Type 2 diabetes is linked to higher physiologic markers of effort during exercise.

Background: People with type 2 diabetes (T2D) have lower rates of physical activity (PA) than the general population. This is significant because insufficient PA is linked to cardiovascular morbidity and mortality, particularly in individuals with T2D. Previously, we identified a novel barrier to physical activity: greater perceived effort during exercise in women. Specifically, women with T2D experienced exercise at low-intensity as greater effort than women without T2D at the same low-intensity - based on self-report and objective lactate measurements. A gap in the literature is whether T2D confers greater exercise effort in both sexes and across a range of work rates. Objectives: Our overarching objective was to address these gaps regarding the influence of T2D and relative work intensity on exercise effort. We hypothesized that T2D status would confer greater effort during exercise across a range of work rates below the aerobic threshold. Methods: This cross-sectional study enrolled males and post-menopausal females aged 50-75 years. Measures of exercise effort included: 1) heart rate, 2) lactate and 3) self-report of Rating of Perceived Exertion (RPE); each assessment was during the final minute of a 5-minute bout of treadmill exercise. Treadmill exercise was performed at 3 work rates: 1.5 mph, 2.0 mph, and 2.5 mph, respectively. To determine factors influencing effort, separate linear mixed effect models assessed the influence of T2D on each outcome of exercise effort, controlling for work rate intensity relative to peak oxygen consumption (%VO2peak). Models were adjusted for any significant demographic associations between effort and age (years), sex (male/female), baseline physical activity, or average blood glucose levels. Results: We enrolled n=19 people with T2D (47.4% female) and n=18 people (55.6% female) with no T2D. In the models adjusted for %VO2peak, T2D status was significantly associated with higher heart rate (p = 0.02) and lactate (p = 0.01), without a significant association with RPE (p = 0.58). Discussions: Across a range of low-to-moderate intensity work rates in older, sedentary males and females, a diagnosis of T2D conferred higher objective markers of effort but did not affect RPE. Greater objective effort cannot be fully attributed to impaired fitness, as it persisted despite adjustment for %VO2peak. In order to promote regular exercise and reduce cardiovascular risk for people with T2D, 1) further efforts to understand the mechanistic targets that influence physiologic exercise effort should be sought, and 2) comparison of the effort and tolerability of alternative exercise training prescriptions is warranted.

Effects of follicle-stimulating hormone on energy balance and tissue metabolic health after loss of ovarian function.

Loss of ovarian function imparts increased susceptibility to obesity and metabolic disease. These effects are largely attributed to decreased estradiol (E2), but the role of increased follicle-stimulating hormone (FSH) in modulating energy balance has not been fully investigated. Previous work that blocked FSH binding to its receptor in mice suggested this hormone may play a part in modulating body weight and energy expenditure after ovariectomy (OVX). We used an alternate approach to isolate the individual and combined contributions of FSH and E2 in mediating energy imbalance and changes in tissue-level metabolic health. Female Wistar rats were ovariectomized and given the gonadotropin releasing hormone (GnRH) antagonist degarelix to suppress FSH production. E2 and FSH were then added back individually and in combination for a period of 3 wk. Energy balance, body mass composition, and transcriptomic profiles of individual tissues were obtained. In contrast to previous studies, suppression and replacement of FSH in our paradigm had no effect on body weight, body composition, food intake, or energy expenditure. We did, however, observe organ-specific effects of FSH that produced unique transcriptomic signatures of FSH in retroperitoneal white adipose tissue. These included reductions in biological processes related to lipogenesis and carbohydrate transport. In addition, rats administered FSH had reduced liver triglyceride concentration (P < 0.001), which correlated with FSH-induced changes at the transcriptomic level. Although not appearing to modulate energy balance after loss of ovarian function in rats, FSH may still impart tissue-specific effects in the liver and white adipose tissue that might affect the metabolic health of those organs.NEW & NOTEWORTHY We find no effect of follicle-stimulating hormone (FSH) on energy balance using a novel model in which rats are ovariectomized, subjected to gonadotropin-releasing hormone antagonism, and systematically given back FSH by osmotic pump. However, tissue-specific effects of FSH on adipose tissue and liver were observed in this study. These include unique transcriptomic signatures induced by the hormone and a stark reduction in hepatic triglyceride accumulation.

Diabetes mellitus in breast cancer survivors: metabolic effects of endocrine therapy.

Breast cancer is the most common invasive malignancy in the world, with millions of survivors living today. Type 2 diabetes mellitus (T2DM) is also a globally prevalent disease that is a widely studied risk factor for breast cancer. Most breast tumours express the oestrogen receptor and are treated with systemic therapies designed to disrupt oestrogen-dependent signalling. Since the advent of targeted endocrine therapy six decades ago, the mortality from breast cancer has steadily declined; however, during the past decade, an elevated risk of T2DM after breast cancer treatment has been reported, particularly for those who received endocrine therapy. In this Review, we highlight key events in the history of endocrine therapies, beginning with the development of tamoxifen. We also summarize the sequence of reported adverse metabolic effects, which include dyslipidaemia, hepatic steatosis and impaired glucose tolerance. We discuss the limitations of determining a causal role for breast cancer treatments in T2DM development from epidemiological data and describe informative preclinical studies that suggest complex mechanisms through which endocrine therapy might drive T2DM risk and progression. We also reinforce the life-saving benefits of endocrine therapy and highlight the need for better predictive biomarkers of T2DM risk and preventive strategies for the growing population of breast cancer survivors.

Sex Differences in the Skeletal Muscle Response to a High Fat, High Sucrose Diet in Rats.

Men are diagnosed with type 2 diabetes at lower body mass indexes than women; the role of skeletal muscle in this sex difference is poorly understood. Type 2 diabetes impacts skeletal muscle, particularly in females who demonstrate a lower oxidative capacity compared to males. To address mechanistic differences underlying this sex disparity, we investigated skeletal muscle mitochondrial respiration in female and male rats in response to chronic high-fat, high-sugar (HFHS) diet consumption. Four-week-old Wistar Rats were fed a standard chow or HFHS diet for 14 weeks to identify sex-specific adaptations in mitochondrial respirometry and characteristics, transcriptional patterns, and protein profiles. Fat mass was greater with the HFHS diet in both sexes when controlled for body mass (p < 0.0001). Blood glucose and insulin resistance were greater in males (p = 0.01) and HFHS-fed rats (p < 0.001). HFHS-fed males had higher mitochondrial respiration compared with females (p < 0.01 sex/diet interaction). No evidence of a difference by sex or diet was found for mitochondrial synthesis, dynamics, or quality to support the mitochondrial respiration sex/diet interaction. However, transcriptomic analyses indicate sex differences in nutrient handling. Sex-specific differences occurred in PI3K/AKT signaling, PPARα/RXRα, and triacylglycerol degradation. These findings may provide insight into the clinical sex differences in body mass index threshold for diabetes development and tissue-specific progression of insulin resistance.

Obesity dominates early effects on cardiac structure and arterial stiffness in people with type 2 diabetes.

OBJECTIVE: Type 2 diabetes (T2D) and obesity are global epidemics leading to excess cardiovascular disease (CVD). This study investigates standard and novel cardiac MRI parameters to detect subclinical cardiac and central vascular dysfunction in inactive people with and without T2D. METHODS: Physically inactive age and BMI-similar premenopausal women and men with ( n  = 22) and without [ n  = 34, controls with overweight/obesity (CWO)] uncomplicated T2D were compared to an age-similar and sex-similar reference control cohort ( n  = 20). Left ventricular (LV) structure, function, and aortic stiffness were assessed by MRI. Global arterial pulse wave velocity (PWV) was assessed using carotid-to-femoral applanation tonometry. Regional PWV was measured via 2D phase-contrast MRI and 4D flow MRI. RESULTS: Global arterial PWV did not differ between CWO and T2D. 2D PC-MRI PWV in the ascending aorta was higher in people with T2D compared with CWOs ( P  < 0.01). 4D flow PWV in the thoracic aorta was higher in CWO ( P  < 0.01), and T2D ( P  < 0.001) compared with RC. End-diastolic volume, end-systolic volume, stroke volume, and cardiac output were lower in CWO and T2D groups compared with reference control. CONCLUSION: Subclinical changes in arterial stiffening and cardiac remodeling in inactive CWO and T2D compared with reference control support obesity and/or physical inactivity as determinants of incipient CVD complications in uncomplicated T2D. Future studies should determine the mechanistic causes of the CVD complications in greater detail in order to create therapeutic targets. CLINICAL TRIAL REGISTRATION: Cardiovascular Mechanisms of Exercise Intolerance in Diabetes and the Role of Sex (NCT03419195).

Sex Differences in Physical Activity Among Individuals With Type 2 Diabetes Across the Life Span: A Systematic Review and Meta-analysis.

BACKGROUND: Physical activity (PA) is a cornerstone of type 2 diabetes mellitus (T2DM) treatment. Sex differences in PA behavior or barriers/facilitators to PA among individuals with T2DM are unclear. PURPOSE: To summarize the evidence related to sex differences in participation in PA and barriers/facilitators to PA among individuals with T2DM across the life span. DATA SOURCES: Systematic searches (CRD42021254246) were conducted with Ovid MEDLINE, Embase, Web of Science, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Allied and Complementary Medicine Database (AMED), APA PsychInfo, and SPORTDiscus. STUDY SELECTION: We included studies with assessment of PA, sedentary behaviors (SB), or barriers/facilitators to PA among individuals with T2DM by sex or gender. DATA EXTRACTION: Participant characteristics, meeting PA guidelines, participation in PA and SB, and barriers/facilitators to PA were extracted by two independent reviewers. DATA SYNTHESIS: A total of 53 articles (65,344 participants) were included in the systematic review and 21 articles in the meta-analysis. Sex differences were not observed in meeting of PA guidelines among adolescents (odds ratio 0.70 [95% CI 0.31, 1.59]), but males were more likely than females to meet PA guidelines among adults (1.65 [1.36, 2.01]) and older adults (1.63 [1.27, 2.09]). Males performed more moderate-to-vigorous PA (MVPA) than females across all age-groups. Common barriers to PA were lack of time (men) and lack of social support and motivation (women). LIMITATIONS: Limitations include heterogeneity of measures used to assess PA and lack of stratification of data by sex. CONCLUSIONS: Sex differences in meeting PA guidelines were not observed among adolescents but were apparent among adults and older adults with T2DM. Females consistently engaged in less MVPA than males across the life span.

Glucose Uptake by Skeletal Muscle within the Contexts of Type 2 Diabetes and Exercise: An Integrated Approach.

Type 2 diabetes continues to negatively impact the health of millions. The inability to respond to insulin to clear blood glucose (insulin resistance) is a key pathogenic driver of the disease. Skeletal muscle is the primary tissue for maintaining glucose homeostasis through glucose uptake via insulin-dependent and -independent mechanisms. Skeletal muscle is also responsive to exercise-meditated glucose transport, and as such, exercise is a cornerstone for glucose management in people with type 2 diabetes. Skeletal muscle glucose uptake requires a concert of events. First, the glucose-rich blood must be transported to the skeletal muscle. Next, the glucose must traverse the endothelium, extracellular matrix, and skeletal muscle membrane. Lastly, intracellular metabolic processes must be activated to maintain the diffusion gradient to facilitate glucose transport into the cell. This review aims to examine the physiology at each of these steps in healthy individuals, analyze the dysregulation affecting these pathways associated with type 2 diabetes, and describe the mechanisms by which exercise acts to increase glucose uptake.

Single-leg exercise training augments in vivo skeletal muscle oxidative flux and vascular content and function in adults with type 2 diabetes.

KEY POINTS: People with type 2 diabetes (T2D) have impaired skeletal muscle oxidative flux due to limited oxygen delivery. In the current study, this impairment in oxidative flux in people with T2D was abrogated with a single-leg exercise training protocol. Additionally, single-leg exercise training increased skeletal muscle CD31 content, calf blood flow and state 4 mitochondrial respiration in all participants. ABSTRACT: Cardiorespiratory fitness is impaired in type 2 diabetes (T2D), conferring significant cardiovascular risk in this population; interventions are needed. Previously, we reported that a T2D-associated decrement in skeletal muscle oxidative flux is ameliorated with acute use of supplemental oxygen, suggesting that skeletal muscle oxygenation is rate-limiting to in vivo mitochondrial oxidative flux during exercise in T2D. We hypothesized that single-leg exercise training (SLET) would improve the T2D-specific impairment in in vivo mitochondrial oxidative flux during exercise. Adults with (n = 19) and without T2D (n = 22) with similar body mass indexes and levels of physical activity participated in two weeks of SLET. Following SLET, in vivo oxidative flux measured by 31 P-MRS increased in participants with T2D, but not people without T2D, measured by the increase in initial phosphocreatine synthesis (P = 0.0455 for the group × exercise interaction) and maximum rate of oxidative ATP synthesis (P = 0.0286 for the interaction). Additionally, oxidative phosphorylation increased in all participants with SLET (P = 0.0209). After SLET, there was no effect of supplemental oxygen on any of the in vivo oxidative flux measurements in either group (P > 0.02), consistent with resolution of the T2D-associated oxygen limitation previously observed at baseline in subjects with T2D. State 4 mitochondrial respiration also improved in muscle fibres ex vivo. Skeletal muscle vasculature content and calf blood flow increased in all participants with SLET (P < 0.0040); oxygen extraction in the calf increased only in T2D (P = 0.0461). SLET resolves the T2D-associated impairment of skeletal muscle in vivo mitochondrial oxidative flux potentially through improved effective blood flow/oxygen delivery.

Breast Cancer Endocrine Therapy Promotes Weight Gain With Distinct Adipose Tissue Effects in Lean and Obese Female Mice.

Breast cancer survivors treated with tamoxifen and aromatase inhibitors report weight gain and have an elevated risk of type 2 diabetes, especially if they have obesity. These patient experiences are inconsistent with, preclinical studies using high doses of tamoxifen which reported acute weight loss. We investigated the impact of breast cancer endocrine therapies in a preclinical model of obesity and in a small group of breast adipose tissue samples from women taking tamoxifen to understand the clinical findings. Mature female mice were housed at thermoneutrality and fed either a low-fat/low-sucrose (LFLS) or a high-fat/high-sucrose (HFHS) diet. Consistent with the high expression of Esr1 observed in mesenchymal stem cells from adipose tissue, endocrine therapy was associated with adipose accumulation and more preadipocytes compared with estrogen-treated control mice but resulted in fewer adipocyte progenitors only in the context of HFHS. Analysis of subcutaneous adipose stromal cells revealed diet- and treatment-dependent effects of endocrine therapies on various cell types and genes, illustrating the complexity of adipose tissue estrogen receptor signaling. Breast cancer therapies supported adipocyte hypertrophy and associated with hepatic steatosis, hyperinsulinemia, and glucose intolerance, particularly in obese females. Current tamoxifen use associated with larger breast adipocyte diameter only in women with obesity. Our translational studies suggest that endocrine therapies may disrupt adipocyte progenitors and support adipocyte hypertrophy, potentially leading to ectopic lipid deposition that may be linked to a greater type 2 diabetes risk. Monitoring glucose tolerance and potential interventions that target insulin action should be considered for some women receiving life-saving endocrine therapies for breast cancer.

Persistent Metabolic Effects of Tamoxifen: Considerations for an Experimental Tool and Clinical Breast Cancer Treatment.

The selective estrogen receptor (ER) modulator tamoxifen is frequently used in preclinical studies to induce Cre recombinase and generate conditional transgenic mice. In addition, it is often prescribed to treat ER-positive breast cancer, which is diagnosed in approximately 150 000 people each year. In mice, protocols to activate Cre-ER transgenes require tamoxifen administration by several methods, including oral gavage, IP injection, or intragastric injection, spanning a wide range of doses to achieve transgene induction. As a result, the reported metabolic effects of tamoxifen treatment are not always consistent with anecdotal reports from breast cancer patients, or with expected outcomes based on the overall metabolically protective role of estrogen. A greater awareness of tamoxifen's adverse metabolic effects is critical to designing studies with appropriate controls, especially those investigations focused on metabolic outcomes.

Acute effects of sedentary breaks on vascular health in adults at risk for type 2 diabetes: A systematic review.

The aim of this systematic review was to evaluate the available evidence regarding the acute effects of interrupting/breaking up prolonged sedentary behavior (SB) on vascular health among individuals at elevated risk for type 2 diabetes (T2D). Searches of MEDLINE, Embase, Web of Science, and Cochrane Library databases were conducted on April 7, 2020. Included studies: (1) examined the effect of breaking up prolonged SB in adults with or at elevated risk for T2D and (2) assessed a vascular health outcome, such as blood pressure (BP), flow-mediated dilation (FMD), pulse-wave velocity, or endothelin-1. A total of 20 articles (17 unique studies) were included. Only three studies reported adequate statistical power for the specified vascular outcome. The available evidence suggests that light and moderate intensity activity breaks are effective in acutely lowering BP when compared to prolonged sitting. The small number of studies that included FMD or other vascular outcomes prohibits conclusions regarding the impact of SB breaks on these outcomes. Few studies evaluating the impact of breaking up SB among adults at risk for T2D have included and been adequately powered to examine vascular outcomes, but our preliminary finding, that certain SB breaks improve BP, provides proof-of-concept for this line of inquiry. Future studies should examine both the acute and chronic vascular effects of breaking up SB among individuals most vulnerable to the effects of SB (e.g. older adults, those with T2D), as these individuals are both highly sedentary and at greatest risk of poor health outcomes. PROSPERO ID: CRD42020183423.

Mechanistic Causes of Reduced Cardiorespiratory Fitness in Type 2 Diabetes.

Type 2 diabetes (T2D) has been rising in prevalence in the United States and worldwide over the past few decades and contributes to significant morbidity and premature mortality, primarily due to cardiovascular disease (CVD). Cardiorespiratory fitness (CRF) is a modifiable cardiovascular (CV) risk factor in the general population and in people with T2D. Young people and adults with T2D have reduced CRF when compared with their peers without T2D who are similarly active and of similar body mass index. Furthermore, the impairment in CRF conferred by T2D is greater in women than in men. Various factors may contribute to this abnormality in people with T2D, including insulin resistance and mitochondrial, vascular, and cardiac dysfunction. As proof of concept that understanding the mediators of impaired CRF in T2D can inform intervention, we previously demonstrated that an insulin sensitizer improved CRF in adults with T2D. This review focuses on how contributing factors influence CRF and why they may be compromised in T2D. Functional exercise capacity is a measure of interrelated systems biology; as such, the contribution of derangement in each of these factors to T2D-mediated impairment in CRF is complex and varied. Therefore, successful approaches to improve CRF in T2D should be multifaceted and individually designed. The current status of this research and future directions are outlined.

Sitagliptin improves diastolic cardiac function but not cardiorespiratory fitness in adults with type 2 diabetes.

BACKGROUND: People with type 2 diabetes mellitus (T2D) have preclinical cardiac and vascular dysfunction associated with low cardiorespiratory fitness (CRF). This is especially concerning because CRF is a powerful predictor of cardiovascular mortality, a primary issue in T2D management. Glucagon-like pepetide-1 (GLP-1) augments cardiovascular function and our previous data in rodents demonstrate that potentiating the GLP-1 signal with a dipeptidyl peptidase-4 (DPP4) inhibitor augments CRF. Lacking are pharmacological treatments which can target T2D-specific physiological barriers to exercise to potentially permit adaptations necessary to improve CRF and thereby health outcomes in people with T2D. We therefore hypothesized that administration of a DPP4-inhibitor (sitagliptin) would improve CRF in adults with T2D. METHODS AND RESULTS: Thirty-eight participants (64 ±â€¯1 years; mean ±â€¯SE) with T2D were randomized in a double-blinded study to receive 100 mg/day sitagliptin, 2 mg/day glimepiride, or placebo for 3 months after baseline measurements. Fasting glucose decreased with both glimepiride and sitagliptin compared with placebo (P = 0.002). CRF did not change in any group (Placebo: Pre: 15.4 ±â€¯0.9 vs. Post: 16.1 ±â€¯1.1 ml/kg/min vs. Glimepiride: 18.5 ±â€¯1.0 vs. 17.7 ±â€¯1.2 ml/kg/min vs. Sitagliptin: 19.1 ±â€¯1.2 vs. 18.3 ±â€¯1.1 ml/kg/min; P = 0.3). Sitagliptin improved measures of cardiac diastolic function, however, measures of vascular function did not change with any treatment. CONCLUSIONS: Three months of sitagliptin improved diastolic cardiac function, however, CRF did not change. These data suggest that targeting the physiological contributors to CRF with sitagliptin alone is not an adequate strategy to improve CRF in people with T2D. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov NCT01951339.

Glucagon-like peptide-1 receptor antagonism impairs basal exercise capacity and vascular adaptation to aerobic exercise training in rats.

Cardiorespiratory fitness (CRF) inversely predicts cardiovascular (CV) mortality and CRF is impaired in people with type 2 diabetes (T2D). Aerobic exercise training (ET) improves CRF and is associated with decreased risk of premature death in healthy and diseased populations. Understanding the mechanisms contributing to ET adaptation may identify targets for reducing CV mortality of relevance to people with T2D. The antihyperglycemic hormone glucagon-like peptide-1 (GLP-1) influences many of the same pathways as exercise and may contribute to CV adaptation to ET. We hypothesized that GLP-1 is necessary for adaptation to ET. Twelve-week-old male Wistar rats were randomized (n = 8-12/group) to receive PBS or GLP-1 receptor antagonist (exendin 9-39 (Ex(9-39)) via osmotic pump for 4 weeks ± ET. CRF was greater with ET (P < 0.01). Ex(9-39) treatment blunted CRF in both sedentary and ET rats (P < 0.001). Ex(9-39) attenuated acetylcholine-mediated vasodilation, while this response was maintained with Ex(9-39)+ET (P = 0.04). Aortic stiffness was greater with Ex(9-39) (P = 0.057) and was made worse when Ex(9-39) was combined with ET (P = 0.004). Ex vivo aortic vasoconstriction with potassium and phenylephrine was lower with Ex(9-39) (P < 0.0001). Carotid strain improved with PBS + ET but did not change in the Ex(9-39) rats with ET (P < 0.0001). Left ventricular mitochondrial respiration was elevated with Ex(9-39) (P < 0.02). GLP-1 receptor antagonism impairs CRF with and without ET, attenuates the vascular adaptation to ET, and elevates cardiac mitochondrial respiration. These data suggest that GLP-1 is integral to the adaptive vascular response to ET.

Mechanisms of Aerobic Exercise Impairment in Diabetes: A Narrative Review.

The prevalence of diabetes in the United States and globally has been rapidly increasing over the last several decades. There are now estimated to be 30.3 million people in the United States and 422 million people worldwide with diabetes. Diabetes is associated with a greatly increased risk of cardiovascular mortality, which is the leading cause of death in adults with diabetes. While exercise training is a cornerstone of diabetes treatment, people with diabetes have well-described aerobic exercise impairments that may create an additional diabetes-specific barrier to adding regular exercise to their lifestyle. Physiologic mechanisms linked to exercise impairment in diabetes include insulin resistance, cardiac abnormalities, mitochondrial function, and the ability of the body to supply oxygen. In this paper, we highlight the abnormalities of exercise in type 2 diabetes as well as potential therapeutic approaches.

Supplemental Oxygen Improves In Vivo Mitochondrial Oxidative Phosphorylation Flux in Sedentary Obese Adults With Type 2 Diabetes.

Type 2 diabetes is associated with impaired exercise capacity. Alterations in both muscle perfusion and mitochondrial function can contribute to exercise impairment. We hypothesized that impaired muscle mitochondrial function in type 2 diabetes is mediated, in part, by decreased tissue oxygen delivery and would improve with oxygen supplementation. Ex vivo muscle mitochondrial content and respiration assessed from biopsy samples demonstrated expected differences in obese individuals with (n = 18) and without (n = 17) diabetes. Similarly, in vivo mitochondrial oxidative phosphorylation capacity measured in the gastrocnemius muscle via 31P-MRS indicated an impairment in the rate of ADP depletion with rest (27 ± 6 s [diabetes], 21 ± 7 s [control subjects]; P = 0.008) and oxidative phosphorylation (P = 0.046) in type 2 diabetes after isometric calf exercise compared with control subjects. Importantly, the in vivo impairment in oxidative capacity resolved with oxygen supplementation in adults with diabetes (ADP depletion rate 5.0 s faster, P = 0.012; oxidative phosphorylation 0.046 ± 0.079 mmol/L/s faster, P = 0.027). Multiple in vivo mitochondrial measures related to HbA1c These data suggest that oxygen availability is rate limiting for in vivo mitochondrial oxidative exercise recovery measured with 31P-MRS in individuals with uncomplicated diabetes. Targeting muscle oxygenation could improve exercise function in type 2 diabetes.

Acute vitamin C improves cardiac function, not exercise capacity, in adults with type 2 diabetes.

BACKGROUND: People with type 2 diabetes (T2D) have impaired exercise capacity, even in the absence of complications, which is predictive of their increased cardiovascular mortality. Cardiovascular dysfunction is one potential cause of this exercise defect. Acute infusion of vitamin C has been separately shown to improve diastolic and endothelial function in prior studies. We hypothesized that acute vitamin C infusion would improve exercise capacity and that these improvements would be associated with improved cardiovascular function. METHODS: Adults with T2D (n = 31, 7 female, 24 male, body mass index (BMI): 31.5 ± 0.8 kg/m2) and BMI-similar healthy adults (n = 21, 11 female, 10 male, BMI: 30.4 ± 0.7 kg/m2) completed two randomly ordered visits: IV infusion of vitamin C (7.5 g) and a volume-matched saline infusion. During each visit peak oxygen uptake (VO2peak), brachial artery flow mediated dilation (FMD), reactive hyperemia (RH; plethysmography), and cardiac echocardiography were measured. General linear mixed models were utilized to assess the differences in all study variables. RESULTS: Acute vitamin C infusion improved diastolic function, assessed by lateral and septal E:E' (P < 0.01), but did not change RH (P = 0.92), or VO2peak (P = 0.33) in any participants. CONCLUSION: Acute vitamin C infusion improved diastolic function but did not change FMD, forearm reactive hyperemia, or peak exercise capacity. Future studies should further clarify the role of endothelial function as well as other possible physiological causes of exercise impairment in order to provide potential therapeutic targets.Trial registration NCT00786019. Prospectively registered May 2008.

Metformin prevents ischaemic ventricular fibrillation in metabolically normal pigs.

AIMS/HYPOTHESIS: Metformin is the drug most often used to treat type 2 diabetes. Evidence suggests that metformin may reduce mortality of individuals with type 2 diabetes, but the mechanism of such an effect is unknown and outcomes of metformin treatment in people without diabetes have not been determined. If metformin favourably affected mortality of non-diabetic individuals, it might have even broader therapeutic utility. We evaluated the effect of metformin on myocardial energetics and ischaemic ventricular fibrillation (VF) in metabolically normal pigs. METHODS: Domestic farm pigs were treated with metformin (30 mg kg-1 day-1 orally for 2-3 weeks; n = 36) or received no treatment (n = 37). Under anaesthesia, pigs underwent up to 90 min low-flow regional myocardial ischaemia followed by 45 min of reperfusion. Pigs were monitored for arrhythmia, monophasic action potential morphology, haemodynamics and myocardial substrate utilisation, AMP-activated protein kinase (AMPK) phosphorylation activity and ATP concentration. RESULTS: Death due to VF occurred in 12% of pigs treated with metformin compared with 50% of untreated controls (p = 0.03). The anti-fibrillatory effect of metformin was associated with attenuation of action potential shortening in ischaemic myocardium (p = 0.02) and attenuation of the difference in action potential duration between ischaemic and non-ischaemic regions (p < 0.001) compared with untreated controls. Metformin had no effect on myocardial contractile function, oxygen consumption, or glucose or lactate utilisation. During ischaemia, however, metformin treatment amplified the activation of AMPK and preserved ATP concentration in myocardium compared with untreated controls (each p < 0.05). CONCLUSIONS/INTERPRETATION: Chronic treatment of metabolically normal pigs with metformin at a clinically relevant dose reduces mortality from ischaemic VF. This protection is associated with preservation of myocardial energetics during ischaemia. Maintenance of myocardial ATP concentration during ischaemia is likely to prevent action potential shortening, heterogeneity of repolarisation, and propensity for lethal arrhythmia. The findings suggest that metformin might be protective in non-diabetic individuals with coronary heart disease.

Ergogenic properties of metformin in simulated high altitude.

Metformin augments glucose/glycogen regulation and may acutely promote fatigue resistance during high-intensity exercise. In hypobaric environments, such as high altitude, the important contribution of carbohydrates to physiological function is accentuated as glucose/glycogen dependence is increased. Because hypoxia/hypobaria decreases insulin sensitivity, replenishing skeletal muscle glycogen in high altitude becomes challenging and subsequent physical performance may be compromised. We hypothesized that in conditions where glycogen repletion was critical to physical outcomes, metformin would attenuate hypoxia-mediated decrements in exercise performance. On three separate randomly ordered occasions, 13 healthy men performed glycogen-depleting exercise and ingested a low-carbohydrate dinner (1200 kcals, <10% carbohydrate). The next morning, in either normoxia or hypoxia (FiO2 =0.15), they ingested a high-carbohydrate breakfast (1225 kcals, 70% carbohydrate). Placebo (719 mg maltodextrin) or metformin (500 mg BID) was consumed 3 days prior to each hypoxia visit. Subjects completed a 12.5 km cycle ergometer time trial 3.5 hours following breakfast. Hypoxia decreased resting and exercise oxyhemoglobin saturation (P<.001). Neither hypoxia nor metformin affected the glucose response to breakfast (P=.977), however, compared with placebo, metformin lowered insulin concentration in hypoxia 45 minutes after breakfast (64.1±6.6 µU/mL vs 48.5±7.8 µU/mL; mean±SE; P<.001). Post-breakfast, pre-exercise vastus lateralis glycogen content increased in normoxia (+33%: P=.025) and in hypoxia with metformin (+81%; P=.006), but not in hypoxia with placebo (+27%; P=.167). Hypoxia decreased time trial performance compared with normoxia (P<.01). This decrement was similar with placebo (+2.6±0.8 minutes) and metformin (+1.6±0.3 minutes). These results indicate that metformin promotes glycogen synthesis but not endurance exercise performance in healthy men exposed to simulated high altitude.

Concurrent Beet Juice and Carbohydrate Ingestion: Influence on Glucose Tolerance in Obese and Nonobese Adults.

Insulin resistance and obesity are characterized by low nitric oxide (NO) bioavailability. Insulin sensitivity is improved with stimulation of NO generating pathways. Consumption of dietary nitrate (NO3-) increases NO formation, via NO3- reduction to nitrite (NO2-) by oral bacteria. We hypothesized that acute dietary nitrate (beet juice) ingestion improves insulin sensitivity in obese but not in nonobese adults. 12 nonobese (body mass index: 26.3 ± 0.8 kg/m2 (mean ± SE)) and 10 obese adults (34.0 ± 0.8 kg/m2) ingested beet juice, supplemented with 25 g of glucose (carbohydrate load: 75 g), with and without prior use of antibacterial mouthwash to inhibit NO3- reduction to NO2-. Blood glucose concentrations after beet juice and glucose ingestion were greater in obese compared with nonobese adults at 60 and 90 minutes (P = 0.004). Insulin sensitivity, as represented by the Matsuda Index (where higher values reflect greater insulin sensitivity), was lower in obese compared with nonobese adults (P = 0.009). Antibacterial mouthwash rinsing decreased insulin sensitivity in obese (5.7 ± 0.7 versus 4.9 ± 0.6) but not in nonobese (8.1 ± 1.0 versus 8.9 ± 0.9) adults (P = 0.048). In conclusion, insulin sensitivity was improved in obese but not in nonobese adults following coingestion of beet juice and glucose when oral bacteria nitrate reduction was not inhibited. Obese adults may benefit from ingestion of healthy nitrate-rich foods during meals.