Muscle mitochondrial function is impaired in adults with type 1 diabetes.

AIMS: Type 1 diabetes has been associated with mitochondrial dysfunction. However, the mechanism of this dysfunction in adults remains unclear. METHODS: A secondary analysis was conducted using data from several clinical trials measuring in-vivo and ex-vivo mitochondrial function in adults with type 1 diabetes (n = 34, age 38.8 ± 14.6 years) and similarly aged controls (n = 59, age 44.6 ± 13.9 years). In-vivo mitochondrial function was assessed before, during, and after isometric exercise with 31phosphorous magnetic resonance spectroscopy. High resolution respirometry of vastus lateralis muscle tissue was used to assess ex-vivo measures. RESULTS: In-vivo data showed higher rates of anaerobic glycolysis (p = 0.013), and a lower maximal mitochondrial oxidative capacity (p = 0.012) and mitochondrial efficiency (p = 0.024) in adults with type 1 diabetes. After adjustment for age and percent body fat maximal mitochondrial capacity (p = 0.014) continued to be lower and anaerobic glycolysis higher (p = 0.040) in adults with type 1 diabetes. Ex-vivo data did not demonstrate significant differences between the two groups. CONCLUSIONS: The in-vivo analysis demonstrates that adults with type 1 diabetes have mitochondrial dysfunction. This builds on previous research showing in-vivo mitochondrial dysfunction in youths with type 1 diabetes and suggests that defects in substrate or oxygen delivery may play a role in in-vivo dysfunction.

Sex Differences Across the Lifespan: A Focus on Cardiometabolism.

Women's health and sex differences research remain understudied. In 2022, to address the topic of sex differences, the Ludeman Family Center for Women's Health Research (LFCWHR) at the University of Colorado (LudemanCenter.org) held its third National Conference, "Sex Differences Across the Lifespan: A Focus on Metabolism." The research presentations and discussions from the 2022 conference addressed cardiometabolic sex differences across the lifespan and included sessions focusing on scientific methods with which to study sex differences, effects of estrogen on metabolism, and sex differences in cardiovascular disease-implications for women and policy among others. Over 100 participants, including basic scientists, clinical scientists, policymakers, advocacy group leaders, and federal agency leadership participated. The meeting proceedings reveal that although exciting advances in the area of sex differences have taken place, significant questions and gaps remain about women's health and sex differences in critical areas of health. Identifying these gaps and the subsequent research that will result may lead to important breakthroughs.

Mitochondrial respiration is lower in the intrauterine growth-restricted fetal sheep heart.

Fetuses affected by intrauterine growth restriction have an increased risk of developing heart disease and failure in adulthood. Compared with controls, late gestation intrauterine growth-restricted (IUGR) fetal sheep have fewer binucleated cardiomyocytes, reflecting a more immature heart, which may reduce mitochondrial capacity to oxidize substrates. We hypothesized that the late gestation IUGR fetal heart has a lower capacity for mitochondrial oxidative phosphorylation. Left (LV) and right (RV) ventricles from IUGR and control (CON) fetal sheep at 90% gestation were harvested. Mitochondrial respiration (states 1-3, LeakOmy, and maximal respiration) in response to carbohydrates and lipids, citrate synthase (CS) activity, protein expression levels of mitochondrial oxidative phosphorylation complexes (CI-CV), and mRNA expression levels of mitochondrial biosynthesis regulators were measured. The carbohydrate and lipid state 3 respiration rates were lower in IUGR than CON, and CS activity was lower in IUGR LV than CON LV. However, relative CII and CV protein levels were higher in IUGR than CON; CV expression level was higher in IUGR than CON. Genes involved in lipid metabolism had lower expression in IUGR than CON. In addition, the LV and RV demonstrated distinct differences in oxygen flux and gene expression levels, which were independent from CON and IUGR status. Low mitochondrial respiration and CS activity in the IUGR heart compared with CON are consistent with delayed cardiomyocyte maturation, and CII and CV protein expression levels may be upregulated to support ATP production. These insights will provide a better understanding of fetal heart development in an adverse in utero environment. KEY POINTS: Growth-restricted fetuses have a higher risk of developing and dying from cardiovascular diseases in adulthood. Mitochondria are the main supplier of energy for the heart. As the heart matures, the substrate preference of the mitochondria switches from carbohydrates to lipids. We used a sheep model of intrauterine growth restriction to study the capacity of the mitochondria in the heart to produce energy using either carbohydrate or lipid substrates by measuring how much oxygen was consumed. Our data show that the mitochondria respiration levels in the growth-restricted fetal heart were lower than in the normally growing fetuses, and the expression levels of genes involved in lipid metabolism were also lower. Differences between the right and left ventricles that are independent of the fetal growth restriction condition were identified. These results indicate an impaired metabolic maturation of the growth-restricted fetal heart associated with a decreased capacity to oxidize lipids postnatally.

Perivascular adipose tissue remodeling impairs vasoreactivity in thermoneutral-housed rats.

Objective: Vascular pathology, characterized by impaired vasoreactivity and mitochondrial respiration, differs between the sexes. Housing rats under thermoneutral (TN) conditions causes vascular dysfunction and perturbed metabolism. We hypothesized that perivascular adipose tissue (PVAT), a vasoregulatory adipose depot with brown adipose tissue (BAT) phenotype, remodels to a white adipose (WAT) phenotype in rats housed at TN, driving diminished vasoreactivity in a sex-dependent manner. Methods: Male and female Wistar rats were housed at either room temperature (RT) or TN. Endpoints included changes in PVAT morphology, vasoreactivity in vessels with intact PVAT or transferred to PVAT of the oppositely-housed animal, vessel stiffness, vessel mitochondrial respiration and cellular signaling. Results: Remodeling of PVAT was observed in rats housed at TN; animals in this environment showed PVAT whitening and displayed diminished aortae vasodilation (p<0.05), different between the sexes. Juxtaposing PVAT from RT rats onto aortae from TN rats in females corrected vasodilation (p<0.05); this did not occur in males. In aortae of all animals housed at TN, mitochondrial respiration was significantly diminished in lipid substrate experiments (p<0.05), and there was significantly less expression of peNOS (p<0.001). Conclusions: These data are consistent with TN-induced remodeling of PVAT, notably associated with sex-specific blunting of vasoreactivity, diminished mitochondrial respiration, and altered cellular signaling.

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.

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.

A narrative review of exercise participation among adults with prediabetes or type 2 diabetes: barriers and solutions.

Type 2 diabetes (T2D) has been rising in prevalence over the past few decades in the US and worldwide. T2D contributes to significant morbidity and premature mortality, primarily due to cardiovascular disease (CVD). Exercise is a major cornerstone of therapy for T2D as a result of its positive effects on glycemic control, blood pressure, weight loss and cardiovascular risk as well as other measures of health. However, studies show that a majority of people with T2D do not exercise regularly. The reasons given as to why exercise goals are not met are varied and include physiological, psychological, social, cultural and environmental barriers to exercise. One potential cause of inactivity in people with T2D is impaired cardiorespiratory fitness, even in the absence of clinically evident complications. The exercise impairment, although present in both sexes, is greater in women than men with T2D. Women with T2D also experience greater perceived exertion with exercise than their counterparts without diabetes. These physiological barriers are in addition to constructed societal barriers including cultural expectations of bearing the burden of childrearing for women and in some cultures, having limited access to exercise because of additional cultural expectations. People at risk for and with diabetes more commonly experience unfavorable social determinants of health (SDOH) than people without diabetes, represented by neighborhood deprivation. Neighborhood deprivation measures lack of resources in an area influencing socioeconomic status including many SDOH such as income, housing conditions, living environment, education and employment. Higher indices of neighborhood deprivation have been associated with increased risk of all-cause, cardiovascular and cancer related mortality. Unfavorable SDOH is also associated with obesity and lower levels of physical activity. Ideally regular physical activity should be incorporated into all communities as part of a productive and healthy lifestyle. One potential solution to improve access to physical activity is designing and building environments with increased walkability, greenspace and safe recreational areas. Other potential solutions include the use of continuous glucose monitors as real-time feedback tools aimed to increase motivation for physical activity, counseling aimed at improving self-efficacy towards exercise and even acquiring a dog to increase walking time. In this narrative review, we aim to examine some traditional and novel barriers to exercise, as well as present evidence on novel interventions or solutions to overcome barriers to increase exercise and physical activity in all people with prediabetes and T2D.

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).

Plasma neurofilament light chain concentrations are elevated in youth-onset type 2 diabetes and associated with neuropathy.

BACKGROUND AND AIMS: The lack of easily measurable biomarkers remains a challenge in executing clinical trials for diabetic neuropathy (DN). Plasma Neurofilament light chain (NFL) concentration is a promising biomarker in immune-mediated neuropathies. Longitudinal studies evaluating NFL in DN have not been performed. METHODS: A nested case-control study was performed on participants with youth-onset type 2 diabetes enrolled in the prospective Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Plasma NFL concentrations were measured at 4-year intervals from 2008 to 2020 in 50 participants who developed DN and 50 participants with type 2 diabetes who did not develop DN. RESULTS: NFL concentrations were similar in the DN and no DN groups at the first assessment. Concentrations were higher in DN participants at all subsequent assessment periods (all p < .01). NFL concentrations increased over time in both groups, with higher degrees of change in DN participants (interaction p = .045). A doubling of the NFL value at Assessment 2 in those without DN increased the odds of ultimate DN outcome by an estimated ratio of 2.86 (95% CI: [1.30, 6.33], p = .0046). At the final study visit, positive Spearman correlations (controlled for age, sex, diabetes duration, and BMI) were observed between NFL and HbA1c (0.48, p < .0001), total cholesterol (0.25, p = .018), and low-density lipoprotein (LDL (0.30, p = .0037)). Negative correlations were observed with measures of heart rate variability (-0.42 to -0.46, p = <.0001). INTERPRETATION: The findings that NFL concentrations are elevated in individuals with youth-onset type 2 diabetes, and increase more rapidly in those who develop DN, suggest that NFL could be a valuable biomarker for DN.

Are fewer cases of diabetes mellitus diagnosed in the months after SARS-CoV-2 infection? A population-level view in the EHR-based RECOVER program.

Long-term sequelae of severe acute respiratory coronavirus-2 (SARS-CoV-2) infection may include increased incidence of diabetes. Here we describe the temporal relationship between new type 2 diabetes and SARS-CoV-2 infection in a nationwide database. We found that while the proportion of newly diagnosed type 2 diabetes increased during the acute period of SARS-CoV-2 infection, the mean proportion of new diabetes cases in the 6 months post-infection was about 83% lower than the 6 months preinfection. These results underscore the need for further investigation to understand the timing of new diabetes after COVID-19, etiology, screening, and treatment strategies.

Bromocriptine Improves Central Aortic Stiffness in Adolescents With Type 1 Diabetes: Arterial Health Results From the BCQR-T1D Study.

BACKGROUND: The presence of vascular dysfunction is a well-recognized feature in youth with type 1 diabetes (T1D), accentuating their lifetime risk of cardiovascular events. Therapeutic strategies to mitigate vascular dysfunction are a high clinical priority. In the bromocriptine quick release T1D study (BCQR-T1D), we tested the hypothesis that BCQR would improve vascular health in youth with T1D. METHODS: BCQR-T1D was a placebo-controlled, random-order, double-blinded, cross-over study investigating the cardiovascular and metabolic impact of BCQR in T1D. Adolescents in the BCQR-T1D study were randomized 1:1 to phase-1: 4 weeks of BCQR or placebo after which blood pressure and central aortic stiffness measurements by pulse wave velocity, relative area change, and distensibility from phase-contrast magnetic resonance imaging were performed. Following a 4-week washout period, phase 2 was performed in identical fashion with the alternate treatment. RESULTS: Thirty-four adolescents (mean age 15.9±2.6 years, hemoglobin A1c 8.6±1.1%, body mass index percentile 71.4±26.1, median T1D duration 5.8 years) with T1D were enrolled and had magnetic resonance imaging data available. Compared with placebo, BCQR therapy decreased systolic (∆=-5 mmHg [95% CI, -3 to -7]; P<0.001) and diastolic blood pressure (∆=-2 mmHg [95% CI, -4 to 0]; P=0.039). BCQR reduced ascending aortic pulse wave velocity (∆=-0.4 m/s; P=0.018) and increased relative area change (∆=-2.6%, P=0.083) and distensibility (∆=0.08%/mmHg; P=0.017). In the thoraco-abdominal aorta, BCQR decreased pulse wave velocity (∆=-0.2 m/s; P=0.007) and increased distensibility (∆=0.05 %/mmHg; P=0.013). CONCLUSIONS: BCQR improved blood pressure and central and peripheral aortic stiffness and pressure hemodynamics in adolescents with T1D over 4 weeks versus placebo. BCQR may improve aortic stiffness in youth with T1D, supporting future longer-term studies.

Understanding heterogeneity of responses to, and optimizing clinical efficacy of, exercise training in older adults: NIH NIA Workshop summary.

Exercise is a cornerstone of preventive medicine and a promising strategy to intervene on the biology of aging. Variation in the response to exercise is a widely accepted concept that dates back to the 1980s with classic genetic studies identifying sequence variations as modifiers of the VO2max response to training. Since that time, the literature of exercise response variance has been populated with retrospective analyses of existing datasets that are limited by a lack of statistical power from technical error of the measurements and small sample sizes, as well as diffuse outcomes, very few of which have included older adults. Prospective studies that are appropriately designed to interrogate exercise response variation in key outcomes identified a priori and inclusive of individuals over the age of 70 are long overdue. Understanding the underlying intrinsic (e.g., genetics and epigenetics) and extrinsic (e.g., medication use, diet, chronic disease) factors that determine robust versus poor responses to various exercise factors will be used to improve exercise prescription to target the pillars of aging and optimize the clinical efficacy of exercise training in older adults. This review summarizes the proceedings of the NIA-sponsored workshop entitled, "Understanding Heterogeneity of Responses to, and Optimizing Clinical Efficacy of, Exercise Training in Older Adults" and highlights the importance and current state of exercise response variation research, particularly in older adults, prevailing challenges, and future directions.

Are fewer cases of diabetes mellitus diagnosed in the months after SARS-CoV-2 infection?

Long-term sequelae of severe acute respiratory coronavirus-2 (SARS-CoV-2) infection may include an increased incidence of diabetes. Our objective was to describe the temporal relationship between new diagnoses of diabetes mellitus and SARS-CoV-2 infection in a nationally representative database. There appears to be a sharp increase in diabetes diagnoses in the 30 days surrounding SARS-CoV-2 infection, followed by a decrease in new diagnoses in the post-acute period, up to 360 days after infection. These results underscore the need for further investigation, as understanding the timing of new diabetes onset after COVID-19 has implications regarding potential etiology and screening and treatment strategies.

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.