Search

Objective: Metabolically healthy obesity (MHO) is often defined as the absence of metabolic syndrome in the presence of obesity. However, phenotypic features of MHO are unclear. Insulin sensitivity in MHO was cross‐sectionally compared with metabolically unhealthy obesity (MUO) and a reference group of young healthy participants without obesity. Methods: Sedentary adults (n = 96) undergoing anthropometric, blood chemistries, maximal aerobic capacity, and euglycemic‐hyperinsulinemic clamp measurements were classified by BMI (<25 and ≥30 kg/m2). MUO was defined as having obesity with metabolic syndrome (≥2 additional risk factors). Data were analyzed using a linear mixed models approach. Results: Body weight was similar between MHO and MUO. Body fat (percentage) and high‐density lipoprotein cholesterol were higher (p < 0.001), and systolic blood pressure, triglycerides, glucose, and insulin were lower in MHO versus MUO (p < 0.03, all). The MHO group also had lower high‐density lipoprotein cholesterol and higher low‐density lipoprotein cholesterol, diastolic blood pressure, and insulin compared with the reference. Both the MHO and MUO groups displayed impaired insulin sensitivity compared with the reference control (p < 0.001). Conclusions: Participants with MHO had distinct clinical measures related to hypertension, lipid metabolism, and glycemic control compared with a healthy reference group. Peripheral insulin resistance in obesity independent of metabolic status portends increased risk for type 2 diabetes in the MHO patient population. [ABSTRACT FROM AUTHOR]

Background There are limited data from randomized control trials to support or refute the contention that whole-grains can enhance protein metabolism in humans. Objectives To examine: 1) the clinical effects of a whole-grain diet on whole-body protein turnover; 2) the cellular effects of whole-grains on protein synthesis in skeletal muscle cells; and 3) the population effects of whole-grain intake on age-related muscle loss. Methods Adults with overweight/obesity (n = 14; age = 40 ± 7 y; BMI = 33 ± 5 kg/m2) were recruited into a crossover, randomized controlled trial (NCT01411540) in which isocaloric, macronutrient-matched whole-grain and refined-grain diets were fully provisioned for two 8-wk periods. Diets differed only in the presence of whole-grains (50 g/1000 kcal). Whole-body protein kinetics were assessed at baseline and after each diet in the fasted-state (13C-leucine) and integrated over 24 h (15N-glycine). In vitro studies using C2C12 cells assessed global protein synthesis by surface sensing of translation and anabolic signaling by Western blot. Complementary epidemiological assessments using the NHANES database assessed the effect of whole-grain intake on muscle function assessed by gait speed in older adults (n = 2783). Results Integrated 24-h net protein balance was 3-fold higher on a whole-grain diet compared with a refined-grain diet (P = 0.04). A whole-grain wheat extract increased submaximal rates of global protein synthesis (27%, P < 0.05) in vitro. In a large sample of older adults, whole-grain intake was associated with greater muscle function (OR = 0.92; 95% CI: 0.86, 0.98). Conclusions Consuming 50 g/1000 kcal whole-grains per day promotes greater protein turnover and enhances net protein balance in adults. Whole-grains impact skeletal muscle at the cellular level, and are associated with greater muscle function in older adults. Collectively, these data point to a new mechanism whereby whole-grain consumption favorably enhances protein turnover and improves health outcomes. This clinical trial is registered on clinicaltrials.gov (identifier: NCT01411540). [ABSTRACT FROM AUTHOR]

The soluble receptor for advanced glycation end products (sRAGE) may be protective against inflammation associated with obesity and type 2 diabetes (T2DM). The aim of this study was to determine the distribution of sRAGE isoforms and whether sRAGE isoforms are associated with risk of T2DM development in subjects spanning the glucose tolerance continuum. In this retrospective analysis, circulating total sRAGE and endogenous secretory RAGE (esRAGE) were quantified via ELISA, and cleaved RAGE (cRAGE) was calculated in 274 individuals stratified by glucose tolerance status (GTS) and obesity. Group differences were probed by ANOVA, and multivariate ordinal logistic regression was used to test the association between sRAGE isoform concentrations and the proportional odds of developing diabetes, vs. normal glucose tolerance (NGT) or impaired glucose tolerance (IGT). When stratified by GTS, total sRAGE, cRAGE, and esRAGE were all lower with IGT and T2DM, while the ratio of cRAGE to esRAGE (cRAGE:esRAGE) was only lower (P < 0.01) with T2DM compared with NGT. When stratified by GTS and obesity, cRAGE:esRAGE was higher with obesity and lower with IGT (P < 0.0001) compared with lean, NGT. In ordinal logistic regression models, greater total sRAGE (odds ratio, 0.91; P < 0.01) and cRAGE (odds ratio, 0.84; P < 0.01) were associated with lower proportional odds of developing T2DM. Reduced values of sRAGE isoforms observed with both obesity and IGT are independently associated with greater proportional odds of developing T2DM. The mechanisms by which each respective isoform contributes to obesity and insulin resistance may reveal novel treatment strategies for diabetes. [ABSTRACT FROM AUTHOR]

Fasting plasma glucose is a composite measure of hepatic glucose production (HGP) and non-insulin-dependent (basal) tissue glucose clearance rate (bGCR). A rise in fasting plasma glucose, within the nondiabetic range, is purported to be regulated by decreased bGCR rather than increased HGP. However, the role of bGCR in improving metabolic syndrome (MetS) is not yet fully understood. We sought to explore the novel impact of weight loss induced by exercise on bGCR in individuals with MetS. Fourteen sedentary adults with MetS (9 females, 68 years, 35.2 kg/m2) participated in a 12-week moderate intensity exercise program (~65% VO2max, 1 hr/day, 5 days/week). MetS was defined using ATP III guidelines. Insulin resistance (IR) was estimated using a hyperinsulinemic (40 mU/m2/min) euglycemic (90 mg/dL) clamp. Rate of glucose disappearance (Rd) was determined using [6,6-2H2]-glucose during fasting and insulin stimulation. GCR was calculated as Rd relative to the prevailing glucose concentration. At baseline, bGCR correlated with IR and adiponectin (r=0.69 and 0.68, P<0.01). Following exercise training and relative to pre-intervention: (i) body weight, VO2max and IR improved (6.6, 17 and 7.7%, respectively; P<0.05); (ii) cardiometabolic risk factors decreased (Triglycerides: 30%; Total Cholesterol: 15%; LDL: 15%; sBP: 11% and dBP: 14.5%; all P<0.05); (iii) fasting glucose and insulin concentration decreased (6% and 32%, P<0.05), and bGCR increased (~1.5 fold, P<0.01). The increase in bGCR correlated positively with changes in body weight, fat mass, suppression of HGP during the clamp, and serum triglycerides (r=0.5, 0.49, 0.61 and 0.62, respectively; P<0.05). Weight loss following aerobic exercise training breaks the vicious cycle of increased insulin resistance and secretion by increasing the contribution of bGCR to fasting glycemia. This evidences the unique and multifactorial benefits of exercise concomitant with weight loss in mediating cardiometabolic risk. Disclosure: A. Hari: None. C.L. Axelrod: None. J.T. Mey: None. J.P. Kirwan: None. Funding: National Institutes of Health; National Center for Research Resources [ABSTRACT FROM AUTHOR]

This narrative review highlights recent advances and ongoing trials using nutrition approaches for healthy aging. Focus will be placed on nutrition therapies that target cognition ("the mind") and mobility ("the muscle"), both critical components to maintaining a high quality of life for older adults. For "the mind," two seemingly incongruent therapies are being investigated to improve cognition-the MIND diet (high in carbohydrates and anti-oxidant fruits and vegetables) and the ketogenic diet (low in carbohydrates, high in fats). For "the muscle," a focus on protein and energy intake has dominated the literature, yet a recent clinical trial supports the use of whole-grains as a tool to improve whole-body protein turnover-a primary regulator of lean body mass and muscle. Finally, emerging data and clinical trials on caloric restriction have solidified this strategy as the only nutritional approach to slow intrinsic factors of whole-body aging, which may positively impact both "the mind" and "the muscle.", Competing Interests: Competing Interests GMM and JTM declare no conflicts of interest with this work.

Background: The breath print is a quantitative measurement of molecules in exhaled breath and represents a new frontier for biomarker identification. It is unknown whether this state-of-the-art, noninvasive method can detect malnutrition. We hypothesize that individuals with malnutrition will present with a distinguishable breath print., Methods: We conducted a retrospective chart review on patients with previously analyzed breath samples to identify malnutrition. Breath was analyzed by selected-ion flow-tube mass spectrometry. Registered dietitians conducted a retrospective chart review to collect malnutrition diagnoses and nutrition status indicators. Patients were categorized into one of four groups: pulmonary arterial hypertension (PAH), PAH with malnutrition (PAH-Mal), control, and control with malnutrition (Control-Mal), based on the malnutrition diagnosis present in the patient's chart. Principle component analysis was conducted to characterize the breath print. A logistic regression model with forward selection was used to detect the best breath predictor combination of malnutrition., Results: A total of 74 patients met inclusion criteria (PAH: 52; PAH-Mal: 10; control: 10; Control-Mal: 2). Levels of 1-octene (PAH-Mal, 5.1 ± 1.2; PAH, 12.5 ± 11.2; P = 0.005) and ammonia (PAH-Mal, 14.6 ± 15.8; PAH, 56.2 ± 64.2; P = 0.013) were reduced in PAH-Mal compared with PAH. The combination of 1-octene (P = 0.010) and 3-methylhexane (P = 0.045) distinguished malnutrition in PAH (receiver operating characteristic area under the curve: 0.8549)., Conclusions: This proof of concept study provides the first evidence that the breath print is altered in malnutrition. Larger prospective studies are needed to validate these results and establish whether breath analysis may be a useful tool to screen for malnutrition in the clinical setting., (© 2021 American Society for Parenteral and Enteral Nutrition.)

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation and impaired insulin sensitivity. Reduced hepatic ketogenesis may promote these pathologies, but data are inconclusive in humans and the link between NAFLD and reduced insulin sensitivity remains obscure. We investigated individuals with obesity-related NAFLD and hypothesized that β-hydroxybutyrate (βOHB; the predominant ketone species) would be reduced and related to hepatic fat accumulation and insulin sensitivity. Furthermore, we hypothesized that ketones would impact skeletal muscle mitochondrial respiration in vitro. Hepatic fat was assessed by 1 H-MRS in 22 participants in a parallel design, case control study [Control: n = 7, age 50 ± 6 yr, body mass index (BMI) 30 ± 1 kg/m 2 ; NAFLD: n = 15, age 57 ± 3 yr, BMI 35 ± 1 kg/m 2 ]. Plasma assessments were conducted in the fasted state. Whole body insulin sensitivity was determined by the gold-standard hyperinsulinemic-euglycemic clamp. The effect of ketone dose (0.5-5.0 mM) on mitochondrial respiration was conducted in human skeletal muscle cell culture. Fasting βOHB, a surrogate measure of hepatic ketogenesis, was reduced in NAFLD (-15.6%, P < 0.01) and correlated negatively with liver fat ( r 2  = 0.21, P = 0.03) and positively with insulin sensitivity ( r 2  = 0.30, P = 0.01). Skeletal muscle mitochondrial oxygen consumption increased with low-dose ketones, attributable to increases in basal respiration (135%, P < 0.05) and ATP-linked oxygen consumption (136%, P < 0.05). NAFLD pathophysiology includes impaired hepatic ketogenesis, which is associated with hepatic fat accumulation and impaired insulin sensitivity. This reduced capacity to produce ketones may be a potential link between NAFLD and NAFLD-associated reductions in whole body insulin sensitivity, whereby ketone concentrations impact skeletal muscle mitochondrial respiration.

Skeletal muscle insulin resistance is a hallmark of Type 2 diabetes (T2DM) and may be exacerbated by protein modifications by methylglyoxal (MG), known as dicarbonyl stress. The glyoxalase enzyme system composed of glyoxalase 1/2 (GLO1/GLO2) is the natural defense against dicarbonyl stress, yet its protein expression, activity, and regulation remain largely unexplored in skeletal muscle. Therefore, this study investigated dicarbonyl stress and the glyoxalase enzyme system in the skeletal muscle of subjects with T2DM (age: 56 ± 5 yr.; BMI: 32 ± 2 kg/m 2 ) compared with lean healthy control subjects (LHC; age: 27 ± 1 yr.; BMI: 22 ± 1 kg/m 2 ). Skeletal muscle biopsies obtained from the vastus lateralis at basal and insulin-stimulated states of the hyperinsulinemic (40 mU·m -2 ·min -1 )-euglycemic (5 mM) clamp were analyzed for proteins related to dicarbonyl stress and glyoxalase biology. At baseline, T2DM had increased carbonyl stress and lower GLO1 protein expression (-78.8%), which inversely correlated with BMI, percent body fat, and HOMA-IR, while positively correlating with clamp-derived glucose disposal rates. T2DM also had lower NRF2 protein expression (-31.6%), which is a positive regulator of GLO1, while Keap1 protein expression, a negative regulator of GLO1, was elevated (207%). Additionally, insulin stimulation during the clamp had a differential effect on NRF2, Keap1, and MG-modified protein expression. These data suggest that dicarbonyl stress and the glyoxalase enzyme system are dysregulated in T2DM skeletal muscle and may underlie skeletal muscle insulin resistance. Whether these phenotypic differences contribute to the development of T2DM warrants further investigation.

The soluble receptor for advanced glycation end products (sRAGE) may be protective against inflammation associated with obesity and type 2 diabetes (T2DM). The aim of this study was to determine the distribution of sRAGE isoforms and whether sRAGE isoforms are associated with risk of T2DM development in subjects spanning the glucose tolerance continuum. In this retrospective analysis, circulating total sRAGE and endogenous secretory RAGE (esRAGE) were quantified via ELISA, and cleaved RAGE (cRAGE) was calculated in 274 individuals stratified by glucose tolerance status (GTS) and obesity. Group differences were probed by ANOVA, and multivariate ordinal logistic regression was used to test the association between sRAGE isoform concentrations and the proportional odds of developing diabetes, vs. normal glucose tolerance (NGT) or impaired glucose tolerance (IGT). When stratified by GTS, total sRAGE, cRAGE, and esRAGE were all lower with IGT and T2DM, while the ratio of cRAGE to esRAGE (cRAGE:esRAGE) was only lower ( P < 0.01) with T2DM compared with NGT. When stratified by GTS and obesity, cRAGE:esRAGE was higher with obesity and lower with IGT ( P < 0.0001) compared with lean, NGT. In ordinal logistic regression models, greater total sRAGE (odds ratio, 0.91; P < 0.01) and cRAGE (odds ratio, 0.84; P < 0.01) were associated with lower proportional odds of developing T2DM. Reduced values of sRAGE isoforms observed with both obesity and IGT are independently associated with greater proportional odds of developing T2DM. The mechanisms by which each respective isoform contributes to obesity and insulin resistance may reveal novel treatment strategies for diabetes., (Copyright © 2017 the American Physiological Society.)

The objective of this study was to establish whether alterations in the REDD1-mTOR axis underlie skeletal muscle insensitivity to insulin in Type 2 diabetic (T2D), obese individuals. Vastus lateralis muscle biopsies were obtained from lean, control and obese, T2D subjects under basal and after a 2-h hyperinsulinemic (40 mU·m(-2)·min(-1))-euglycemic (5 mM) clamp. Muscle lysates were examined for total REDD1, and phosphorylated Akt, S6 kinase 1 (S6K1), 4E-BP1, ERK1/2, and MEK1/2 via Western blot analysis. Under basal conditions [(-) insulin], T2D muscle exhibited higher S6K1 and ERK1/2 and lower 4E-BP1 phosphorylation (P < 0.05), as well as elevations in blood cortisol, glucose, insulin, glycosylated hemoglobin (P < 0.05) vs. lean controls. Following insulin infusion, whole body glucose disposal rates (GDR; mg/kg/min) were lower (P < 0.05) in the T2D vs. the control group. The basal-to-insulin percent change in REDD1 expression was higher (P < 0.05) in muscle from the T2D vs. the control group. Whereas, the basal-to-insulin percent change in muscle Akt, S6K1, ERK1/2, and MEK1/2 phosphorylation was significantly lower (P < 0.05) in the T2D vs. the control group. Findings from this study propose a REDD1-regulated mechanism in T2D skeletal muscle that may contribute to whole body insulin resistance and may be a target to improve insulin action in insulin-resistant individuals., (Copyright © 2015 the American Physiological Society.)