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Effect of alternate day fasting combined with aerobic exercise on non-alcoholic fatty liver disease: A randomized controlled trial.
Ezpeleta, M, Gabel, K, Cienfuegos, S, Kalam, F, Lin, S, Pavlou, V, Song, Z, Haus, JM, Koppe, S, Alexandria, SJ, et al
Cell metabolism. 2023;(1):56-70.e3
Abstract
Innovative non-pharmacological lifestyle strategies to treat non-alcoholic fatty liver disease (NAFLD) are critically needed. This study compared the effects of alternate day fasting (ADF) combined with exercise to fasting alone, or exercise alone, on intrahepatic triglyceride (IHTG) content. Adults with obesity and NAFLD (n = 80, 81% female, age: 23-65 years) were randomized to 1 of 4 groups for 3 months: combination of ADF (600 kcal/2,500 kJ "fast day" alternated with an ad libitum intake "feast day") and moderate-intensity aerobic exercise (5 session per week, 60 min/session); ADF alone; exercise alone; or a no-intervention control group. By month 3, IHTG content was significantly reduced in the combination group (-5.48%; 95% CI, -7.77% to -3.18%), compared with the exercise group (-1.30%; 95% CI, -3.80% to 1.20%; p = 0.02) and the control group (-0.17%; 95% CI, -2.17% to 1.83%; p < 0.01) but was not significantly different versus the ADF group (-2.25%; 95% CI, -4.46% to -0.04%; p = 0.05). Body weight, fat mass, waist circumference, and alanine transaminase (ALT) levels significantly decreased, while insulin sensitivity significantly increased in the combination group compared with the control group. Lean mass, aspartate transaminase (AST), HbA1c, blood pressure, plasma lipids, liver fibrosis score, and hepatokines (fetuin-A, FGF-21, and selenoprotein P) did not differ between groups. Combining intermittent fasting with exercise is effective for reducing hepatic steatosis in patients with NAFLD but may offer no additional benefit versus fasting alone.
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Glyoxalase I is a novel target for the prevention of metabolic derangement.
Miranda, ER, Haus, JM
Pharmacology & therapeutics. 2023;:108524
Abstract
Obesity prevalence in the US has nearly tripled since 1975 and a parallel increase in prevalence of type 2 diabetes (T2D). Obesity promotes a myriad of metabolic derangements with insulin resistance (IR) being perhaps the most responsible for the development of T2D and other related diseases such as cardiovascular disease. The precarious nature of IR development is such that it provides a valuable target for the prevention of further disease development. However, the mechanisms driving IR are numerous and complex making the development of viable interventions difficult. The development of metabolic derangement in the context of obesity promotes accumulation of reactive metabolites such as the reactive alpha-dicarbonyl methylglyoxal (MG). MG accumulation has long been appreciated as a marker of disease progression in patients with T2D as well as the development of diabetic complications. However, recent evidence suggests that the accumulation of MG occurs with obesity prior to T2D onset and may be a primary driving factor for the development of IR and T2D. Further, emerging evidence also suggests that this accumulation of MG with obesity may be a result in a loss of MG detoxifying capacity of glyoxalase I. In this review, we will discuss the evidence that posits MG accumulation because of GLO1 attenuation is a novel target mechanism of the development of metabolic derangement. In addition, we will also explore the regulation of GLO1 and the strategies that have been investigated so far to target GLO1 regulation for the prevention and treatment of metabolic derangement.
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Plasma undercarboxylated osteocalcin dynamics with glycemic stress reflects insulin sensitivity and beta-cell function in humans with and without T2DM.
Fuller, KNZ, Bohne, EM, Mey, JT, Blackburn, BK, Miranda, VR, Varady, KA, Danielson, KK, Haus, JM
Metabolism open. 2023;:100264
Abstract
This study aimed to better understand the relationship between bone-related biomarkers and nutrient stress in the context of metabolic health. We investigated plasma osteocalcin (OC) during an oral glucose challenge and experimental hyperinsulinemia in Type 2 diabetes (T2DM) and lean healthy controls (LHC). Older individuals with obesity and T2DM (n = 9) and young LHCs (n = 9) underwent a 75g oral glucose tolerance test (OGTT) and a 40 mU/m2/min hyperinsulinemic-euglycemic clamp. Plasma undercarboxylated OC (ucOC) and total OC were measured at baseline, 60mins, and 120mins of the OGTT and clamp via ELISA. In addition, plasma alkaline phosphatase (ALP), leptin, adiponectin, Vitamin D and insulin were measured and indices of insulin sensitivity and β-cell function were derived. The T2DM group had lower (p<0.05) ucOC and ucOC:total OC ratio than LHC during both the OGTT and clamp. Further, baseline ucOC was positively correlated to indices of β-cell function and negatively correlated to indices of insulin resistance when both groups were combined (all p<0.05). Suppression of OC observed in T2DM may be related to glucose intolerance and insulin resistance. Similarly, our data suggest that the observed phenotypic differences between groups are likely a product of long-term glucose dysregulation rather than acute flux in glucose or insulin.
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Exerkines in health, resilience and disease.
Chow, LS, Gerszten, RE, Taylor, JM, Pedersen, BK, van Praag, H, Trappe, S, Febbraio, MA, Galis, ZS, Gao, Y, Haus, JM, et al
Nature reviews. Endocrinology. 2022;(5):273-289
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Abstract
The health benefits of exercise are well-recognized and are observed across multiple organ systems. These beneficial effects enhance overall resilience, healthspan and longevity. The molecular mechanisms that underlie the beneficial effects of exercise, however, remain poorly understood. Since the discovery in 2000 that muscle contraction releases IL-6, the number of exercise-associated signalling molecules that have been identified has multiplied. Exerkines are defined as signalling moieties released in response to acute and/or chronic exercise, which exert their effects through endocrine, paracrine and/or autocrine pathways. A multitude of organs, cells and tissues release these factors, including skeletal muscle (myokines), the heart (cardiokines), liver (hepatokines), white adipose tissue (adipokines), brown adipose tissue (baptokines) and neurons (neurokines). Exerkines have potential roles in improving cardiovascular, metabolic, immune and neurological health. As such, exerkines have potential for the treatment of cardiovascular disease, type 2 diabetes mellitus and obesity, and possibly in the facilitation of healthy ageing. This Review summarizes the importance and current state of exerkine research, prevailing challenges and future directions.
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Study in Parkinson's disease of exercise phase 3 (SPARX3): study protocol for a randomized controlled trial.
Patterson, CG, Joslin, E, Gil, AB, Spigle, W, Nemet, T, Chahine, L, Christiansen, CL, Melanson, E, Kohrt, WM, Mancini, M, et al
Trials. 2022;(1):855
Abstract
BACKGROUND To date, no medication has slowed the progression of Parkinson's disease (PD). Preclinical, epidemiological, and experimental data on humans all support many benefits of endurance exercise among persons with PD. The key question is whether there is a definitive additional benefit of exercising at high intensity, in terms of slowing disease progression, beyond the well-documented benefit of endurance training on a treadmill for fitness, gait, and functional mobility. This study will determine the efficacy of high-intensity endurance exercise as first-line therapy for persons diagnosed with PD within 3 years, and untreated with symptomatic therapy at baseline. METHODS This is a multicenter, randomized, evaluator-blinded study of endurance exercise training. The exercise intervention will be delivered by treadmill at 2 doses over 18 months: moderate intensity (4 days/week for 30 min per session at 60-65% maximum heart rate) and high intensity (4 days/week for 30 min per session at 80-85% maximum heart rate). We will randomize 370 participants and follow them at multiple time points for 24 months. The primary outcome is the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor score (Part III) with the primary analysis assessing the change in MDS-UPDRS motor score (Part III) over 12 months, or until initiation of symptomatic antiparkinsonian treatment if before 12 months. Secondary outcomes are striatal dopamine transporter binding, 6-min walk distance, number of daily steps, cognitive function, physical fitness, quality of life, time to initiate dopaminergic medication, circulating levels of C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF). Tertiary outcomes are walking stride length and turning velocity. DISCUSSION SPARX3 is a Phase 3 clinical trial designed to determine the efficacy of high-intensity, endurance treadmill exercise to slow the progression of PD as measured by the MDS-UPDRS motor score. Establishing whether high-intensity endurance treadmill exercise can slow the progression of PD would mark a significant breakthrough in treating PD. It would have a meaningful impact on the quality of life of people with PD, their caregivers and public health. TRIAL REGISTRATION ClinicalTrials.gov NCT04284436 . Registered on February 25, 2020.
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Exercise-induced improvements in glucose effectiveness are blunted by a high glycemic diet in adults with prediabetes.
Hari, A, Fealy, C, Solomon, TPJ, Haus, JM, Kelly, KR, Barkoukis, H, Kirwan, JP
Acta diabetologica. 2019;(2):211-217
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Abstract
AIMS: Glucose effectiveness (GE) refers to the ability of glucose to influence its own metabolism through insulin-independent mechanisms. Diminished GE is a predictor of progression to type 2 diabetes. Exercise training improves GE, however, little is known about how dietary interventions, such as manipulating the glycemic index of diets, interact with exercise-induced improvements in GE in at-risk populations. METHODS We enrolled 33 adults with obesity and pre-diabetes (17 males, 65.7 ± 4.3 years, 34.9 ± 4.2 kg m-2) into a 12-week exercise training program (1 h day-1 and 5 day week-1 at ~ 85% of maximum heart rate) while being randomized to concurrently receive either a low (EX-LOG: 40 ± 0.3 au) or high (EX-HIG: 80 ± 0.6 au) glycemic index diet. A 75-g oral-glucose-tolerance test (OGTT) was performed before and after the intervention and GE was calculated using the Nagasaka equation. Insulin resistance was estimated using a hyperinsulinemic-euglycemic clamp and cardiorespiratory fitness using a VO2max test. RESULTS Both EX-LOG and EX-HIG groups had similar improvements in weight (8.6 ± 5.1 kg, P < 0.001), VO2max (6 ± 3.5 mL kg-1 min-1, P < 0.001) and clamp-measured peripheral insulin resistance (1.7 ± 0.9 mg kg-1 min-1, P < 0.001), relative to baseline data. GE in EX-LOG and EX-HIG was similar at baseline (1.9 ± 0.38 vs. 1.85 ± 0.3 mg dL-1 min-1, respectively; P > 0.05) and increased by ~ 20% post-intervention in the EX-LOG arm (∆GE: 0.07-0.57 mg dL-1 min-1, P < 0.05). Plasma free fatty acid (FFA) concentrations also decreased only in the EX-LOG arm (∆FFA: 0.13 ± 0.23 mmol L-1, P < 0.05). CONCLUSIONS Our data suggest that a high glycemic index diet may suppress exercise-induced enhancement of GE, and this may be mediated through plasma FFAs.
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Skeletal muscle Nur77 and NOR1 insulin responsiveness is blunted in obesity and type 2 diabetes but improved after exercise training.
Mey, JT, Solomon, TPJ, Kirwan, JP, Haus, JM
Physiological reports. 2019;(6):e14042
Abstract
Obesity and type 2 diabetes (T2DM) are characterized by a blunted metabolic response to insulin, and strongly manifests in skeletal muscle insulin resistance. The orphan nuclear receptors, Nur77 and NOR1, regulate insulin-stimulated nutrient metabolism where Nur77 and NOR1 gene expression is increased with acute aerobic exercise and acute insulin stimulation. Whether Nur77 or NOR1 are associated with the insulin-sensitizing effects of chronic aerobic exercise training has yet to be elucidated. Fourteen lean healthy controls (LHC), 12 obese (OB), and 10 T2DM individuals (T2DM) underwent hyperinsulinemic-euglycemic clamps with skeletal muscle biopsies. Muscle was analyzed for Nur77 and NOR1 gene and protein expression at basal and insulin-stimulated conditions. Furthermore, a subcohort of 18 participants (OB, n = 12; T2DM, n = 6) underwent a 12-week aerobic exercise intervention (85% HRmax , 60 min/day, 5 days/week). In response to insulin infusion, LHC increased protein expression of Nur77 (8.7 ± 3.2-fold) and NOR1 (3.6 ± 1.1-fold), whereas OB and T2DM remained unaffected. Clamp-derived glucose disposal rates correlated with Nur77 (r2 = 0.14) and NOR1 (r2 = 0.12) protein expression responses to insulin, whereas age (Nur77: r2 = 0.22; NOR1: r2 = 0.25) and BMI (Nur77: r2 = 0.22; NOR1: r2 = 0.42) showed inverse correlations, corroborating preclinical data. In the intervention cohort, exercise improved Nur77 protein expression in response to insulin (PRE: -1.2 ± 0.3%, POST 6.2 ± 1.5%). Also, insulin treatment of primary human skeletal muscle cells increased Nur77 and NOR1 protein. These findings highlight the multifactorial nature of insulin resistance in human obesity and T2DM. Understanding the regulation of Nur77 and NOR1 in skeletal muscle and other insulin-sensitive tissues will create opportunities to advance therapies for T2DM.
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Experimental Hyperglycemia Alters Circulating Concentrations and Renal Clearance of Oxidative and Advanced Glycation End Products in Healthy Obese Humans.
Perkins, RK, Miranda, ER, Karstoft, K, Beisswenger, PJ, Solomon, TPJ, Haus, JM
Nutrients. 2019;(3)
Abstract
The purpose of this investigation was to evaluate the effects of experimental hyperglycemia on oxidative damage (OX), advanced glycation end products (AGEs), and the receptor for AGEs (RAGE) through an in vivo approach. Obese subjects (n = 10; 31.2 ± 1.2 kg·m-2; 56 ± 3 years) underwent 24 h of hyperglycemic clamp (+5.4 mM above basal), where plasma at basal and after 2 h and 24 h of hyperglycemic challenge were assayed for OX (methionine sulfoxide, MetSO, and aminoadipic acid, AAA) and AGE-free adducts (Ne-carboxymethyllysine, CML; Ne-carboxyethyllysine, CEL; glyoxal hydroimidazolone-1, GH-1; methylglyoxal hydroimidazolone-1, MG-H1; and 3-deoxyglucosone hydroimidazolone, 3DG-H) via liquid chromatography⁻tandem mass spectrometry (LC⁻MS/MS). Urine was also analyzed at basal and after 24 h for OX and AGE-free adducts and plasma soluble RAGE (sRAGE) isoforms (endogenous secretory RAGE, esRAGE, and cleaved RAGE, cRAGE), and inflammatory markers were determined via enzyme-linked immunosorbent assay (ELISA). Skeletal muscle tissue collected via biopsy was probed at basal, 2 h, and 24 h for RAGE and OST48 protein expression. Plasma MetSO, AAA, CEL, MG-H1, and G-H1 decreased (-18% to -47%; p < 0.05), while CML increased (72% at 24 h; p < 0.05) and 3DG-H remained unchanged (p > 0.05) with the hyperglycemic challenge. Renal clearance of MetSO, AAA, and G-H1 increased (599% to 1077%; p < 0.05), CML decreased (-30%; p < 0.05), and 3DG-H, CEL, and MG-H1 remained unchanged (p > 0.05). Fractional excretion of MetSO, AAA, CEL, G-H1, and MG-H1 increased (5.8% to 532%; p < 0.05) and CML and 3DG-H remained unchanged (p > 0.05). Muscle RAGE and OST48 expression, plasma sRAGE, IL-1β, IL-1Ra, and TNFα remained unchanged (p > 0.05), while IL-6 increased (159% vs. basal; p > 0.05). These findings suggest that individuals who are obese but otherwise healthy have the capacity to prevent accumulation of OX and AGEs during metabolic stress by increasing fractional excretion and renal clearance.
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A single high-fat meal alters human soluble RAGE profiles and PBMC RAGE expression with no effect of prior aerobic exercise.
Fuller, KNZ, Valentine, RJ, Miranda, ER, Kumar, P, Prabhakar, BS, Haus, JM
Physiological reports. 2018;(14):e13811
Abstract
A high-fat diet can induce inflammation and metabolic diseases such as diabetes and atherosclerosis. The receptor for advanced glycation endproducts (RAGE) plays a critical role in metabolic disease pathophysiology and the soluble form of the receptor (sRAGE) can mitigate these effects. However, little is known about RAGE in the postprandial condition and the effect of exercise in this context. Thus, we aimed to determine the effects of a single high-fat meal (HFM) with and without prior exercise on peripheral blood mononuclear cell (PBMC) RAGE biology. Healthy males (n = 12) consumed a HFM on two occasions, one without prior exercise and one 16-18 hours following acute aerobic exercise. Total soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE) were determined via ELISA and cleaved RAGE (cRAGE) was calculated as the difference between the two. Isolated PBMCs were analyzed for RAGE, ADAM10, TLR4, and MyD88 protein expression and ADAM10 activity. The HFM significantly (P < 0.01) attenuated sRAGE, esRAGE, and cRAGE by 9.7%, 6.9%, and 10.5%, respectively. Whereas, the HFM increased PBMC RAGE protein expression by 10.3% (P < 0.01), there was no meal effect on PBMC TLR4, MYD88, or ADAM10 protein expression, nor ADAM10 activity. There was also no exercise effect on any experimental outcomes. These findings suggest that PBMC RAGE and soluble RAGE may be important in the postprandial response to a HFM, and that prior aerobic exercise does not alter these processes in young healthy adult males. The mechanisms by which a HFM induces RAGE expression and reduces circulating soluble RAGE isoforms requires further study.
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A whole-grain diet reduces peripheral insulin resistance and improves glucose kinetics in obese adults: A randomized-controlled trial.
Malin, SK, Kullman, EL, Scelsi, AR, Haus, JM, Filion, J, Pagadala, MR, Godin, JP, Kochhar, S, Ross, AB, Kirwan, JP
Metabolism: clinical and experimental. 2018;82:111-117
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Plain language summary
Literature shows that dietary whole-grain intake is associated with a lower incidence of type 2 diabetes. The aim of the study was to investigate the association between a whole-grain diet and insulin resistance and glucose use in individuals at risk for type 2 diabetes. The study was a randomized, double-blind, controlled crossover trial involving fourteen middle-aged, obese adults at risk for diabetes. Randomisation was carried out prior to metabolic testing. Results indicate that whole-grain intake as part of a mixed-meal diet significantly improved post-prandial (after a meal) glucose metabolism in middle-aged obese adults. Furthermore, both whole-grain and refined-grain interventions induced about 3–6% weight and fat loss. Authors conclude that whole-grain intake effectively promotes glycaemic control by improving insulin action.
Abstract
BACKGROUND Whole-grain intake is associated with lower risk of type 2 diabetes but the mechanisms are unclear. PURPOSE We tested the hypothesis that a WG diet reduces insulin resistance and improves glucose use in individuals at risk for type 2 diabetes compared with an isocaloric-matched refined-grain diet. METHODS A double-blind, randomized, controlled, crossover trial of 14 moderately obese adults (Age, 38 ± 2 y; BMI, 34.0 ± 1.1 kg/m2). Insulin resistance and glucose metabolism was assessed using an oral glucose tolerance test combined with isotopic tracers of [6,6-2H2]-glucose and [U-13C]-glucose, and indirect calorimetry. Peripheral and hepatic insulin resistance was assessed as 1/(rate of disposal/insulin), and endogenous glucose rates of appearance (Ra) iAUC60-240 × insulin iAUC60-240, respectively. Both diets met ADA nutritional guidelines and contained either whole-grain (50 g per 1000 kcal) or equivalent refined-grain. All food was provided for 8 wk. with an 8-10 wk. washout period between diets. RESULTS Post-prandial glucose tolerance, peripheral insulin sensitivity, and metabolic flexibility (insulin-stimulated - fasting carbohydrate oxidation) improvements were greater after whole-grain compared to the refined-grain diet (P < 0.05). Compared to baseline, body fat (~2 kg) and hepatic Ra insulin resistance was reduced by both diets, while fasting glucose and exogenous glucose-meal were unchanged after both interventions. Changes in peripheral insulin resistance and metabolic flexibility correlated with improved glucose tolerance (P < 0.05). CONCLUSION Whole-grains reduced diabetes risk and the mechanisms appear to work through reduced post-prandial blood glucose and peripheral insulin resistance that were statistically linked to enhanced metabolic flexibility.