycline was removed from the diet at 12 weeks old to permit post-development brain IGF-1 overexpression, and animals were monitored up to 24 months. Brain IGF-1 levels were increased approximately twofold in bIGF-1 mice, along with greater brain weights, volume, and myelin density (P < 0.05). Age-related changes in rotarod performance, exercise capacity, depressive-like behavior, and hippocampal gliosis were all attenuated specifically in bIGF-1 male mice (P < 0.05). However, chronic brain IGF-1 failed to prevent declines in cognitive function or neurovascular coupling. Therefore, we performed a short-term intranasal (IN) treatment of either IGF-1 or saline in 24-month-old male C57BL/6 mice and found that IN IGF-1 treatment tended to reduce depressive (P = 0.09) and anxiety-like behavior (P = 0.08) and improve motor coordination (P = 0.07) and unlike transgenic mice improved motor learning (P < 0.05) and visuospatial and working memory (P < 0.05). These data highlight important sex differences in how brain IGF-1 action impacts healthspan and suggest that translational approaches that target IGF-1 centrally can restore cognitive function, a possibility that should be explored as a strategy to combat age-related cognitive decline.

Fingernail and toenail clippings as a non-invasive measure of chronic cortisol levels in adult cancer survivors.

PURPOSE: Cancer survivors are at greater risk of comorbidities and functional decline due to physiological and psychological stress which can be measured by salivary cortisol. If saliva is used, multiple samples must be collected to accurately quantify long-term stress; however, fingernail (FN) and toenail (TN) clippings offer an opportunity to measure retrospective cortisol levels in a non-invasive manner. METHODS: Three sets of FN and TN clippings were collected at 12-month intervals in conjunction with saliva samples from cancer survivors (n = 109) participating in two clinical trials. FN and TN samples were stored at room temperature (RT); a subset underwent additional processing and freezing before analysis. Cortisol levels were determined via enzyme immunoassay, and correlation coefficients were generated to determine overall correspondence of the individual measures. RESULTS: Matched RT and frozen samples were highly correlated for TN (r = 0.950, p = 5.44 × 10-37) and FN (r = 0.784, p = 1.05 × 10-10). Correlations between RT FN and TN were statistically significant (r = 0.621, p = 3.61 × 10- 17), as were frozen FN and TN (r = 0.310, p = 0.0283). RT, but not frozen TN and FN correlated with salivary cortisol (r = 0.580, p = 1.65 × 10- 16 and r = 0.287, p = 0.00042 for TN and FN, respectively). CONCLUSIONS: FN and TN cortisol levels correlate with salivary cortisol in adult cancer survivors and may offer a less invasive and convenient means for measuring chronic cortisol levels.

Associations of Mitochondrial Fatty Acid Oxidation with Body Fat in Premenopausal Women.

Higher in vivo fatty acid (FA) oxidation rates have been reported in obese individuals compared to lean counterparts; however whether this reflects a shift in substrate-specific oxidative capacity at the level of the skeletal muscle mitochondria has not been examined. The purpose of this study was to test the hypothesis that in situ measures of skeletal muscle mitochondria FA oxidation would be positively associated with total body fat. Participants were 38 premenopausal women (BMI = 26.5 ± 4.3 kg/m2). Total and regional fat were assessed by dual-energy X-ray absorptiometry (DXA). Mitochondrial FA oxidation was assessed in permeabilized myofibers using high-resolution respirometry and a palmitoyl carnitine substrate. We found positive associations of total fat mass with State 3 (ADP-stimulated respiration) (r = 0.379, p < 0.05) and the respiratory control ratio (RCR, measure of mitochondrial coupling) (r = 0.348, p < 0.05). When participants were dichotomized by high or low body fat percent, participants with high total body fat displayed a higher RCR compared to those with low body fat (p < 0.05). There were no associations between any measure of regional fat and mitochondrial FA oxidation independent of total fat mass. In conclusion, greater FA oxidation in obesity may reflect molecular processes that enhance FA oxidation capacity at the mitochondrial level.

Potential Causes of Elevated REE after High-Intensity Exercise.

INTRODUCTION: Resting energy expenditure (REE) increases after an intense exercise; however, little is known concerning mechanisms. PURPOSE: The purpose of this study was to determine effects of a single bout of moderate-intensity continuous (MIC) aerobic exercise, or high-intensity interval (HII) exercise on REE under energy balance conditions. METHODS: Thirty-three untrained premenopausal women were evaluated at baseline, after 8-16 wk of training, 22 h after either MIC (50% peak V˙O2) or HII (84% peak V˙O2). Participants were in a room calorimeter during and after the exercise challenge. Food intake was adjusted to obtain energy balance across 23 h. REE was measured after 22 h after all conditions. Twenty-three-hour urine norepinephrine concentration and serum creatine kinase activity (CrKact) were obtained. Muscle biopsies were obtained in a subset of 15 participants to examine muscle mitochondrial state 2, 3, and 4 fat oxidation. RESULTS: REE was increased 22 h after MIC (64 ± 119 kcal) and HII (103 ± 137 kcal). Markers of muscle damage (CrKact) increased after HII (9.6 ± 25.5 U·L) and MIC (22.2 ± 22.8 U·L), whereas sympathetic tone (urine norepinephrine) increased after HII (1.1 ± 10.6 ng·mg). Uncoupled phosphorylation (states 2 and 4) fat oxidation were related to REE (r = 0.65 and r = 0.55, respectively); however, neither state 2 nor state 4 fat oxidation increased after MIC or HII. REE was not increased after 8 wk of aerobic training when exercise was restrained for 60 h. CONCLUSIONS: Under energy balance conditions, REE increased 22 h after both moderate-intensity and high-intensity exercise. Exercise-induced muscle damage/repair and increased sympathetic tone may contribute to increased REE, whereas uncoupled phosphorylation does not. These results suggest that moderate- to high-intensity exercise may be valuable for increasing energy expenditure for at least 22 h after the exercise.

Identification of Small Molecule Inhibitors of Human Cytochrome c Oxidase That Target Chemoresistant Glioma Cells.

The enzyme cytochrome c oxidase (CcO) or complex IV (EC 1.9.3.1) is a large transmembrane protein complex that serves as the last enzyme in the respiratory electron transport chain of eukaryotic mitochondria. CcO promotes the switch from glycolytic to oxidative phosphorylation (OXPHOS) metabolism and has been associated with increased self-renewal characteristics in gliomas. Increased CcO activity in tumors has been associated with tumor progression after chemotherapy failure, and patients with primary glioblastoma multiforme and high tumor CcO activity have worse clinical outcomes than those with low tumor CcO activity. Therefore, CcO is an attractive target for cancer therapy. We report here the characterization of a CcO inhibitor (ADDA 5) that was identified using a high throughput screening paradigm. ADDA 5 demonstrated specificity for CcO, with no inhibition of other mitochondrial complexes or other relevant enzymes, and biochemical characterization showed that this compound is a non-competitive inhibitor of cytochrome c When tested in cellular assays, ADDA 5 dose-dependently inhibited the proliferation of chemosensitive and chemoresistant glioma cells but did not display toxicity against non-cancer cells. Furthermore, treatment with ADDA 5 led to significant inhibition of tumor growth in flank xenograft mouse models. Importantly, ADDA 5 inhibited CcO activity and blocked cell proliferation and neurosphere formation in cultures of glioma stem cells, the cells implicated in tumor recurrence and resistance to therapy in patients with glioblastoma. In summary, we have identified ADDA 5 as a lead CcO inhibitor for further optimization as a novel approach for the treatment of glioblastoma and related cancers.

Detailed methods of two home-based vegetable gardening intervention trials to improve diet, physical activity, and quality of life in two different populations of cancer survivors.

BACKGROUND: Cancer survivors suffer from long-term adverse effects that reduce health-related quality of life (QOL) and physical functioning, creating an urgent need to develop effective, durable, and disseminable interventions. Harvest for Health, a home-based vegetable gardening intervention, holds promise for these domains. METHODS: This report describes the methods and recruitment experiences from two randomized controlled feasibility trials that employ a waitlist-controlled design. Delivered in partnership with Cooperative Extension Master Gardeners, this intervention provides one-on-one mentorship of cancer survivors in planning and maintaining three seasonal vegetable gardens over 12months. The primary aim is to determine intervention feasibility and acceptability; secondary aims are to explore effects on objective and subjective measures of diet, physical activity and function, and QOL and examine participant factors associated with potential effects. One trial is conducted exclusively among 82 female breast cancer survivors residing in the Birmingham, AL metropolitan area (BBCS); another broadly throughout Alabama among 46 older cancer survivors aged >60 (ASCS). RESULTS: Response rates were 32.6% (BBCS) and 52.3% (ASCS). Both trials exceeded 80% of their accrual target. Leading reasons for ineligibility were removal of >10 lymph nodes (lymphedema risk factor), lack of physician approval, and unwillingness to be randomized to the waitlist. CONCLUSION: To date, recruitment and implementation of Harvest for Health appears feasible. DISCUSSION: Although both studies encountered recruitment challenges, lessons learned can inform future larger-scale studies. Vegetable gardening interventions are of interest to cancer survivors and may provide opportunities to gain life skills leading to improvements in overall health and QOL.

Endothelial Cell Bioenergetics and Mitochondrial DNA Damage Differ in Humans Having African or West Eurasian Maternal Ancestry.

BACKGROUND: We hypothesized that endothelial cells having distinct mitochondrial genetic backgrounds would show variation in mitochondrial function and oxidative stress markers concordant with known differential cardiovascular disease susceptibilities. To test this hypothesis, mitochondrial bioenergetics were determined in endothelial cells from healthy individuals with African versus European maternal ancestries. METHODS AND RESULTS: Bioenergetics and mitochondrial DNA (mtDNA) damage were assessed in single-donor human umbilical vein endothelial cells belonging to mtDNA haplogroups H and L, representing West Eurasian and African maternal ancestries, respectively. Human umbilical vein endothelial cells from haplogroup L used less oxygen for ATP production and had increased levels of mtDNA damage compared with those in haplogroup H. Differences in bioenergetic capacity were also observed in that human umbilical vein endothelial cells belonging to haplogroup L had decreased maximal bioenergetic capacities compared with haplogroup H. Analysis of peripheral blood mononuclear cells from age-matched healthy controls with West Eurasian or African maternal ancestries showed that haplogroups sharing an A to G mtDNA mutation at nucleotide pair 10398 had increased mtDNA damage compared with those lacking this mutation. Further study of angiographically proven patients with coronary artery disease and age-matched healthy controls revealed that mtDNA damage was associated with vascular function and remodeling and that age of disease onset was later in individuals from haplogroups lacking the A to G mutation at nucleotide pair 10398. CONCLUSIONS: Differences in mitochondrial bioenergetics and mtDNA damage associated with maternal ancestry may contribute to endothelial dysfunction and vascular disease.

Pyruvate dehydrogenase kinase 1 participates in macrophage polarization via regulating glucose metabolism.

The M1 and M2 polarized phenotypes dictate distinctive roles for macrophages as they participate in inflammatory disorders. There has been growing interest in the role of cellular metabolism in macrophage polarization. However, it is currently unclear whether different aspects of a specific metabolic program coordinately regulate this cellular process. In this study, we found that pyruvate dehydrogenase kinase 1 (PDK1), a key regulatory enzyme in glucose metabolism, plays an important role in the differential activation of macrophages. Knockdown of PDK1 diminished M1, whereas it enhanced M2 activation of macrophages. Mechanistically, PDK1 knockdown led to diminished aerobic glycolysis in M1 macrophages, which likely accounts for the attenuated inflammatory response in these cells. Furthermore, we found that mitochondrial respiration is enhanced during and required by the early activation of M2 macrophages. Suppression of glucose oxidation, but not that of fatty acids, inhibits this process. Consistent with its inhibitory role in early M2 activation, knockdown of PDK1 enhanced mitochondrial respiration in macrophages. Our data suggest that two arms of the glucose metabolism synergistically regulate the differential activation of macrophages. Our findings also highlight the central role of PDK1 in this event via controlling glycolysis and glucose oxidation.

Use of HbA1c for diagnoses of diabetes and prediabetes: comparison with diagnoses based on fasting and 2-hr glucose values and effects of gender, race, and age.

BACKGROUND: Glycated hemoglobin (HbA1c) has been advocated for the diagnosis of diabetes and prediabetes. Its performance has been commonly assessed in corroboration with elevated fasting plasma glucose (FPG), but not the combination of FPG and 2-hr glucose values. This study assesses receiver operating characteristics (ROC) curves of HbA1c pertaining to the diagnoses of prediabetes and diabetes by FPG and/or 2-hr glucose, and the effects of age, gender, and race. METHODS: We assessed the utility of HbA1c for diagnosing diabetes and prediabetes among 5395 adults without known diabetes from the National Health and Nutrition Examination Survey (NHANES) 2005-2010. RESULTS: Current cutoffs of HbA1c for diabetes (6.5%) or prediabetes (5.7%) exhibited low sensitivity (0.249 and 0.354, respectively) and high specificity in identifying patients diagnosed using both FPG and 2-hr glucose, resulting in large false-negative rates (75.1% and 64.9%). Misdiagnosis rates increased with age and in non-Hispanic whites and Mexican Americans. When HbA1c was combined with FPG for diagnoses, the false-negative rate remained high for diabetes (45.7%), but was reduced for prediabetes (9.2%). CONCLUSIONS: When assessed against diagnoses using both FPG and 2-hr glucose, HbA1c had low sensitivity and high specificity for identifying diabetes and prediabetes, which varied as a function of age and race. Regarding recently released American Diabetes Association (ADA) and joint European guidelines, it is important to consider that HbA1c values below 6.5% and 5.7% do not reliably exclude the presence of diabetes and prediabetes, respectively. Overall, the data argue for greater use of oral glucose tolerance tests (OGTTs) and both FPG and 2-hr glucose values for diagnosis of diabetes and prediabetes.

Novel, high-intensity exercise prescription improves muscle mass, mitochondrial function, and physical capacity in individuals with Parkinson's disease.

We conducted, in persons with Parkinson's disease (PD), a thorough assessment of neuromotor function and performance in conjunction with phenotypic analyses of skeletal muscle tissue, and further tested the adaptability of PD muscle to high-intensity exercise training. Fifteen participants with PD (Hoehn and Yahr stage 2-3) completed 16 wk of high-intensity exercise training designed to simultaneously challenge strength, power, endurance, balance, and mobility function. Skeletal muscle adaptations (P < 0.05) to exercise training in PD included myofiber hypertrophy (type I: +14%, type II: +36%), shift to less fatigable myofiber type profile, and increased mitochondrial complex activity in both subsarcolemmal and intermyofibrillar fractions (I: +45-56%, IV: +39-54%). These adaptations were accompanied by a host of functional and clinical improvements (P < 0.05): total body strength (+30-56%); leg power (+42%); single leg balance (+34%); sit-to-stand motor unit activation requirement (-30%); 6-min walk (+43 m), Parkinson's Disease Quality of Life Scale (PDQ-39, -7.8pts); Unified Parkinson's Disease Rating Scale (UPDRS) total (-5.7 pts) and motor (-2.7 pts); and fatigue severity (-17%). Additionally, PD subjects in the pretraining state were compared with a group of matched, non-PD controls (CON; did not exercise). A combined assessment of muscle tissue phenotype and neuromuscular function revealed a higher distribution and larger cross-sectional area of type I myofibers and greater type II myofiber size heterogeneity in PD vs. CON (P < 0.05). In conclusion, persons with moderately advanced PD adapt to high-intensity exercise training with favorable changes in skeletal muscle at the cellular and subcellular levels that are associated with improvements in motor function, physical capacity, and fatigue perception.

The progression of cardiometabolic disease: validation of a new cardiometabolic disease staging system applicable to obesity.

OBJECTIVE: To validate a Cardiometabolic Disease Staging (CMDS) system for assigning risk level for diabetes, and all-cause and cardiovascular disease (CVD) mortality. DESIGN AND METHODS: Two large national cohorts, CARDIA and NHANES III, were used to validate CMDS. CMDS: Stage 0: metabolically healthy; Stage 1: one or two metabolic syndrome risk factors [other than impaired fasting glucose (IFG)]; Stage 2: IFG or impaired glucose tolerance (IGT) or metabolic syndrome (without IFG); Stage 3: two of three (IFG, IGT, and/or metabolic syndrome); and Stage 4: type 2 diabetes mellitus/CVD. RESULTS: In the CARDIA study, compared with Stage 0 metabolically healthy subjects, adjusted risk for diabetes exponentially increased from Stage 1 [hazard ratio (HR) 2.83, 95% confidence interval (CI): 1.76-4.55], to Stage 2 (HR 8.06, 95% CI 4.91-13.2), to Stage 3 (HR 23.5, 95% CI 13.7-40.1) (P for trend <0.001). In NHANES III, both cumulative incidence and multivariable adjusted HRs markedly increased for both all-cause and CVD mortality with advancement of the risk stage from Stages 0 to 4. Adjustment for body mass index (BMI) minimally affected the risks for diabetes and all-cause/CVD mortality using CMDS. CONCLUSION: CMDS can discriminate a wide range of risk for diabetes, CVD mortality, and all-cause mortality independent of BMI, and should be studied as a risk assessment tool to guide interventions that prevent and treat cardiometabolic disease.

Mitochondrial genetic background modulates bioenergetics and susceptibility to acute cardiac volume overload.

Dysfunctional bioenergetics has emerged as a key feature in many chronic pathologies such as diabetes and cardiovascular disease. This has led to the mitochondrial paradigm in which it has been proposed that mtDNA sequence variation contributes to disease susceptibility. In the present study we show a novel animal model of mtDNA polymorphisms, the MNX (mitochondrial-nuclear exchange) mouse, in which the mtDNA from the C3H/HeN mouse has been inserted on to the C57/BL6 nuclear background and vice versa to test this concept. Our data show a major contribution of the C57/BL6 mtDNA to the susceptibility to the pathological stress of cardiac volume overload which is independent of the nuclear background. Mitochondria harbouring the C57/BL6J mtDNA generate more ROS (reactive oxygen species) and have a higher mitochondrial membrane potential relative to those with C3H/HeN mtDNA, independent of nuclear background. We propose this is the primary mechanism associated with increased bioenergetic dysfunction in response to volume overload. In summary, these studies support the 'mitochondrial paradigm' for the development of disease susceptibility, and show that the mtDNA modulates cellular bioenergetics, mitochondrial ROS generation and susceptibility to cardiac stress.