We investigated serotonergic and dopaminergic terminal integrity role in PRKN-associated Parkinsonism (PRKN-PD) using [¹¹C]DASB Positron Emission Tomography (PET) and [¹²³I]FP-CIT Single Photon Emission Computerised Tomography (SPECT). Fourteen PRKN-PD patients (mean age 49.70 ± 10.83, disease duration 10.95 ± 7.59 years, H Y 2.0 ± 0.68), and twelve iPD patients (mean age 65.40 ± 7.48 years, disease duration 5.05 ± 4.50 years, H Y 2.0 ± 0.93) underwent clinical assessments, 3-Tesla MRI, [11C]DASB PET-CT, and [123I]FP-CIT SPECT, and compared with previously acquired healthy control (HCs) data. [11C]DASB distribution volume ratio (DVR) parametric images were generated and DVR-1 values, equivalent to BPND, sampled from a priori selected regions-of-interest (ROIs) with the posterior cerebellum as reference. [123I]FP-CIT images underwent reconstruction and normalization to standard space, and striatal Specific Binding Ratio (SBR) calculated from the eight hottest consecutive slices. PRKN-PD patients showed 20.8

Introduction: Exercise remodels adipose tissue, improving systemic metabolism. While recent studies suggest that subcutaneous white adipose tissue (scWAT) remodeling involves epigenetic mechanisms, the role of long non-coding RNAs (lncRNAs) remains unclear. lncRNAs regulate adipogenesis and fatty-acid metabolism in scWAT. In a human study from our lab, 10 weeks of endurance training regulated 160 lncRNAs in obese individuals' scWAT and 340 in lean individuals' scWAT. Among exercise-responsive lncRNAs, four show broad expression across cell types in mouse scWAT— Malat1 and Neat1, which promote adipogenesis via the PPAR signaling; Pvt1, which enhances fatty acid synthesis; and H19, which is downregulated in obesity. Given their roles, these lncRNAs may contribute to adipose tissue remodeling. However, no studies have investigated their regulation by acute and chronic endurance exercise. Aim and Hypothesis: We aim to determine how acute and chronic endurance exercise regulates lncRNA expression in scWAT of male mice, hypothesizing that exercise alters the expression of candidate lncRNAs. Methods: Candidate lncRNAs were chosen for (1) established roles in adipogenesis or metabolism, (2) expression across cell types in human and mouse scWAT, and (3) limited knowledge of their exercise responses. For acute exercise, 9-week-old C57BL6J male mice (n=8) were exercised on a treadmill for 1 hour, 5° incline, 18 m/min; scWAT was collected 1 hour post-exercise. For exercise training, 6-week-old DBA2J mice (n=6) were exercised for 4 weeks, 5~6 km daily; scWAT was collected 24 hours post-exercise. Gene expression was analyzed by real-time PCR (qPCR). Results: Acute exercise significantly reduced blood glucose concentrations (Sedentary: 216.3 ± 12.5 mg/dL vs. Exercise: 186.1 ± 5.1 mg/dL; p = 0.0422), without changing body or scWAT mass. Acute exercise significantly increased Neat1 (p = 0.0327) and Pvt1 (p = 0.0052) expression, while Malat1 and H19 expression remained unchanged. Exercise training did not affect body weight or fasting glucose but significantly reduced scWAT mass (Sedentary: 25.45 ± 1.27 mg vs. Training: 17.55 ± 2.93 mg; p = 0.0438). Training significantly upregulated Malat1 (p = 0.0343) and Pvt1 (p = 0.0284) expression, while Neat1 and H19 remained unchanged. In the training model, scWAT weight correlated negatively with Malat1 (r = -0.70, p = 0.0142) and H19 (r = -0.68, p = 0.0185) expression. Conclusion: Exercise differentially regulates lncRNA expression in scWAT, identifying Malat1, Neat1, Pvt1, and H19 as potential mediators of exercise-induced scWAT remodeling. Elevated Malat1 and H19 expression correlates with reduced scWAT mass, suggesting potential therapeutic value. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Objective Olfactory dysfunction is a relatively frequent manifestation in systemic lupus erythematosus (SLE). The Italian Olfactory Identification Test (IOIT) may represent a suitable tool for detecting olfactory impairment in patients with SLE, due to its reliability and easiness of administration. This study aimed to evaluate the prevalence of smell impairment in patients with SLE and its correlation with clinical and serologic features. Methods Consecutive patients with SLE and healthy controls were enrolled. Clinical history, disease indices, and main laboratory parameters were collected. Olfactory function was assessed using the IOIT, testing 33 cards with different microencapsulated odorants. Results The cohort included 100 subjects: 50 patients with SLE (mean age ± SD: 51.3 ± 14.2; disease duration ± SD: 20.9 ± 13.2; female‐to‐male ratio: 5:1) and 50 age‐ and sex‐matched healthy controls. Hyposmia was observed in 30% of patients with SLE and 4% of healthy subjects. IOIT scores correlated significantly with cumulative organ damage measured by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (P = 0.017, r = 0.336). Hyposmia was associated with anti–β2‐glycoprotein I (anti‐β2GPI) antibodies (P = 0.029) and antidepressant therapy (P = 0.019). Cumulative damage was demonstrated to be an independent risk factor for hyposmia (odds ratio = 1.42, 95% confidence interval 1.02–1.98; P = 0.038). Conclusion The IOIT appears to be a suitable tool for evaluating olfactory dysfunction in SLE. The significant association between hyposmia and cumulative damage suggests that olfactory impairment may represent a clinical marker of long‐term organ damage. The association between hyposmia and the use of antidepressant therapy confirms the close relationship between the sense of smell and mood regulation. Furthermore, the association with anti‐β2GPI reinforces the link between olfactory dysfunction and chronic damage in SLE.

White adipose tissue (WAT) dysfunction contributes to obesity-associated metabolic disease and type 2 diabetes (T2D). Rodent studies have demonstrated that exercise training improves WAT function, but molecular studies investigating exercise training effects on WAT in humans have been limited, particularly in the context of metabolic disease. Here, we defined the subcutaneous WAT (scWAT) transcriptome in middle-aged adults (10 male, 19 female) that were classified by lower BMI (<27 kg/m2), higher BMI (≥27 kg/m2), and T2D status before and after a 10-week endurance exercise regimen. At baseline, 624 genes were significantly upregulated and 112 genes downregulated in the scWAT from higher BMI participants compared to lower BMI. There was a spectrum of pathway dysregulation in scWAT in higher BMI individuals, ranging from increased markers of extracellular matrix (ECM) deposition and inflammation to decreased circadian rhythm gene expression. In people with T2D, there were additional transcriptomic differences such as translation-related pathways, selenoamino acid metabolism, and proteoglycans. Exercise training had robust effects on the transcriptome regardless of metabolic status, and notably, for the high BMI and T2D groups, training reversed several of the detrimental gene expression patterns in a cell-type-specific manner. These beneficial exercise-induced transcriptomic adaptations significantly correlated with lower levels of free fatty acids and blood pressure, particularly in participants with higher BMI and T2D. By integrating our exercise training-modulated genes with GWAS meta-analysis of physical activity, genes influenced by exercise training in the higher BMI group showed a significant enrichment in genetic associations of exercise traits in the population. A circadian rhythm-related transcription factor NR1D1 was enriched in enhancers linked with both the exercise differentially expressed genes (DEGs) and GWAS signals, suggesting a link between the circadian rhythm and training-induced adaptations. These findings demonstrate that obesity and T2D result in marked, progressive alterations in cell-type specific gene transcription in scWAT, while endurance exercise training reverses many of the metabolic disease-associated adaptations. Identification of novel molecular pathways regulated by exercise training can lead to therapeutic targets for obesity and metabolic disease.

Introduction:olfactory impairment is a clinical feature of Parkinson's disease (PD) even in the early phases. Diffusion tensor imaging fiber tracking analysis (DTI-FTA) has been able to highlight changes in the olfactory tract in PD, however in early phases of PD this analysis has not been investigated. We investigated the olfactory tract by DTI-FTA in early stages of PD (ePD). Methods:All patients were assessed using the Italian Olfactory Identification Test (IOIT), the Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III) and the Hoehn and Yahr (H&Y) scale. Diffusion imaging was conducted by 3 T MRI. Results:Overall, 26 PD patients and 20 healthy subject were recruited. Hyposmia was observed in all PD patients. DTI-FTA of the olfactory tract showed significant mean diffusivity (MD) increases and a tract volume decrease for PD group. MD and age, only in the PD group, were significant for multiple correlations. Conclusion:DTI-FTA identified microstructural changes in the olfactory tract even in hyposmic ePD patients.

Exposure to a younger system can induce organismal rejuvenation, yet whether all tissues can be rejuvenated and by what mechanisms remains understudied. We performed heterochronic and isochronic transplantation of subcutaneous white adipose tissue (WAT) between young and old mice and longitudinally tracked changes in biological age. Transplantation accelerated tissue aging, and the molecular age of grafts shifted toward that of the host. Most importantly, old WAT was rejuvenated in a young body. Epigenetic and transcriptomic clocks revealed a reduction of predicted age, accompanied by coordinated activation of canonical and previously unrecognized thermogenic pathways. Molecular rejuvenation was further supported by architectural changes toward a youthful state, including reduced lipid droplet size and decreased cellular heterogeneity. Mitochondrial abundance and morphology remained unchanged, while collagen deposition increased. These results demonstrate that WAT biological age is partially reversible and identify molecular and cellular features underlying its rejuvenation.

Background: Maternal obesity during pregnancy can lead to increased risk for metabolic disease in offspring during adulthood, helping fuel the worldwide increase in obesity. Fortunately, studies in rodent models have established that female dams (F0) that perform voluntary wheel running exercise during pregnancy have first-generation (F1) offspring with improved glucose tolerance, suggesting a potential means to reduce the burden of generational metabolic disease transmission. We have shown that maternal exercise also affects F1 male offspring as sires, as their progeny (F2) have similarly improved metabolic health. Whether maternal exercise can affect F1 females in a manner that improves F2 offspring metabolism is not known. Here, we determined whether voluntary exercise by F0 grandmothers, via their F1 female progeny, produced F2 male and female offspring with an improved metabolic phenotype. Methods: Six-week-old C57BL/6 N female mice (F0) were fed a chow diet and either kept sedentary or exercise trained by voluntary wheel running for 2 weeks preconception and during pregnancy. Chow-fed sedentary F1 female offspring at 8 weeks of age were bred with age-matched untreated virgin males to generate F2 offspring. F2 were kept sedentary and chow fed and studied up to 52 weeks of age. Metabolic parameters were assessed, including food intake, body weight, body composition, glucose tolerance, systemic glucose and insulin levels, and liver metabolism. Results: Grandmaternal exercise did not significantly alter male and female F2 offspring body weights measured throughout the first year of life, nor was there an effect of grandmaternal exercise on F2 offspring fat mass or lean mass. Remarkably, despite the lack of effect on body weight parameters, grandmaternal exercise resulted in improved glucose tolerance and homeostatic model assessment for insulin resistance (HOMA-IR) in F2 offspring at 52 weeks of age, effects that were more pronounced in male F2 offspring. Conclusion: Voluntary wheel running exercise in female mice during pregnancy leads to metabolic improvements in her grand offspring, despite no direct intervention of the intermediate maternal generation. Maternal physical activity during pregnancy may reduce metabolic diseases in later generations.

Exercise training and cold exposure both improve systemic metabolism, but the mechanisms are not well established. Here, we tested the hypothesis that inguinal white adipose tissue (iWAT) adaptations are critical for these beneficial effects and determined the impact of exercise-trained and cold-exposed iWAT on systemic glucose metabolism and the iWAT proteome and secretome. Transplanting trained iWAT into sedentary mice improves glucose tolerance, while cold-exposed iWAT transplantation shows no such benefit. Compared to training, cold leads to more pronounced alterations in the iWAT proteome and secretome, downregulating >2,000 proteins but also boosting the thermogenic capacity of iWAT. In contrast, only training increases extracellular space and vesicle transport proteins, and only training upregulates proteins that correlate with favorable fasting glucose, suggesting fundamental changes in trained iWAT that mediate tissue-to-tissue communication. This study defines the unique exercise training- and cold exposure-induced iWAT proteomes, revealing distinct mechanisms for the beneficial effects of these interventions on metabolic health.

Background Olfactory dysfunction is a non-motor symptom and an important biomarker of Parkinson’s disease (PD) because of its high prevalence (> 90%). Whether hyposmia correlates with motor symptoms is unclear. In the present study, we aim to investigate the relationship between olfactory impairment with both motor and non-motor features and disease variables (disease duration, stage, and severity). Methods One-hundred fifty-four PD patients were evaluated. Odor identification ability was tested using Italian Olfactory Identification Test (IOIT). A comprehensive spectrum of motor and non-motor features was assessed. Cognitive function was investigated through MMSE. Patients were divided into 3 different clinical phenotypes using UPDRS-III: tremor-dominant type (TDT), akinetic-rigid type (ART), and mixed type (MXT). Results Three of the 33 IOIT items were most frequently misidentified: basil (74.3%), coffee (66.9%), and mushroom (59.6%). Hyposmia was found in 93%. Hyposmic patients were older than controls ( p = 0.01). Hoehn & Yahr (H&Y) score of 2 or greater was associated with higher probability of being hyposmic (OR = 5.2, p = 0.01). IOIT score did not significantly differ between TDT, ART, and MXT of analyzed PD patients. Performance to IOIT inversely correlated with age ( p < 0.01), disease duration ( p = 0.01), and H&Y score of 2 or higher ( p < 0.01). Clinical features that associated with higher IOIT score were freezing of gait (FOG) ( p < 0.001) and camptocormia ( p < 0.05). Conclusions In our cohort, IOIT scores showed a positive correlation with axial motor signs, but not with non-motor symptoms. IOIT may be a useful tool not only for supporting PD diagnosis but also for providing prognostic information about motor function.

Subcutaneous white adipose tissue (scWAT) is a dynamic storage and secretory organ that regulates systemic homeostasis, yet the impact of endurance exercise training (ExT) and sex on its molecular landscape is not fully established. Utilizing an integrative multi-omics approach, and leveraging data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we show profound sexual dimorphism in the scWAT of sedentary rats and in the dynamic response of this tissue to ExT. Specifically, the scWAT of sedentary females displays -omic signatures related to insulin signaling and adipogenesis, whereas the scWAT of sedentary males is enriched in terms related to aerobic metabolism. These sex-specific -omic signatures are preserved or amplified with ExT. Integration of multi-omic analyses with phenotypic measures identifies molecular hubs predicted to drive sexually distinct responses to training. Overall, this study underscores the powerful impact of sex on adipose tissue biology and provides a rich resource to investigate the scWAT response to ExT. Using a multi-omics approach, the authors examine the molecular drivers of sexual dimorphism in the subcutaneous adipose tissue from sedentary and endurance-trained rats. These data provide a valuable resource for adipose tissue-related research.

Abstract Disclosure: A. Shalit: None. M. Vamvini: None. P. Nigro: None. L.K. Simpson: None. H. Pan: None. J.M. Dreyfuss: None. L.J. Goodyear: Grant Recipient; Self; Daiichi Sankyo. R.J. Middelbeek: None. Exercise training induces a plethora of health benefits including improved glucose homeostasis, decreased cardiovascular disease, and improved cognitive function. An emerging concept is that many of these beneficial effects of exercise are mediated through the secretion of humoral factors into the blood. Identification of these exercise-regulated factors hold promise for novel treatments for disease. Here, we performed proteomic analysis to discover novel circulating factors in response to endurance exercise training in human participants. Given that nutritional status can affect the circulating proteome, another aim was to determine if proteomic adaptations to exercise training have similar effects under both fasted and random-fed conditions. Sedentary normoglycemic participants (3M/5F, age 22-41y) performed a supervised 10-week exercise training program, which by week 4 was 4x60 min exercise at 65-70% V̇O2peak. Fasted and random-sampling morning blood draws were collected pre-training and between 24-72 hours following the final training session. Proteomic detection was by SOMAscan. Exercise training significantly improved V̇O2peak by 17% (p=0.003). Out of 1,310 detected proteins, exercise training significantly changed 293 proteins in the fasted state and 360 proteins in the random-sampling state (p<0.05). Integration showed that 172 proteins were changed under both nutritional conditions (123 upregulated and 49 downregulated). Gene Set Enrichment Analysis (GSEA) of the commonly upregulated proteins showed that training resulted in enrichment in neuronal, hemostatic, and apoptotic pathways, whereas the downregulated proteins were enriched in neuronal and extracellular matrix processes. Since neuronal pathways were identified in both up and downregulated proteins, we focused our analysis there, identifying 31 upregulated and 4 downregulated neuronally-associated proteins. Importantly, exercise training reduced levels of CDK5, a protein that is hyperactivated in neurodegeneration and Alzheimer's disease. Moreover, GSTP1, a direct inhibitor of CDK5, along with downstream proteins inhibited by CDK5 (RAC1, STUB1, 14-3-3ε/YWHAE, HSP90AA1, CFL1), were significantly increased following exercise training.In conclusion, exercise training regulates circulating factors involved in neuronal, hemostatic, apoptotic, and extracellular matrix pathways, with these effects being independent of nutritional status. Our finding of exercise training-induced decreases in multiple proteins of the CDK5 pathway, a pathway whose downregulation is associated with neuroprotection, identify CDK5 as a novel and potentially important mediator of the beneficial effects of exercise training on cognitive function. Presentation: 6/1/2024

Freezing of gait is a frequent phenomenon and can be one of the most debilitating motor impairments in Parkinson’s disease, especially in the advanced stages. It is currently defined as a brief episodic absence or any marked reduction in the forward progression of the feet, despite the intention to walk. Greater severity of freezing of gait has been associated with more frequent falls, postural instability, and executive dysfunction. However, botulinum neurotoxin is one of the most widely administered therapies for motor and non-motor symptoms, including freezing of gait, in parkinsonism. To date, the literature has had conflicting results on the use of botulinum toxin in the treatment of freezing of gait in Parkinson’s disease patients. In light of this, we reviewed the findings of past studies that specifically investigated the effects of botulinum toxin on freezing of gait in Parkinson’s disease in order to better understand this issue.

Anti-IgLON5 disease is a rare and likely underdiagnosed subtype of autoimmune encephalitis. The disease displays a heterogeneous phenotype that includes sleep, movement and bulbar-associated dysfunction. The presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01∼DQB1*05:01, supports an autoimmune basis. In this study, a multicentric human leukocyte antigen (HLA) study of 87 anti-IgLON5 patients revealed a stronger association with HLA-DQ than HLA-DR. Specifically, we identified a predisposing rank-wise association with HLA-DQA1*01:05∼DQB1*05:01, HLA-DQA1*01:01∼DQB1*05:01 and HLA-DQA1*01:04∼DQB1*05:03 in 85% of patients. HLA sequences and binding cores for these three DQ heterodimers were similar, unlike those of linked DRB1 alleles, supporting a causal link to HLA-DQ. This association was further reflected in an increasingly later age of onset across each genotype group, with a delay of up to 11 years, while HLA-DQ-dosage dependent effects were also suggested by reduced risk in the presence of non-predisposing DQ1 alleles. The functional relevance of the observed HLA-DQ molecules was studied with competition binding assays. These proof-of-concept experiments revealed preferential binding of IgLON5 in a post-translationally modified, but not native, state to all three risk-associated HLA-DQ receptors. Further, a deamidated peptide from the Ig2-domain of IgLON5 activated T cells in two patients, compared with one control carrying HLA-DQA1*01:05∼DQB1*05:01. Taken together, these data support a HLA-DQ-mediated T-cell response to IgLON5 as a potentially key step in the initiation of autoimmunity in this disease.

Background: This is a retrospective longitudinal study comparing 374 patients with Parkinson’s disease (PD) who were treated in centers offering a specialized program of enhanced rehabilitation therapy in addition to expert outpatient care to 387 patients with PD, who only received expert outpatient care at movement disorders centers in Italy. Methods: The data are from subjects recruited in the Parkinson’s Outcome Project (POP) at six Italian centers that are part of a multicenter collaboration for care quality improvement (the Fresco Network). The effects were measured with a baseline and a follow-up clinical evaluation of the Timed-Up-and-Go test (TUG), Parkinson’s Disease Questionnaire (PDQ-39), and Multidimensional Caregiver Strain Index (MCSI), the number of falls and hospitalizations for any cause. We used a generalized linear mixed model with the dependent variables being the response variable, which included the covariates demographics, evaluation, and treatment variables. Results: We found that the subjects who underwent specialized enhanced rehabilitation had a better motor outcome over time than those who were managed by expert neurologists but had participated in community programs for exercise and other allied health interventions. The greatest effects were seen in patients in the early stages of the disease with a high amount of vigorous exercise per week in the last six months. Similar effects were seen for PDQ39, MCSI, the number of falls, and hospitalization. Conclusions: Long-term benefits to motor function and the quality of life in patients with PD and burden reduction in their caregivers can be achieved through a systematic program of specialized enhanced rehabilitation interventions.

Emerging data suggest that single bouts of exercise increase circulating hormones, cytokines, and EVs, and that these circulating factors may play a fundamental role in the beneficial effects of exercise on health. Here, we identify circulating factors in response to both acute exercise and exercise training and determine the effects of nutritional status on these responses. Blood samples were first collected before and immediately after an acute bout of maximal exercise in healthy, lean subjects (N=8, 3M/5F; age=27±2, V̇O2peak=28.4±1.2ml/kg/min). Subjects then completed a 10 wk moderate-intensity aerobic exercise training program (up to 65-70% VO2peak, 4x/week) with the same post-training sample collection. Proteomics (SOMAscan) quantified 1,310 circulating factors. In the untrained state, acute exercise upregulated 196 proteins and after training exercise upregulated only 65 proteins, with 47 proteins simultaneously upregulated in both the untrained and trained state. Interestingly, cellular component analysis showed that 1/3 of these shared proteins are localized in EVs. Next, we determined the baseline effects of exercise training in the fed and fasted state in the absence of acute exercise. Training upregulated 220 and 178 proteins in fed and fasted state, respectively. Exercise training commonly upregulated 120 proteins in the fed and fasted state with 1/3 localized in EVs. Integration using Vesiclepedia of the upregulated proteins in all 4 comparison groups showed 3 upregulated proteins in both acute exercise and training regardless of nutritional status: PPIF, PTPN6, and CLEC1B. These proteins are found in macrophages and neutrophils, and mediate immunomodulatory effects, promote tissue remodeling, and mitochondrial function. As EVs deliver molecules to cells altering their metabolism, they may play an important role in mediating the beneficial effects of exercise and warrant further mechanistic studies. Disclosure M.Vamvini: None. P.Nigro: None. L.Goodyear: None. R.J.W.Middelbeek: Research Support; Novo Nordisk. Funding Daiichi Sankyo; National Institutes of Health (R01DK099511 to L.G.), (5P30DK36836), (F32DK126432), (K23DK114550 to R.J.W.M.); Joslin Diabetes Center (to M.V.); Boston Area Diabetes Endocrinology Research Center (to R.J.W.M.)

Recent studies suggest that exercise-induced circulating factors are critical for the health benefits of exercise. In rodent models, we have identified NEGR1 as a cell adhesion molecule that is essential for remodeling white adipose tissue (WAT) innervation via sympathetic neurite outgrowth, and that NEGR1 is a secreted factor that may be involved inter-tissue communication. In humans, exercise training increases NEGR1 mRNA in subcutaneous WAT, but whether exercise regulates circulating NEGR1 in humans is not known. Here, we investigated the effects of a single bout of maximal exercise and exercise training on plasma NEGR1 in two different cohorts of obese subjects. Acute exercise (single bout until VO2MAX achieved) increased NEGR1 in plasma in all subjects (p<0.05; n=M3/F4). For the training study, obese subjects were randomized to one of three protocols: two different high intensity interval training (HIIT) protocols and one moderate continuous training (MCT) (Table), and blood samples were taken four days after the last training session. 1-HIIT and 4-HIIT similarly increased plasma NEGR1 concentrations, while there was no significant effect of MCT on NEGR1. In conclusion, we identify NEGR1 as a novel exercise-induced circulating factor in human subjects. We hypothesize that NEGR1 plays a role in tissue cross-talk mediating neuronal refinement in several tissues. Disclosure P.Nigro: None. N.P.Carbone: None. C.Bueno junior: None. M.Vamvini: None. L.Simpson: None. G.A.Hansbury: None. M.F.Hirshman: Stock/Shareholder; Abbott, AbbVie Inc., Amgen Inc., Colgate-Palmolive, Eli Lilly and Company, Medtronic. R.J.W.Middelbeek: Research Support; Novo Nordisk. L.Goodyear: None. Funding National Institutes of Health (R01DK099511, R01DK101043, K23DK114550, 5T32DK00726042, F32DK12643201); Joslin Diabetes Center (P30DK36836)

Maximal oxygen consumption (VO2peak), a measure of cardiorespiratory fitness (CRF), is a strong predictor of mortality. People with type 2 diabetes (T2D) have lower VO2peak compared to healthy controls, and unfortunately, studies suggest that training has limited effects to improve VO2peak in T2D. Although VO2peak is a key component, additional respiratory functions may also be important markers of cardio-metabolic fitness. Here, we determined the effects of a 10-week moderate-intensity exercise training program on VO2peak, power (indicator of muscle strength), VO2/work (index of the body’s efficiency at producing work), OUES (protective in heart failure), and ventilatory threshold (marker of aerobic endurance) in lean, obese, and T2D subjects. Training improved VO2peak in lean and obese, but not in T2D (Table 1). Likewise, training increased power, and tended to increase OUES in lean and obese, but not T2D. However, training was effective in increasing ventilatory threshold (VT) and VO2/Work in T2D, and also improved glycemic control (HbA1c). We hypothesize that the increased VT functions to improve training-induced muscular efficiency and capillary delivery, contributing to improved glycemic control. In conclusion, despite no change in VO2peak, exercise training increases multiple CRF and metabolic parameters in people with T2D, and should continue to be a mainstay in treatment of T2D. Disclosure R.Middelbeek: Research Support; Novo Nordisk. L.Simpson: None. G.A.Hansbury: None. N.P.Carbone: None. P.Nigro: None. S.J.Lessard: None. M.Vamvini: None. L.Goodyear: None. Funding National Institutes of Health (K23DK114550 to R.M.), (R01DK112283 to L.G.); Joslin Diabetes Center (T32DK07260-038, 5P30DK36836)