Hepatic insulin resistance and muscle insulin resistance are characterized by distinct postprandial plasma metabolite profiles: a cross-sectional study.

BACKGROUND: Tissue-specific insulin resistance (IR) predominantly in muscle (muscle IR) or liver (liver IR) has previously been linked to distinct fasting metabolite profiles, but postprandial metabolite profiles have not been investigated in tissue-specific IR yet. Given the importance of postprandial metabolic impairments in the pathophysiology of cardiometabolic diseases, we compared postprandial plasma metabolite profiles in response to a high-fat mixed meal between individuals with predominant muscle IR or liver IR. METHODS: This cross-sectional study included data from 214 women and men with BMI 25-40 kg/m2, aged 40-75 years, and with predominant muscle IR or liver IR. Tissue-specific IR was assessed using the muscle insulin sensitivity index (MISI) and hepatic insulin resistance index (HIRI), which were calculated from the glucose and insulin responses during a 7-point oral glucose tolerance test. Plasma samples were collected before (T = 0) and after (T = 30, 60, 120, 240 min) consumption of a high-fat mixed meal and 247 metabolite measures, including lipoproteins, cholesterol, triacylglycerol (TAG), ketone bodies, and amino acids, were quantified using nuclear magnetic resonance spectroscopy. Differences in postprandial plasma metabolite iAUCs between muscle and liver IR were tested using ANCOVA with adjustment for age, sex, center, BMI, and waist-to-hip ratio. P-values were adjusted for a false discovery rate (FDR) of 0.05 using the Benjamini-Hochberg method. RESULTS: Sixty-eight postprandial metabolite iAUCs were significantly different between liver and muscle IR. Liver IR was characterized by greater plasma iAUCs of large VLDL (p = 0.004), very large VLDL (p = 0.002), and medium-sized LDL particles (p = 0.026), and by greater iAUCs of TAG in small VLDL (p = 0.025), large VLDL (p = 0.003), very large VLDL (p = 0.002), all LDL subclasses (all p < 0.05), and small HDL particles (p = 0.011), compared to muscle IR. In liver IR, the postprandial plasma fatty acid (FA) profile consisted of a higher percentage of saturated FA (p = 0.013), and a lower percentage of polyunsaturated FA (p = 0.008), compared to muscle IR. CONCLUSION: People with muscle IR or liver IR have distinct postprandial plasma metabolite profiles, with more unfavorable postprandial metabolite responses in those with liver IR compared to muscle IR.

Effects of hypoxic exercise on 24-hour glucose profile and substrate metabolism in overweight and obese men with impaired glucose metabolism.

Hypoxic exercise (HE) may have more pronounced effects on glucose homeostasis than exercise under normoxic conditions (NE), but effects on 24-h glucose profile and substrate utilization remain unclear. We investigated the effects of moderate-intensity HE compared with NE on 24-h glucose profile and substrate metabolism in overweight/obese individuals. Ten overweight/obese men with impaired glucose homeostasis participated in a randomized, single-blind, crossover trial. Participants performed moderate-intensity cycling exercise for 4 consecutive days under mild normobaric hypoxic ([Formula: see text]: 15%) or normoxic ([Formula: see text]: 21%) conditions at similar relative exercise intensity (2 × 30 min/day at 50% of maximal heart rate, with a ∼4-wk washout period. Twenty-four-hour glucose levels and systemic oxygen saturation ([Formula: see text]) were monitored throughout the study. At day 5, plasma metabolites and substrate oxidation were determined during a mixed-meal test under normoxic conditions. [Formula: see text] and absolute workload were lower (both P < 0.001), whereas heart rate was comparable during HE compared with NE. HE did not alter mean 24-h, daytime, and nighttime glucose concentrations, and measures of glycemic variability. However, the HE-induced decrease in [Formula: see text] was positively correlated with HE-induced improvements in mean 24-h (rs = 0.683, P = 0.042) and daytime (rs = 0.783, P = 0.013) glucose concentrations. HE at similar relative exercise intensity reduces [Formula: see text] and has comparable effects on mean 24-h glucose concentration and glycemic variability than NE in overweight/obese men with impaired glucose metabolism. Nevertheless, a more pronounced reduction in [Formula: see text] during HE was associated with lower 24-h glucose concentrations, suggesting that a marked hypoxic stimulus is needed to improve glucose homeostasis.NEW & NOTEWORTHY We demonstrate that hypoxic exercise at similar relative exercise intensity (i.e. lower absolute workload) reduces systemic oxygen saturation ([Formula: see text]) and has comparable effects on mean 24-h glucose concentrations and glycemic variability than normoxic exercise in men with overweight/obesity and impaired glucose metabolism. A more pronounced reduction in [Formula: see text] during hypoxic exercise, however, was associated with lower 24-h and daytime glucose concentrations. Our findings suggest that a marked hypoxic stimulus may improve glucose homeostasis.

The impact of mild hypoxia exposure on myokine secretion in human obesity.

BACKGROUND/OBJECTIVE: Compelling evidence indicates that myokines act in an autocrine, paracrine and endocrine manner to alter metabolic homeostasis. The mechanisms underlying exercise-induced changes in myokine secretion remain to be elucidated. Since exercise acutely decreases oxygen partial pressure (pO2) in skeletal muscle (SM), the present study was designed to test the hypothesis that (1) hypoxia exposure impacts myokine secretion in primary human myotubes and (2) exposure to mild hypoxia in vivo alters fasting and postprandial plasma myokine concentrations in humans. METHODS: Differentiated primary human myotubes were exposed to different physiological pO2 levels for 24 h, and cell culture medium was harvested to determine myokine secretion. Furthermore, we performed a randomized single-blind crossover trial to investigate the impact of mild intermittent hypoxia exposure (MIH: 7-day exposure to 15% O2, 3x2h/day vs. normoxia: 21% O2) on in vivo SM pO2 and plasma myokine concentrations in 12 individuals with overweight and obesity (body-mass index ≥ 28 kg/m2). RESULTS: Hypoxia exposure (1% O2) increased secreted protein acidic and rich in cysteine (SPARC, p = 0.043) and follistatin like 1 (FSTL1, p = 0.021), and reduced leukemia inhibitory factor (LIF) secretion (p = 0.009) compared to 3% O2 in primary human myotubes. In addition, 1% O2 exposure increased interleukin-6 (IL-6, p = 0.004) and SPARC secretion (p = 0.021), whilst reducing fatty acid binding protein 3 (FABP3) secretion (p = 0.021) compared to 21% O2. MIH exposure in vivo markedly decreased SM pO2 (≈40%, p = 0.002) but did not alter plasma myokine concentrations. CONCLUSIONS: Hypoxia exposure altered the secretion of several myokines in primary human myotubes, revealing hypoxia as a novel modulator of myokine secretion. However, both acute and 7-day MIH exposure did not induce alterations in plasma myokine concentrations in individuals with overweight and obesity. CLINICAL TRIALS IDENTIFIER: This study is registered at the Netherlands Trial Register (NL7120/NTR7325).

Metabolic phenotyping in people living with obesity: Implications for dietary prevention.

Given the increasing number of people living with obesity and related chronic metabolic disease, precision nutrition approaches are required to increase the effectiveness of prevention strategies. This review addresses these approaches in different metabolic phenotypes (metabotypes) in obesity. Although obesity is typically associated with an increased cardiometabolic disease risk, some people with obesity are relatively protected against the detrimental effects of excess adiposity on cardiometabolic health, also referred to as 'metabolically healthy obesity' (MHO). Underlying mechanisms, the extent to which MHO is a transient state as well as lifestyle strategies to counteract the transition from MHO to metabolically unhealthy obesity (MUO) are discussed. Based on the limited resources that are available for dietary lifestyle interventions, it may be reasonable to prioritize interventions for people with MUO, since targeting high-risk patients for specific nutritional, lifestyle or weight-loss strategies may enhance the cost-effectiveness of these interventions. Additionally, the concept of tissue insulin resistant (IR) metabotypes is discussed, representing distinct etiologies towards type 2 diabetes (T2D) as well as cardiovascular disease (CVD). Recent evidence indicates that these tissue IR metabotypes, already present in individuals with obesity with a normal glucose homeostasis, respond differentially to diet. Modulation of dietary macronutrient composition according to these metabotypes may considerably improve cardiometabolic health benefits. Thus, nutritional or lifestyle intervention may improve cardiometabolic health, even with only minor or no weight loss, which stresses the importance of focusing on a healthy lifestyle and not on weight loss only. Targeting different metabotypes towards T2D and cardiometabolic diseases may lead to more effective lifestyle prevention and treatment strategies. Age and sex-related differences in tissue metabotypes and related microbial composition and functionality (fermentation), as important drivers and/or mediators of dietary intervention response, have to be taken into account. For the implementation of these approaches, more prospective trials are required to provide the knowledge base for precision nutrition in the prevention of chronic metabolic diseases.

Dietary macronutrients and the gut microbiome: a precision nutrition approach to improve cardiometabolic health.

Accumulating evidence indicates that the gut microbiome is an important regulator of body weight, glucose and lipid metabolism, and inflammatory processes, and may thereby play a key role in the aetiology of obesity, insulin resistance and type 2 diabetes. Interindividual responsiveness to specific dietary interventions may be partially determined by differences in baseline gut microbiota composition and functionality between individuals with distinct metabolic phenotypes. However, the relationship between an individual's diet, gut microbiome and host metabolic phenotype is multidirectional and complex, yielding a challenge for practical implementation of targeted dietary guidelines. In this review, we discuss the latest research describing interactions between dietary composition, the gut microbiome and host metabolism. Furthermore, we describe how this knowledge can be integrated to develop precision-based nutritional strategies to improve bodyweight control and metabolic health in humans. Specifically, we will address that (1) insight in the role of the baseline gut microbial and metabolic phenotype in dietary intervention response may provide leads for precision-based nutritional strategies; that (2) the balance between carbohydrate and protein fermentation by the gut microbiota, as well as the site of fermentation in the colon, seems important determinants of host metabolism; and that (3) 'big data', including multiple omics and advanced modelling, are of undeniable importance in predicting (non-)response to dietary interventions. Clearly, detailed metabolic and microbial phenotyping in humans is necessary to better understand the link between diet, the gut microbiome and host metabolism, which is required to develop targeted dietary strategies and guidelines for different subgroups of the population.

The impact of hypoxia exposure on glucose homeostasis in metabolically compromised humans: A systematic review.

Humans living at a higher altitude are less prone to suffer from impaired glucose homeostasis and type 2 diabetes mellitus (T2DM), which might at least partly be explained by lower oxygen availability at higher altitudes. The present systematic review aimed to provide an overview of the current literature on the effects of hypoxia exposure on glucose homeostasis in metabolically compromised humans. Several databases were searched up to August 10th, 2020. The search strategy identified 368 unique records. Following assessment for eligibility based on the selection criteria, 16 studies were included in this review. Six studies (2 controlled studies; 4 uncontrolled studies) demonstrated beneficial effects of hypoxia exposure on glucose homeostasis, while 10 studies (8 controlled studies; 2 uncontrolled studies) reported no improvement in glucose homeostasis following hypoxia exposure. Notably, passive hypoxia exposure seemed to improve glucose homeostasis, whereas hypoxic exercise training (2-8 weeks) appeared to have no additional/synergistic effects on glucose homeostasis compared to normoxia exposure. Due to the heterogeneity in study populations and intervention duration (acute studies / 2-8 wks training), it is difficult to indicate which factors may explain conflicting study outcomes. Moreover, these results should be interpreted with some caution, as several studies did not include a control group. Taken together, hypoxia exposure under resting and exercise conditions might provide a novel therapeutic strategy to improve glucose homeostasis in metabolically compromised individuals, but more randomized controlled trials are warranted before strong conclusions on the effects of hypoxia exposure on glucose homeostasis can be drawn.

Plasma cathepsin D activity is negatively associated with hepatic insulin sensitivity in overweight and obese humans.

AIMS/HYPOTHESIS: Insulin resistance in skeletal muscle and liver plays a major role in the pathophysiology of type 2 diabetes. The hyperinsulinaemic-euglycaemic clamp is considered the gold standard for assessing peripheral and hepatic insulin sensitivity, yet it is a costly and labour-intensive procedure. Therefore, easy-to-measure, cost-effective approaches to determine insulin sensitivity are needed to enable organ-specific interventions. Recently, evidence emerged that plasma cathepsin D (CTSD) is associated with insulin sensitivity and hepatic inflammation. Here, we aimed to investigate whether plasma CTSD is associated with hepatic and/or peripheral insulin sensitivity in humans. METHODS: As part of two large clinical trials (one designed to investigate the effects of antibiotics, and the other to investigate polyphenol supplementation, on insulin sensitivity), 94 overweight and obese adults (BMI 25-35 kg/m2) previously underwent a two-step hyperinsulinaemic-euglycaemic clamp (using [6,6-2H2]glucose) to assess hepatic and peripheral insulin sensitivity (per cent suppression of endogenous glucose output during the low-insulin-infusion step, and the rate of glucose disappearance during high-insulin infusion [40 mU/(m2 × min)], respectively). In this secondary analysis, plasma CTSD levels, CTSD activity and plasma inflammatory cytokines were measured. RESULTS: Plasma CTSD levels were positively associated with the proinflammatory cytokines IL-8 and TNF-α (IL-8: standardised ß = 0.495, p < 0.001; TNF-α: standardised ß = 0.264, p = 0.012). Plasma CTSD activity was negatively associated with hepatic insulin sensitivity (standardised ß = -0.206, p = 0.043), independent of age, sex, BMI and waist circumference, but it was not associated with peripheral insulin sensitivity. However, plasma IL-8 and TNF-α were not significantly correlated with hepatic insulin sensitivity. CONCLUSIONS/INTERPRETATION: We demonstrate that plasma CTSD activity, but not systemic inflammation, is inversely related to hepatic insulin sensitivity, suggesting that plasma CTSD activity may be used as a non-invasive marker for hepatic insulin sensitivity in humans.

Short-term bed rest-induced insulin resistance cannot be explained by increased mitochondrial H2 O2 emission.

KEY POINTS: We determined if bed rest increased mitochondrially derived reactive oxygen species and cellular redox stress, contributing to the induction of insulin resistance. Bed rest decreased maximal and submaximal ADP-stimulated mitochondrial respiration. Bed rest did not alter mitochondrial H2 O2 emission in the presence of ADP concentrations indicative of resting muscle, the ratio of H2 O2 emission to mitochondrial O2 consumption or markers of oxidative stress The present data suggest strongly that mitochondrial H2 O2 does not contribute to bed rest-induced insulin resistance ABSTRACT: Mitochondrial H2 O2 has been causally linked to diet-induced insulin resistance, although it remains unclear if muscle disuse similarly increases mitochondrial H2 O2 . Therefore, we investigated the potential that an increase in skeletal muscle mitochondrial H2 O2 emission, potentially as a result of decreased ADP sensitivity, contributes to cellular redox stress and the induction of insulin resistance during short-term bed rest in 20 healthy males. Bed rest led to a decline in glucose infusion rate during a hyperinsulinaemic-euglycaemic clamp (-42 ± 2%; P < 0.001), and in permeabilized skeletal muscle fibres it decreased OXPHOS protein content (-16 ± 8%) and mitochondrial respiration across a range of ADP concentrations (-13 ± 5%). While bed rest tended to increase maximal mitochondrial H2 O2 emission rates (P = 0.053), H2 O2 emission in the presence of ADP concentrations indicative of resting muscle, the ratio of H2 O2 emission to mitochondrial O2 consumption, and markers of oxidative stress were not altered following bed rest. Altogether, while bed rest impairs mitochondrial ADP-stimulated respiration, an increase in mitochondrial H2 O2 emission does not contribute to the induction of insulin resistance following short-term bed rest.

Metabolic profiling of tissue-specific insulin resistance in human obesity: results from the Diogenes study and the Maastricht Study.

BACKGROUND: Recent evidence indicates that insulin resistance (IR) in obesity may develop independently in different organs, representing different etiologies toward type 2 diabetes and other cardiometabolic diseases. The aim of this study was to investigate whether IR in the liver and IR in skeletal muscle are associated with distinct metabolic profiles. METHODS: This study includes baseline data from 634 adults with overweight or obesity (BMI ≥ 27 kg/m2) (≤65 years; 63% women) without diabetes of the European Diogenes Study. Hepatic insulin resistance index (HIRI) and muscle insulin sensitivity index (MISI), were derived from a five-point OGTT. At baseline 17 serum metabolites were identified and quantified by nuclear-magnetic-resonance spectroscopy. Linear mixed model analyses (adjusting for center, sex, body mass index (BMI), waist-to-hip ratio) were used to associate HIRI and MISI with these metabolites. In an independent sample of 540 participants without diabetes (BMI ≥ 27 kg/m2; 40-65 years; 46% women) of the Maastricht Study, an observational prospective population-based cohort study, 11 plasma metabolites and a seven-point OGTT were available for validation. RESULTS: Both HIRI and MISI were associated with higher levels of valine, isoleucine, oxo-isovaleric acid, alanine, lactate, and triglycerides, and lower levels of glycine (all p < 0.05). HIRI was also associated with higher levels of leucine, hydroxyisobutyrate, tyrosine, proline, creatine, and n-acetyl and lower levels of acetoacetate and 3-OH-butyrate (all p < 0.05). Except for valine, these results were replicated for all available metabolites in the Maastricht Study. CONCLUSIONS: In persons with obesity without diabetes, both liver and muscle IR show a circulating metabolic profile of elevated (branched-chain) amino acids, lactate, and triglycerides, and lower glycine levels, but only liver IR associates with lower ketone body levels and elevated ketogenic amino acids in circulation, suggestive of decreased ketogenesis. This knowledge might enhance developments of more targeted tissue-specific interventions to prevent progression to more severe disease stages.

Blood flow restricted resistance exercise and reductions in oxygen tension attenuate mitochondrial H2 O2 emission rates in human skeletal muscle.

KEY POINTS: Blood flow restricted resistance exercise (BFR-RE) is capable of inducing comparable adaptations to traditional resistance exercise (RE), despite a lower total exercise volume. It has been suggested that an increase in reactive oxygen species (ROS) production may be involved in this response; however, oxygen partial pressure ( PO2 ) is reduced during BFR-RE, and the influence of PO2 on mitochondrial redox balance remains poorly understood. In human skeletal muscle tissue, we demonstrate that both maximal and submaximal mitochondrial ROS emission rates are acutely decreased 2 h following BFR-RE, but not RE, occurring along with a reduction in tissue oxygenation during BFR-RE. We further suggest that PO2 is involved in this response because an in vitro analysis revealed that reducing PO2 dramatically decreased mitochondrial ROS emissions and electron leak to ROS. Altogether, these data indicate that mitochondrial ROS emission rates are attenuated following BFR-RE, and such a response is likely influenced by reductions in PO2 . ABSTRACT: Low-load blood flow restricted resistance exercise (BFR-RE) training has been proposed to induce comparable adaptations to traditional resistance exercise (RE) training, however, the acute signalling events remain unknown. Although a suggested mechanism of BFR-RE is an increase in reactive oxygen species (ROS) production, oxygen partial pressure ( PO2 ) is reduced during BFR-RE, and the influence of O2 tension on mitochondrial redox balance remains ambiguous. We therefore aimed to determine whether skeletal muscle mitochondrial bioenergetics were altered following an acute bout of BFR-RE or RE, and to further examine the role of PO2 in this response. Accordingly, muscle biopsies were obtained from 10 males at rest and 2 h after performing three sets of single-leg squats (RE or BFR-RE) to failure at 30% one-repetition maximum. We determined that mitochondrial respiratory capacity and ADP sensitivity were not altered in response to RE or BFR-RE. Although maximal (succinate) and submaximal (non-saturating ADP) mitochondrial ROS emission rates were unchanged following RE, BFR-RE attenuated these responses by ∼30% compared to pre-exercise, occurring along with a reduction in skeletal muscle tissue oxygenation during BFR-RE (P < 0.01 vs. RE). In a separate cohort of participants, evaluation of mitochondrial bioenergetics in vitro revealed that mild O2 restriction (50 µm) dramatically attenuated maximal (∼4-fold) and submaximal (∼50-fold) mitochondrial ROS emission rates and the fraction of electron leak to ROS compared to room air (200 µm). Combined, these data demonstrate that mitochondrial ROS emissions are attenuated following BFR-RE, a response which may be mediated by a reduction in skeletal muscle PO2 .

Supplementation of Diet With Galacto-oligosaccharides Increases Bifidobacteria, but Not Insulin Sensitivity, in Obese Prediabetic Individuals.

BACKGROUND & AIMS: The gut microbiota affects host lipid and glucose metabolism, satiety, and chronic low-grade inflammation to contribute to obesity and type 2 diabetes. Fermentation end products, in particular the short-chain fatty acid (SCFA) acetate, are believed to be involved in these processes. We investigated the long-term effects of supplementation with galacto-oligosaccharides (GOS), an acetogenic fiber, on the composition of the human gut microbiota and human metabolism. METHODS: We performed a double-blinded, placebo-controlled, parallel intervention study of 44 overweight or obese (body mass index, 28-40 kg/m2) prediabetic men and women (ages, 45-70 y) from October 2014 through October 2015 in Maastricht, The Netherlands. The participants were assigned randomly to groups who ingested 15 g GOS or isocaloric placebo (maltodextrin) daily with their regular meals for 12 weeks. Before and after this period, we collected data on peripheral and adipose tissue insulin sensitivity, fecal microbiota composition, plasma and fecal SCFA, energy expenditure and substrate oxidation, body composition, and hormonal and inflammatory responses. The primary outcome was the effect of GOS on peripheral insulin sensitivity, measured by the hyperinsulinemic-euglycemic clamp method. RESULTS: Supplementation of diets with GOS, but not placebo, increased the abundance of Bifidobacterium species in feces by 5-fold (P = .009; q = 0.144). Microbial richness or diversity in fecal samples were not affected. We did not observe any differences in fecal or fasting plasma SCFA concentrations or in systemic concentrations of gut-derived hormones, incretins, lipopolysaccharide-binding protein, or other markers of inflammation. In addition, no significant alterations in peripheral and adipose tissue insulin sensitivity, body composition, and energy and substrate metabolism were found. CONCLUSIONS: Twelve-week supplementation of GOS selectively increased fecal Bifidobacterium species abundance, but this did not produce significant changes in insulin sensitivity or related substrate and energy metabolism in overweight or obese prediabetic men and women. ClincialTrials.gov number, NCT02271776.

Adrenergically and non-adrenergically mediated human adipose tissue lipolysis during acute exercise and exercise training.

Obesity-related adipose tissue (AT) dysfunction, in particular subcutaneous AT (SCAT) lipolysis, is characterized by catecholamine resistance and impaired atrial natriuretic peptide (ANP) responsiveness. It remains unknown whether exercise training improves (non-)adrenergically mediated lipolysis in metabolically compromised conditions. We investigated the effects of local combined α-/ß-adrenoceptor blockade on abdominal SCAT lipolysis in lean insulin sensitive (IS) (n=10), obese IS (n=10), and obese insulin resistant (IR) (n=10) men. Obese men participated in a 12-week exercise training intervention to determine the effects on SCAT lipolysis. Abdominal SCAT extracellular glycerol concentration and blood flow (ATBF) were investigated using microdialysis, with/without locally combined α-/ß-adrenoceptor blockade at rest, during low-intensity endurance-type exercise and post-exercise recovery. In obese IR men, microdialysis was repeated after exercise intervention. The exercise-induced increase in SCAT extracellular glycerol was more pronounced in obese IS compared with lean IS men, possibly resulting from lower ATBF in obese IS men. The exercise-induced increase in extracellular glycerol was blunted in obese IR compared with obese IS men, despite comparable local ATBF. Abdominal SCAT extracellular glycerol was markedly reduced (remaining ~60% of exercise-induced SCAT extracellular glycerol) following the local α-/ß-adrenoceptor blockade in obese IS but not in IR men, suggesting reduced catecholamine-mediated lipolysis during exercise in obese IR men. Exercise training did not affect (non-)adrenergically mediated lipolysis in obese IR men. Our findings showed a major contribution of non-adrenergically-mediated lipolysis during exercise in male abdominal SCAT. Furthermore, catecholamine-mediated lipolysis may be blunted during exercise in obese IR men but could not be improved by exercise intervention, despite an improved metabolic profile and body composition.

Adipose tissue oxygenation is associated with insulin sensitivity independently of adiposity in obese men and women.

Adipose tissue (AT) dysfunction contributes to the pathophysiology of insulin resistance and type 2 diabetes. Previous studies have shown that altered AT oxygenation affects adipocyte functionality, but it remains to be elucidated whether altered AT oxygenation is more strongly related to obesity or insulin sensitivity. In the present study, we tested the hypothesis that AT oxygenation is associated with insulin sensitivity rather than adiposity in humans. Thirty-five lean and obese individuals (21 men and 14 women, aged 40-65 years) with either normal or impaired glucose metabolism participated in a cross-sectional single-centre study. We measured abdominal subcutaneous AT oxygenation, body composition and insulin sensitivity. AT oxygenation was higher in obese insulin resistant as compared to obese insulin sensitive (IS) individuals with similar age, body mass index and body fat percentage, both in men and women. No significant differences in AT oxygenation were found between obese IS and lean IS men. Moreover, AT oxygenation was positively associated with insulin resistance (r = 0.465; P = .005), even after adjustment for age, sex and body fat percentage (standardized ß = 0.479; P = .005). In conclusion, abdominal subcutaneous AT oxygenation is associated with insulin sensitivity both in men and women, independently of adiposity. AT oxygenation may therefore be a promising target to improve insulin sensitivity.

Altered skeletal muscle fatty acid handling is associated with the degree of insulin resistance in overweight and obese humans.

INTRODUCTION/HYPOTHESIS: Disturbances in skeletal muscle fatty acid (FA) handling may contribute to the development and progression of whole-body insulin resistance (IR). In this study, we compared fasting and postprandial skeletal muscle FA handling in individuals with varying degrees of IR. METHODS: Seventy-four overweight/obese participants (62 men) were divided into two groups based on the HOMA-IR median (3.35). Fasting and postprandial skeletal muscle FA handling were determined by combining the forearm muscle balance technique with stable isotopes. [2H2]palmitate was infused i.v. to label VLDL-triacylglycerol (VLDL-TAG) and NEFA in the circulation, whereas [U-13C]palmitate was incorporated in a high-saturated FA mixed-meal labelling chylomicron-TAG. Skeletal muscle biopsies were taken to assess intramuscular lipid content, fractional synthetic rate (FSR) and the transcriptional regulation of FA metabolism. RESULTS: Postprandial forearm muscle VLDL-TAG extraction was elevated in the high-IR vs the mild-IR group (AUC0-4h: 0.57 ± 0.32 vs -0.43 ± 0.38 nmol [100 ml tissue]-1 min-1, respectively, p = 0.045). Although no differences in skeletal muscle TAG, diacylglycerol, NEFA content and FSR were present between groups, the high-IR group showed increased saturation of the intramuscular NEFA pool (p = 0.039). This was accompanied by lower muscle GPAT1 (also known as GPAM) expression (p = 0.050). CONCLUSIONS/INTERPRETATION: Participants with high-IR demonstrated increased postprandial skeletal muscle VLDL-TAG extraction and higher saturation of the intramuscular NEFA pool vs individuals with mild-IR. These data support the involvement of disturbances in skeletal muscle FA handling in the progression of whole-body IR.

Nε-(carboxymethyl)lysine-receptor for advanced glycation end product axis is a key modulator of obesity-induced dysregulation of adipokine expression and insulin resistance.

OBJECTIVE: Dysregulation of inflammatory adipokines by the adipose tissue plays an important role in obesity-associated insulin resistance. Pathways leading to this dysregulation remain largely unknown. We hypothesized that the receptor for advanced glycation end products (RAGE) and the ligand N(ε)-(carboxymethyl)lysine (CML) are increased in adipose tissue and, moreover, that activation of the CML-RAGE axis plays an important role in obesity-associated inflammation and insulin resistance. APPROACH AND RESULTS: In this study, we observed a strong CML accumulation and increased expression of RAGE in adipose tissue in obesity. We confirmed in cultured human preadipocytes that adipogenesis is associated with increased levels of CML and RAGE. Moreover, CML induced a dysregulation of inflammatory adipokines in adipocytes via a RAGE-dependent pathway. To test the role of RAGE in obesity-associated inflammation further, we constructed an obese mouse model that is deficient for RAGE (ie, RAGE(-/-)/Leptr(Db-/-) mice). RAGE(-/-)/Leptr(Db-/-) mice displayed an improved inflammatory profile and glucose homeostasis when compared with RAGE(+/+)/Leptr(Db-/-) mice. In addition, CML was trapped in adipose tissue in RAGE(+/+)/Leptr(Db-/-) mice but not in RAGE(-/-)/Leptr(Db-/-). RAGE-mediated trapping in adipose tissue provides a mechanism underlying CML accumulation in adipose tissue and explaining decreased CML plasma levels in obese subjects. Decreased CML plasma levels in obese individuals were strongly associated with insulin resistance. CONCLUSIONS: RAGE-mediated CML accumulation in adipose tissue and the activation of the CML-RAGE axis are important mechanisms involved in the dysregulation of adipokines in obesity, thereby contributing to the development of obesity-associated insulin resistance.

The impact of duration and severity of obesity exposure on cardiometabolic health.

PURPOSE: Duration and severity of exposure to excess adipose tissue are important risk factors for complications, but are generally not examined in conjunction. We developed a metric considering both factors to examine the relationship between obesity-related complications and parameters of cardiometabolic health in patients undergoing a metabolic bariatric procedure (MBS). MATERIALS & METHODS: Data from patients screened for primary MBS between 2017 and 2021 were analyzed. The Obesity Exposure score (OBES), based on self-reported years of life with a BMI ≥ 25 kg/m2, was calculated with increased weighting applied for higher BMI categories. Multivariate logistic regression analysis was performed, adjusting for multiple potential confounders. RESULTS: In total, 2441 patients were included (76% female, age 42.1 ± 11.9 years, BMI 42.0 ± 4.9 kg/m2). OBES was positively related to myocardial infarction, atrial fibrillation and renal function loss (per 10 OBES-units: OR 1.31, 95%CI [1.11-1.52], p = 0.002; OR 1.23, 95% CI [1.06-1.44], p = 0.008; and OR 1.26, 95% CI [1.04-1.51], p = 0.02). OBES was negatively associated with obstructive sleep apnea syndrome (OSAS) (OR 0.90, 95% CI [0.83-0.98], p = 0.02). In patients without obesity-related complications, OBES was related to lower HbA1c and higher HDL-cholesterol levels (ß -0.5 95% CI [-0.08-.0.02] p < 0.001 and ß 0.02 [0.00-0.04] p = 0.01). CONCLUSION: OBES was related to myocardial infarction, atrial fibrillation and renal function loss in patients applying for MBS. OBES was negatively related to OSAS, possibly because undiagnosed years were not taken into account. In the absence of obesity-related complications, OBES was not related to metabolic blood markers. Our data may aid in improving perioperative risk assessments.

Fasting and postprandial plasma metabolite responses to a 12-wk dietary intervention in tissue-specific insulin resistance: a secondary analysis of the PERSonalized glucose Optimization through Nutritional intervention (PERSON) randomized trial.

BACKGROUND: We previously showed that dietary intervention effects on cardiometabolic health were driven by tissue-specific insulin resistance (IR) phenotype: individuals with predominant muscle IR (MIR) benefited more from a low-fat, high-protein, and high-fiber (LFHP) diet, whereas individuals with predominant liver insulin resistance (LIR) benefited more from a high-monounsaturated fatty acid (HMUFA) diet. OBJECTIVES: To further characterize the effects of LFHP and HMUFA diets and their interaction with tissue-specific IR, we investigated dietary intervention effects on fasting and postprandial plasma metabolite profile. METHODS: Adults with MIR or LIR (40-75 y, BMI 25-40 kg/m2) were randomly assigned to a 12-wk HMUFA or LFHP diet (n = 242). After the exclusion of statin use, 214 participants were included in this prespecified secondary analysis. Plasma samples were collected before (T = 0) and after (T = 30, 60, 120, and 240 min) a high-fat mixed meal for quantification of 247 metabolite measures using nuclear magnetic resonance spectroscopy. RESULTS: A larger reduction in fasting VLDL-triacylglycerol (TAG) and VLDL particle size was observed in individuals with MIR following the LFHP diet and those with LIR following the HMUFA diet, although no longer statistically significant after false discovery rate (FDR) adjustment. No IR phenotype-by-diet interactions were found for postprandial plasma metabolites assessed as total area under the curve (tAUC). Irrespective of IR phenotype, the LFHP diet induced greater reductions in postprandial plasma tAUC of the larger VLDL particles and small HDL particles, and TAG content in most VLDL subclasses and the smaller LDL and HDL subclasses (for example, VLDL-TAG tAUC standardized mean change [95% CI] LFHP = -0.29 [-0.43, -0.16] compared with HMUFA = -0.04 [-0.16, 0.09]; FDR-adjusted P for diet × time = 0.041). CONCLUSIONS: Diet effects on plasma metabolite profiles were more pronounced than phenotype-by-diet interactions. An LFHP diet may be more effective than an HMUFA diet for reducing cardiometabolic risk in individuals with tissue-specific IR, irrespective of IR phenotype. Am J Clin Nutr 20xx;x:xx. This trial was registered at the clinicaltrials.gov registration (https://clinicaltrials.gov/study/NCT03708419?term=NCT03708419&rank=1) as NCT03708419 and CCMO registration (https://www.toetsingonline.nl/to/ccmo_search.nsf/fABRpop?readform&unids=3969AABCD9BA27FEC12587F1001BCC65) as NL63768.068.17.

Impaired mitochondrial respiration in upper compared to lower body differentiated human adipocytes and adipose tissue.

CONTEXT: Abdominal obesity is associated with increased cardiometabolic disease risk, while lower body fat seems to confer protection against obesity-related complications. The functional differences between upper and lower body adipose tissue (AT) remain poorly understood. OBJECTIVE: We aimed to examine whether mitochondrial respiration is impaired in abdominal as compared to femoral differentiated human multipotent adipose-derived stem cells (hMADS; primary outcome) and AT in postmenopausal women. DESIGN: In this cross-sectional study, 23 postmenopausal women with normal weight or obesity were recruited at the University of Birmingham/Queen Elizabeth Hospital Birmingham (Birmingham, UK). We collected abdominal and femoral subcutaneous AT biopsies to determine mitochondrial oxygen consumption rates in differentiated abdominal and femoral hMADS. Furthermore, we assessed OXPHOS protein expression and mtDNA content in abdominal and femoral AT as well as hMADS. Finally, we explored in vivo fractional oxygen extraction and carbon dioxide release across abdominal and femoral subcutaneous AT in a subgroup of the same individuals with normal weight or obesity. RESULTS: We found lower basal and maximal uncoupled mitochondrial oxygen consumption rates in abdominal compared to femoral hMADS. In line, in vivo fractional oxygen extraction and carbon dioxide release were lower across abdominal than femoral AT. OXPHOS protein expression and mtDNA content did not significantly differ between abdominal and femoral differentiated hMADS and AT. CONCLUSION: The present findings demonstrate that in vitro mitochondrial respiration and in vivo oxygen fractional extraction are lower in upper compared to lower body differentiated hMADS and AT, respectively, in postmenopausal women.

Fetuin B in white adipose tissue induces inflammation and is associated with peripheral insulin resistance in mice and humans.

OBJECTIVE: Fetuin B is a steatosis-responsive hepatokine that causes glucose intolerance in mice, but the underlying mechanisms remain incompletely described. This study aimed to elucidate the mechanisms of action of fetuin B by investigating its putative effects on white adipose tissue metabolism. METHODS: First, fetuin B gene and protein expression was measured in multiple organs in mice and in cultured adipocytes. Next, the authors performed a hyperinsulinemic-euglycemic clamp in mice and in humans to examine the link between white adipose tissue fetuin B content and indices of insulin sensitivity. Finally, the effect of fetuin B on inflammation was investigated in cultured adipocytes by quantitative polymerase chain reaction and full RNA sequencing. RESULTS: This study demonstrated in adipocytes and mice that fetuin B was produced and secreted by the liver and taken up by adipocytes and adipose tissue. There was a strong negative correlation between white adipose tissue fetuin B content and peripheral insulin sensitivity in mice and in humans. RNA sequencing and polymerase chain reaction analysis revealed that fetuin B induced an inflammatory response in adipocytes. CONCLUSIONS: Fetuin B content in white adipose tissue strongly associated with peripheral insulin resistance in mice and humans. Furthermore, fetuin B induced a proinflammatory response in adipocytes, which might drive peripheral insulin resistance.