Search

Objective: The E23K variant in the Kir6.2 subunit of the ATP-sensitive K(+) channel (K(ATP) channel) is associated with increased risk of type 2 diabetes. The present study was undertaken to increase our understanding of the mechanisms responsible. To avoid confounding effects of hyperglycemia, insulin secretion and action were studied in subjects with the variant who had normal glucose tolerance.Research Design and Methods: Nine subjects with the E23K genotype K/K and nine matched subjects with the E/E genotype underwent 5-h oral glucose tolerance tests (OGTTs), graded glucose infusion, and hyperinsulinemic-euglycemic clamp with stable-isotope-labeled tracer infusions to assess insulin secretion, action, and clearance. A total of 461 volunteers consecutively genotyped for the E23K variant also underwent OGTTs. Functional studies of the wild-type and E23K variant potassium channels were conducted.Results: Insulin secretory responses to oral and intravenous glucose were reduced by approximately 40% in glucose-tolerant subjects homozygous for E23K. Normal glucose tolerance with reduced insulin secretion suggests a change in insulin sensitivity. The hyperinsulinemic-euglycemic clamp revealed that hepatic insulin sensitivity is approximately 40% greater in subjects with the E23K variant, and these subjects demonstrate increased insulin sensitivity after oral glucose. The reconstituted E23K channels confirm reduced sensitivity to inhibitory ATP and increase in open probability, a direct molecular explanation for reduced insulin secretion.Conclusions: The E23K variant leads to overactivity of the K(ATP) channel, resulting in reduced insulin secretion. Initially, insulin sensitivity is enhanced, thereby maintaining normal glucose tolerance. Presumably, over time, as insulin secretion falls further or insulin resistance develops, glucose levels rise resulting in type 2 diabetes. [ABSTRACT FROM AUTHOR]

BACKGROUND: Weight loss, through calorie restriction or increases in energy expenditure via exercise, improves glucose tolerance and insulin action. However, exercise-induced energy expenditure may further improve glucoregulation through mechanisms independent of weight loss. OBJECTIVE: The objective was to assess the hypothesis that weight loss through exercise-induced energy expenditure improves glucoregulation and circulating factors involved in insulin action to a greater extent than does similar weight loss through calorie restriction. DESIGN: Sedentary men and women aged 50-60 y with a body mass index (kg/m(2)) of 23.5-29.9 were randomly assigned to 1 of 2 weight-loss interventions [12 mo of exercise training (EX group; n = 18) or calorie restriction (CR group; n = 18)] or to a healthy lifestyle (HL) control group (n = 10). The insulin sensitivity index and areas under the curve for glucose and insulin were assessed with an oral-glucose-tolerance test. Adiponectin and tumor necrosis factor alpha concentrations were measured in fasting serum. Fat mass was measured by dual-energy X-ray absorptiometry. RESULTS: Yearlong energy deficits were not significantly different between the EX and CR groups, as evidenced by body weight and fat mass changes. The insulin sensitivity index increased and the glucose and insulin areas under the curve decreased in the EX and CR groups, remained unchanged in the HL group, and did not differ significantly between the EX and CR groups. Marginally significant increases in adiponectin and decreases in the ratio of tumor necrosis factor alpha to adiponectin occurred in the EX and CR groups but not in the HL group. CONCLUSIONS: Weight loss induced by exercise training or calorie restriction improves glucose tolerance and insulin action in nonobese, healthy, middle-aged men and women. However, it does not appear that exercise training-induced weight loss results in greater improvements than those that result from calorie restriction alone. Copyright © 2006 American Society for Nutrition [ABSTRACT FROM AUTHOR]

Background: Caloric restriction (CR) increases maximal life span in short-lived organisms, and its effects are being explored in nonhuman primates. The objectives of this study were to determine the feasibility of prolonged CR in nonobese adults and to compare the effects of CR- and exercise-induced weight loss on body composition and abdominal adiposity.Methods: A randomized, controlled trial was conducted with 48 healthy, nonobese women and men, aged 57 +/- 1 (mean +/- standard error [SE]) years, with body mass index 27.3 +/- 0.3 kg/m2. Participants were randomly assigned to a 20% calorically-restricted diet (CR, n = 19), exercise designed to produce a similar energy deficit (EX, n = 19), or a healthy lifestyle control group (HL, n = 10) for 1 year. Assessments included weight, body composition by dual-energy x-ray absorptiometry, abdominal adipose tissue by magnetic resonance imaging, and energy intake by doubly labeled water.Results: The average level of CR achieved by the CR group was 11.5 +/- 2.1%, and the EX group completed 59 +/- 6.7% of their prescribed exercise. Weight changes were greater (p Conclusions: CR for 1 year was feasible, but the level of CR achieved was less than prescribed. CR and exercise were equally effective in reducing weight and adiposity. [ABSTRACT FROM AUTHOR]

Osteoporosis is a common bone disease that will be frequently encountered by physical therapists. Characterized by low bone mass and microarchitectural changes that increase the susceptibility to fracture, approximately 30 million postmenopausal women in the United States have either osteoporosis or osteopenia, and the incidence is likely to increase with the aging of the population. Physical therapists need to be aware of osteoporosis and its consequences. Modifiable risk factors represent an opportunity to intervene and help young women develop healthy bones long before osteoporosis develops. Therefore, this paper will address the epidemiology and demographics of osteoporosis including known risk factors. Normal physiologic development of healthy bone will be presented as a precursor to discussion of the pathphysiology of the osteoporosis disease process. [ABSTRACT FROM AUTHOR]

Context: Although hormone replacement therapy (HRT) is an established approach for osteoporosis prevention, little is known about the osteoprotective effects of HRT in frail elderly women.Objective: To determine whether HRT increases bone mineral density (BMD) in frail elderly women.Design and Setting: Randomized, double-blind, placebo-controlled trial conducted in a US university-based research center from September 1995 to August 2000.Participants: Sixty-seven women aged 75 years or older with mild-to-moderate physical frailty.Intervention: Participants were randomly assigned to receive conjugated estrogens, 0.625 mg/d, plus trimonthly medroxyprogesterone acetate, 5 mg/d for 13 days (n = 45), or matching placebo (n = 22), for 9 months.Main Outcome Measures: The primary outcome measure was 9-month change in BMD of the lumbar spine and hip, measured by dual-energy x-ray absorptiometry. Secondary outcomes were changes in markers of bone turnover.Results: Based on intention-to-treat analyses, HRT resulted in significantly larger increases in BMD of the lumbar spine than placebo (mean change, 4.3% vs 0.4%; between-group difference, 3.9%; 95% confidence interval [CI], 3.5%-4.3%) and total hip (mean change, 1.7% vs -0.1%; between-group difference, 1.8%; 95% CI, 1.5%-2.1%). Compared with placebo, HRT resulted in significant decreases in serum bone-specific alkaline phosphatase levels (mean change, -24% vs 6%; between-group difference, -30%; 95% CI, -26% to -33%) and urine N-telopeptide levels (mean change, -48% vs 4%; between-group difference, -52%; 95% CI, -47% to -55%).Conclusions: In physically frail elderly women, 9 months of HRT significantly increased BMD compared with placebo in clinically important skeletal regions. Further studies are needed to determine whether these osteogenic effects of HRT in elderly women are associated with a reduction in osteoporotic fractures. [ABSTRACT FROM AUTHOR]

Background: Testosterone (T) therapy increases lean mass and reduces total body and truncal fat mass in hypogonadal men. However, the underlying molecular mechanisms for the reciprocal changes in fat and lean mass in humans are not entirely clear., Methods: Secondary analysis of specimens obtained from a single-arm, open-label clinical trial on pharmacogenetics of response to T therapy in men with late-onset hypogonadism, conducted between 2011 and 2016 involving 105 men (40-74 years old), who were given intramuscular T cypionate 200 mg every 2 weeks for 18 months. Subcutaneous fat (SCF), peripheral blood mononuclear cells (PBMC) and serum were obtained from the participants at different time points of the study. We measured transcription factors for adipogenesis and myogenesis in the SCF, and PBMC, respectively, by real-time quantitative PCR at baseline and 6 months. Serum levels of FOLLISTATIN, PAX7, MYOSTATIN, ADIPSIN, and PRDM16 were measured by ELISA., Results: As expected, there was a significant increase in T and estradiol levels after 6 months of T therapy. There was also a reduction in fat mass and an increase in lean mass after 6 months of T therapy. Gene-protein studies showed a significant reduction in the expression of the adipogenic markers PPARγ in SCF and ADIPSIN levels in the serum, together with a concomitant significant increase in the expression of myogenic markers, MYOD in PBMC and PAX7 and FOLLISTATIN levels in the serum after 6 months of T therapy compared to baseline. Interestingly, there was a significant increase in the adipo-myogenic switch, PRDM16 , expression in SCF and PBMC, and in circulating protein levels in the serum after 6 months of T therapy, which is likely from increased estradiol., Conclusion: Our study supports that molecular shift from the adipogenic to the myogenic pathway in men with hypogonadism treated with T could be mediated directly or indirectly by enhanced PRDM16 activity, in turn a result from increased estradiol level. This might have led to the reduction in body fat and increase in lean mass commonly seen in hypogonadal men treated with T., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Bathina, Colleluori, Villareal, Aguirre, Chen and Armamento-Villareal.)

Objectives: To test the hypothesis that depressive symptoms vary with high-sensitivity C-reactive protein (hs-CRP), among older adults with obesity., Methods: This was a cross-sectional, secondary analysis of baseline data from two related lifestyle intervention trials. The study sample comprises 148 consecutively recruited, community-dwelling older adults (age >=65 years) without severe psychiatric illness and with body mass index >=30 kg/m 2 . Logarithmically transformed GDS was analyzed as the dependent variable. Independent variables included log-transformed hs-CRP and covariates: sex, age, and concurrent use of antidepressant medication at baseline. An additional analysis was performed using binary conversion of the GDS scores, wherein a cutoff score of 5 was considered positive for depressive symptoms., Results: Sample mean GDS score was 2.7 (SD 3.0, range 0 - 14). A significant multivariate model of GDS scores (R 2 = .089, F = 3.5, P = .010) revealed log-transformed hs-CRP ( P = .017) and male sex ( P = .012) as associated with depressive symptoms. Supplemental analysis demonstrated associations between depressive symptoms and log-transformed hs-CRP (OR 2.17, P = .001) and between depressive symptoms and male sex (OR 3.78, P = .013). Univariate logistic regression found hs-CRP to be associated with depressive symptoms., Conclusions: In older adults with obese BMI, male sex and higher hs-CRP are associated with depression, even in a group with relatively minimal depressive symptoms. Hs-CRP may offer clinical utility as a biomarker for depression among older adults with obese BMI, even among those with non-severe psychiatric symptomatology., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Kunik is an unpaid member of the board of the Houston & Southeast Chapter of the Alzheimer’s Association, and he performs guardianship evaluations for the county probate court. Dr. Villareal is on the Clinical Trials Advisory Panel (CTAP) for the NIH-National Institute on Aging (NIA) and the Data and Safety Monitoring Board (DSMB) for several NIH-supported clinical trials. The other authors have nothing to disclose.

Background: Whether testosterone replacement therapy (TRT) conveys additional cardiometabolic benefit to an intensive lifestyle therapy (LT) in older men with obesity and hypogonadism remains unclear., Objective: To determine whether TRT augments the effect of LT on metabolic outcomes in older men with obesity and hypogonadism., Design: Secondary analysis of a randomized, double-blind, placebo-controlled trial., Setting: Veterans Affairs Medical Center., Participants: 83 older (age ≥ 65 years) men with obesity (BMI ≥ 30 kg/m2) and persistently low AM testosterone (< 10.4 nmol/L) associated with frailty., Interventions: LT (weight management and exercise training) plus either testosterone (LT+TRT) or placebo (LT+Pbo) for six months., Outcome Measures: Primary outcome was change in glycated hemoglobin (HbA1c). Secondary outcomes included changes in other glucometabolic and lipid profile components, liver enzymes, inflammatory markers, adipokines; subcutaneous, visceral, intramuscular, and hepatic fat; blood pressure, and metabolic syndrome score., Results: HbA1c decreased similarly in LT+TRT and LT+Pbo groups (-0.5% vs. -0.6%, respectively; p= 0.35). While TRT showed no synergistic effect with LT on ameliorating secondary outcomes, it eliminated the augmentative effect of LT on high-density lipoprotein cholesterol concentration (5.4 ± 1.0 mg/dL in LT+Pbo group vs. 0.2 ± 1.1 mg/dL in LT+TRT group, p= 0.01) and adiponectin levels (-408 ± 489 ng/mL in TRT+LT group vs 1832 ± 468 ng/mL in LT+Pbo group, p= 0.02)., Conclusion: In older men with obesity and hypogonadism, adding TRT for six months to LT does not result in further improved cardiometabolic profiles, and could potentially blunt some of the metabolic benefits induced by LT., (Published by Oxford University Press on behalf of the Endocrine Society 2024.)

Background: The expanding population of older adults with obesity is a public health challenge, in part, because of the increased risk of fractures despite normal or high bone mineral density. Potential factors predisposing to fractures in this group include sarcopenia associated with obesity and impaired bone quality. We aimed to determine the contribution of sarcopenic obesity (SO) indices to bone strength as assessed by microfinite element analysis (μFEA) of high-resolution peripheral quantitative computed tomography (HR-pQCT)., Methods: One-hundred eighty-nine older (age ≥ 65 years) adults with obesity (BMI ≥ 30 kg/m 2 ) participated in lifestyle intervention trials at our medical center. All underwent baseline measurements of bone strength (failure load and stiffness) using μFEA from HR-pQCT of the distal radius and tibia. In addition, SO indices [appendicular lean mass/weight (ALM/W) and percent body fat (FM%)] by dual-energy X-ray absorptiometry and handgrip strength (HGS) by dynamometry were assessed. SO was diagnosed and staged based on the 2022 ESPEN and EASO expert consensus statement., Results: Both ALM/W and HGS were positively correlated explaining 28% to 36% of the variance in failure load and stiffness at the distal radius and tibia (all p < 0.001). In contrast, FM% was negatively correlated explaining 22% to 31% of the variance in failure load and stiffness at the distal radius and tibia (all p < 0.001). The associations of SO indices with failure load and stiffness remained significant after controlling for age, sex, race/ethnicity, diabetes, and 25-OH vitamin D (ALM/W: R 2 =  0.301 to 0.448, HGS: R 2 =  0.346 to 0.472, FM%: R 2 =  0.299 to 0.432) ( p < 0.001 to 0.011). SO was diagnosed in 75/189 (40%) participants with 66/75 (88%) having functional or metabolic complications (stage II). Participants with SO had lower failure load and stiffness at the distal radius than participants with no SO (both p < 0.05)., Conclusion: These findings demonstrate that lower muscle mass and strength and higher fat mass may impair bone quality. Therefore, interventions that focus on preserving muscle mass and strength while reducing fat mass may be important to decrease fracture risk when older adults with obesity undertake lifestyle intervention therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Gregori, Paudyal, Barnouin, Celli, Segoviano-Escobar, Armamento-Villareal, Napoli, Qualls and Villareal.)

The population worldwide is getting older as a result of advances in public health, medicine, and technology. Older individuals are living longer with a higher prevalence of subclinical and clinical cardiovascular disease (CVD). In 2010, the American Heart Association introduced a list of key prevention targets, known as "Life's Simple 7" to increase CVD-free survival, longevity, and quality of life. In 2022, sleep health was added to expand the recommendations to "Life's Essential 8" (eat better, be more active, stop smoking, get adequate sleep, manage weight, manage cholesterol, manage blood pressure, and manage diabetes). These prevention targets are intended to apply regardless of chronologic age. During this same time, the understanding of aging biology and goals of care for older adults further enhanced the relevance of prevention across the range of functions. From a biological perspective, aging is a complex cellular process characterized by genomic instability, telomere attrition, loss of proteostasis, inflammation, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. These aging hallmarks are triggered by and enhanced by traditional CVD risk factors leading to geriatric syndromes (eg, frailty, sarcopenia, functional limitation, and cognitive impairment) which complicate efforts toward prevention. Therefore, we review Life's Essential 8 through the lens of aging biology, geroscience, and geriatric precepts to guide clinicians taking care of older adults.

With the rise in obesity across age groups, it has been a hindrance to engaging in physical activity and mobility in older adults. Daily calorie restriction (CR) up to 25% has been the cornerstone of obesity management even though the safety in older adults remains incompletely understood. Although some adults can follow CR with clinically significant weight loss and improved health metrics, CR faces 2 obstacles-many fail to adopt CR and even among those who can adopt it short term, long-term compliance can be difficult. Furthermore, there is a continuing debate about the net benefits of CR-induced weight loss in older adults because of the concern that CR may worsen sarcopenia, osteopenia, and frailty. The science of circadian rhythm and its plasticity toward the timing of nutrition offer promise to alleviate some challenges of CR. The new concept of Time-Restricted Feeding/Eating (TRF for animal studies and TRE for human studies) can be an actionable approach to sustaining the circadian regulation of physiology, metabolism, and behavior. TRE can often (not always) lead to CR. Hence, the combined effect of TRE through circadian optimization and CR can potentially reduce weight and improve cardiometabolic and functional health while lessening the detrimental effects of CR. However, the science and efficacy of TRE as a sustainable lifestyle in humans are in its infancy, whereas animal studies have offered many desirable outcomes and underlying mechanisms. In this article, we will discuss the scope and opportunities to combine CR, exercise, and TRE to improve functional capacity among older adults with obesity., (Published by Oxford University Press on behalf of The Gerontological Society of America 2023.)

Purpose of Review: Along with the marked increase in the population of older adults with obesity is the need for effective strategies to treat aging- and obesity-related complications. This review highlights recent progress in obesity management in older adults., Recent Findings: Although calorie restriction is needed to significantly reduce fat mass, an exercise protocol is crucial to ameliorate functional outcomes. The addition of a resistance exercise protocol improves the response of muscle protein synthesis to anabolic stimuli, preventing the calorie restriction-induced reduction in muscle and bone mass. The addition of an aerobic exercise protocol improves cardiorespiratory fitness and cognitive function. However, the addition of both aerobic and resistance exercise protocols to calorie restriction provides the greatest improvements in myocellular quality, frailty, and cardiometabolic and cognitive outcomes, translating into the greatest improvement in quality of life. Such comprehensive lifestyle intervention effectively improves glucometabolic control and age-relevant outcomes in older adults with diabetes. When combined with testosterone therapy, such lifestyle intervention also preserves muscle and bone mass in older, men with obesity and hypogonadism., Summary: We conclude that calorie restriction among older adults with obesity should be prescribed in combination with both aerobic and resistance exercise to maximize benefits on overall health., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Obesity and sarcopenic obesity (SO) are characterized by excess body fat with or without low muscle mass affecting bio-psycho-social health, functioning, and subsequently quality of life in older adults. We mapped outcomes addressed in randomized controlled trials (RCTs) on lifestyle interventions in community-dwelling older people with (sarcopenic) obesity. Systematic searches in Medline, Embase, Cochrane Central, CINAHL, PsycInfo, Web of Science were conducted. Two reviewers independently performed screening and extracted data on outcomes, outcome domains, assessment methods, units, and measurement time. A bubble chart and heat maps were generated to visually display results. Fifty-four RCTs (7 in SO) reporting 464 outcomes in the outcome domains: physical function (n = 42), body composition/anthropometry (n = 120), biomarkers (n = 190), physiological (n = 30), psychological (n = 47), quality of life (n = 14), pain (n = 4), sleep (n = 2), medications (n = 3), and risk of adverse health events (n = 5) were included. Heterogeneity in terms of outcome definition, assessment methods, measurement units, and measurement times was found. Psychological and quality of life domains were investigated in a minority of studies. There is almost no information beyond 52 weeks. This evidence map is the first step of a harmonization process to improve comparability of RCTs in older people with (sarcopenic) obesity and facilitate the derivation of evidence-based clinical decisions., (© 2022 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Introduction: Type 2 diabetes mellitus (T2DM) is well-known to be associated with normal bone density but, concurrently, low bone turnover and increased risk for fracture. One of the proposed mechanisms is possible derangement in bone precursor cells, which could be represented by deficiencies in circulating osteogenic progenitor (COP) cells and osteoclast precursors (OCP). The objective of our study is to understand whether extent of glycemic control has an impact on these cells, and to identify other factors that may as well., Methods: This was a secondary analysis of baseline data from 51 male participants, aged 37-65 in an ongoing clinical trial at Michael E. DeBakey VA Medical Center, Houston, Texas, USA. At study entry serum Hemoglobin A1c was measured by high-performance liquid chromatography osteocalcin (OCN) and C-terminal telopeptide of type 1 collagen (CTx) were measured by ELISA, and testosterone and estradiol by liquid-chromatography/mass-spectrometry. Areal bone mineral density (BMD), trabecular bone score and body composition were measured by dual energy x-ray absorptiometry, while COP and OCP were measured by flow cytometry., Results: When adjusted for serum testosterone, parathyroid hormone, and 25-hydroxyvitamin D, those with poor long-term glycemic control had significantly higher percentage of COP (p = 0.04). COP correlated positively with visceral adipose tissue (VAT) volume (r = 0.37, p = 0.01) and negatively with free testosterone (r = -0.28, p = 0.05) and OCN (r = -0.28, p = 0.07), although only borderline for the latter. OCP correlated positively with age, FSH, lumbar spine BMD, and COP levels, and negatively with glucose, triglycerides, and free estradiol. Multivariable regression analyses revealed that, in addition to being predictors for each other, another independent predictor for COP was VAT volume while age, glucose, and vitamin D for OCP., Conclusion: Our results suggest that high COP could be a marker of poor metabolic control. However, given the complex nature and the multitude of factors influencing osteoblastogenesis/adipogenesis, it is possible that the increase in COP is a physiologic response of the bone marrow to increased osteoblast apoptosis from poor glycemic control. Alternatively, it is also likely that a metabolically unhealthy profile may retard the development of osteogenic precursors to fully mature osteoblastic cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ballato, Deepika, Prado, Russo, Fuenmayor, Bathina, Villareal, Qualls and Armamento-Villareal.)

Introduction: Type 2 diabetes mellitus (T2DM) is associated with normal or slightly elevated bone mineral density (BMD) but paradoxically increased fracture risk. Although multiple mechanisms have been proposed to explain this observation, one thing is clear from prior studies, T2DM is associated with poor bone quality rather than a defect in bone quantity. The objective of our study is to evaluate the effect of longitudinal glycemic control on bone quality and bone turnover in men with T2DM., Methods: This was a secondary analysis of baseline data from 169 male participants, aged 35-65 in 3 clinical trials. Participants were grouped according to the average of all their A1C measurements between 9 and 15 months prior to study entry (group 1: no T2DM, group 2: T2DM with A1C ≤ 7%, group 3: T2DM with A1C > 7%). At study entry serum osteocalcin and C-terminal telopeptide of type 1 collagen (CTx) were measured by ELISA, and testosterone and estradiol by liquid-chromatography/mass-spectrometry. Areal BMD, trabecular bone score and body composition were measured by dual-energy X-ray absorptiometry while volumetric BMD, bone microarchitecture, and bone strength were assessed by high-resolution peripheral quantitative computed tomography., Results: At the tibia, trabecular separation was higher and trabecular number was significantly lower in group 3 compared to both groups 2 and 1, even after adjustments for covariates (p = 0.02 for both). Bone strength indices at the tibia such as stiffness and failure load were lowest in group 3, the difference being significant when compared to group 1 (p = 0.01, p = 0.009 respectively) but not to group 2, after adjustments for covariates. Bone turnover markers (osteocalcin and CTx) were significantly lower in group 3 relative to group 1, with CTx also being significantly lower in group 3 compared with group 2 (p < 0.001, p = 0.001 respectively)., Conclusion: Poor glycemic control over the course of a year in men with T2DM is associated with poorer bone microarchitecture and strength, and reduced bone turnover. Conversely, good glycemic control in the setting of T2DM appears to attenuate this observed impairment in bone quality., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Objective: Lifestyle intervention is recommended as first-line treatment of diabetes at all ages; however, little is known about the efficacy of lifestyle intervention in older adults with diabetes. We aimed to determine whether lifestyle intervention would improve glycemic control and age-relevant outcomes in older adults with diabetes and comorbidities., Research Design and Methods: A total of 100 older adults with diabetes were randomly assigned to 1-year intensive lifestyle intervention (ILI) (diet and exercise at a facility transitioned into community-fitness centers and homes) or healthy lifestyle (HL) group. The primary outcome was change in HbA1c. Secondary outcomes included glucoregulation, body composition, physical function, and quality of life. Changes between groups were analyzed with mixed-model repeated-measures ANCOVA following the intention-to-treat principle., Results: HbA1c improved more in the ILI than the HL group (mean ± SE -0.8 ± 0.1 vs. 0.1 ± 0.1%), associated with improved insulin sensitivity (1.2 ± 0.2 vs. -0.4 ± 0.2) and disposition (26.0 ± 8.9 vs. -13.0 ± 8.4 109 min-1) indices (between-group P < 0.001 to 0.04). Body weight and visceral fat decreased more in the ILI than HL group (-8.4 ± 0.6 vs. -0.3 ± 0.6 kg, P < 0.001, and -261 ± 29 vs. -30 ± 27 cm3, P < 0.001, respectively). Physical Performance Test score increased more in the ILI than HL group (2.9 ± 0.6 vs. -0.1 ± 0.4, P < 0.001) as did VO2peak (2.2 ± 0.3 vs. -1.2 ± 0.2 mL/kg/min, P < 0.001). Strength, gait, and 36-Item Short Form Survey (SF-36) Physical Component Summary score also improved more in the ILI group (all P < 0.001). Total insulin dose decreased in the ILI group by 19.8 ± 4.4 units/day. Adverse events included increased episodes of mild hypoglycemia in the ILI group., Conclusions: A lifestyle intervention strategy is highly successful in improving metabolic and functional health of older adults with diabetes., (© 2022 by the American Diabetes Association.)

Context: Male hypogonadism adversely affects body composition, bone mineral density (BMD), and metabolic health. A previous report showed that pre-treatment testosterone (T) levels of <200 ng/dl is associated with greater improvement in spine BMD with T therapy. However, to date, there is no study that investigates whether baseline T levels also influence body composition and metabolic response to T therapy., Objective: The aim of this study is to determine if there are differences in the changes in body composition, metabolic profile, and bone turnover markers, in addition to BMD, in response to T therapy in men with a baseline T level of <264 ng/dl compared to those with levels ≥264 ng/dl., Methods: This is a secondary analysis of a single-arm, open-label clinical trial (NCT01378299) on pharmacogenetics of response to T therapy conducted between 2011 and 2016 involving 105 men (40-74 years old), with average morning T < 300 ng/dl, given intramuscular T cypionate 200 mg every 2 weeks for 18 months. Subjects were divided into those with baseline T levels of <264 ng/dl ( N = 43) and those with ≥264 ng/dl ( N = 57). T and estradiol (E2) were measured by liquid chromatography/mass spectrometry; serum bone turnover markers (C-telopeptide [CTX], osteocalcin, and sclerostin), adiponectin, and leptin were measured by enzyme-linked immunosorbent assay; glycated hemoglobin (HbA1c) was measured by high-performance liquid chromatography; and areal BMD and body composition was measured by dual-energy x-ray absorptiometry (DXA)., Results: Men with T < 264 ng/dl showed greater increases in total fat-free mass (FFM) at 18 months compared to those with T ≥ 264 ng/dl (4.2 ± 4.1 vs. 2.7 ± 3.8%; p = 0.047) and unadjusted appendicular FFM at 6 and 18 months (8.7 ± 11.5 vs. 4.4 ± 4.3%, 7.3 ± 11.6 vs. 2.4 ± 6.8%; p = 0.033 and p = 0.043, respectively). Men with T ≥ 264 ng/dl showed significant decreases in HbA1c at 12 months (-3.1 ± 9.2 vs. 3.2 ± 13.9%; p = 0.005), fasting glucose at 18 months (-4.2 ± 31.9 vs. 13.0 ± 57.3%; p = 0.040), LDL at 6 months (-6.4 ± 27.5 vs. 12.8 ± 44.1%; p = 0.034), and leptin at 18 months (-40.2 ± 35.1 vs. -27.6 ± 31.0%; p = 0.034) compared to those with T < 264 ng/dl. No significant differences in BMD and bone turnover markers were observed., Conclusion: T therapy results in improvement in body composition irrespective of baseline T levels but T < 264 ng/dl is associated with greater improvement in FFM, whereas a T level of ≥264 ng/dl favors improvement in metabolic profile., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Deepika, Ballato, Colleluori, Aguirre, Chen, Qualls, Villareal and Armamento-Villareal.)

Introduction: Loss of skeletal muscle mass and function (sarcopenia) is common in individuals with obesity due to metabolic changes associated with a sedentary lifestyle, adipose tissue derangements, comorbidities (acute and chronic diseases), and during the ageing process. Co-existence of excess adiposity and low muscle mass/function is referred to as sarcopenic obesity (SO), a condition increasingly recognized for its clinical and functional features that negatively influence important patient-centred outcomes. Effective prevention and treatment strategies for SO are urgently needed, but efforts are hampered by the lack of an universally established SO Definition and diagnostic criteria. Resulting inconsistencies in the literature also negatively affect the ability to define prevalence as well as clinical relevance of SO for negative health outcomes., Aims and Methods: The European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of Obesity (EASO) launched an initiative to reach expert consensus on a Definition and diagnostic criteria for SO. The jointly appointed international expert panel proposes that SO is defined as the co-existence of excess adiposity and low muscle mass/function. The diagnosis of SO should be considered in at-risk individuals who screen positive for a co-occurring elevated body mass index or waist circumference, and markers of low skeletal muscle mass and function (risk factors, clinical symptoms, or validated questionnaires). Diagnostic procedures should initially include assessment of skeletal muscle function, followed by assessment of body composition where presence of excess adiposity and low skeletal muscle mass or related body compartments confirm the diagnosis of SO. Individuals with SO should be further stratified into Stage I in the absence of clinical complications, or Stage II if cases are associated with complications linked to altered body composition or skeletal muscle dysfunction., Conclusions: ESPEN and EASO, as well as the expert international panel, advocate that the proposed SO Definition and diagnostic criteria be implemented into routine clinical practice. The panel also encourages prospective studies in addition to secondary analysis of existing datasets, to study the predictive value, treatment efficacy, and clinical impact of this SO definition., Competing Interests: Conflict of interest None of the authors display any conflict of interest in the production of this manuscript., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Obesity exacerbates age-related effects on body composition and physical and metabolic function. Which exercise mode is most effective in mitigating these deleterious changes in dieting older adults with obesity is unknown., Methods: In a randomized controlled trial, we performed a head-to-head comparison of aerobic (AEX), resistance (REX), or combination (COMB) exercise during matched ~10% weight loss in 160 obese older adults. Prespecified analyses compared 6-month changes in intermuscular adipose tissue (IMAT) and visceral adipose tissue (VAT) assessed using MRI, insulin sensitivity index (ISI) by oral glucose tolerance test, physical function using Modified Physical Performance Test (PPT), VO2peak, gait speed, and knee strength by dynamometry., Results: IMAT and VAT decreased more in COMB than AEX and REX groups (IMAT; -41% vs -28% and -23% and VAT: -36% vs -19% and -21%; p = .003 to .01); IMAT and VAT decreased in all groups more than control (between-group p < .001). ISI increased more in COMB than AEX and REX groups (86% vs 50% and 39%; p = .005 to .03). PPT improved more in COMB than AEX and REX groups, while VO2peak improved more in COMB and AEX than REX group (all p < .05). Knee strength improved more in COMB and REX than AEX group (all p < .05). Changes in IMAT and VAT correlated with PPT (r = -0.28 and -0.39), VO2peak (r = -0.49 and -0.52), gait speed (r = -0.25 and -0.36), and ISI (r = -0.49 and -0.52; all p < .05)., Conclusions: Weight loss plus combination aerobic and resistance exercise was most effective in improving ectopic fat deposition and physical and metabolic function in older adults with obesity., (Published by Oxford University Press on behalf of The Gerontological Society of America 2021.)

Objectives: To explore associations among cognition, frailty, and obesity in older adults., Design: Descriptive, secondary analysis of baseline data from two related lifestyle intervention trials., Setting: Clinical study open to civilian population through the Center for Translational Research on Inflammatory Diseases at the Veterans Affairs Medical Center in Houston, TX., Participants: One hundred eight community-dwelling adults with obesity, aged 65 or older, recruited consecutively from two lifestyle intervention trials., Measurements: Cognition was assessed using Composite Age-Adjusted Scale Score from the National Institutes of Health Toolbox Cognition Battery: Obesity was assessed by body mass index (BMI) and also by truncal fat mas via dual energy x-ray absorptiometry. Frailty was assessed using the Physical Performance Test., Results: A significant linear regression model for cognition revealed frailty as the strongest predictor, followed by sex, and then truncal fat (R2=0.340, p<0.001)., Conclusion: Cognition among community-dwelling older adults with obese BMI may worsen with greater truncal fat mass. Frailty appears to be an important predictor of cognitive performance in this population., Competing Interests: Dr. Kunik is an unpaid member of the board of the Houston and Southeast Chapter of the Alzheimer’s Association, and he performs guardianship evaluation for the county probate court. Dr. Villareal is on the Clinical Trials Advisory Panel (CTAP) for the NIH-National Institute on Aging (NIA) and Data and Safety Monitoring Board (DSMB) for several NIH-supported clinical trials. The other authors have nothing to disclose.

Objectives: To determine the effect of diet, exercise, and diet-exercise in combination on measures of biological age., Design: Secondary analysis of a 1-year randomized, controlled trial., Setting: University-based Medical Center., Participants: One-hundred-seven older (age≥65 yrs.) adults with obesity (BMI≥30 kg/m2) were randomized and 93 completed the study. Analyses used intention-to-treat., Interventions: Participants were randomized to a control group, a weight-management (diet) group, an exercise group, or a weight-management-plus-exercise (diet-exercise) group., Main Outcome Measures: We calculated Klemera-Doubal Method (KDM) biological age, Homeostatic Dysregulation (HD) score, and Health Aging Index (HAI) score at baseline, and changes at 6- and 12-months., Results: Diet and diet-exercise decreased KDM biological age more than exercise and control (-2.4±0.4, -2.2±0.3, -0.2±0.4, and 0.2±0.5, respectively, P<0.05 for the between group-differences). Diet and diet-exercise also decreased HD score more than exercise and control (-1.0±0.3, -1.1±0.3, 0.1±0.3, and 0.3±0.3 respectively, P<0.05). Moreover, diet-exercise decreased HAI score more than exercise, diet, or control (-1.1±0.2, -0.5±0.2, -0.5±0.2, and 0.0±0.2, respectively, P<0.05)., Conclusions: These findings suggest that diet and diet-exercise are both effective methods of improving biological age, and that biological age may be a valuable method of assessing geroprotective interventions in older humans., Competing Interests: The authors declare no conflicts of interest relevant to this article.

Background: Emerging data suggest that type 2 diabetes mellitus (T2D) is associated with an increased risk for fractures despite relatively normal or increased bone mineral density (BMD). Although the mechanism for bone fragility in T2D patients is multifactorial, whether glycemic control is important in generating this impairment in bone metabolism remains unclear. The purpose of our study is to identify a hemoglobin A1c (A1c) threshold level by which reduction in bone turnover begins in men with T2D., Method: A cross-sectional analysis of baseline data was obtained from 217 men, ages 35-65, regardless of the presence or absence of hypogonadism or T2D, who participated in 2 clinical trials. The following data were obtained: A1c by HPLC, testosterone and estradiol by LC/MS, bone turnover markers Osteocalcin [OC], C-terminal telopeptide [CTx], and sclerostin by ELISA, and BMD by DXA. Patients were grouped into 4 categories based of A1c (group I: <6%, group II: 6.0-6.4%, group III: 6.5-6.9%, and group IV: ≥7%). Threshold models were fit to the data using nonlinear regression and group comparisons among the different A1c categories performed by ANOVA., Results: Threshold model and nonlinear regression showed an A1c cut-off of 7.0, among all choices of A1cs, yields the least sum of squared errors. A comparison of bone turnover markers revealed relatively lower OC (p = 0.002) and CTx (p = 0.0002) in group IV (A1c ≥7%), compared to the other groups. An analysis of men with T2D (n = 94) showed relatively lower OC (p=0.001) and CTx (p=0.002) in those with A1c ≥7% compared to those with <7%, respectively. The significance between groups persisted even after adjusting for medications and duration of diabetes., Conclusion: An analysis across our entire study population showed a breakpoint A1c level of 7% or greater is associated with lower bone turnover. Also in men with T2D, an A1c ≥7% is associated with low bone turnover., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Joad, Ballato, Deepika, Gregori, Fleires-Gutierrez, Colleluori, Aguirre, Chen, Russo, Fuenmayor Lopez, Qualls, Villareal and Armamento-Villareal.)

Background: Both obesity and hypogonadism are common in older men which could additively exacerbate age-related declines in cognitive function. However, little is known about the effects of lifestyle intervention plus testosterone replacement therapy in this population., Objectives: In this secondary analysis of the LITROS (Lifestyle Intervention and Testosterone Replacement in Obese Seniors) trial, we examined whether testosterone replacement therapy would improve cognitive function when added to intensive lifestyle intervention in older men with obesity and hypogonadism., Methods: Eighty-three older, obese hypogonadal men with frailty were randomly assigned to lifestyle therapy (weight management and exercise training) plus testosterone (LT + Test) or lifestyle therapy plus placebo (LT + Pbo) for 6 mo. For this report, the primary outcome was change in the global cognition composite z score. Secondary outcomes included changes in z score subcomponents: attention/information processing, memory, executive function, and language. Changes between groups were analyzed using mixed-model repeated-measures ANCOVAs following the intention-to-treat principle., Results: Global cognition z score increased more in the LT + Test than in the LT + Pbo group (mean change: 0.49 compared with 0.21; between-group difference: -0.28; 95% CI: -0.45, -0.11; Cohen's d = 0.74). Moreover, attention/information z score and memory z score increased more in the LT + Test than in the LT + Pbo group (mean change: 0.55 compared with 0.23; between-group difference: -0.32; 95% CI: -0.55, -0.09; Cohen's d = 0.49 and mean change: 0.90 compared with 0.37; between-group difference: -0.53; 95% CI: -0.93, -0.13; Cohen's d = 1.43, respectively). Multiple regression analyses showed that changes in peak oxygen consumption, strength, total testosterone, and luteinizing hormone were independent predictors of the improvement in global cognition (R2 = 0.38; P < 0.001)., Conclusions: These findings suggest that in the high-risk population of older men with obesity and hypogonadism, testosterone replacement may improve cognitive function with lifestyle behaviors controlled via lifestyle intervention therapy.This trial was registered at clinicaltrials.gov as NCT02367105., (Published by Oxford University Press on behalf of the American Society for Nutrition 2021.)

The number of adults 65 years and older is increasing worldwide and will represent the 20% of the population by 2030. Half of them will suffer from obesity. The decline in muscle mass and strength, known as sarcopenia, is very common among older adults with obesity (sarcopenic obesity). Sarcopenic obesity is strongly associated with frailty, cardiometabolic dysfunction, physical disability, and mortality. Increasing efforts have been hence made to identify effective strategies able to promote healthy aging and curb the obesity pandemic. Among these, lifestyle interventions consisting of diet and exercise protocols have been extensively explored. Importantly, diet-induced weight loss is associated with fat, muscle, and bone mass losses, and may further exacerbate age-related sarcopenia and frailty outcomes in older adults. Successful approaches to induce fat mass loss while preserving lean and bone mass are critical to reduce the aging- and obesity-related physical and metabolic complications and at the same time ameliorate frailty. In this review article, we discuss the most recent evidence on the age-related alterations in adipose tissue and muscle health and on the effect of calorie restriction and exercise approaches for older adults with obesity and sarcopenia, emphasizing the existing gaps in the literature that need further investigation., (Published by Elsevier Inc.)

Background: Metabolic syndrome and insulin resistance are associated with worsened outcomes of chronic lung disease. The triglyceride-glucose index (TyG), a measure of metabolic dysfunction, is associated with metabolic syndrome and insulin resistance, but its relationship to lung health is unknown., Research Question: What is the relationship of TyG to respiratory symptoms, chronic lung disease, and lung function?, Study Design and Methods: This study analyzed data from the National Health and Nutrition Examination Survey from 1999 to 2012. Participants included fasting adults age ≥ 40 years (N = 6,893) with lung function measurements in a subset (n = 3,383). Associations of TyG with respiratory symptoms (cough, phlegm production, wheeze, and exertional dyspnea), chronic lung disease (diagnosed asthma, chronic bronchitis, and emphysema), and lung function (FEV 1 , FVC, and obstructive or restrictive spirometry pattern) were evaluated, adjusting for sociodemographic variables, comorbidities, and smoking. TyG was compared vs insulin resistance, represented by the homeostatic model assessment of insulin resistance (HOMA-IR), and vs the metabolic syndrome., Results: TyG was moderately correlated with HOMA-IR (Spearman ρ = 0.51) and had good discrimination for metabolic syndrome (area under the receiver-operating characteristic curve, 0.80). A one-unit increase in TyG was associated with higher odds of cough (adjusted OR [aOR], 1.28; 95% CI, 1.06-1.54), phlegm production (aOR, 1.20; 95% CI, 1.01-1.43), wheeze (aOR, 1.18; 95% CI, 1.03-1.35), exertional dyspnea (aOR, 1.21; 95% CI, 1.07-1.38), and a diagnosis of chronic bronchitis (aOR, 1.21; 95% CI, 1.02-1.43). TyG was associated with higher relative risk of a restrictive spirometry pattern (adjusted relative risk ratio, 1.45; 95% CI, 1.11-1.90). Many associations were maintained with additional adjustment for HOMA-IR or metabolic syndrome., Interpretation: TyG was associated with respiratory symptoms, chronic bronchitis, and a restrictive spirometry pattern. Associations were not fully explained by insulin resistance or metabolic syndrome. TyG is a satisfactory measure of metabolic dysfunction with relevance to pulmonary outcomes. Prospective study to define TyG as a biomarker for impaired lung health is warranted., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Context: Male hypogonadism is associated with low bone mineral density (BMD) and increased fragility fracture risk. Patients with type 2 diabetes (T2D) have relatively higher BMD, but greater fracture risk., Objective: Evaluate the skeletal response to testosterone therapy in hypogonadal men with T2D compared with hypogonadal men without T2D., Methods: Single arm, open-label clinical trial (NCT01378299) involving 105 men (40-74 years old), with average morning testosterone <300 ng/dL. Subjects were injected intramuscularly with testosterone cypionate (200 mg) every 2 weeks for 18 months. Testosterone and estradiol were assessed by liquid chromatography/mass spectrometry; serum C-terminal telopeptide of type I collagen (CTX), osteocalcin and sclerostin by enzyme-linked immunosorbent assay; glycated hemoglobin (HbA1c) by high-performance liquid chromatography, areal BMD (aBMD) and body composition by dual-energy x-ray absorptiometry; tibial volumetric BMD (vBMD) and bone geometry by peripheral quantitative computed tomography., Results: Among our population of hypogonadal men, 49 had T2D and 56 were non-T2D. After 18 months of testosterone therapy, there were no differences in circulating testosterone and estradiol between the groups. Hypogonadal men with T2D had increased osteocalcin, reflecting increased osteoblast activity, compared with non-T2D men (P < .01). T2D men increased lumbar spine aBMD (P < .05), total area at 38% tibia (P < .01) and periosteal and endosteal circumferences at the same site (P < .01 for both). T2D men had reduced tibial vBMD (P < .01), but preserved bone mineral content (P = .01). Changes in HbA1c or body composition were similar between the 2 groups., Conclusion: Testosterone therapy results in greater improvements in the skeletal health of hypogonadal men with T2D than their nondiabetic counterparts., (Published by Oxford University Press on behalf of the Endocrine Society 2021.)

Introduction: Obesity and type 2 Diabetes (T2D) are both associated with greater bone mineral density (BMD) but increased risk of fractures. The effect of the combination of both conditions on bone metabolism, microarchitecture, and strength in the obese population remains unknown., Methods: Data from 112 obese men were collected. Bone turnover and biochemical markers were measured by enzyme-linked immunosorbent assay, body composition and BMD at all sites were assessed by dual energy X-ray absorptiometry, whereas bone microarchitecture and strength (stiffness and failure load) were measured by high-resolution peripheral computed tomography. Data were compared among metabolically healthy obese (MHO) and metabolically unhealthy obese (MUHO) with and without T2D and between obese without and with T2D., Results: Compared to MHO and MUHO without T2D, MUHO with T2D had significantly lower levels of osteocalcin ((7.49 ± 3.0 and 6.03 ± 2.47 vs 4.24 ± 2.72 ng/mL, respectively, P = 0.003) and C-terminal telopeptide of type I collagen (CTx) (0.28 ± 0.10 and 0.29 ± 0.13 vs 0.21 ± 0.15 ng/mL, respectively, P = 0.02). Dividing our subjects simply into those with and without T2D showed that obese men with T2D had significantly lower levels of osteocalcin (P = 0.003) and CTx (P = 0.005), greater trabecular separation at the tibia and radius (P = 0.03 and P = 0.04, respectively), and lower tibial failure load and stiffness (both P = 0.04), relative to obese men without T2D., Conclusion: In men, the combination of obesity and T2D is associated with reduced bone turnover and poorer trabecular bone microarchitecture and bone strength compared to those who are obese but without T2D, suggesting worse bone disease., (Published by Oxford University Press on behalf of the Endocrine Society 2021.)

Background: Obesity and hypogonadism additively contribute to frailty in older men; however, appropriate treatment remains controversial., Objective: Determine whether testosterone replacement augments the effect of lifestyle therapy on physical function in older men with obesity and hypogonadism., Design: Randomized, double-blind, placebo-controlled trial., Setting: VA Medical Center., Participants: 83 older (age ≥65 years) men with obesity (body mass index ≥30 kg/m2) and persistently low am testosterone (<10.4 nmol/L) associated with frailty., Interventions: Participants were randomized to lifestyle therapy (weight management and exercise training) plus either testosterone (LT+Test) or placebo (LT+Pbo) for 6 months., Outcome Measures: Primary outcome was change in Physical Performance Test (PPT) score. Secondary outcomes included other frailty measures, body composition, hip bone mineral density (BMD), physical functions, hematocrit, prostate specific antigen (PSA), and sex hormones., Results: PPT score increased similarly in LT+Test and LT+Pbo group (17% vs. 16%; P = 0.58). VO2peak increased more in LT+Test than LT+Pbo (23% vs. 16%; P = 0.03). Despite similar -9% weight loss, lean body mass and thigh muscle volume decreased less in LT+Test than LT+Pbo (-2% vs. -3%; P = 0.01 and -2% vs -4%; P = 0.04). Hip BMD was preserved in LT+Test compared with LT+Pbo (0.5% vs -1.1%; P = 0.003). Strength increased similarly in LT+Test and LT+Pbo (23% vs 22%; P = 0.94). Hematocrit but not PSA increased more in LT+Test than LT+Pbo (5% vs 1%; P < 0.001). Testosterone levels increased more in LT+Test than LT+Pbo (167% vs 27%; P < 0.001)., Conclusion: In older, obese hypogonadal men, adding testosterone for 6 months to lifestyle therapy does not further improve overall physical function. However, our findings suggest that testosterone may attenuate the weight loss-induced reduction in muscle mass and hip BMD and may further improve aerobic capacity., (Published by Oxford University Press on behalf of the Endocrine Society 2020.)

Context: Type 2 diabetes mellitus (T2D) is often accompanied by male hypogonadism and both conditions are associated with increased risk for fractures. Testosterone (T) has been shown to improve the bone health of hypogonadal men but has not been tested in patients who also have T2D in addition to low T. To date, there is no treatment that is specifically recommended for bone disease among patients with T2D. This study will evaluate the effect of T therapy on the bone health of male veterans with low T who also have T2D., Methods: This is a randomized double-blind placebo-controlled trial of 166 male veterans 35-65 years old, with T2D and hypogonadism, randomized to either T gel 1.62% or placebo for 12 months. We will evaluate the effect of T therapy on the following primary outcomes:1) changes in bone strength as measured by microfinite elements analysis (μFEA) using high-resolution peripheral quantitative computer tomography, 2) changes in bone turnover markers, and 3) changes in circulating osteoblast progenitors (COP) and osteoclast precursors cells., Discussion: We anticipate that T therapy will result in improvement in bone strength owing to improvement in bone remodeling through an increase in osteoblastic differentiation and proliferation in patients with hypogonadism and T2D., (© 2021 Published by Elsevier Inc.)

The human ageing process is universal, ubiquitous and inevitable. Every physiological function is being continuously diminished. There is a range between two distinct phenotypes of ageing, shaped by patterns of living - experiences and behaviours, and in particular by the presence or absence of physical activity (PA) and structured exercise (i.e., a sedentary lifestyle). Ageing and a sedentary lifestyle are associated with declines in muscle function and cardiorespiratory fitness, resulting in an impaired capacity to perform daily activities and maintain independent functioning. However, in the presence of adequate exercise/PA these changes in muscular and aerobic capacity with age are substantially attenuated. Additionally, both structured exercise and overall PA play important roles as preventive strategies for many chronic diseases, including cardiovascular disease, stroke, diabetes, osteoporosis, and obesity; improvement of mobility, mental health, and quality of life; and reduction in mortality, among other benefits. Notably, exercise intervention programmes improve the hallmarks of frailty (low body mass, strength, mobility, PA level, energy) and cognition, thus optimising functional capacity during ageing. In these pathological conditions exercise is used as a therapeutic agent and follows the precepts of identifying the cause of a disease and then using an agent in an evidence-based dose to eliminate or moderate the disease. Prescription of PA/structured exercise should therefore be based on the intended outcome (e.g., primary prevention, improvement in fitness or functional status or disease treatment), and individualised, adjusted and controlled like any other medical treatment. In addition, in line with other therapeutic agents, exercise shows a dose-response effect and can be individualised using different modalities, volumes and/or intensities as appropriate to the health state or medical condition. Importantly, exercise therapy is often directed at several physiological systems simultaneously, rather than targeted to a single outcome as is generally the case with pharmacological approaches to disease management. There are diseases for which exercise is an alternative to pharmacological treatment (such as depression), thus contributing to the goal of deprescribing of potentially inappropriate medications (PIMS). There are other conditions where no effective drug therapy is currently available (such as sarcopenia or dementia), where it may serve a primary role in prevention and treatment. Therefore, this consensus statement provides an evidence-based rationale for using exercise and PA for health promotion and disease prevention and treatment in older adults. Exercise prescription is discussed in terms of the specific modalities and doses that have been studied in randomised controlled trials for their effectiveness in attenuating physiological changes of ageing, disease prevention, and/or improvement of older adults with chronic disease and disability. Recommendations are proposed to bridge gaps in the current literature and to optimise the use of exercise/PA both as a preventative medicine and as a therapeutic agent., Competing Interests: Dr. Anker reports grants and personal fees from Vifor Int, personal fees from Bayer, personal fees from Boehringer Ingelheim, personal fees from Servier, grants and personal fees from Abbott Vascular, personal fees from Cardiac Dimensions, personal fees from Actimed, personal fees from Astra Zeneca, personal fees from Amgen, personal fees from Bioventrix, personal fees from Janssen, personal fees from Respicardia, personal fees from V-Wave, personal fees from Brahms, personal fees from Cordio, personal fees from Occlutech, outside the submitted work. Dr. Ruiz reports grants from Longeveron Inc, outside the submitted work. Dr. Marzetti reports personal fees from Abbott, personal fees from Nestlè, personal fees from Nutricia, personal fees from ThermoFisher, outside the submitted work. All the other authors have nothing to disclose.

Obesity fosters low-grade inflammation in white adipose tissue (WAT) that may contribute to the insulin resistance that characterizes type 2 diabetes. However, the causal relationship of these events remains unclear. The established dominance of STAT1 function in the immune response suggests an obligate link between inflammation and the comorbidities of obesity. To this end, we sought to determine how STAT1 activity in white adipocytes affects insulin sensitivity. STAT1 expression in WAT inversely correlated with fasting plasma glucose in both obese mice and humans. Metabolomic and gene expression profiling established STAT1 deletion in adipocytes ( STAT1 a-KO ) enhanced mitochondrial function and accelerated tricarboxylic acid cycle flux coupled with reduced fat cell size in subcutaneous WAT depots. STAT1 a-KO reduced WAT inflammation, but insulin resistance persisted in obese mice. Rather, elimination of type I cytokine interferon-γ activity enhanced insulin sensitivity in diet-induced obesity. Our findings reveal a permissive mechanism that bridges WAT inflammation to whole-body insulin sensitivity., (© 2020 by the American Diabetes Association.)

Context: Lower dehydroepiandrosterone-sulfate (DHEA-S) levels have been inconsistently associated with coronary heart disease (CHD) and mortality. Data are limited for heart failure (HF) and association between DHEA-S change and events., Objective: Assess associations between low DHEA-S/DHEA-S change and incident HF hospitalization, CHD, and mortality in older adults., Design: DHEA-S was measured in stored plasma from visits 4 (1996-1998) and 5 (2011-2013) of the Atherosclerosis Risk in Communities study. Follow-up for incident events: 18 years for DHEA-S level; 5.5 years for DHEA-S change., Setting: General community., Participants: Individuals without prevalent cardiovascular disease (n = 8143, mean age 63 years)., Main Outcome Measure: Associations between DHEA-S and incident HF hospitalization, CHD, or mortality; associations between 15-year change in DHEA-S (n = 3706) and cardiovascular events., Results: DHEA-S below the 15th sex-specific percentile of the study population (men: 55.4 µg/dL; women: 27.4 µg/dL) was associated with increased HF hospitalization (men: hazard ratio [HR] 1.30, 95% confidence interval [CI], 1.07-1.58; women: HR 1.42, 95% CI, 1.13-1.79); DHEA-S below the 25th sex-specific percentile (men: 70.0 µg/dL; women: 37.1 µg/dL) was associated with increased death (men: HR 1.12, 95% CI, 1.01-1.25; women: HR 1.19, 95% CI, 1.03-1.37). In men, but not women, greater percentage decrease in DHEA-S was associated with increased HF hospitalization (HR 1.94, 95% CI, 1.11-3.39). Low DHEA-S and change in DHEA-S were not associated with incident CHD., Conclusions: Low DHEA-S is associated with increased risk for HF and mortality but not CHD. Further investigation is warranted to evaluate mechanisms underlying these associations., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)