Effect of Small and Large Energy Surpluses on Strength, Muscle, and Skinfold Thickness in Resistance-Trained Individuals: A Parallel Groups Design.

BACKGROUND: Many perform resistance training (RT) to increase muscle mass and strength. Energy surpluses are advised to support such gains; however, if too large, could cause unnecessary fat gain. We randomized 21 trained lifters performing RT 3 d/wk for eight weeks into maintenance energy (MAIN), moderate (5% [MOD]), and high (15% [HIGH]) energy surplus groups to determine if skinfold thicknesses (ST), squat and bench one-repetition maximum (1-RM), or biceps brachii, triceps brachii, or quadriceps muscle thicknesses (MT) differed by group. COVID-19 reduced our sample, leaving 17 completers. Thus, in addition to Bayesian ANCOVA comparisons, we analyzed changes in body mass (BM) with ST, 1-RM, and MT changes via regression. We reported Bayes factors (BF10) indicating odds ratios of the relative likelihood of hypotheses (e.g., BF10 = 2 indicates the hypothesis is twice as likely as another) and coefficients of determination (R2) for regressions. RESULTS: ANCOVAs provided no evidence supporting the group model for MT or squat 1-RM. However, moderate (BF10 = 9.9) and strong evidence (BF10 = 14.5) indicated HIGH increased bench 1-RM more than MOD and MAIN, respectively. Further, there was moderate evidence (BF10 = 4.2) HIGH increased ST more than MAIN and weak evidence (BF10 = 2.4) MOD increased ST more than MAIN. Regression provided strong evidence that BM change predicts ST change (BF10 = 14.3, R2 = 0.49) and weak evidence predicting biceps brachii MT change (BF10 = 1.4, R2 = 0.24). CONCLUSIONS: While some group-based differences were found, our larger N regression provides the most generalizable evidence. Therefore, we conclude faster rates of BM gain (and by proxy larger surpluses) primarily increase rates of fat gain rather than augmenting 1-RM or MT. However, biceps brachii, the muscle which received the greatest stimulus in this study, may have been positively impacted by greater BM gain, albeit slightly. Our findings are limited to the confines of this study, where a group of lifters with mixed training experience performed moderate volumes 3 d/wk for 8 weeks. Thus, future work is needed to evaluate the relationship between BM gains, increases in ST and RT adaptations in other contexts.

Is an Energy Surplus Required to Maximize Skeletal Muscle Hypertrophy Associated With Resistance Training.

Resistance training is commonly prescribed to enhance strength/power qualities and is achieved via improved neuromuscular recruitment, fiber type transition, and/ or skeletal muscle hypertrophy. The rate and amount of muscle hypertrophy associated with resistance training is influenced by a wide array of variables including the training program, plus training experience, gender, genetic predisposition, and nutritional status of the individual. Various dietary interventions have been proposed to influence muscle hypertrophy, including manipulation of protein intake, specific supplement prescription, and creation of an energy surplus. While recent research has provided significant insight into optimization of dietary protein intake and application of evidence based supplements, the specific energy surplus required to facilitate muscle hypertrophy is unknown. However, there is clear evidence of an anabolic stimulus possible from an energy surplus, even independent of resistance training. Common textbook recommendations are often based solely on the assumed energy stored within the tissue being assimilated. Unfortunately, such guidance likely fails to account for other energetically expensive processes associated with muscle hypertrophy, the acute metabolic adjustments that occur in response to an energy surplus, or individual nuances like training experience and energy status of the individual. Given the ambiguous nature of these calculations, it is not surprising to see broad ranging guidance on energy needs. These estimates have never been validated in a resistance training population to confirm the "sweet spot" for an energy surplus that facilitates optimal rates of muscle gain relative to fat mass. This review not only addresses the influence of an energy surplus on resistance training outcomes, but also explores other pertinent issues, including "how much should energy intake be increased," "where should this extra energy come from," and "when should this extra energy be consumed." Several gaps in the literature are identified, with the hope this will stimulate further research interest in this area. Having a broader appreciation of these issues will assist practitioners in the establishment of dietary strategies that facilitate resistance training adaptations while also addressing other important nutrition related issues such as optimization of fuelling and recovery goals. Practical issues like the management of satiety when attempting to increase energy intake are also addressed.

Association of Acute Kidney Injury with Cardiovascular Events and Death in Systolic Blood Pressure Intervention Trial.

RATIONALE AND OBJECTIVE: In the Systolic Blood Pressure Intervention Trial, the possible relationships between acute kidney injury (AKI) and risk of major cardiovascular events and death are not known. STUDY DESIGN: Post hoc analysis of a multicenter, randomized, controlled, open-label clinical trial. SETTING AND PARTICIPANTS: Hypertensive adults without diabetes who were ≥50 years of age with prior cardiovascular disease, chronic kidney disease (CKD), 10-year Framingham risk score > 15%, or age > 75 years were assigned to a systolic blood pressure target of < 120 mm Hg (intensive) or < 140 mm Hg (standard). PREDICTOR: AKI episodes. OUTCOMES: The primary outcome was a composite of myocardial infarction, acute coronary syndrome, stroke, decompensated heart failure, or cardiovascular death. The secondary outcome was death from any cause. Analytical Approach: AKI was defined using the Kidney Disease: Improving Global Outcomes modified criteria based solely upon serum creatinine. AKI episodes were identified by serious adverse events or emergency room visits. Cox proportional hazards models assessed the risk for the primary and secondary outcomes by AKI status. RESULTS: Participants were 68 ± 9 years of age, 36% women (3,332/9,361), and 30% Black race (2,802/9,361), and 17% (1,562/9,361) with cardiovascular disease. Systolic blood pressure was 140 ± 16 mm Hg at study entry. AKI occurred in 4.4% (204/4,678) and 2.6% (120/4,683) in the intensive and standard treatment groups respectively (p < 0.001). Those who experienced AKI had higher risk of cardiovascular events (hazard ratio [HR] 1.52, 95% CI 1.05-2.20, p = 0.026) and death from any cause (HR 2.33, 95% CI 1.56-3.48, p < 0.001) controlling for age, sex, race, baseline systolic blood pressure, body mass index, number of antihypertensive medications, cardiovascular disease and CKD status, hypotensive episodes, and treatment assignment. LIMITATIONS: The study was not prospectively designed to determine relationships between AKI, cardiovascular events, and death. CONCLUSIONS: Among older adults with hypertension at high cardiovascular risk, intensive treatment of blood pressure independently increased risk of AKI, which substantially raised risks of major cardiovascular events and death.

Serum amyloid A and Janus kinase 2 in a mouse model of diabetic kidney disease.

BACKGROUND: Serum amyloid A (SAA), a potent inflammatory mediator, and Janus kinase 2 (JAK2), an intracellular signaling kinase, are increased by diabetes. The aims were to elucidate: 1) a JAK2-mediated pathway for increased SAA in the kidneys of diabetic mice; 2) a JAK2-SAA pathway for inflammation in podocytes. METHODS: Akita diabetic mice (129S6) with podocyte JAK2 overexpression and angiotensin II infusion (4 weeks) were given a JAK1,2 inhibitor (LY03103801, 3 mg/kg/day orally for the last two weeks). Kidneys were immunostained for SAA isoform 3 (SAA3). SAA3 knockout and control mouse podocytes were exposed to advanced glycation end products (AGE) or exogenous SAA with JAK2 inhibition (Tyrphostin AG 490, 50µM). JAK2 activity (phosphorylation, Western blot, 1 hour) and mRNA for SAA3 and associated inflammatory genes (Cxcl5, Ccl2, and Ccl5) were measured by RT-PCR (20 hours). RESULTS: SAA3 protein was present throughout the diabetic kidney, and podocyte JAK2 overexpression increased tubulointerstitial SAA3 compared to wild type diabetic controls, 43% versus 14% (p = 0.007); JAK1,2 inhibition attenuated the increase in SAA3 to 15% (p = 0.003). Urine albumin-to-creatinine ratio (r = 0.49, p = 0.03), mesangial index (r = 0.64, p = 0.001), and glomerulosclerosis score (r = 0.51, p = 0.02) were associated with SAA3 immunostaining scores across mouse groups. Exposing podocytes to AGE or exogenous SAA increased JAK2 activity within one hour and mRNA for associated inflammatory genes after 20 hours. JAK2 inhibition reduced SAA3 mRNA expression in podocytes exposed to AGE or SAA. SAA3 knockout podocytes had >85% lower AGE-induced inflammatory genes. CONCLUSION: JAK1,2 inhibition reduced SAA and histological features of DKD in podocyte JAK2-overexpressing mice. In podocytes exposed to a diabetes-like condition, JAK2 inhibition reduced expression of SAA, while SAA knockout blocked expression of associated pro-inflammatory mediators. SAA may promote JAK2-dependent inflammation in the diabetic kidney.

GLP-1 receptor agonists in diabetic kidney disease: from the patient-side to the bench-side.

Diabetic kidney disease (DKD), one of the most common and severe microvascular complications of diabetes, is the leading cause of chronic kidney disease and end-stage kidney disease worldwide. Since the development of renin-angiotensin system inhibition nearly three decades ago, no new therapeutic agents have received regulatory approval for treatment of DKD. Glucagon-like peptide-1 (GLP-1) receptor agonists, a class of newer antihyperglycemic agents, have shown promise for prevention of DKD onset and progression. This perspective summarizes clinical and experimental observations to give insight into biological mechanisms beyond glycemic control, such as natriuresis and anti-inflammatory actions, for preservation of kidney function in patients with diabetes.

Medication Therapy Management after Hospitalization in CKD: A Randomized Clinical Trial.

BACKGROUND AND OBJECTIVES: CKD is characterized by remarkably high hospitalization and readmission rates. Our study aim was to test a medication therapy management intervention to reduce subsequent acute care utilization. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The CKD Medication Intervention Trial was a single-blind (investigators), randomized clinical trial conducted at Providence Health Care in Spokane, Washington. Patients with CKD stages 3-5 not treated by dialysis who were hospitalized for acute illness were recruited. The intervention was designed to improve posthospitalization care by medication therapy management. A pharmacist delivered the intervention as a single home visit within 7 days of discharge. The intervention included these fundamental elements: comprehensive medication review, medication action plan, and a personal medication list. The primary outcome was a composite of acute care utilization (hospital readmissions and emergency department and urgent care visits) for 90 days after hospitalization. RESULTS: Baseline characteristics of participants (n=141) included the following: age, 69±11 (mean±SD) years old; women, 48% (67 of 141); diabetes, 56% (79 of 141); hypertension, 83% (117 of 141); eGFR, 41±14 ml/min per 1.73 m2 (serum creatinine-based Chronic Kidney Disease Epidemiology Collaboration equation); and urine albumin-to-creatinine ratio median, 43 mg/g (interquartile range, 8-528) creatinine. The most common primary diagnoses for hospitalization were the following: cardiovascular events, 36% (51 of 141); infections, 18% (26 of 141); and kidney diseases, 12% (17 of 141). The primary outcome occurred in 32 of 72 (44%) of the medication intervention group and 28 of 69 (41%) of those in usual care (log rank P=0.72). For only hospital readmission, the rate was 19 of 72 (26%) in the medication intervention group and 18 of 69 (26%) in the usual care group (log rank P=0.95). There was no between-group difference in achievement of guideline-based goals for use of renin-angiotensin system inhibition or for BP, hemoglobin, phosphorus, or parathyroid hormone. CONCLUSIONS: Acute care utilization after hospitalization was not reduced by a pharmacist-led medication therapy management intervention at the transition from hospital to home.

The Association Between Handgrip Strength and Diabetes on Activities of Daily Living Disability in Older Mexican Americans.

OBJECTIVE: The aim of this study is to determine the independent and joint effects of muscle weakness and diabetes on incident activities of daily living (ADL) disability in older Mexican Americans. METHOD: A subsample of 2,270 Mexican Americans aged at least 65 years at baseline were followed for 19 years. Handgrip strength was normalized to body weight (normalized grip strength [NGS]). Weakness was defined as NGS ≤0.46 in males and ≤0.30 in females. Diabetes and ADL disability were self-reported. RESULTS: Compared with participants that were not weak and did not have diabetes, those that had diabetes only, were weak only, and were both weak and had diabetes experienced a 1.94 (95% confidence interval [CI] = [1.89, 1.98]), 1.17 (CI = [1.16, 1.19]), and 2.12 (CI = [2.08, 2.16]) higher rate for ADL disability, respectively. DISCUSSION: Muscle weakness and diabetes were independently and jointly associated with higher rates for ADL disability in older Mexican Americans.

Association of Serum Amyloid A with Kidney Outcomes and All-Cause Mortality in American Indians with Type 2 Diabetes.

BACKGROUND: Serum amyloid A (SAA) induces inflammation and apoptosis in kidney cells and is found to be causing the pathologic changes that are associated with diabetic kidney disease (DKD). Higher serum SAA concentrations were previously associated with increased risk of end-stage renal disease (ESRD) and death in persons with type 2 diabetes and advanced DKD. We explored the prognostic value of SAA in American Indians with type 2 diabetes without DKD or with early DKD. METHODS: SAA concentration was measured in serum samples obtained at the start of follow-up. Multivariate proportional hazards models were employed to examine the magnitude of the risk of ESRD or death across tertiles of SAA concentration after adjustment for traditional risk factors. The C statistic was used to assess the additional predictive value of SAA relative to traditional risk factors. RESULTS: Of 256 participants (mean ± SD glomerular filtration rate [iothalamate] = 148 ± 45 mL/min, and median [interquartile range] urine albumin/creatinine = 39 [14-221] mg/g), 76 developed ESRD and 125 died during a median follow-up period of 15.2 and 15.7 years, respectively. After multivariable proportional hazards regression, participants in the 2 highest SAA tertiles together exhibited a 53% lower risk of ESRD (hazard ratio [HR] 0.47, 95% CI 0.29-0.78), and a 30% lower risk of death (HR 0.70, 95% CI 0.48-1.02), compared with participants in the lowest SAA tertile, although the lower risk of death was not statistically significant. Addition of SAA to the ESRD model increased the C statistic from 0.814 to 0.815 (p = 0.005). CONCLUSIONS: Higher circulating SAA concentration is associated with a reduced risk of ESRD in American Indians with type 2 diabetes.

Effects of macro- and micronutrients on exercise-induced hepcidin response in highly trained endurance athletes.

Iron deficiency has ergolytic effects on athletic performance. Exercise-induced inflammation impedes iron absorption in the digestive tract by upregulating the expression of the iron regulatory protein, hepcidin. Limited research indicates the potential of specific macro- and micronutrients on blunting exercise-induced hepcidin. Therefore, we investigated the effects of postexercise supplementation with protein and carbohydrate (CHO) and vitamins D3 and K2 on the postexercise hepcidin response. Ten highly trained male cyclists (age: 26.9 ± 6.4 years; maximal oxygen uptake: 67.4 ± 4.4 mL·kg-1·min-1 completed 4 cycling sessions in a randomized, placebo-controlled, single-blinded, triple-crossover study. Experimental days consisted of an 8-min warm-up at 50% power output at maximal oxygen uptake, followed by 8 × 3-min intervals at 85% power output at maximal oxygen uptake with 1.5 min at 60% power output at maximal oxygen uptake between each interval. Blood samples were collected pre- and postexercise, and at 3 h postexercise. Three different drinks consisting of CHO (75 g) and protein (25 g) with (VPRO) or without (PRO) vitamins D3 (5000 IU) and K2 (1000 µg), or a zero-calorie control drink (PLA) were consumed immediately after the postexercise blood sample. Results showed that the postexercise drinks had no significant (p ≥ 0.05) effect on any biomarker measured. There was a significant (p < 0.05) increase in hepcidin and interleukin-6 following intense cycling intervals in the participants. Hepcidin increased significantly (p < 0.05) from baseline (nmol·L-1: 9.94 ± 8.93, 14.18 ± 14.90, 10.44 ± 14.62) to 3 h postexercise (nmol·L-1: 22.27 ± 13.41, 25.44 ± 11.91, 22.57 ± 15.57) in VPRO, PRO, and PLA, respectively. Contrary to our hypothesis, the drink compositions used did not blunt the postexercise hepcidin response in highly trained athletes.

Dietary strategies for cardiovascular health.

Cardiovascular disease is developed across a lifetime accumulation of risk. Numerous independent and synergistic cardiovascular risk factors can be induced by unhealthy dietary patterns. Epidemiological, mechanistic, clinical, and translational research point to refined sugars, processed and fatty meats, synthetic oils, and sodium as major dietary risk factors. The purpose of this review is to integrate these learnings into key principles for dietary frameworks aimed at improving overall cardiovascular health.

Immunity and inflammation in diabetic kidney disease: translating mechanisms to biomarkers and treatment targets.

Increasing incidences of obesity and diabetes have made diabetic kidney disease (DKD) the leading cause of chronic kidney disease and end-stage renal disease worldwide. Despite current pharmacological treatments, including strategies for optimizing glycemic control and inhibitors of the renin-angiotensin system, DKD still makes up almost one-half of all cases of end-stage renal disease in the United States. Compelling and mounting evidence has clearly demonstrated that immunity and inflammation play a paramount role in the pathogenesis of DKD. This article reviews the involvement of the immune system in DKD and identifies important roles of key immune and inflammatory mediators. One of the most recently identified biomarkers is serum amyloid A, which appears to be relatively specific for DKD. Novel and evolving treatment approaches target protein kinases, transcription factors, chemokines, adhesion molecules, growth factors, advanced glycation end-products, and other inflammatory molecules. This is the beginning of a new era in the understanding and treatment of DKD, and we may have finally reached a tipping point in our fight against the growing burden of DKD.

Serum amyloid a and risk of death and end-stage renal disease in diabetic kidney disease.

AIMS: To determine if serum levels of serum amyloid A (SAA) predict death and end-stage renal disease in a cohort of people with diabetic kidney disease. METHODS: In a longitudinal cohort study of 135 participants with type 2 diabetes and diabetic kidney disease, serum samples were assayed for SAA. Censored time-to-event analyses in Cox-proportional hazard models were utilized to assess SAA as a predictor of the primary outcome of death and end-stage renal disease. RESULTS: Participants were 73% Mexican-American (99/135) and 55% men (75/135), with a mean±SD age of 57±7.5years. At baseline, participants had hemoglobin A1c of 8.6±2.3%, systolic blood pressure of 153±27mm Hg, body mass index of 31±9kg/m2, median urine-albumin-to-creatinine ratio of 1861mg/g (interquartile range 720-3912mg/g), and estimated glomerular filtration rate of 55.7±22.3ml/min/1.73m2. Over a median duration of follow-up of 3.5years, 44% (60/135) of participants experienced a primary outcome event. The hazards ratio for the primary outcome was 3.03 (95% CI 1.43-6.40, p=0.003) in the highest (>1.0 µg/ml) compared to the lowest (<0.55 µg/ml) SAA tertile in a model adjusted for urine-albumin-to-creatinine ratio, estimated glomerular filtration rate, age, sex, and race/ethnicity. Addition of SAA as a covariate improved the model C-statistic (Δ c=0.017). CONCLUSIONS: In a longitudinal cohort study of participants with type 2 diabetes and DKD, higher levels of serum SAA predicted higher risk of death and ESRD. SAA is a promising targetable biomarker for DKD.

Medication Intervention for Chronic Kidney Disease Patients Transitioning from Hospital to Home: Study Design and Baseline Characteristics.

BACKGROUND: The hospital readmission rate in the population with chronic kidney disease (CKD) is high and strategies to reduce this risk are urgently needed. METHODS: The CKD-Medication Intervention Trial (CKD-MIT; www.clinicaltrials.gov; NCTO1459770) is a single-blind (investigators), randomized, clinical trial conducted at Providence Health Care in Spokane, Washington. Study participants are hospitalized patients with CKD stages 3-5 (not treated with kidney replacement therapy) and acute illness. The study intervention is a pharmacist-led, home-based, medication management intervention delivered within 7 days after hospital discharge. The primary outcome is a composite of hospital readmissions and visits to emergency departments and urgent care centers for 90 days following hospital discharge. Secondary outcomes are achievements of guideline-based targets for CKD risk factors and complications. RESULTS: Enrollment began in February 2012 and ended in May 2015. At baseline, the age of participants was 69 ± 11 years (mean ± SD), 50% (77 of 155) were women, 83% (117 of 141) had hypertension and 56% (79 of 141) had diabetes. At baseline, the estimated glomerular filtration rate was 41 ± 14 ml/min/1.73 m2 and urine albumin-to-creatinine ratio was 43 mg/g (interquartile range 8-528 mg/g). The most frequent diagnosis category for the index hospital admission was cardiovascular diseases at 34% (53 of 155), but the most common single diagnosis for admission was community-acquired acute kidney injury at 10% (16 of 155). CONCLUSION: Participants in CKD-MIT are typical of acutely ill hospitalized patients with CKD. A medication management intervention after hospital discharge is under study to reduce post-hospitalization acute care utilization and to improve CKD management.

The data do not seem to support a benefit to BCAA supplementation during periods of caloric restriction.

J Int Soc Sports Nutr 13:1-015-0112-9, 2016 describe the efficacy of branched chain amino acid (BCAA) supplementation and resistance training for maintaining lean body mass during a calorie-restricted diet, and claim that this occurs with concurrent losses in fat mass. However, the reported results appear to be at odds with the data presented on changes in fat mass. This letter discusses the issues with the paper.

Novel Therapies for Diabetic Kidney Disease: Storied Past and Forward Paths.

IN BRIEF Current therapeutic approaches are only moderately efficacious at preventing the progression of diabetic kidney disease (DKD). As the number of people with DKD continues to rise worldwide, there is an urgent need for novel therapies. A better understanding of the root causes and molecular mechanisms of DKD pathogenesis has enabled the identification of numerous new therapeutic targets, including advanced glycation end products, reactive oxygen species, protein kinase C, and serum amyloid A. Although experimental studies have illustrated the potential of such approaches, challenges in clinical translation remain a barrier in therapeutic development. Advances in preclinical safety and efficacy evaluations and improved delivery systems may aid in clinical translation of novel DKD therapies.

Plausible ergogenic effects of vitamin D on athletic performance and recovery.

The purpose of this review is to examine vitamin D in the context of sport nutrition and its potential role in optimizing athletic performance. Vitamin D receptors (VDR) and vitamin D response elements (VDREs) are located in almost every tissue within the human body including skeletal muscle. The hormonally-active form of vitamin D, 1,25-dihydroxyvitamin D, has been shown to play critical roles in the human body and regulates over 900 gene variants. Based on the literature presented, it is plausible that vitamin D levels above the normal reference range (up to 100 nmol/L) might increase skeletal muscle function, decrease recovery time from training, increase both force and power production, and increase testosterone production, each of which could potentiate athletic performance. Therefore, maintaining higher levels of vitamin D could prove beneficial for athletic performance. Despite this situation, large portions of athletic populations are vitamin D deficient. Currently, the research is inconclusive with regards to the optimal intake of vitamin D, the specific forms of vitamin D one should ingest, and the distinct nutrient-nutrient interactions of vitamin D with vitamin K that affect arterial calcification and hypervitaminosis. Furthermore, it is possible that dosages exceeding the recommendations for vitamin D (i.e. dosages up to 4000-5000 IU/day), in combination with 50 to 1000 mcg/day of vitamin K1 and K2 could aid athletic performance. This review will investigate these topics, and specifically their relevance to athletic performance.

Evidence for distinct effects of exercise in different cardiac hypertrophic disorders.

Aerobic exercise training (AET) attenuates or reverses pathological cardiac remodeling after insults such as chronic hypertension and myocardial infarction. The phenotype of the pathologically hypertrophied heart depends on the insult; therefore, it is likely that distinct types of pathological hypertrophy require different exercise regimens. However, the mechanisms by which AET improves the structure and function of the pathologically hypertrophied heart are not well understood, and exercise research uses highly inconsistent exercise regimens in diverse patient populations. There is a clear need for systematic research to identify precise exercise prescriptions for different conditions of pathological hypertrophy. Therefore, this review synthesizes existing evidence for the distinct mechanisms by which AET benefits the heart in different pathological hypertrophy conditions, suggests strategic exercise prescriptions for these conditions, and highlights areas for future research.

A proposed mechanism for exercise attenuated methylglyoxal accumulation: activation of the ARE-Nrf pathway and increased glutathione biosynthesis.

The dicarbonyl methylglyoxal (MGO) is an endogenous metabolite and a known intracellular precursor of advanced glycation endproducts (AGEs). High serum levels of MGO have been correlated with MGO-derived AGEs in individuals with type 2 diabetes (T2DM). Furthermore, there is human and animal evidence to suggest that MGO is causal in copious pathologies related to AGE accumulation including heart disease, hypertension, nephropathy and insulin resistance. MGO is detoxified through the glutathione (GSH) dependent glyoxalase system and diminished glutathione status results in impaired MGO detoxification. Individuals with uncontrolled T2DM have diminished GSH status, suggesting the increase in serum MGO can be partially attributed to impaired MGO detoxification. GSH biosynthesis is heavily dependent upon the antioxidant response element-nuclear respiratory factor pathway (ARE-Nrf) and pharmacological and dietary intervention studies have demonstrated that activation of the ARE-Nrf pathway increases intracellular GSH and glyoxalase enzymes and reduces MGO levels. Acute and chronic exercise has also been shown to increase activation of the ARE-Nrf pathway and GSH biosynthesis, and to improve GSH status. Therefore, we propose that exercise improves MGO detoxification and attenuates MGO accumulation by increasing GSH biosynthesis and improving GSH status through activation of the ARE-Nrf pathway.