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.

Novel approach to investigate the association between type 2 diabetes risk and dietary fats in a dietary pattern context: a scoping review.

The effect of dietary fat on type 2 diabetes (T2D) risk is unclear. A posteriori dietary pattern methods have been increasingly used to investigate how dietary fats impact T2D risk. However, the diverse nutrients, foods and dietary patterns reported in these studies requires examination to better understand the role of dietary fats. This scoping review aimed to systematically search and synthesize the literature regarding the association between dietary patterns characterized by dietary fats and T2D risk using reduced rank regression. Medline and Embase were searched for cross-sectional, cohort or case-control studies published in English. Of the included studies (n = 8), five high-fat dietary patterns, mostly high in SFA, were associated with higher T2D risk or fasting glucose, insulin and Homeostasis Model Assessment (HOMA) levels. These were mostly low-fiber (n = 5) and high energy-density (n = 3) dietary patterns characterized by low fruit and vegetables intake, reduced fat dairy products and higher processed meats and butter intake. Findings from this review suggest that a posteriori dietary patterns high in SFA that increase T2D risk are often accompanied by lower fruits, vegetables and other fiber-rich foods intake. Therefore, healthy dietary fats consumption for T2D prevention should be encouraged as part of a healthful dietary pattern.

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.

Cross-sectional associations of dietary patterns characterized by fat type with markers of cardiometabolic health.

BACKGROUND AND AIMS: Individual dietary fats can differentially impact on cardiometabolic health. However, their impact within a dietary pattern is not well understood, and warrants comparison with diet quality scores with a dietary fat focus. The aim of this study was to investigate cross-sectional associations between a posteriori dietary patterns characterized by fat type and cardiometabolic health markers, and compare these with two diet quality scores. METHODS AND RESULTS: UK Biobank adults with ≥two 24-h dietary assessments and data on cardiometabolic health were included (n = 24 553; mean age: 55.9 y). A posteriori dietary patterns (DP1; DP2) were generated through reduced rank regression (response variables: SFA, MUFA, PUFA). Mediterranean Diet Score (MDS) and Dietary Approaches to Stop Hypertension (DASH) dietary patterns were created. Multiple linear regression analyses were used to investigate associations between standardized dietary patterns and cardiometabolic health (total cholesterol, HDL-C, LDL-C and VLDL-C cholesterol, triglycerides, C-reactive protein [CRP], glycated hemoglobin [HbA1c]). DP1, positively correlated with SFAs, MUFAs and PUFAs, characterized by higher nuts, seeds and vegetables intake and lower fruits and low-fat yoghurt intake, was associated with lower HDL-C (ß: -0.07; 95% CI: -0.10, -0.03) and triglycerides (-0.17; -0.23, -0.10) and higher LDL-C (0.07; 0.01,0.12), CRP (0.01; 0.01, 0.03) and HbA1c (0.16; 0.11,0.21). DP2, positively correlated with SFAs, negatively correlated with PUFAs, characterized by higher butter and high-fat cheese intake and lower nuts, seeds and vegetable intake, was associated with higher total cholesterol (0.10; 0.01, 0.21), VLDL-C (0.05; 0.02, 0.07), triglycerides (0.07; 0.01, 0.13), CRP (0.03; 0.02, 0,04) and HbA1c (0.06; 0.01, 0.11). Higher adherence to MDS and DASH was associated with favorable cardiometabolic health markers concentration. CONCLUSIONS: Irrespective of the method used, dietary patterns that encourage healthy fat consumption were associated with favorable cardiometabolic health biomarkers. This study strengthens the evidence for incorporation of dietary fat type into policy and practice guidelines for CVD prevention.

Development of a behavioural support intervention for e-bike use in Australia.

BACKGROUND: Insufficient physical activity (PA) is a risk factor for the development of many non-communicable diseases. Electric bicycles (e-bikes) offer considerable potential to support people to be physically active, however, no previous e-bike intervention studies have supported e-bike use with behavioural support. The aim of this study was to co-develop theory-based intervention components which can be used to increase physical activity through e-cycling among people who are overweight or obese and physically inactive. METHODS: We conducted a mixed-methods study using an online survey and virtual co-design workshops. We utilised the Behaviour Change Wheel (BCW) to inform the development of the behavioural support intervention to facilitate day-to-day e-cycling. RESULTS: One hundred participants completed an online survey and seven participated in the online co-design workshops. The development of the intervention identified five intervention functions (enablement, training, environmental restructuring, education, and persuasion) and 16 behaviour change techniques (BCTs) from 11 BCT groups (goals and planning, feedback and monitoring, social support, shaping knowledge, natural consequences, comparison of behaviour, associations, repetition and substitution, comparison of outcomes, antecedents, and self-belief). CONCLUSION: To our knowledge, this is the first study to combine co-design and the BCW to develop a comprehensive behavioural support intervention for e-bike use. Theory based intervention options should be considered when providing e-bikes to individuals to help them increase their habitual PA levels.

Associations between three diet quality indices, genetic risk and body composition: A prospective cohort study.

BACKGROUND & AIMS: Diet and genetic predisposition to adiposity are independent predictors of body composition, yet few cohort studies have examined the association between overall diet quality indices, genetic risk and body composition. This study examined the prospective association of three diet quality indices and a polygenic risk score (PRS) with trunk fat mass, total fat mass, lean mass and bone mineral content. METHODS: Adults from UK Biobank cohort were included. Dietary intake was assessed using the Oxford WebQ and three diet quality indices calculated: Recommended Food Score (RFS); Mediterranean Diet Score (MDS); Healthy Diet Indicator (HDI). Bioimpedance data were available for trunk fat, total fat and lean mass (kg). Trunk fat mass (kg), total fat mass (kg) and lean mass (kg) were assessed using bioelectrical impedance (BIA) in 17,478 adults. Bone mineral content (g) was available from dual energy x-ray absorptiometry (DXA) scans in 11,887 participants. Linear regression analyses, adjusted for demographic and lifestyle confounders, were used to estimate prospective associations between each diet quality index and body composition outcomes. A PRS created from 97 adiposity-related single nucleotide polymorphisms was used to examine interaction effects. RESULTS: A total of 17,478 adults (M = 55.9, SD 7.5 years) were followed up for up to 10 years. RFS, HDI and MDS were inversely associated with trunk fat (RFS: B -0.29; 95% CI: -0.33, -0.25; HDI: -0.23; -0.27, -0.19; MDS: -0.22; -0.26, -0.18), total fat (RFS: B -0.49; 95% CI: -0.56, -0.42; HDI: -0.38; -0.45, -0.32; MDS: -0.38; -0.44, -0.32) and lean (RFS: B -0.10; 95% CI: -0.14, -0.06; HDI: -0.07; -0.11, -0.03; MDS: -0.07; -0.11, -0.04) mass. Diet quality was positively associated with bone mineral content (RFS: B 8.23; 95% CI: 2.14, 14.3; HDI: 6.77; 1.00, 12.5). There was evidence of non-linear associations between diet quality (RFS and HDI only) and trunk fat (p < 0.01) and total fat mass (p < 0.05). There was limited evidence PRS was associated with body composition, with interaction effects of PRS and HDI (p-interaction = 0.039) and MDS (p-interaction = 0.031) on total fat mass. CONCLUSION: Higher diet quality was associated with lower trunk fat, total fat and lean mass, regardless of the diet quality index examined (RFS, HDI or MDS), while higher diet quality (RFS and HDI only) was associated with higher bone mineral content. The benefit of higher diet quality on reducing total fat mass was most evident in individuals with higher generic risk of adiposity. These findings underscore the importance of a high-quality diet for maintaining optimal body composition, particularly in individuals with genetic pre-disposition to adiposity.

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.

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.

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.

Longitudinal Associations Between Fat-Derived Dietary Patterns and Early Markers of Cardiovascular Disease Risk in the UK Biobank Study.

Background Although the impact of dietary fats on cardiovascular disease (CVD) risk is widely researched, longitudinal associations between dietary patterns (DPs) based on fat type and early markers of CVD risk remain unclear. Methods and Results UK Biobank participants (46.9% men, mean age 55 years) with data on early markers of CVD risk (n=12 706) were followed longitudinally (2014-2020; mean 8.4 years). Two DPs (DP1, DP2) were derived using reduced rank regression (response variables: monounsaturated fat, polyunsaturated fat, and saturated fat based on two 24-hour dietary assessments. Multivariable logistic and linear regression were used to investigate associations between DPs and odds of elevated CVD risk (using the nonlaboratory Framingham Risk Score) and changes in early CVD markers, respectively. DP1 (characterized by higher nuts and seeds and lower fruit and legumes intake) was positively correlated with saturated fat, monounsaturated fat, and polyunsaturated fat; DP2 (characterized by higher butter and high-fat cheese, lower nuts and seeds intake) was positively correlated with saturated fat and negatively with polyunsaturated fat and monounsaturated fat. DP2 was associated with slightly higher odds of elevated CVD risk (odds ratio, 1.04 [95% CI, 1.00-1.07]). DP1 was associated with higher diastolic blood pressure (ß, 0.20 [95% CI, 0.01-0.37]) and lower cardiac index (ß, -0.02 [95% CI, -0.04 to -0.01]); DP2 was associated with higher carotid intima medial thickness (ß, 1.80 [95% CI, 0.01-3.59]) and lower left ventricular ejection fraction (ß, -0.15 [95% CI, -0.24 to -0.07]) and cardiac index (ß, -0.01 [95% CI, -0.02 to -0.01]). Conclusions This study suggests small but statistically significant associations between DPs based on fat type and some early markers of CVD risk. Further research is needed to confirm these associations.

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.

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.

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.

Role of skeletal muscle perfusion and insulin resistance in the effect of dietary sodium on heart function in overweight.

AIMS: Weight excess and insulin resistance predispose to heart failure. High sodium consumption may contribute to the development of cardiac impairment in insulin-resistant individuals by promoting inadequate skeletal muscle microvascular perfusion response to insulin. We sought to investigate the association of dietary sodium reduction with muscle perfusion, insulin sensitivity, and cardiac function in overweight/obese insulin-resistant (O-IR) normotensive subjects. METHODS AND RESULTS: Fifty O-IR individuals with higher than recommended sodium intake were randomized to usual or reduced sodium diet for 8 weeks; 25 lean, healthy subjects served as controls for pre-intervention measurements. Echocardiography and muscle perfusion were performed during fasting and under stable euglycaemic-hyperinsulinaemic clamp conditions. O-IR patients demonstrated subclinical cardiac dysfunction as evidenced by lower left ventricular global longitudinal strain (GLS), e' tissue velocity, and left atrial strain and reduced muscle perfusion. The intervention arm showed improvements in insulin resistance [glucose infusion rate (GIR)], GLS, e', atrial strain, and muscle perfusion in fasting conditions, as well as improved responses of GLS and muscle perfusion to insulin during clamp. Significant interactions were found between the allocation to low-salt diet and improvement in muscle perfusion on change in GIR at follow-up (P = 0.030), and between improvement in muscle perfusion and change in GIR on change in GLS response to insulin at follow-up (P = 0.026). Mediation analysis revealed that the relationship between the reduction of sodium intake and improvement in GLS was mediated by improvements in muscle perfusion and GIR (decrease in beta coefficient from -0.29 to -0.16 after the inclusion of mediator variables to the model). CONCLUSIONS: The reduction of dietary sodium in the normotensive O-IR population improves cardiac function, and this effect may be associated with the concomitant improvements in skeletal muscle perfusion and insulin resistance. These findings might contribute to refining heart failure preventive strategies.

Dietary Patterns Characterized by Fat Type in Association with Obesity and Type 2 Diabetes: A Longitudinal Study of UK Biobank Participants.

BACKGROUND: The fat type consumed is considered a risk factor for developing obesity and type 2 diabetes (T2D). However, these associations have not been investigated using a dietary patterns approach, which can capture combinations of foods and fat type consumed. OBJECTIVES: This study aimed to investigate associations between dietary patterns with varying proportions of SFAs, MUFAs, or PUFAs and obesity, abdominal obesity, and self-reported T2D incidence. METHODS: This study included UK Biobank participants with 2 or more 24-h dietary assessments, free from the outcome of interest at recruitment, and with outcome data at follow-up (n = 16,523; mean follow-up: 6.3 y). Reduced rank regression was used to derive dietary patterns with SFAs, MUFAs, and PUFAs (% of energy intake) as response variables. Logistic regression, adjusted for sociodemographic and health characteristics, was used to investigate the associations between dietary patterns and obesity [BMI (kg/m2) ≥30], abdominal obesity (waist circumference; men: ≥102 cm; women: ≥88 cm) and T2D incidence. RESULTS: Two dietary patterns, DP1 and DP2, were identified: DP1 positively correlated with SFAs (r = 0.48), MUFAs (r = 0.67), and PUFAs (r = 0.56), characterized by higher intake of nuts, seeds, and butter and lower intake of fruit and low-fat yogurt; DP2 positively correlated with SFAs (r = 0.76) and negatively with PUFAs (r = -0.64) and MUFAs (r = -0.01), characterized by higher intake of butter and high-fat cheese and lower intake of nuts and seeds. Only DP2 was associated with higher obesity and abdominal obesity incidence (OR: 1.24; 95% CI: 1.02, 1.45; and OR: 1.19; 95% CI: 1.02, 1.38, respectively). Neither of the dietary patterns was associated with T2D incidence. CONCLUSIONS: These findings provide evidence that a dietary pattern characterized by higher SFA and lower PUFA foods is associated with obesity and abdominal obesity incidence, but not T2D.

Discovery Genome-Wide Association Study of Body Composition in 4,386 Adults From the UK Biobank's Pilot Imaging Enhancement Study.

Body composition (fat, skeletal muscle and bone mass) is an important determinant of overall health and risk of endocrine disorders such as type 2 diabetes and osteoporosis. Although diet and physical activity are strongly implicated, body composition is also heritable. We conducted a discovery genome-wide association study on 31 phenotypes from the three-compartment body composition model (fat, lean and bone mass) in a set of 4 386 individuals (n = 2 109 males, n = 2 294 females) from the UK Biobank pilot imaging enhancement program that underwent a dual energy X-ray absorptiometry (DXA) scan for assessment of body composition and genetic screening. From 6 137 607 imputed single nucleotide polymorphisms (SNPs) we identified 17 body composition loci (P<5.0 x 10-8). GWAS from the combined dataset identified four statistically significant SNPs (rs7592270, rs145972737, rs13212044, rs77772562). In sex-stratified GWAS, 10 male specific SNPs across all traits were identified and five female specific SNPs. Of the 17 SNPs, six were in or close to a gene where there was a plausible functional connection. Three SNPs (rs7592270, rs77772562 and rs7552312) were correlated with obesity phenotypes, one SNP (rs2236705) with lean phenotypes and two with bone mass phenotypes (rs112098641 and rs113380185). These results highlight candidate genes and biological pathways related to body composition, including glucose metabolism and estrogen regulation, that are of interest to replicate in future studies.

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.