Association of metabolic flexibility indexes after an oral glucose tolerance test with cardiometabolic risk factors.

BACKGROUND & AIMS: Metabolic flexibility (MetF) is considered a metabolic health biomarker, as excess body weight is associated with lower MetF. We aimed to identify whether MetF indexes were associated with cardiometabolic risk factors before and after adjustment for body size-related factors (body weight, fat-free mass, and resting metabolic rate). METHODS: We studied 51 participants (55% women; 33.6 ± 8.7 years; 26.3 ± 3.8 kg/m²) who consumed a 75-g glucose load. We measured gas exchange before (fasting) and for 3 h after glucose ingestion. MetF indexes were assessed, including the change after each hour and the 3-hour incremental area under the curve (iAUC) in respiratory exchange ratio (RER). These indexes were then related to cardiometabolic risk factors before and after adjusting for body size-related factors. RESULTS: MetF indexes correlated with each other (r ≥ 0.51; P < 0.001) and related to body weight (adjusted R2 ≥ 0.09; P < 0.03). A similar pattern was noted for fat-free mass and resting metabolic rate. MetF, regardless of the index, was not related to cardiometabolic risk factors except to BMI and high-density lipoprotein-cholesterol (HDL-C). The association between BMI and MetF disappeared after adjusting for body size-related factors. Similar adjustments did not modify the association between HDL-C and MetF, especially when approached by the change in RER after the first hour (adjusted R2 = 0.20-0.22; all P < 0.02). CONCLUSIONS: Inter-individual body size differences fully accounted for the associations between BMI and MetF. However, variability in body size-related factors appeared less relevant in affecting the associations of other cardiometabolic risk factors with MetF.

Validity of four commercially available metabolic carts for assessing resting metabolic rate and respiratory exchange ratio in non-ventilated humans.

BACKGROUND & AIMS: The validity of most commercially available metabolic cart is mostly unknown. Thus, we aimed to determine the accuracy, precision, within-subject reproducibility, and concordance of RMR and RER measured by four commercially available metabolic carts [Cosmed Q-NRG, Vyaire Vyntus CPX, Maastricht Instruments Omnical, and Medgraphics Ultima CardiO2]. Further, we studied whether a previously proposed simulation-based post-calorimetric calibration of cart readouts [individual calibration control evaluation (ICcE)] modify the RMR and RER reproducibility and concordance. METHODS: Three experiments simulating different RMR and RER by controlled pure gas (N2 and CO2) infusions were conducted on 5 non-consecutive days. Moreover, 30-min methanol burns were performed on 3 non-consecutive days. Lastly, the RMR and RER of 29 young non-ventilated adults (11 women; 25 ± 4 years-old; BMI: 24.1 ± 3.2 kg/m2) were assessed twice using each instrument, 24 hours apart, under standardized conditions. RESULTS: The Omnical presented the lowest measurement error for RER (Omnical = 1.7 ± 0.9%; Vyntus = 4.5 ± 2.0%; Q-NRG = 6.6 ± 1.9%; Ultima = 6.8 ± 6.5%) and EE (Omnical = 1.5 ± 0.5%; Q-NRG = 2.5 ± 1.3%; Ultima = 10.7 ± 11.0%; Vyntus = 13.8 ± 5.0%) in all in vitro experiments (controlled pure gas infusions and methanol burns). In humans, the 4 metabolic carts provided discordant RMR and RER estimations (all P < 0.001). No differences were detected in RMR within-subject reproducibility (P = 0.058; Q-NRG inter-day coefficient of variance = 3.6 ± 2.5%; Omnical = 4.8 ± 3.5%; Vyntus = 5.0 ± 5.6%; Ultima = 5.7 ± 4.6%), although the Ultima CardiO2 provided larger RER inter-day differences (4.6 ± 3.5%) than the others carts (P = 0.001; Omnical = 1.9 ± 1.7%; Vyntus = 2.1 ± 1.3%; Q-NRG = 2.4 ± 2.1%). The ICcE procedure did not modify the RMR or RER concordance and did not reduce the inter-day differences in any of the carts. CONCLUSIONS: The 4 metabolic carts provided discordant measurements of RMR and RER. Overall, the Omnical provides more accurate and precise estimations of RMR and RER than the Q-NRG, Vyntus and Ultima CardiO2, and might be considered the best for assessing RMR and RER in non-ventilated humans. Finally, our results do not support the use of an ICcE procedure.

Anthropometric and blood pressure changes in patients with or without nutritional counselling during cardiac rehabilitation: a retrospective study.

BACKGROUND: Whether a patient's outcomes are better when receiving nutritional counselling during cardiac rehabilitation (CR) has been scarcely described. We compared changes in weight, waist circumference (WC) and blood pressure (BP) in patients attending CR with and without nutritional counselling. METHODS: A retrospective analytical study was conducted in which two groups of patients who completed a phase II CR (36 sessions) were compared: CONTROL [n = 144, mean (SD) age = 59 (12) years, 17% females], comprising patients without nutritional counselling (attended between 2003 and 2009), and NUT [n = 128, mean (SD) age = 60 (13) years, 27% females], comprising patients with dietitian-delivered nutritional counselling (attended between 2010 and 2019). Repeated-measures analysis of variance was used to compare changes in weight, WC, and BP during CR between groups. Logistic regression models determined the probability of reducing weight and systolic BP (SBP). RESULTS: NUT group decreased weight [-1.3 (3.1) kg; P < 0.0001] and WC [-3.0 (3.8) cm; P < 0.0001] to a greater extent than CONTROL [weight: -0.4 (3.1) kg; P = 0.51; WC: -1.4 (4.5) cm; P = 0.02]. In CONTROL, 7% reduced ≥ 5% weight and 31% reduced ≥ 10 mmHg SBP, whereas, in the NUT group, 18% reduced ≥ 5% weight and 47% reduced ≥ 10 mmHg SBP. Patients in NUT (versus CONTROL) were more likely to lose ≥ 5% of weight (odds ratio = 4.27, 95% confidence interval = 1.69-10.80; P < 0.01) and reduce SBP ≥ 10 mmHg (odds ratio = 3.15, 95% confidence interval = 1.58-6.27; P < 0.01). CONCLUSIONS: Patients who received nutritional counselling during CR improved anthropometric measures and were more likely to lose weight and reduce SBP than patients without nutritional counselling.

Serotonin- and Dopamine-Related Gene Expression in db/db Mice Islets and in MIN6 ß-Cells Treated with Palmitate and Oleate.

High circulating nonesterified fatty acids (NEFAs) concentration, often reported in diabetes, leads to impaired glucose-stimulated insulin secretion (GSIS) through not yet well-defined mechanisms. Serotonin and dopamine might contribute to NEFA-dependent ß-cell dysfunction, since extracellular signal of these monoamines decreases GSIS. Moreover, palmitate-treated ß-cells may enhance the expression of the serotonin receptor Htr2c, affecting insulin secretion. Additionally, the expression of monoamine-oxidase type B (Maob) seems to be lower in islets from humans and mice with diabetes compared to nondiabetic islets, which may lead to increased monoamine concentrations. We assessed the expression of serotonin- and dopamine-related genes in islets from db/db and wild-type (WT) mice. In addition, the effect of palmitate and oleate on the expression of such genes, 5HT content, and GSIS in MIN6 ß-cell was determined. Lower Maob expression was found in islets from db/db versus WT mice and in MIN6 ß-cells in response to palmitate and oleate treatment compared to vehicle. Reduced 5HT content and impaired GSIS in response to palmitate (-25%; p < 0.0001) and oleate (-43%; p < 0.0001) were detected in MIN6 ß-cells. In conclusion, known defects of GSIS in islets from db/db mice and MIN6 ß-cells treated with NEFAs are accompanied by reduced Maob expression and reduced 5HT content.

Fluoxetine impairs insulin secretion without modifying extracellular serotonin levels in MIN6 ß-cells.

INTRODUCTION: Pancreatic ß-cells synthetize and store Serotonin (5-Hydroxytriptamine, 5HT) which is co-released with insulin. It has been proposed that extracellular 5HT binds to specific cell surface receptors and modulate insulin secretion. On the other hand, Selective Serotonin Reuptake Inhibitor (SSRI) fluoxetine seems to reduce Glucose-Stimulated Insulin Secretion (GSIS). However, it is unknown whether this effect results from changes in extracellular 5HT concentration owed to the blockade of 5HT transporter (SERT) or from non-5HT dependent actions. The aims of this work were: 1) to quantify extracellular 5HT levels and GSIS in ß-cell lines, 2) to determine whether extracellular 5HT levels and GSIS are changed by fluoxetine or 5-Hydroxytryptophan (5HTP, the immediate 5HT biosynthetic precursor), and 3) to quantify the expression of Slc6a4 gene (encoding SERT) in ß-cell lines in relation to other genes involved in 5HT system. MATERIAL AND METHODS: ß-cell lines MIN6 and RINm5f were subjected to GSIS protocols, after treatment with fluoxetine, 5HTP or 5HT. Insulin and 5HT were quantified by ELISA and HPLC, respectively. Relative mRNA expression was quantified by RT-qPCR. RESULTS: MIN6 ß-cells secretes 5HT in response to glucose, showing a sharp increase in 5HT release when cells were preloaded with 5HTP. Treatment with 5HT or fluoxetine reduces GSIS. Fluoxetine fails to further increases 5HTP-induced elevation of secreted 5HT. MIN6 ß-cells express both isoforms of Tryptophan Hydroxylase (Tph1 and Tph2), and have high expression levels of L-Dopa decarboxylase (Ddc), both enzymes involved in 5HT biosynthetic pathway, but do not express the 5HT transporters Slc6a4 or Slc6a3 (the Dopamine-5HT transporter) genes. CONCLUSION: The inhibitory effect of fluoxetine on ß-cell glucose stimulated insulin secretion is not mediated by blockage of 5HT transporter through SERT.

Potential role of skeletal muscle glucose metabolism on the regulation of insulin secretion.

Pancreatic beta cells sense glucose flux and release as much insulin as required in order to maintain glycaemia within a narrow range. Insulin secretion is regulated by many factors including glucose, incretins, and sympathetic and parasympathetic tones among other physiological factors. To identify the mechanisms linking obesity-related insulin resistance with impaired insulin secretion represents a central challenge. Recently, it has been argued that a crosstalk between skeletal muscle and the pancreas may regulate insulin secretion. Considering that skeletal muscle is the largest organ in non-obese subjects and a major site of insulin- and exercise-stimulated glucose disposal, it appears plausible that muscle might interact with the pancreas and modulate insulin secretion for appropriate peripheral intracellular glucose utilization. There is growing evidence that muscle can secrete so-called myokines that can have auto/para/endocrine actions. Although it is unclear in which direction they act, interleukin-6 seems to be a possible muscle-derived candidate protein mediating such inter-organ communication. We herein review some of the putative skeletal muscle-derived factors mediating this interaction. In addition, the evidence coming from in vitro, animal and human studies that support such inter-organ crosstalk is thoroughly discussed.

Exercise sensitizes skeletal muscle to extracellular ATP for IL-6 expression in mice.

Active skeletal muscle synthesizes and releases interleukin-6 (IL-6), which plays important roles in the organism's adaptation to exercise. Autocrine/paracrine ATP signaling has been shown to modulate IL-6 expression. The aim of this study was to determine whether a period of physical activity modifies the ATP-induced IL-6 expression. BalbC mice were either subject to 5 weeks voluntary wheel running (VA) or kept sedentary (SED). Flexor digitorum brevis muscles were dissected, stimulated with different ATP concentrations (0-100 µM) and IL-6 mRNA levels were measured using qPCR. ATP evoked a concentration-dependent rise in IL-6 mRNA in both SED and VA mice. VA mice however, had significantly higher ATP sensitivity (pD2 pharmacological values: VA=5.58±0.02 vs. SED=4.95±0.04, p<0.05). Interestingly, in VA mice we observed a positive correlation between the level of physical activity and the IL-6 mRNA increase following fiber stimulation with 10 µM ATP. In addition, there were lower P2Y2- and higher P2Y14-receptor mRNA levels in skeletal muscles of VA compared to SED mice, showing plasticity of nucleotide receptors with exercise. These results suggest that exercise increases skeletal muscle ATP sensitivity, a response dependent on the level of physical activity performed. This could have an important role in the mechanisms controlling skeletal muscle adaptation to exercise and training.

Postprandial whole-body glycolysis is similar in insulin-resistant and insulin-sensitive non-diabetic humans.

AIMS/HYPOTHESIS: Insulin resistance is characterised by impaired glucose utilisation when measured by a euglycaemic-hyperinsulinaemic clamp. We hypothesised that, in response to postprandial conditions, non-diabetic individuals would have similar intracellular glycolytic and oxidative glucose metabolism independent of the degree of insulin resistance. METHODS: Fourteen (seven male) sedentary, insulin-sensitive participants (mean ± SD: BMI 25 ± 4 kg/m²; age 39 ± 10 years; glucose disposal rate 9.4 ± 2.1 mg [kg estimated metabolic body size]⁻¹ min⁻¹) and 14 (six male) sedentary, non-diabetic, insulin-resistant volunteers (29 ± 4 kg/m²; 34 ± 13 years; 5.3 ± 1.2 mg [kg estimated metabolic body size]⁻¹ min⁻¹) received after a 10 h fast 60 g glucose plus 15 g [6,6-²H2]glucose. Serum glucose and insulin concentrations, plasma ²H enrichment and whole-body gas exchange were determined before glucose ingestion and hourly thereafter for 4 h. Plasma ²H2O production is an index of glycolytic disposal. On day 2, participants received a weight-maintenance diet. On day 3, a euglycaemic-hyperinsulinaemic clamp was performed. RESULTS: Insulin-resistant individuals had about a twofold higher postprandial insulin response than insulin-sensitive individuals (p = 0.003). Resting metabolic rate was similar in the two groups before (p = 0.29) and after (p = 0.33-0.99 over time) glucose ingestion, whereas a trend for blunted glucose-induced thermogenesis was observed in insulin-resistant vs insulin-sensitive individuals (p = 0.06). However, over the 4 h after the 75 g glucose ingestion, glycolytic glucose disposal was the same in insulin-sensitive and insulin-resistant individuals (36.5 ± 3.7 and 36.2 ± 6.4 mmol, respectively; p = 0.99). Similarly, whole-body carbohydrate oxidation did not differ between the groups either before or after glucose ingestion (p = 0.41). CONCLUSIONS/INTERPRETATION: Postprandial hyperinsulinaemia and modest hyperglycaemia overcome insulin resistance by enhancing tissue glucose uptake and intracellular glucose utilisation.

Assessment of EchoMRI-AH versus dual-energy X-ray absorptiometry to measure human body composition.

BACKGROUND: The sensitivity to detect small changes in body composition (fat mass and fat-free mass) largely depends on the precision of the instrument. We compared EchoMRI-AH and dual-energy X-ray absorptiometry (DXA) (Hologic QDR-4500A) for estimating fat mass in 301 volunteers. METHODS: Body composition was evaluated in 136 males and 165 females with a large range of body mass index (BMI) (19-49 kg m(-2)) and age (19-91 years old) using DXA and EchoMRI-AH. In a subsample of 13 lean (BMI=19-25 kg m(-2)) and 21 overweight/obese (BMI>25 kg m(-2)) individuals, within-subject precision was evaluated from repeated measurements taken within 1 h (n=3) and 1 week apart (mean of three measurements taken on each day). RESULTS: Using Bland-Altman analysis, we compared the mean of the fat mass measurements versus the difference in fat mass measured by both instruments. We found that EchoMRI-AH quantified larger amount of fat versus DXA in non-obese (BMI<30 kg m(-2) (1.1 kg, 95% confidence interval (CI(95)):-3.7 to 6.0)) and obese (BMI ≥ 30 kg m(-2) (4.2 kg, CI(95):-1.4 to 9.8)) participants. Within-subject precision (coefficient of variation, %) in fat mass measured within 1 h was remarkably better when measured by EchoMRI-AH than DXA (<0.5 versus <1.5%, respectively; P<0.001). However, 1-week apart within-subject variability showed similar values for both instruments (<2.2%; P=0.15). CONCLUSIONS: EchoMRI-AH yielded greater fat mass values when compared with DXA (Hologic QDR-4500A), particularly in fatter subjects. EchoMRI-AH and DXA showed similar 1-week apart precision when fat mass was measured both in lean and overweight/obese individuals.

Effect of a 3-day high-fat feeding period on carbohydrate balance and ad libitum energy intake in humans.

OBJECTIVE: A reduction in glycogen after the switch to an isoenergetic high-fat diet (HFD) might promote a compensatory increase in food intake to reestablish carbohydrate balance. We assessed the effect of an isoenergetic switch from a 49%-carbohydrate to 50%-fat diet on nutrient balance and ad libitum food intake. We hypothesized that carbohydrate balance would be inversely related to ad libitum energy intake. METHODS: In 47 men and 11 women (22.6+/-0.4 years; 26.1+/-0.5 kg m(-2)), fuel balance was measured in a respiration chamber over 4 days. During the first day, an isoenergetic, high-carbohydrate diet was provided followed by a 3-day isoenergetic, HFD. At the end of this period and after 16 h of fasting, three options of foods (cookies, fruit salad and turkey sandwich) were offered ad libitum for 4 h. The relationships between post-chamber ad libitum intake and macronutrient oxidation and balance measured day-to-day and over the 4-day respiration chamber stay were studied. RESULTS: After switching to a HFD, 24-h respiratory quotient decreased from 0.87+/-0.02 to 0.83+/-0.02 (P<0.0001) resulting in a 4-day cumulative carbohydrate, fat and protein balances of -183+/-368, 342+/-480 and 65+/-267 kcal, respectively. Cumulative energy balance (224+/-362 kcal per 4 days) did not influence ad libitum energy intake. However, we detected that 4-day carbohydrate balance was a positive and independent predictor of post-chamber ad libitum energy intake (R (2)=0.10; P=0.01), whereas no significant influence of fat and protein balances was found. CONCLUSION: In response to an isoenergetic change from a high-carbohydrate to HFD, higher carbohydrate balance related to increased energy intake.

Glycaemic index effects on fuel partitioning in humans.

The purpose of this review was to examine the role of glycaemic index in fuel partitioning and body composition with emphasis on fat oxidation/storage in humans. This relationship is based on the hypothesis postulating that a higher serum glucose and insulin response induced by high-glycaemic carbohydrates promotes lower fat oxidation and higher fat storage in comparison with low-glycaemic carbohydrates. Thus, high-glycaemic index meals could contribute to the maintenance of excess weight in obese individuals and/or predispose obesity-prone subjects to weight gain. Several studies comparing the effects of meals with contrasting glycaemic carbohydrates for hours, days or weeks have failed to demonstrate any differential effect on fuel partitioning when either substrate oxidation or body composition measurements were performed. Apparently, the glycaemic index-induced serum insulin differences are not sufficient in magnitude and/or duration to modify fuel oxidation.

Effect of glycemic index on whole-body substrate oxidation in obese women.

BACKGROUND: Glycemic index is hypothesized to determine fuel partitioning through serum plasma insulin modifications induced by dietary carbohydrates, thereby modulating fat accretion or oxidation. OBJECTIVE: To assess the glycemic effects on postprandial fuel oxidation and blood response. DESIGN: In all, 12 obese women were fed on a randomized crossover design with two test meals (breakfast+lunch). High- or low-glycemic meals were provided on separate days. Energy intake on high-glycemic meal was 7758+/-148 kJ and for low-glycemic meal was 7806+/-179 kJ. Carbohydrates supplied were 273+/-5 and 275+/-6 g, respectively. Macronutrient distribution was 55% carbohydrates, 30% fat and 15% protein. Fuel oxidation was measured continuously in a respiratory chamber for 10 h. Serum glucose, free fatty acids (FFA), insulin and glucagon samples were taken for 5 h after breakfast. RESULTS: Glucose AUC changed significantly in response to different glycemic breakfast. Low- vs high-glycemic breakfast was 211+/-84 and 379+/-164 mmol/l (P<0.05). Similarly, insulin changed from 94+/-37 and 170+/-87 nmol/l (P<0.05), respectively. The rate of increment for serum glucose and insulin reached by the high- vs low-glycemic meal was 1.8 times more with the high-glycemic breakfast. Serum FFA were similarly suppressed by both meal types by 3 h after meal intake, but then raised significantly more with the low-glycemic meal by the fourth and fifth hour (P<0.05). Plasma glucagon did not show a significant variation with glycemic index. Carbohydrate and fat oxidation was not modified by glycemic meal characteristics, being virtually the same for low- vs high-glycemic comparisons in the 5 h following breakfast and lunch (P=NS). CONCLUSION: This study demonstrates that dietary glycemic characteristics were unable to modify fuel partitioning in sedentary obese women.