Anti-inflammatory effect of Trichospira verticillata via suppression of the NLRP3 inflammasome in neutrophilic asthma.

Trichospira verticillata is an annual herb that belongs to the family Asteraceae. Trichospira verticillata extract (TVE) elicits anti-plasmodial activity; however, there has been no detailed report about its anti-inflammatory effects and molecular mechanisms. In addition, herbal plants exhibit anti-inflammatory effects by suppressing the NLRP3 inflammasome. Therefore, the primary goal of this study was to examine the effects of TVE on NLRP3 inflammasome activation by measuring interleukin-1ß (IL-1ß) secretion. We treated lipopolysaccharides (LPS)-primed J774A.1 and THP-1 cells with TVE, which attenuated NLRP3 inflammasome activation. Notably, TVE did not affect nuclear factor-kappa B (NF-κB) signalling or intracellular reactive oxygen species (ROS) production and potassium efflux, suggesting that it inactivates the NLRP3 inflammasome via other mechanisms. Moreover, TVE suppressed the formation of apoptosis-associated speck-like protein (ASC) speck and oligomerization. Immunoprecipitation data revealed that TVE reduced the binding of NLRP3 to NIMA-related kinase 7 (NEK7), resulting in reduced ASC oligomerization and speck formation. Moreover, TVE alleviated neutrophilic asthma (NA) symptoms in mice. This study demonstrates that TVE modulates the binding of NLPR3 to NEK7, thereby reporting novel insights into the mechanism by which TVE inhibits NLRP3 inflammasome. These findings suggest TVE as a potential therapeutic of NLRP3 inflammasome-mediated diseases, particularly NA.

Magnolia kobus Extract Inhibits Periodontitis-Inducing Mediators in Porphyromonas gingivalis Lipopolysaccharide-Activated RAW 264.7 Cells.

Periodontitis, a disease caused by inflammation of oral bacteria, contributes to the loss of alveolar bone and destruction of connective tissues. Porphyromonas gingivalis, a Gram-negative bacterium, is known to possess important pathogenic factors for periodontal disease. In this study, we investigated the anti-periodontitis effects of Magnolia kobus extract (MKE) and magnolin as a component of Magnolia kobus (MK) in murine macrophage RAW 264.7 cells stimulated with Porphyromonas gingivalis lipopolysaccharide (LPS). Effects of MKE and magnolin on the mechanism of RAW 264.7 cellular inflammation were determined by analyzing nitric oxide (NO) production and Western blot protein expression (n = 3). MKE/magnolin inhibited NO production without affecting cell survival. MKE/magnolin treatment inhibited LPS-induced pro-inflammatory cytokines, expression levels of matrix metalloproteinases (MMPs such as MMP-1, 3, 8, 9, and 13), and protein levels of inflammatory mediators (such as TNF-α, IL-1ß, and mPGES-1). MKE/magnolin also suppressed NF-κB activation by inhibiting the TLR4 signaling pathway. These findings suggest that MKE has a therapeutic effect on inflammatory periodontal disease caused by oral bacterium P. gingivalis and that magnolin is a major functional component in the anti-inflammatory effect of MKE.

Anthropometric Equations to Predict Visceral Adipose Tissue in European and American Youth.

OBJECTIVE: To investigate whether prediction equations including a limited but selected number of anthropometrics that consider differences in subcutaneous abdominal adipose tissue may improve prediction of the visceral adipose tissue (VAT) in youth. STUDY DESIGN: Anthropometrics and abdominal adipose tissue by MRI were available in 7-18 years old youth with overweight or obesity: 181 White Europeans and 186 White and Black Americans. Multivariable regressions were performed to develop and validate the VAT anthropometric predictive equations in a cross-sectional study. RESULTS: A model with both waist circumference (WaistC) and hip circumference (HipC) (VAT = [1.594 × WaistC] - [0.681 × HipC] + [1.74 × Age] - 48.95) more strongly predicted VAT in girls of White European ethnicity (R2 = 50.8%; standard error of the estimate [SEE] = 13.47 cm2), White American ethnicity (R2 = 41.9%; SEE, 15.63 cm2), and Black American ethnicity (R2 = 25.1%; SEE, 16.34 cm2) (P < .001), than WaistC or BMI. In boys, WaistC was the strongest predictor of VAT; HipC did not significantly improve VAT prediction. CONCLUSIONS: A model including both WaistC and HipC that considers differences in subcutaneous abdominal adipose tissue more accurately predicts VAT in girls and is superior to commonly measured anthropometrics used individually. In boys, other anthropometric measures did not significantly contribute to the prediction of VAT beyond WaistC alone. This demonstrates that selected anthropometric predictive equations for VAT can be an accessible, cost-effective alternative to imaging methods that can be used in both clinics and research.

Perceptions on good-life, good-death, and advance care planning in Koreans with non-cancerous chronic diseases.

AIMS: This study explored perceptions on a good-life, good-death, and advance care planning in Koreans with non-cancerous chronic diseases with the goal to develop a culture-specific advance care planning intervention in this population. DESIGN: A qualitative descriptive design was used. METHODS: Data collections were conducted between September 2017 - June 2018. Twenty-nine patients aged 41-82 years (85.8% men) participated in the interviews lasting 40-60 min. The verbatim transcriptions of the semi-structured interview data were analysed using conventional content analysis. RESULTS: Good-life was described as 'present with physical and financial independence,' 'not burdensome to the family,' 'completed life responsibility', and 'helping others.' Some participants described good-death as 'prepared death' while others considered it as 'sudden death during sleep.' All participants wanted to have a painless death and not burden the family. Advance care planning was a new concept to many participants. It was likened to 'insurance.' Some participants believed that decision-making on life-sustaining treatment should be done by their family, not themselves, because of economic or emotional distress. Some participants wanted to discuss medical and non-medical care services to reduce the burden on self and family. CONCLUSION: Family is key when it comes to the meaning of good-life and good-death. Cultural adaptation is necessary to meet the advance care planning needs of Koreans with non-cancerous chronic diseases. IMPACT: Successfully implementing advance care planning in Koreans with non-cancerous chronic diseases depends on how it is adapted to the disease-specific characteristics compared with cancer, and the cultural norms and social context. Nurses need to be prepared to offer advance care planning to persons with non-cancerous chronic diseases based on a keen sense of and empathetic cultural competence.

ß-cell function, incretin response, and insulin sensitivity of glucose and fat metabolism in obese youth: Relationship to OGTT-time-to-glucose-peak.

BACKGROUND: In adults, the time-to-glucose-peak at or after 30 minutes during an oral glucose tolerance test (OGTT) identifies physiologically distinct groups with differences in insulin sensitivity, ß-cell function and risk for type 2 diabetes. In obese non-diabetic adolescents, we investigated if the OGTT-time-to-glucose-peak also reflects incretin and free fatty acid (FFA) responses besides insulin sensitivity and ß-cell function, measured by the clamp. METHODS: Obese adolescents (n = 278) were categorized according to their OGTT-time-to-glucose-peak by Early-peak (at 30 minutes) vs Late-peak (>30 minutes) groups. Body composition, visceral adipose tissue, oral disposition index and OGTT-area under the curve (AUC) were examined. A subset of 102 participants had both hyperinsulinemic-euglycemic and hyperglycemic clamps to measure in vivo insulin sensitivity, insulin secretion, and ß-cell function relative to insulin sensitivity. RESULTS: Compared with the Early-peak group, the Late-peak group had impaired ß-cell function relative to insulin sensitivity, lower glucose-dependent insulinotropic polypeptide-AUC, and higher FFA-AUC despite higher insulin- and C-peptide-AUC. They also had lower hepatic and peripheral insulin sensitivity despite similar percent body fat and visceral adipose tissue, and had higher prevalence of impaired glucose tolerance (all P < .05). CONCLUSIONS: In obese non-diabetic youth, those with a Late-peak vs an Early-peak glucose during an OGTT showed diminished ß-cell function, blunted incretin secretion, and lower insulin sensitivity of glucose and FFA metabolism. It remains to be determined if Late-peak glucose predicts the future development of type 2 diabetes in these high-risk youth.

Sex and Ethnic Differences in the Relationship between Changes in Anthropometric Measurements and Visceral Fat in Adolescents with Obesity.

OBJECTIVE: To examine sex and ethnic differences in how baseline and changes in anthropometric measures relate with change in visceral fat with interventions in adolescents. STUDY DESIGN: Black and white adolescents (n = 143: body mass index [BMI] ≥85th percentile, 12-18 years) who participated in intervention studies (3-6 months) were included and had assessments of anthropometric measures (weight, BMI, waist circumference, waist-to-hip ratio [WHR], and waist-to-thigh ratio) and visceral fat at L4-L5 by magnetic resonance imaging before and after interventions. RESULTS: At baseline, all of the anthropometric measures were positively associated with visceral fat (P < .05), with weight, waist circumference, and WHR having the largest variance explained (model adjusted R2 = 0.35-0.47 vs 0.32-0.35). Blacks had 11.5-23.3 cm2 less visceral fat compared with whites for a given anthropometric value. Girls tended to have less visceral fat for a given anthropometric value, but the sex differences were not consistently significant (range: 0.7-12.9 cm2). Changes in waist circumference, BMI, and weight, but not WHR, remained significantly associated with changes in visceral fat. There were no sex differences, and much more minimal ethnic differences (<4.9 cm2). CONCLUSIONS: At baseline, there are sex and ethnic differences in how anthropometric measures correlate with visceral fat. However, there were minimal sex and ethnic differences in how changes in anthropometric measures related with changes in visceral fat. Although all of the anthropometric measures were associated with visceral fat at baseline, waist circumference, BMI, and weight, but not WHR were associated with changes in visceral fat. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00739180, NCT01323088, and NCT01938950.

Effects of Exercise Modality on Insulin Resistance and Ectopic Fat in Adolescents with Overweight and Obesity: A Randomized Clinical Trial.

OBJECTIVE: To examine whether a combined aerobic exercise and resistance exercise is more effective than either aerobic exercise or resistance exercise alone in improving insulin sensitivity and reducing total adiposity and ectopic fat in adolescents. STUDY DESIGN: A total of 118 sedentary adolescents with overweight/obesity (body mass index >85th percentile, 12-17 years) were recruited from October 2013 through April 2017 at Children's Hospital of Pittsburgh. Participants were randomized to 1 of the following 6-month exercise groups (3 d/wk, 180 min/wk): aerobic exercise (n = 38), resistance exercise (n = 40), and combined aerobic exercise and resistance exercise (n = 40). The primary outcome was the change in insulin-stimulated glucose disposal by a 3-hour hyperinsulinemic-euglycemic clamp. The secondary outcomes were changes in liver fat by proton magnetic resonance spectroscopy and intermuscular adipose tissue by computed tomography. RESULTS: Of the 118 participants randomized, 85 participants (72%) completed the study with 90% exercise attendance. Total adiposity reduced similarly in all groups (-2%, P < .05). After adjusting for age and sex, insulin-stimulated glucose disposal increased (P < .05) in all groups, with the increase in the aerobic exercise group being greater than the resistance exercise group (1.7 ± 0.1 vs 0.7 ± 0.1 mg/kg/min, P < .05) but not different from the combined group (1.2 ± 0.1 mg/kg/min). Liver fat was reduced (P < .05) in the aerobic exercise (-0.6%) and combined (-0.6%) groups but not in the resistance exercise group (-0.3%, P > .05). Intermuscular adipose tissue decreased (P < .05) similarly in all groups. CONCLUSION: Combined aerobic exercise and resistance exercise and aerobic exercise alone are similarly beneficial in improving insulin sensitivity and reducing ectopic fat in adolescents with obesity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01938950.

Results from South Korea's 2018 Report Card on physical activity for children and youth.

BACKGROUND/OBJECTIVE: South Korea's 2018 Report Card on Physical Activity for Children and Youth is the second comprehensive evaluation of physical activity and the sources of influence based on the 10 core indicators provided by the Active Healthy Kids Global Alliance. It will serve as an advocacy tool to promote physical activity among children and youth. METHODS: Three national surveillance data (i.e., 2017 Korea Youth Risk Behavior Web-based Survey, 2016 Korea National Health and Nutrition Examination Survey, 2016 Physical Activity Promotion System) were used as main sources to evaluate the indicators. Descriptive statistics were performed to obtain prevalence estimates of physical activity-related indicators. In addition, expert opinions as well as the most recently available published or unpublished relevant sources were synthesized. RESULTS: South Korea's 2018 Report Card, compared to the 2016 Report Card, showed favourable changes in the Active Transportation (B+), Organized Sports Participation (C), Sedentary Behaviours (D), and School (D+) indicators, while unfavourable changes were shown in Overall Physical Activity (F) and Government (D). Physical Fitness was graded as D+. In parallel with the 2016 Report Card, Active Play, Family and Peers, and Community and Environment remain ungraded due to insufficient data. CONCLUSIONS: Successes as well as gaps and research needs were identified in the 2018 Report Card. Though some indicators have shown improvement, most children and youth continue to be insufficiently physically active with overall poor grades (Average of D+). To achieve substantial improvement in all grades in future Report Cards, more institutional and governmental support and investment is needed to promote physical activity. Furthermore, effort should be made to generate data pertaining to the indicators that were ungraded.

sRAGE prolonged stem cell survival and suppressed RAGE-related inflammatory cell and T lymphocyte accumulations in an Alzheimer's disease model.

The main causes of Alzheimer's disease (AD) have not determined and effective treatment has not been developed yet, even though extensive researches and several clinical trials have been conducted.. Fortunately, stem cell transplantation is emerging as a potential therapeutic candidate for AD, but the success of stem cell based therapy depends on the survival of transplanted cells. Here, we generated sRAGE secreting mesenchymal stem cells (sRAGE-MSCs) and then injected these MSCs or control MSCs with amyloid beta 1-42 (Aß1-42) into the entorhinal cortices of male Sprague Dawley rats. The survival of transplanted cell, the number of T lymphocytes and microglia, expression of RAGE and its ligands and neuronal cell death were determined, 4 weeks after sRAGE-MSC transplantation. Transplanted sRAGE-MSCs survived longer than control MSCs and sRAGE-MSCs showed reduced level of CD4 and CD3d positive T lymphocyte. Furthermore, the number of M1 microglia in MSCs was more than that of sRAGE-MSCs as well. On the other hand, the number of M2 microglia in sRAGE-MSCs was increased compared with that of MSCs. In addition, sRAGE-MSCs decreased RAGE and RAGE ligand expressions and their interactions more effectively than those of MSCs. Finally, sRAGE-MSC transplantation protected from apoptosis and prevented decreasing numbers of neuron in Aß1-42 treated rat brains. These observations suggest continuous sRAGE secretion from sRAGE-MSCs might appreciably improve the effectiveness of cell therapy in Aß1-42 injected rat brains.

Insulin sensitivity across the lifespan from obese adolescents to obese adults with impaired glucose tolerance: Who is worse off?

OBJECTIVE: Youth type 2 diabetes mellitus (T2DM) occurs decades earlier than adult T2DM and is characterized by high therapeutic failure rates and decreased response to insulin sensitizers suggesting a more severe disease process than in adults. To explain these observations, we hypothesized that insulin resistance is worse in obese youth than adults with impaired glucose tolerance (IGT), a state of high-risk for T2DM. As proof-of-concept, we compared insulin sensitivity between BMI-, sex-, and race-matched obese youth vs adults with IGT. METHODS: This retrospective analysis of IGT youth and adults included 34 obese adolescents matched (2:1) for BMI, sex, and race to 17 adults. Hepatic and peripheral insulin sensitivity were measured by [6,6-2 H2 ]glucose and hyperinsulinemic-euglycemic clamp. Body composition (DEXA) and serum lipid profile were examined. RESULTS: Despite similar percent body fat, obese adolescents had 2-fold higher fasting insulin concentration, lower hepatic (~53%) and peripheral (~42%) insulin sensitivity and lower HDL compared with adults (all P < .01). Surrogate estimate of insulin sensitivity, 1/fasting insulin was lower and HOMA-IR was higher in adolescents vs adults. Adults had a more atherogenic lipid profile with higher total-, LDL-, and non-HDL cholesterol. CONCLUSIONS: Obese youth and adults with IGT differ in that youth are more insulin resistant than adults in spite of similar adiposity. This could potentially explain the earlier onset of T2DM in youth through an early and amplified burden on a ß-cell destined to decompensate, and explicate their lower therapeutic response to insulin sensitizers.

Direct Activation of the Large-Conductance Calcium-Activated Potassium Channel by Flavonoids Isolated from Sophora flavescens.

In our recent study, we reported that kurarinone, one of the most abundant flavonoids found in the dry root of Sophora flavescens (Kushen), is a potent activator of the large-conductance Ca2+-activated K+ (BKCa) channel. Herein, we isolated and characterized other flavonoid components from Kushen. Among the 13 compounds tested, six flavonoids were found to activate the BKCa channel, three of which, 7,4'-dihydroxy-5-methoxy-8-(γ,γ-dimethylallyl)-flavanone, kuraridin, and kuraridinol, are new activators of the BKCa channel.

Protection against RAGE-mediated neuronal cell death by sRAGE-secreting human mesenchymal stem cells in 5xFAD transgenic mouse model.

Alzheimer's disease (AD), which is the most commonly encountered neurodegenerative disease, causes synaptic dysfunction and neuronal loss due to various pathological processes that include tau abnormality and amyloid beta (Aß) accumulation. Aß stimulates the secretion and the synthesis of Receptor for Advanced Glycation End products (RAGE) ligand by activating microglial cells, and has been reported to cause neuronal cell death in Aß1-42 treated rats and in mice with neurotoxin-induced Parkinson's disease. The soluble form of RAGE (sRAGE) is known to reduce inflammation, and to decrease microglial cell activation and Aß deposition, and thus, it protects from neuronal cell death in AD. However, sRAGE protein has too a short half-life for therapeutic purposes. We developed sRAGE-secreting umbilical cord derived mesenchymal stem cells (sRAGE-MSCs) to enhance the inhibitory effects of sRAGE on Aß deposition and to reduce the secretion and synthesis of RAGE ligands in 5xFAD mice. In addition, these cells improved the viability of injected MSCs, and enhanced the protective effects of sRAGE by inhibiting the binding of RAGE and RAGE ligands in 5xFAD mice. These findings suggest sRAGE protein from sRAGE-MSCs has better protection against neuronal cell death than sRAGE protein or single MSC treatment by inhibiting the RAGE cell death cascade and RAGE-induce inflammation.

Visceral fat is associated with the racial differences in liver fat between black and white adolescent boys with obesity.

OBJECTIVE: We examined whether racial differences in liver fat are associated with the differences in abdominal fat distribution or cardiorespiratory fitness (CRF). METHODS: Participants included 57 black and white obese boys (12-18 years). Total and abdominal fat was measured by dual-energy X-ray absorptiometry (DXA) and magnetic resonance imaging, respectively. CRF was measured using a maximal graded treadmill test with the use of standard open-circuit spirometry techniques until volitional fatigue. Liver fat was measured using a 3T proton magnetic resonance spectroscopy. Fatty liver was defined as having liver fat ≥5%. RESULTS: In the sample, 16.1% of black boys and 30.8% of white boys had fatty liver. Liver fat was associated (P ≤ .05) with body mass index (BMI) percentile (r = 0.28), total fat (r = 0.31), waist circumference (r = 0.38), visceral fat (r = 0.62), abdominal subcutaneous adipose tissue (r = 0.30), and CRF (r = -0.27) adjusting for age and race. White boys had greater liver fat than black boys with adjustment for age and differences in BMI percentile or CRF, but not with waist circumference or visceral fat (P > .05). In a model with age, ethnicity, total body fat, fat-free mass, visceral fat, abdominal subcutaneous fat, and CRF, visceral fat was the only factor to be independently associated with increased odds of having fatty liver (OR = 1.12; 95% CI: 1.04-1.21; P = .003). CONCLUSION: The racial disparities in liver fat between obese black vs white adolescents are explained, in part, by differences in visceral fat.

Differences in ß-cell function and insulin secretion in Black vs. White obese adolescents: do incretin hormones play a role?

Black youth are at higher risk for type 2 diabetes (T2D) than their White peers. Previously we demonstrated that for the same degree of insulin sensitivity, Black youth have an upregulated ß-cell function and insulin hypersecretion, in response to intravenous (iv) glucose, compared with Whites. To investigate if the same holds true during an oral glucose challenge and because of the important role of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in augmenting insulin secretion, we examined ß-cell function and incretin hormones in 85 Black and 78 White obese adolescents, with normal glucose tolerance (NGT), during a 2-h oral glucose tolerance test (OGTT) with mathematical modeling of plasma glucose and C-peptide concentrations to assess ß-cell glucose sensitivity (ßCGS), rate sensitivity, potentiation factor, and insulin sensitivity. Incretin, pancreatic polypeptide, and glucagon concentrations were measured during the OGTT. Black obese youth had a heightened early insulin secretion together with significantly greater ßCGS, rate sensitivity, and potentiation factor compared with Whites, with no differences in incretin and glucagon concentrations. Basal and stimulated insulin clearance was lower (p = 0.001) in Black vs. White youth. In conclusion, during an OGTT Black obese youth with NGT demonstrate a pronounced early insulin secretion jointly with heightened ß-cell glucose sensitivity, rate sensitivity, and potentiation factor. These racial disparities in ß-cell function and the pathophysiological components of T2D are unlikely to be attributed to incretin hormones and remain to be investigated further to explain the metabolic basis for the enhanced risk of T2D in back youth.

High-intensity interval training programme for obese youth (HIP4YOUTH): A pilot feasibility study.

Recently, there has been growing interest in high-intensity interval training (HIT) as a strategy to improve health. In this pilot study, we examined the feasibility of a 4-week low-volume HIT and its effects on cardiorespiratory fitness (CRF), blood pressure (BP) and enjoyment in overweight and obese youth. Twelve adolescents (body mass index (BMI): 34.8 ± 3.9 kg · m‒2, 14.9 ± 1.5 years) participated in 12 sessions of HIT (10 × 60 s cycling bouts eliciting ~90% maximal heart rate, interspersed with 90 s recovery, 30 min/session, 3 sessions/week) over ~4 weeks. All the participants completed the study and exercise attendance averaged 92%. Despite no changes in body weight and total fat, HIT resulted in significant (P < 0.01) increases in CRF (pre: 20.1 versus post: 22.2 ml · kg‒1 · min‒1) and exercise time (pre: 425 versus post: 509 s) during peak oxygen uptake test, and a reduction in resting systolic BP (pre: 115.8 versus post: 107.6 mmHg). The majority of study participants (83%) enjoyed HIT and more than half of the participants (58%) reported that HIT is a more enjoyable form of exercise compared to other types of exercises. Low-volume HIT is a useful strategy to promote exercise participation and improve cardiovascular health in overweight and obese youth.

Urinary Bladder-Relaxant Effect of Kurarinone Depending on Potentiation of Large-Conductance Ca2+-Activated K+ Channels.

The large-conductance calcium-activated potassium channel (BKCa channel) plays critical roles in smooth muscle relaxation. In urinary bladder smooth muscle, BKCa channel activity underlies the maintenance of the resting membrane potential and repolarization of the spontaneous action potential triggering the phasic contraction. To identify novel BKCa channel activators, we screened a library of natural compounds using a cell-based fluorescence assay and a hyperactive mutant BKCa channel (Lee et al., 2013). From 794 natural compounds, kurarinone, a flavanone from Sophora flavescens, strongly potentiated BKCa channels. When treated from the extracellular side, this compound progressively shifted the conductance-voltage relationship of BKCa channels to more negative voltages and increased the maximum conductance in a dose-dependent manner. Whereas kurarinone strongly potentiated the homomeric BKCa channel composed of only the α subunit, its effects were much smaller on heteromeric channels coassembled with auxiliary ß subunits. Although the activation kinetics was not altered significantly, the deactivation of BKCa channels was dramatically slowed by kurarinone treatment. At the single-channel level, kurarinone increased the open probability of the BKCa channel without affecting its single-channel conductance. Kurarinone potently relaxed acetylcholine-induced contraction of rat bladder smooth muscle and thus decreased the micturition frequency of rats with overactive bladder symptoms. These results indicate that kurarinone can directly potentiate BKCa channels and demonstrate the therapeutic potentials of kurarinone and its derivatives for developing antioveractive bladder medications and supplements.

Triglyceride glucose index as a surrogate measure of insulin sensitivity in obese adolescents with normoglycemia, prediabetes, and type 2 diabetes mellitus: comparison with the hyperinsulinemic-euglycemic clamp.

BACKGROUND: There is a need for simple surrogate estimates of insulin sensitivity in epidemiological studies of obese youth because the hyperinsulinemic-euglycemic clamp is not feasible on a large scale. OBJECTIVE: (i) To examine the triglyceride glucose (TyG) index (Ln[fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]) and its relationship to in vivo insulin sensitivity in obese adolescents (OB) along the spectrum of glucose tolerance and (ii) to compare TyG index with triglyceride/high-density lipoprotein TG/HDL and 1/fasting insulin (1/IF ), other surrogates of insulin sensitivity. PATIENTS AND DESIGN: Cross-sectional data in 225 OB with normal glucose tolerance (NGT), prediabetes (preDM), and type 2 diabetes (T2DM) who had a 3-h hyperinsulinemic-euglycemic clamp and fasting lipid measurement. RESULTS: Insulin-stimulated glucose disposal (Rd) declined significantly across the glycemic groups from OB-NGT to OB-preDM to OB-T2DM with a corresponding increase in TyG index (8.3 ± 0.5, 8.6 ± 0.5, 8.9 ± 0.6, p < 0.0001). The correlation of TyG index to Rd was -0.419 (p < 0.0001). The optimal TyG index for diagnosis of insulin resistance was 8.52 [receiver operating characteristic-area under the ROC curves (ROC-AUC) 0.750, p < 0.0001]. The ROC-AUC for 1/IF was 0.836. In multiple regression analysis, 64.8% of the variance in Rd was explained by TyG index, 1/IF , body mass index (BMI) z-score, glycemic group, and sex. CONCLUSION: The TyG index affords an easily and widely available simple laboratory method as a surrogate estimate of insulin sensitivity that could be used repeatedly in large-scale observational and/or interventional cohorts of OB. Although not superior to 1/IF , TyG index offers the advantage of having a standardized method of measuring triglyceride and glucose, which is not the case for insulin assays.

Associations between visceral fat and liver fat with insulin sensitivity and metabolic risk in obese adolescents.

We examined the joint and independent associations between VAT and LF with insulin sensitivity (IS) and lipids in seventy-one obese adolescents (BMI ≥ 95th, 14.9 ± 1.8 years). VAT was assessed by magnetic resonance imaging, and LF was quantified by proton magnetic resonance spectroscopy. IS was evaluated by a 3 -h hyperinsulinemic (80 mU·m(-2)·min(-1)) euglycemic clamp. Independent associations between VAT and LF on metabolic variables were assessed in mutually adjusted multivariate models. The joint association between VAT and LF on metabolic variables was assessed by categorizing participants into a low VAT + low LF group (n = 35), high VAT + low LF group (n = 26), or high VAT + high LF group (n = 10), based on a VAT median split (1.17 kg) and high (≥5%) and low (<5%) LF. Both VAT and LF were independently associated with fasting insulin, 2 h insulin, insulin AUC, IS, and triglycerides (P < 0.05). Adolescents with high VAT + high LF had higher 2 h glucose, glucose AUC, 2 h insulin, triglycerides, and lower insulin sensitivity compared to adolescents with high VAT only (P < 0.025 for all). In obese adolescents, VAT and LF were independently associated with insulin sensitivity and dyslipidemia, and the concomitant presence of VAT and LF is strongly associated with metabolic risk factors.

Metabolic inflexibility and insulin resistance in obese adolescents with non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a comorbidity of childhood obesity. OBJECTIVE: We examined whole-body substrate metabolism and metabolic characteristics in obese adolescents with vs. without NAFLD. SUBJECTS: Twelve obese (BMI ≥ 95th percentile) adolescents with and without NAFLD [intrahepatic triglyceride (IHTG) ≥5.0% vs. <5.0%] were pair-matched for race, gender, age and % body fat. METHODS: Insulin sensitivity (IS) was assessed by a 3-h hyperinsulinemic-euglycemic clamp and whole-body substrate oxidation by indirect calorimetry during fasting and insulin-stimulated conditions. RESULTS: Adolescents with NAFLD had increased (p < 0.05) abdominal fat, lipids, and liver enzymes compared with those without NAFLD. Fasting glucose concentration was not different between groups, but fasting insulin concentration was higher (p < 0.05) in the NAFLD group compared with those without. Fasting hepatic glucose production and hepatic IS did not differ (p > 0.1) between groups. Adolescents with NAFLD had higher (p < 0.05) fasting glucose oxidation and a tendency for lower fat oxidation. Adolescents with NAFLD had lower (p < 0.05) insulin-stimulated glucose disposal and lower peripheral IS compared with those without NAFLD. Although respiratory quotient (RQ) increased significantly from fasting to insulin-stimulated conditions in both groups (main effect, p < 0.001), the increase in RQ was lower in adolescents with NAFLD vs. those without (interaction, p = 0.037). CONCLUSION: NAFLD in obese adolescents is associated with adverse cardiometabolic profile, peripheral insulin resistance and metabolic inflexibility.

Effect of Aerobic versus Resistance Exercise on Pulse Wave Velocity, Intima Media Thickness and Left Ventricular Mass in Obese Adolescents.

A cardiovascular comorbidity in obese adolescents is increased aortic pulse wave velocity (aPWV), carotid intima-media thickness (cIMT) and left ventricular mass (LVM). We investigated in obese adolescents 1) the risk factors associated with aPWV, cIMT and LVM, and 2) the effects of aerobic (AE) versus resistance (RE) exercise alone (without calorie restriction) on aPWV, cIMT, LVM index (LVMI) and cardiometabolic risk factors. Eighty-one obese adolescents (12-18 yrs, BMI ≥95th percentile) were randomized to 3 months of AE (n = 30), RE (n = 27) or a control group (n = 24). Outcome measures included aPWV, cIMT, LVMI, body composition, cardiorespiratory fitness (CRF), blood pressure (BP) and lipids. At baseline, the strongest correlates of aPWV were body weight (r = .31) and diastolic BP (r = .28); of cIMT were body weight (r=0.26) and CRF (r=-0.25); and of LVMI was CRF (r=0.32) after adjusting for sex and race (p < .05 for all). Despite significant reductions in total fat and improvements in CRF in the AE and RE groups, aPWV, cIMT, LVMI, BP, lipids and body weight did not change as compared with controls (p > .05 for all). Interventions of longer duration or together with weight loss may be required to improve these early biomarkers of CVD in obese adolescents.