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AIMS: This study examined serum cytochrome P450-soluble epoxide hydrolase (CYP450-sEH) oxylipins and depressive symptoms together in relation to cognitive performance in individuals with type 2 diabetes mellitus (T2DM). METHODS: Clinically cognitively normal T2DM individuals were recruited (NCT04455867). Depressive symptom severity was assessed using the Beck Depression Inventory-II (BDI-II; total scores ≤13 indicated minimal depressive symptoms and ≥ 14 indicated significant depressive symptoms). Executive function and verbal memory were assessed. Fasting serum oxylipins were quantified by ultra-high-performance liquid chromatography tandem mass-spectrometry. RESULTS: The study included 85 participants with minimal depressive symptoms and 27 with significant symptoms (mean age: 63.3 ± 9.8 years, 49 % women). In all participants, higher concentrations of linoleic acid derived sEH (12,13-dihydroxyoctadecamonoenoic acid; DiHOME) and CYP450 (12(13)-epoxyoctadecamonoenoic acid; EpOME) metabolites were associated with poorer executive function (F1,101 = 6.094, p = 0.015 and F1,101 = 5.598, p = 0.020, respectively). Concentrations of multiple sEH substrates interacted with depressive symptoms to predict 1) poorer executive function, including 9(10)-EpOME (F1,100 = 12.137, p < 0.001), 5(6)-epoxyeicosatrienoic acid (5(6)-EpETrE; F1,100 = 6.481, p = 0.012) and 11(12)-EpETrE (F1,100 = 4.409, p = 0.038), and 2) verbal memory, including 9(10)-EpOME (F1,100 = 4.286, p = 0.041), 5(6)-EpETrE (F1,100 = 6.845, p = 0.010), 11(12)-EpETrE (F1,100 = 3.981, p = 0.049) and 14(15)-EpETrE (F1,100 = 5.019, p = 0.027). CONCLUSIONS: Associations of CYP450-sEH metabolites and depressive symptoms with cognition highlight the biomarker and therapeutic potential of the CYP450-sEH pathway in T2DM.

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BACKGROUND: Low serum osteocalcin is a risk factor for type 2 diabetes mellitus (T2DM), and osteocalcin release from bone is associated with an acute stress response in mice. Both diabetes and stress are associated with depression. Here, we assess relationships between serum osteocalcin, depression and subjective stress in people with T2DM. METHODS: Participants with T2DM (HbA1c above 6.4 %, impaired fasting glucose or impaired glucose tolerance) were assessed for a major depressive episode using the research version of the Structured Clinical Interview for DSM-5 depression criteria (SCID-5RV). Subjective stress over the past month was assessed using the Perceived Stress Scale (PSS). Serum carboxylated (cOCN) and fully decarboxylated (dcOCN) osteocalcin were assayed from fasting morning blood by commercial enzyme-linked immunosorbent assay. RESULTS: Among 95 participants (mean age 62.4 ± 9.9, 51 % women), 22 % were experiencing a depressive episode (9 men, 12 women). The presence of a depressive episode was not associated with dcOCN or cOCN concentrations; however, higher concentrations of cOCN were associated with higher PSS scores in participants with depression (r = 0.585, p = 0.005). In an analysis of covariance model controlling for age, sex, body mass index, glycemic control (glycosylated hemoglobin), insulin resistance (homeostatic model), depression, and antidepressant use, cOCN was associated with PSS scores (F=10.302, p = 0.002), and this relationship was stronger in those with depression (depression × cOCN interaction F=4.978, p = 0.028). Although associations between dcOCN concentrations and PSS scores did not reach significance, the same trend seen with cOCN concentrations was observed in participants with depression for dcOCN (r=0.365, p=0.10), and for a depression × dcOCN interaction associated with PSS scores in the whole group (F=2.165, p = 0.15). CONCLUSIONS: Osteocalcin is a neuroendocrine marker associated with perceived chronic stress among people with T2DM experiencing a depressive episode.

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INTRODUCTION: Few studies have examined memory decline among patients with type 2 diabetes using different oral hypoglycemic drugs. METHODS: Participants with normal cognition (NC) or Alzheimer's disease (AD) dementia using a hypoglycemic medication (2005 to 2019) were identified from the National Alzheimer's Coordinating Center database. Delayed memory was assessed using the Wechsler Memory Scale Revised-Logical Memory test. Associations between oral drug classes and memory over time were examined using mixed-effects models with inverse probability treatment weights. RESULTS: In NC (n = 1192), metformin use was associated with better memory performance over time, whereas in AD (n = 807), dipeptidyl peptidase-4 (DPP4) inhibitor use was associated with a slower rate of memory decline. Interaction effects suggested greater benefit associated with DPP4 inhibitor use among APOE ε4 carriers. DISCUSSION: Associations between different oral hypoglycemic drugs and memory change were not consistent between cognitively normal elderly and those with AD dementia. APOE ε4 genotype modified some relationships.

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AIM: To compare different volumes and intensities of resistance training (RT) combined with aerobic training (AT) for improvements in glycemic control and cardiovascular health for persons with type 2 diabetes (T2DM). METHODS: Participants with T2DM were stratified by HbA1c and randomized: "usual care" (RT1), which consisted of moderate intensity (50% 1-repetition maximum [1-RM]), low volumeRT (initiated half-way through program); higher intensity (75% 1-RM) and higher volume (initiated at program onset) RT (RT2); or moderate intensity but higher volume RT (RT3). RT sets and repetitions were adjusted to maintain similar work and volume between RT2 and RT3. Walking or cycling (60-80% aerobic capacity)was prescribed 5 times/week, and RT was prescribed 2 times/week. An ANCOVA, adjusted for baseline and gender, assessed changes post-6months in glycemic control (HbA1c- primary outcome), aerobic capacity and anthropometrics. RESULTS: Sixty-two participants (52.3±1.2years, 48% female) were randomized (RT1, n=20; RT2, n=20; RT3, n=22). Only post-training fasting glucose, without significant HbA1c change, was different between groups (RT1-RT3=-1.7mmol/L, p=0.046). Pre-post differences were found in pooled HbA1c (7.4±0.2%[57±2.2mmol/mol] vs. 6.7±0.2%[50±2.2mmol/mol], p<0.001), aerobic capacity (21.5±0.8vs. 25.2±0.8ml/kg/min, p<0.001), body mass (84.0±2.7vs. 83.0±2.7kg, p=0.022[DXA]), body mass index (30.8±0.9vs. 30.3±0.8kg/m2, p=0.02) and body fat (32.3±1.1vs. 31.3±1.2%, p<0.001). The trial was discontinued early; no HbA1c advantage was found with either RT2 or RT3 over RT1. CONCLUSIONS: Combined AT+RT exercise improved glycemic control, cardiovascular risk factors and body composition after 6months for participants with T2DM, but differential effects between the prescribed intensities and volumes of RT were not found to effect HbA1c.

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OBJECTIVE: Depressive symptoms are common among people with Type 2 diabetes mellitus (T2DM). This study aimed to validate the 3-factor structure of the 14-item Center for Epidemiological Studies Depression (CES-D) scale proposed by Carleton et al. (2013) in a T2DM population. METHODS: The CES-D was administered to consecutive patients with T2DM entering a rehabilitation program. Construct validity was assessed using confirmatory factor analysis. Subscale viability, differential item functioning, and associations with clinical characteristics were tested in bifactor models. RESULTS: Among adults with T2DM (n=305, age 56.9±11.1, 44.9% male, duration of diabetes 7.8±7.9years, HbA1c 0.076±0.014%), the construct validity of Carleton's 3-factor solution (negative affective, positive affective and somatic symptoms) was confirmed, although negative affective and somatic symptoms were highly correlated (r=0.926). The CES-D items can be summed to arrive at a total score (ωH=0.869), but not subscale scores (ωS>0.7). Differential item functioning was not found based on age or body mass index (BMI), but Item 1 ("I was bothered by things that don't usually bother me") was inflated in women and Item 7 ("I felt that everything I did was an effort") was inflated in those with higher glycosylated haemoglobin (HbA1c). The general depression factor decreased with age (ß=-0.247, p<0.001) and increased with BMI (ß=0.102, p=0.041) but not HbA1c (ß=0.065, p=0.461). Negative affective symptoms (ß=0.743, p=0.001), but not other depressive symptoms, were higher in women. CONCLUSIONS: The 14-item CES-D retained construct validity in adults with T2DM. Depressive symptoms were associated with younger age, female gender and BMI, but not with glycemic control.

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OBJECTIVE: Structured, gym-based exercise training has been shown to be effective at improving aerobic fitness and glycemic control in persons with type 2 diabetes. However, community-based diabetes programs more commonly incorporate less structured programming, promoting exercise at home. The objectives of this study were to evaluate a community-based, hybrid exercise program encouraging home-based exercise for improving aerobic fitness, and to examine the components of exercise prescription that contribute to this fitness change. METHODS: A retrospective analysis of 583 persons with type 2 diabetes who had participated in the Toronto Rehabilitation Institute's diabetes exercise program was performed. All subjects completed 6 months of structured aerobic and resistance exercise supervised once per week on-site, with 4 more unsupervised sessions per week completed at home. Cardiopulmonary fitness testing and anthropometric measures were performed at baseline and at program completion. A multivariate regression analysis examined the outcome of aerobic fitness (peak oxygen consumption), controlling for age, sex, body mass index, weight change, initial fitness at entry into the program and walking exercise performed (distance, duration and pace). RESULTS: Peak oxygen consumption improved significantly from 19.1±0.2 at baseline to 21.9±0.3 mL·kg(-1)·min(-1) at 6 months (p<0.001). Weight and body mass index also improved significantly (p<0.001). The regression model was able to predict 76.9% of the variance in aerobic fitness, with distance walked contributing the most to improved exercise capacity. CONCLUSIONS: A 6-month hybrid exercise program delivered in a community rehabilitation program setting successfully improved aerobic fitness in people living with type 2 diabetes.

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We aimed to compare the level of agreement between leg-to-leg bioelectrical impedance analysis (LBIA) and dual-energy X-ray absorptiometry (DXA) for assessing changes in body composition following exercise intervention among individuals with Type 2 diabetes mellitus (T2DM). Forty-four adults with T2DM, age 53.2 ± 9.1 years; BMI 30.8 ± 5.9 kg/m(2) participated in a 6-month exercise program with pre and post intervention assessments of body composition. Fat free mass (FFM), % body fat (%FM) and fat mass (FM) were measured by LBIA (TBF-300A) and DXA. LBIA assessments of changes in %FM and FM post intervention showed good relative agreements with DXA variables (P < 0.001). However, Bland-Altman plot(s) indicated that there were systematic errors in the assessment of the changes in body composition using LBIA compared to DXA such that, the greater the changes in participant body composition, the greater the disparity in body composition data obtained via LBIA versus DXA data (FFM, P = 0.013; %FM, P < 0.001; FM, P < 0.001). In conclusion, assessment of pre and post intervention body composition implies that LBIA is a good tool for assessment qualitative change in body composition (gain or loss) among people with T2DM but is not sufficiently sensitive to track quantitative changes in an individual's body composition.

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INTRODUCTION: Prolonged +G,-exposure eventually decreases a pilot's ability to maintain an effective anti-G straining maneuver (AGSM). Previous studies have implicated the respiratory muscles (RMs) as main contributors to this AGSM-induced fatigue. Thus, this study aimed to investigate if respiratory muscle training (RMT) may be of benefit to improve RM strength, endurance, and performance of the AGSM. METHODS: Subjects (N=14; 27 +/- 5.3 yrs) trained with a commercially available RM trainer for 6 wk, 4 times/wk 20 min per session. Data collection consisted of pulmonary function tests (PFTs) and a RM testing protocol simulating the AGSM. Testing occurred every 2 wk for the duration of RMT, and similarly during the 6-wk control (CON) phase where subjects did not train. The simulated AGSM performance was evaluated through measures of peak respiratory pressures, peak systolic arterial pressure (SAP), mean arterial pressure (MAP), and tidal volumes. RESULTS: Training significantly improved (P < 0.05) RM strength after 6 wk of RMT measured in maximal expiratory pressures (RMT = 207.8 +/- 15.8 cmH2O; CON = 181.3 +/- 13.7 cmH2O) and maximal inspiratory pressures (RMT = -154.7 +/- 8.9 cmH2O; CON = -141.9 +/- 8.5 cmH2O). All other PFTs were unchanged. During performance of the AGSM, only peak expiratory pressure demonstrated an increased performance benefit (RMT = 91.5 +/- 5.9 cmH2O; CON = 82.8 +/- 4.3 cmH2O). Peak inspiratory pressure, SAP, MAP, and tidal volumes remained unchanged. CONCLUSION: Without evident translation of the increased RM strength to performance of the AGSM at +1 Gz, the benefits of RMT for ameliorating AGSM-induced fatigue within the high +G, environment are limited.

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