Short-term high-calorie high-fat feeding induces hyperinsulinemia and blunts skeletal muscle microvascular blood flow in healthy humans.

Skeletal muscle microvascular blood flow (MBF) plays an important role in glucose disposal in muscle. Impairments in muscle MBF contribute to insulin resistance and pre-diabetes. Animal studies show that short-term (3 day) high-fat feeding blunts skeletal muscle MBF prior to impairing insulin-stimulated glucose disposal. It is not known if this occurs in humans. We investigated the temporal impact of a 7-day high-calorie high-fat (HCHF) diet intervention (+52% kJ; 41% fat) on fasting and postprandial cardiometabolic outcomes in 14 healthy adults (18-37 years). Metabolic health and vascular responses to a mixed meal challenge (MMC) were measured at pre- (day 0), mid- (day 4) and post-intervention (day 8). There were no significant differences in body weight, body fat %, fasting blood glucose, and fasting plasma insulin concentrations at pre-, mid- and post-intervention. Compared to pre-intervention there was a significant increase in insulin (but not glucose) total area under the curve, in response to the MMC at mid-intervention (p=0.041) and at post-intervention (p=0.028). Unlike at pre- and mid-intervention, at post-intervention muscle MBF decreased at 60 min (p=0.024) and 120 min (p=0.023) following the MMC. However, macrovascular blood flow was significantly increased from 0 to 60 mins (p<0.001) and 120 mins (p<0.001) following the MMC at pre-, mid- and post-intervention. Therefore, short-term HCHF feeding in healthy individuals leads to elevated postprandial insulin but not glucose levels and a blunting of meal-induced skeletal muscle MBF responses but not macrovascular blood flow responses.

Is high salt intake inducing obesity via production of cortisol? A novel working hypothesis and pilot study.

PURPOSE: Evidence is growing that high salt intake is an independent risk factor for obesity, but the mechanisms are unknown. Our novel working hypothesis is that high salt intake drives cortisol production, which in turn, drives obesity. The current study aimed to demonstrate an acute cortisol response following a single high salt meal. METHODS: Eight participants (age 30.5 ± 9.8 years [mean ± SD], 50% female), consumed high salt (3.82 g; 1529 mg sodium) and low salt (0.02 g; 9 mg sodium) meals in a randomized cross-over design. RESULTS: Urinary and salivary cortisol and plasma adrenocorticotropic hormone (ACTH) demonstrated order effects. When high salt was given second, there was a peak above baseline for urinary cortisol (26.3%), salivary cortisol (9.4%) and plasma ACTH (4.1%) followed by a significant decline in each hormone (treatment*time, F[9, 18] = 2.641, p = 0.038, partial η2 = 0.569; treatment*time, F[12, 24] = 2.668, p = 0.020, partial η2 = 0.572; treatment*time, F[12, 24] = 2.580, p = 0.023, partial η2 = 0.563, respectively), but not when high salt was given first (p > 0.05 for all). CONCLUSION: These intriguing findings provide partial support for our hypothesis and support a need for further research to elucidate the role of high salt intake in cortisol production and, in turn, in the aetiology of obesity. TRIAL REGISTRATION NUMBER: ACTRN12623000490673; date of registration 12/05/2023; retrospectively registered.

Cluster Sets to Prescribe Interval Resistance Training: A Potential Method to Optimise Resistance Training Safety, Feasibility and Efficacy in Cardiac Patients.

The integration of resistance training for cardiac patients leads to important health outcomes that are not optimally obtained with aerobic exercise; these include an increase in muscle mass, maintenance of bone mineral density, and improvements in muscular fitness parameters. Despite the proliferation of evidence supporting resistance exercise in recent decades, the implementation of resistance training is underutilised, and prescription is often sub-optimal in cardiac patients. This is frequently associated with safety concerns and inadequate methods of practical exercise prescription. This review discusses the potential application of cluster sets to prescribe interval resistance training in cardiac populations. The addition of planned, regular passive intra-set rest periods (cluster sets) in resistance training (i.e., interval resistance training) may be a practical solution for reducing the magnitude of haemodynamic responses observed with traditional resistance training. This interval resistance training approach may be a more suitable option for cardiac patients. Additionally, many cardiac patients present with impaired exercise tolerance; this model of interval resistance training may be a more suitable option to reduce fatigue, increase patient tolerance and enhance performance to these workloads. Practical strategies to implement interval resistance training for cardiac patients are also discussed. Preliminary evidence suggests that interval resistance training may lead to safer acute haemodynamic responses in cardiac patients. Future research is needed to determine the efficacy and feasibility of interval resistance training for health outcomes in this population.

Detecting the vitamin D receptor (VDR) protein in mouse and human skeletal muscle: Strain-specific, species-specific and inter-individual variation.

Vitamin D, and its receptor (VDR), play roles in muscle development/function, however, VDR detection in muscle has been controversial. Using different sample preparation methods and antibodies, we examined differences in muscle VDR protein abundance between two mouse strains and between mice and humans. The mouse D-6 VDR antibody was not reliable for detecting VDR in mouse muscle, but was suitable for human muscle, while the rabbit D2K6W antibody was valid for mouse and human muscle. VDR protein was generally lower in muscles from C57 B l/6 than FVB/N mice and was higher in human than mouse muscle. Two putative VDR bands were detected in human muscle, possibly representing VDR isoforms/splice variants, with marked inter-individual differences. This study provides new information on detecting VDR in muscle and on inter-mouse strain and inter-human individual differences in VDR expression. These findings may have implications for future pre-clinical and clinical studies and prompt further investigation to confirm possible VDR isoforms in human muscle.

Acute exercise and high-glucose ingestion elicit dynamic and individualized responses in systemic markers of redox homeostasis.

Background: Biomarkers of oxidation-reduction (redox) homeostasis are commonly measured in human blood to assess whether certain stimuli (e.g., high-glucose ingestion or acute exercise) lead to a state of oxidative distress (detrimental to health) or oxidative eustress (beneficial to health). Emerging research indicates that redox responses are likely to be highly individualized, yet few studies report individual responses. Furthermore, the effects of complex redox stimuli (e.g., high-glucose-ingestion after exercise) on redox homeostasis remains unclear. We investigated the effect of acute exercise (oxidative eustress), high-glucose ingestion (oxidative distress), and high-glucose ingestion after exercise (both oxidative eu/distress), on commonly measured redox biomarkers in serum/plasma. Methods: In a randomized crossover fashion, eight healthy men (age: 28 ± 4 years; BMI: 24.5 ± 1.5 kg/m2 [mean ± SD]) completed two separate testing conditions; 1) consumption of a high-glucose mixed-nutrient meal (45% carbohydrate [1.1 g glucose.kg-1], 20% protein, and 35% fat) at rest (control trial), and 2) consumption of the same meal 3 h and 24 h after 1 h of moderate-intensity cycling exercise (exercise trial). Plasma and serum were analyzed for an array of commonly studied redox biomarkers. Results: Oxidative stress and antioxidant defense markers (hydrogen peroxide, 8-isoprostanes, catalase, superoxide dismutase, and nitrate levels) increased immediately after exercise (p < 0.05), whereas nitric oxide activity and thiobarbituric acid reactive substances (TBARS) remained similar to baseline (p > 0.118). Nitric oxide activity and nitrate levels decreased at 3 h post-exercise compared to pre-exercise baseline levels. Depending on when the high-glucose mixed nutrient meal was ingested and the postprandial timepoint investigated, oxidative stress and antioxidant defense biomarkers either increased (hydrogen peroxide, TBARS, and superoxide dismutase), decreased (hydrogen peroxide, 8-isoprostanes, superoxide dismutase, nitric oxide activity, nitrate, and nitrite), or remained similar to pre-meal baseline levels (hydrogen peroxide, 8-isoprostanes, TBARS, catalase, superoxide dismutase and nitrite). Redox responses exhibited large inter-individual variability in the magnitude and/or direction of responses. Conclusion: Findings highlight the necessity to interpret redox biomarkers in the context of the individual, biomarker measured, and stimuli observed. Individual redox responsiveness may be of physiological relevance and should be explored as a potential means to inform personalized redox intervention.

Vitamin C supplementation for diabetes management: A comprehensive narrative review.

Growing evidence suggests that vitamin C supplementation may be an effective adjunct therapy in the management of people with diabetes. This paper critically reviews the current evidence on effects of vitamin C supplementation and its potential mechanisms in diabetes management. Evidence from meta-analyses of randomized controlled trials (RCTs) show favourable effects of vitamin C on glycaemic control and blood pressure that may be clinically meaningful, and mixed effects on blood lipids and endothelial function. However, evidence is mostly of low evidence certainty. Emerging evidence is promising for effects of vitamin C supplementation on some diabetes complications, particularly diabetic foot ulcers. However, there is a notable lack of robust and well-designed studies exploring effects of vitamin C as a single compound supplement on diabetes prevention and patient-important outcomes (i.e. prevention and amelioration of diabetes complications). RCTs are also required to investigate potential preventative or ameliorative effects of vitamin C on gestational diabetes outcomes. Oral vitamin C doses of 500-1000 mg per day are potentially effective, safe, and affordable for many individuals with diabetes. However, personalisation of supplementation regimens that consider factors such as vitamin C status, disease status, current glycaemic control, vitamin C intake, redox status, and genotype is important to optimize vitamin C's therapeutic effects safely. Finally, given a high prevalence of vitamin C deficiency in patients with complications, it is recommended that plasma vitamin C concentration be measured and monitored in the clinic setting.

The Effects of Acute High-Intensity Interval Exercise and Hyperinsulinemic-Euglycemic Clamp on Osteoglycin Levels in Young and Middle-Aged Men.

Osteoglycin (OGN) is a leucine-rich proteoglycan that has been implicated in the regulation of glucose in animal models. However, its relationship with glucose control in humans is unclear. We examined the effect of high-intensity interval exercise (HIIE) and hyperinsulinemic-euglycemic clamp on circulating levels of OGN as well as whether circulating OGN levels are associated with markers of glycemic control and cardio-metabolic health. Serum was analyzed for OGN (ELISA) levels from 9 middle-aged obese men (58.1 ± 2.2 years, body mass index [BMI] = 33.1 ± 1.4 kg∙m-2, mean ± SEM) and 9 young men (27.8 ± 1.6 years, BMI = 24.4 ± 0.08 kg∙m-2) who previously completed a study involving a euglycemic-hyperinsulinemic clamp at rest and after HIIE (4x4 minutes cycling at approximately 95% peak heart rate (HRpeak), interspersed with 2 minutes of active recovery). Blood pressure, body composition (dual-energy X-ray absorptiometry), and insulin sensitivity (hyperinsulinemic-euglycemic clamp) were assessed. Serum OGN was higher in the young cohort compared with the middle-aged cohort (65.2 ± 10.1 ng/mL versus 36.5 ± 4. 5 ng/mL, p ≤ 0.05). Serum OGN was unaffected by acute HIIE but decreased after the insulin clamp compared with baseline (~-27%, p = 0.01), post-exercise (~-35%, p = 0.01), and pre-clamp (~-32%, p = 0.02) time points, irrespective of age. At baseline, lower circulating OGN levels were associated with increased age, BMI, and fat mass, whereas higher OGN levels were related to lower fasting glucose. Higher OGN levels were associated with a higher glucose infusion rate. Exercise had a limited effect on circulating OGN. The mechanisms by which OGN affects glucose regulation should be explored in the future. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Long non-coding RNA Tug1 modulates mitochondrial and myogenic responses to exercise in skeletal muscle.

BACKGROUND: Mitochondria have an essential role in regulating metabolism and integrate environmental and physiological signals to affect processes such as cellular bioenergetics and response to stress. In the metabolically active skeletal muscle, mitochondrial biogenesis is one important component contributing to a broad set of mitochondrial adaptations occurring in response to signals, which converge on the biogenesis transcriptional regulator peroxisome proliferator-activated receptor coactivator 1-alpha (PGC-1α), and is central to the beneficial effects of exercise in skeletal muscle. We investigated the role of long non-coding RNA (lncRNA) taurine-upregulated gene 1 (TUG1), which interacts with PGC-1α in regulating transcriptional responses to exercise in skeletal muscle. RESULTS: In human skeletal muscle, TUG1 gene expression was upregulated post-exercise and was also positively correlated with the increase in PGC-1α gene expression (PPARGC1A). Tug1 knockdown (KD) in differentiating mouse myotubes led to decreased Ppargc1a gene expression, impaired mitochondrial respiration and morphology, and enhanced myosin heavy chain slow isoform protein expression. In response to a Ca2+-mediated stimulus, Tug1 KD prevented an increase in Ppargc1a expression. RNA sequencing revealed that Tug1 KD impacted mitochondrial Ca2+ transport genes and several downstream PGC-1α targets. Finally, Tug1 KD modulated the expression of ~300 genes that were upregulated in response to an in vitro model of exercise in myotubes, including genes involved in regulating myogenesis. CONCLUSIONS: We found that TUG1 is upregulated in human skeletal muscle after a single session of exercise, and mechanistically, Tug1 regulates transcriptional networks associated with mitochondrial calcium handling, muscle differentiation and myogenesis. These data demonstrate that lncRNA Tug1 exerts regulation over fundamental aspects of skeletal muscle biology and response to exercise stimuli.

Is vascular insulin resistance an early step in diet-induced whole-body insulin resistance?

There is increasing evidence that skeletal muscle microvascular (capillary) blood flow plays an important role in glucose metabolism by increasing the delivery of glucose and insulin to the myocytes. This process is impaired in insulin-resistant individuals. Studies suggest that in diet-induced insulin-resistant rodents, insulin-mediated skeletal muscle microvascular blood flow is impaired post-short-term high fat feeding, and this occurs before the development of myocyte or whole-body insulin resistance. These data suggest that impaired skeletal muscle microvascular blood flow is an early vascular step before the onset of insulin resistance. However, evidence of this is still lacking in humans. In this review, we summarise what is known about short-term high-calorie and/or high-fat feeding in humans. We also explore selected animal studies to identify potential mechanisms. We discuss future directions aimed at better understanding the 'early' vascular mechanisms that lead to insulin resistance as this will provide the opportunity for much earlier screening and timing of intervention to assist in preventing type 2 diabetes.

Impaired postprandial adipose tissue microvascular blood flow responses to a mixed-nutrient meal in first-degree relatives of adults with type 2 diabetes.

Adipose tissue microvascular blood flow (MBF) is stimulated postprandially to augment delivery of nutrients and hormones to adipocytes. Adipose tissue MBF is impaired in type 2 diabetes (T2D). Whether healthy individuals at-risk of T2D show similar impairments is unknown. We aimed to determine whether adipose tissue MBF is impaired in apparently healthy individuals with a family history of T2D. Overnight-fasted individuals with no family history of T2D for two generations (FH-, n = 13), with at least one parent with T2D (FH+, n = 14) and clinically diagnosed T2D (n = 11) underwent a mixed meal challenge (MMC). Metabolic responses [blood glucose, plasma insulin, plasma nonesterified fatty acids (NEFAs), and fat oxidation] were measured before and during the MMC. MBF in truncal subcutaneous adipose tissue was assessed by contrast ultrasound while fasting and 60 min post-MMC. FH+ had normal blood glucoses, increased adiposity, and impaired post-MMC adipose tissue MBF (Δ0.70 ± 0.22 vs. 2.45 ± 0.60 acoustic intensity/s, P = 0.007) and post-MMC adipose tissue insulin resistance (Adipo-IR index; Δ45.5 ± 13.9 vs. 7.8 ± 5.1 mmol/L × pmol/L, P = 0.007) compared with FH-. FH+ and T2D had an impaired ability to suppress fat oxidation post-MMC. Fat oxidation incremental area under the curve (iAUC) (35-55 min post-MMC, iAUC) was higher in FH+ and T2D than in FH- (P = 0.005 and 0.009, respectively). Postprandial MBF was negatively associated with postprandial fat oxidation iAUC (P = 0.01). We conclude that apparently healthy FH+ individuals display blunted postprandial adipose tissue MBF that occurs in parallel with adipose tissue insulin resistance and impaired suppression of fat oxidation, which may help explain their heightened risk for developing T2D.NEW & NOTEWORTHY Adipose tissue blood flow plays a key role in postprandial nutrient storage. People at-risk of type 2 diabetes have impaired postmeal adipose tissue blood flow. Impaired adipose tissue blood flow is associated with altered fat oxidation. Risk of type 2 diabetes may be elevated by poor adipose tissue blood flow.

Prior aerobic exercise mitigates the decrease in serum osteoglycin and lipocalin-2 following high-glucose mixed-nutrient meal ingestion in young men.

Osteoglycin (OGN) and lipocalin-2 (LCN2) are hormones that can be secreted by bone and have been linked to glucose homeostasis in rodents. However, the endocrine role of these hormones in humans is contradictory and unclear. We examined the effects of exercise and meal ingestion on circulating serum OGN and LCN2 levels in eight healthy males {age: 28 [25, 30] years [median ± interquartile range (IQR)] and body mass index [BMI]: 24.3 [23.6, 25.5] kg/m2}. In a randomized crossover design, participants ingested a high-glucose (1.1 g glucose/kg body wt) mixed-nutrient meal (45% carbohydrate, 20% protein, and 35% fat) on a rest-control day and 3 and 24 h after aerobic cycling exercise (1 h at 70%-75% V̇o2peak). Acute aerobic exercise increased serum LCN2 levels immediately after exercise (∼61%), which remained elevated 3-h postexercise (∼55%). In contrast, serum OGN remained similar to baseline levels throughout the 3-h postexercise recovery period. The ingestion of a high-glucose mixed-nutrient meal led to a decrease in serum OGN at 90-min (approximately -17%) and 120-min postprandial (approximately -44%), and a decrease in LCN2 at 120-min postprandial (approximately -26%). Compared with the control meal, prior exercise elevated serum OGN and LCN2 levels at 120-min postprandial when the meal was ingested 3-h (OGN: ∼74% and LCN2: ∼68%) and 24-h postexercise (OGN: ∼56% and LCN2: ∼16%). Acute exercise increases serum LCN2 and attenuates the postprandial decrease in OGN and LCN2 following high-glucose mixed-nutrient meal ingestion. The potential endocrine role of circulating OGN and LCN2 in humans warrants further investigation.NEW & NOTEWORTHY We provide novel evidence that OGN and LCN2 decrease 120 min after ingesting a high-glucose mixed-nutrient meal in healthy adults. Acute aerobic exercise increases circulating LCN2 for up to 3-h postexercise, whereas circulating OGN remains similar to baseline. Despite differing postexercise responses, postprandial LCN2 and OGN are elevated when the high-glucose meal is ingested 3-h and 24-h postexercise. Findings support that OGN and LCN2 are dynamically linked to energy homeostasis in humans.

Systematic review and meta-analysis evaluating the effects electric bikes have on physiological parameters.

BACKGROUND: There is a universal need to increase the number of adults meeting physical activity (PA) recommendations to help improve health. In recent years, electrically assisted bicycles (e-bikes) have emerged as a promising method for supporting people to initiate and maintain physical activity levels. To the best of our knowledge, there have been no meta-analyses conducted to quantify the difference in physiological responses between e-cycling with electrical assistance, e-cycling without assistance, conventional cycling, and walking. METHODS: A systematic review and meta-analysis was conducted following PRISMA guidelines. We identified short-term e-bike studies, which utilized a crossover design comparing physiological outcomes when e-cycling with electrical assistance, e-cycling without electrical assistance, conventional cycling, or walking. Energy expenditure (EE), heart rate (HR), oxygen consumption (VO2 ), power output (PO), and metabolic equivalents (METs) outcomes were included within the meta-analysis. RESULTS: Fourteen studies met our inclusion criteria (N = 239). E-cycling with electrical assistance resulted in a lower energy expenditure (EE) [SMD = -0.46 (-0.98, 0.06), p = 0.08], heart rate (HR) [MD = -11.41 (-17.15, -5.68), p < 0.000, beats per minute], oxygen uptake (VO2 ) [SMD = -0.57 (-0.96, -0.17), p = 0.005], power output (PO) [MD = -31.19 (-47.19 to -15.18), p = 0.000, Watts], and metabolic equivalent (MET) response [MD = -0.83 (-1.52, -0.14), p = 0.02, METs], compared with conventional cycling. E-cycling with moderate electrical assistance resulted in a greater HR response [MD 10.38 (-1.48, 22.23) p = 0.09, beats per minute], and VO2 response [SMD 0.34 (-0.14, 0.82) p = 0.16] compared with walking. CONCLUSIONS: E-cycling was associated with increased physiological responses that can confer health benefits.

Effect of mitochondrial-targeted antioxidants on glycaemic control, cardiovascular health, and oxidative stress in humans: A systematic review and meta-analysis of randomized controlled trials.

AIM: To investigate the effects of mitochondrial-targeted antioxidants (mitoAOXs) on glycaemic control, cardiovascular health, and oxidative stress outcomes in humans. MATERIALS AND METHODS: Randomized controlled trials investigating mitoAOX interventions in humans were searched for in databases (MEDLINE-PubMed, Scopus, EMBASE and Cochrane Library) and clinical trial registries up to 10 June 2021. The Cochrane Collaboration's tool for assessing risk of bias and Grading of Recommendations, Assessment, Development and Evaluations were used to assess trial quality and evidence certainty, respectively. RESULTS: Nineteen studies (n = 884 participants) using mitoAOXs (including Elamipretide, MitoQ and MitoTEMPO) were included in the systematic review. There were limited studies investigating the effects of mitoAOXs on glycaemic control; and outcomes and population groups in studies focusing on cardiovascular health were diverse. MitoAOXs significantly improved brachial flow-mediated dilation (n = 3 trials; standardized mean difference: 1.19, 95% CI: 0.28, 2.16; I2 : 67%) with very low evidence certainty. No significant effects were found for any other glycaemic, cardiovascular or oxidative stress-related outcomes with mitoAOXs in quantitative analyses, with evidence certainty rated mostly as low. There was a lack of serious treatment-emergent adverse events with mitoAOXs, although subcutaneous injection of Elamipretide increased mild-moderate injection site-related events. CONCLUSION: While short-term studies indicate that mitoAOXs are generally well tolerated, there is currently limited evidence to support the use of mitoAOXs in the management of glycaemic control and cardiovascular health. Review findings suggest that future research should focus on the effects of mitoAOXs on glycaemic control and endothelial function in target clinical population groups.

Oral and intravenous glucose administration elicit opposing microvascular blood flow responses in skeletal muscle of healthy people: role of incretins.

Insulin infusion increases skeletal muscle microvascular blood flow (MBF) in healthy people but is impaired during insulin resistance. However, we have shown that eliciting insulin secretion via oral glucose loading in healthy people impairs muscle MBF, whilst others have demonstrated intravenous glucose infusion stimulates MBF. We aimed to show that the route of glucose administration (oral versus intravenous) influences muscle MBF, and explore potential gut-derived hormones that may explain these divergent responses. Ten healthy individuals underwent a 120 min oral glucose tolerance test (OGTT; 75 g glucose) and on a subsequent occasion an intravenous glucose tolerance test (IVGTT, bypassing the gut) matched for similar blood glucose excursions. Femoral artery and thigh muscle microvascular (contrast-enhanced ultrasound) haemodynamics were measured at baseline and during the OGTT/IVGTT. Plasma insulin, C-peptide, glucagon, non-esterified fatty acids and a range of gut-derived hormones and incretins (gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1(GLP-1)) were measured at baseline and throughout the OGTT/IVGTT. The IVGTT increased whereas the OGTT impaired MBF (1.3-fold versus 0.5-fold from baseline, respectively, P = 0.0006). The impairment in MBF during the OGTT occurred despite producing 2.8-fold higher plasma insulin concentrations (P = 0.0001). The change in MBF from baseline (ΔMBF) negatively correlated with ΔGIP concentrations (r = -0.665, P < 0.0001). The natural log ratio of incretins GLP-1:GIP was positively associated with ΔMBF (r = 0.658, P < 0.0001), suggesting they have opposing actions on the microvasculature. Postprandial hyperglycaemia per se does not acutely determine opposing microvascular responses between OGTT and IVGTT. Incretins may play a role in modulating skeletal muscle MBF in humans. KEY POINTS: Insulin or mixed nutrient meals stimulate skeletal muscle microvascular blood flow (MBF) to aid in the delivery of nutrients; however, this vascular effect is lost during insulin resistance. Food/drinks containing large glucose loads impair MBF in healthy people; however, this impairment is not observed when glucose is infused intravenously (bypassing the gut). We investigated skeletal muscle MBF responses to a 75 g oral glucose tolerance test and intravenous glucose infusion and aimed to identify potential gut hormones responsible for glucose-mediated changes in MBF. Despite similar blood glucose concentrations, orally ingested glucose impaired, whereas intravenously infused glucose augmented, skeletal muscle MBF. The incretin gastric inhibitory polypeptide was negatively associated with MBF, suggestive of an incretin-mediated MBF response to oral glucose ingestion. This work provides new insight into why diets high in glucose may be detrimental to vascular health and provides new avenues for novel treatment strategies targeting microvascular dysfunction.

Osteoglycin Across the Adult Lifespan.

CONTEXT: Osteoglycin (OGN) is a proteoglycan released from bone and muscle which has been associated with markers of metabolic health. However, it is not clear whether the levels of circulating OGN change throughout the adult lifespan or if they are associated with clinical metabolic markers or fitness. OBJECTIVE: We aimed to identify the levels of circulating OGN across the lifespan and to further explore the relationship between OGN and aerobic capacity as well as OGN's association with glucose and HOMA-IR. METHODS: 107 individuals (46 males and 61 females) aged 21-87 years were included in the study. Serum OGN levels, aerobic capacity (VO2peak), glucose, and homeostatic model assessment for insulin resistance (HOMA-IR) were assessed. T-tests were used to compare participant characteristics between sexes. Regression analyses were performed to assess the relationship between OGN and age, and OGN and fitness and metabolic markers. RESULTS: OGN displayed a nonlinear, weak "U-shaped" relationship with age across both sexes. Men had higher levels of OGN than women across the lifespan (ß = 0.23, P = .03). Age and sex explained 16% of the variance in OGN (adjusted R2 = 0.16; P < .001). Higher OGN was associated with higher VO2peak (ß = 0.02, P = .001); however, those aged <50 showed a stronger positive relationship than those aged >50. A higher OGN level was associated with a higher circulating glucose level (ß = 0.17, P < .01). No association was observed between OGN and HOMA-IR. CONCLUSION: OGN was characterized by a U-shaped curve across the lifespan which was similar between sexes. Those with a higher aerobic capacity or higher glucose concentration had higher OGN levels. Our data suggest an association between OGN and aerobic fitness and glucose regulation. Future studies should focus on exploring the potential of OGN as a biomarker for chronic disease.

Impaired postprandial skeletal muscle vascular responses to a mixed meal challenge in normoglycaemic people with a parent with type 2 diabetes.

AIMS/HYPOTHESIS: Microvascular blood flow (MBF) increases in skeletal muscle postprandially to aid in glucose delivery and uptake in muscle. This vascular action is impaired in individuals who are obese or have type 2 diabetes. Whether MBF is impaired in normoglycaemic people at risk of type 2 diabetes is unknown. We aimed to determine whether apparently healthy people at risk of type 2 diabetes display impaired skeletal muscle microvascular responses to a mixed-nutrient meal. METHODS: In this cross-sectional study, participants with no family history of type 2 diabetes (FH-) for two generations (n = 18), participants with a positive family history of type 2 diabetes (FH+; i.e. a parent with type 2 diabetes; n = 16) and those with type 2 diabetes (n = 12) underwent a mixed meal challenge (MMC). Metabolic responses (blood glucose, plasma insulin and indirect calorimetry) were measured before and during the MMC. Skeletal muscle large artery haemodynamics (2D and Doppler ultrasound, and Mobil-O-graph) and microvascular responses (contrast-enhanced ultrasound) were measured at baseline and 1 h post MMC. RESULTS: Despite normal blood glucose concentrations, FH+ individuals displayed impaired metabolic flexibility (reduced ability to switch from fat to carbohydrate oxidation vs FH-; p < 0.05) during the MMC. The MMC increased forearm muscle microvascular blood volume in both the FH- (1.3-fold, p < 0.01) and FH+ (1.3-fold, p < 0.05) groups but not in participants with type 2 diabetes. However, the MMC increased MBF (1.9-fold, p < 0.01), brachial artery diameter (1.1-fold, p < 0.01) and brachial artery blood flow (1.7-fold, p < 0.001) and reduced vascular resistance (0.7-fold, p < 0.001) only in FH- participants, with these changes being absent in FH+ and type 2 diabetes. Participants with type 2 diabetes displayed significantly higher vascular stiffness (p < 0.001) compared with those in the FH- and FH+ groups; however, vascular stiffness did not change during the MMC in any participant group. CONCLUSIONS/INTERPRETATION: Normoglycaemic FH+ participants display impaired postprandial skeletal muscle macro- and microvascular responses, suggesting that poor vascular responses to a meal may contribute to their increased risk of type 2 diabetes. We conclude that vascular insulin resistance may be an early precursor to type 2 diabetes in humans, which can be revealed using an MMC.

Reactive oxygen species in exercise and insulin resistance: Working towards personalized antioxidant treatment.

Reactive oxygen species (ROS) are well known for their role in insulin resistance and the development of cardiometabolic disease including type 2 diabetes mellitus (T2D). Conversely, evidence supports the notion that ROS are a necessary component for glucose cell transport and adaptation to physiological stress including exercise and muscle contraction. Although genetic rodent models and cell culture studies indicate antioxidant treatment to be an effective strategy for targeting ROS to promote health, human findings are largely inconsistent. In this review we discuss human research that has investigated antioxidant treatment and glycemic control in the context of health (healthy individuals and during exercise) and disease (insulin resistance and T2D). We have identified key factors that are likely to influence the effectiveness of antioxidant treatment: 1) the context of treatment including whether oxidative distress or eustress is present (e.g., hyperglycemia/lipidaemia or during exercise and muscle contraction); 2) whether specific endogenous antioxidant deficiencies are identified (redox screening); 3) whether antioxidant treatment is specifically designed to target and restore identified deficiencies (antioxidant specificity); 4) and the bioavailability and bioactivity of the antioxidant which are influenced by treatment dose, duration, and method of administration. The majority of human research has failed to account for these factors, limiting their ability to robustly test the effectiveness of antioxidants for health promotion and disease prevention. We propose that a modern "redox screening" and "personalized antioxidant treatment" approach is required to robustly explore redox regulation of human physiology and to elicit more effective antioxidant treatment in humans.

Reduced post-exercise muscle microvascular perfusion with compression is offset by increased muscle oxygen extraction: Assessment by contrast-enhanced ultrasound.

The microvasculature is important for both health and exercise tolerance in a range of populations. However, methodological limitations have meant changes in microvascular blood flow are rarely assessed in humans during interventions designed to affect skeletal muscle blood flow such as the wearing of compression garments. The aim of this study is, for the first time, to use contrast-enhanced ultrasound to directly measure the effects of compression on muscle microvascular blood flow alongside measures of femoral artery blood flow and muscle oxygenation following intense exercise in healthy adults. It was hypothesized that both muscle microvascular and femoral artery blood flows would be augmented with compression garments as compared with a control condition. Ten recreationally active participants completed two repeated-sprint exercise sessions, with and without lower-limb compression tights. Muscle microvascular blood flow, femoral arterial blood flow (2D and Doppler ultrasound), muscle oxygenation (near-infrared spectroscopy), cycling performance, and venous blood samples were measured/taken throughout exercise and the 1-hour post-exercise recovery period. Compared with control, compression reduced muscle microvascular blood volume and attenuated the exercise-induced increase in microvascular velocity and flow immediately after exercise and 1 hour post-exercise. Compression increased femoral artery diameter and augmented the exercise-induced increase in femoral arterial blood flow during exercise. Markers of blood oxygen extraction in muscle were increased with compression during and after exercise. Compression had no effect on blood lactate, glucose, or exercise performance. We provide new evidence that lower-limb compression attenuates the exercise-induced increase in skeletal muscle microvascular blood flow following exercise, despite a divergent increase in femoral artery blood flow. Decreased muscle microvascular perfusion is offset by increased muscle oxygen extraction, a potential mechanism allowing for the maintenance of exercise performance.

Whole-Body Vibration Stimulates Microvascular Blood Flow in Skeletal Muscle.

PURPOSE: Whole-body vibration (WBV) therapy has been reported to potentially act as an exercise mimetic by improving muscle function and exercise capacity in a variety of healthy and clinical populations. Considering the important role that microvascular blood flow plays in muscle metabolism and exercise capacity, we investigated the muscle microvascular responses of acute WBV to knee extension exercise (KEX) in healthy individuals. METHODS: Eleven healthy adults (age: 33 ± 2 yr; body mass index: 23.6 ± 1.1 kg·m-2) underwent 3 min of WBV, or 3 min of KEX at 25% of one-repetition maximum, in a randomized order separated by a minimum of 72 h. Femoral arterial blood flow was measured via Doppler ultrasound, and thigh muscle microvascular blood flow was measured via contrast-enhanced ultrasound at baseline and throughout the 3-min postintervention recovery period. RESULTS: Both WBV and KEX significantly increased peak microvascular blood flow (WBV, 5.6-fold; KEX, 21-fold; both P < 0.05) during the 3-min recovery period. Despite a similar increase in femoral arterial blood flow (~4-fold; both P < 0.05 vs baseline) and whole-body oxygen consumption measured by indirect calorimetry (WBV, 48%; KEX, 60%; both P < 0.05 vs baseline) in both conditions, microvascular blood flow was stimulated to a greater extent after KEX. CONCLUSION: A single 3-min session of WBV in healthy individuals is sufficient to significantly enhance muscle microvascular blood flow. Despite KEX providing a more potent stimulus, WBV may be an effective method for improving microvascular blood flow in populations reported to exhibit microvascular dysfunction such as patients with type 2 diabetes.