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Objective: To evaluate the cardiometabolic outcomes associated with discordant visceral adipose tissue (VAT) and liver fat (LF) phenotypes in 2 cohorts., Patients and Methods: Participants in the Dallas Heart Study underwent baseline imaging from January 1, 2000, through December 31, 2002, and were followed for incident cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) through 2013. Associations between VAT-LF groups (low-low, high-low, low-high, and high-high) and outcomes were assessed using multivariable-adjusted regression and were replicated in the independent UK Biobank., Results: The Dallas Heart Study included 2064 participants (mean ± SD age, 44±9 years; 54% female; 47% black). High VAT-high LF and high VAT-low LF were associated with prevalent atherosclerosis, whereas low VAT-high LF was not. Of 1731 participants without CVD/T2DM, 128 (7.4%) developed CVD and 95 (5.5%) T2DM over a median of 12 years. High VAT-high LF and high VAT-low LF were associated with increased risk of CVD (hazard ratios [HRs], 2.0 [95% CI, 1.3 to 3.2] and 2.4 [95% CI, 1.4 to 4.1], respectively) and T2DM (odds ratios [ORs], 7.8 [95% CI, 3.8 to 15.8] and 3.3 [95% CI, 1.4 to 7.8], respectively), whereas low VAT-high LF was associated with T2DM (OR, 2.7 [95% CI, 1.1 to 6.7]). In the UK Biobank (N=22,354; April 2014-May 2020), only high VAT-low LF remained associated with CVD after multivariable adjustment for age and body mass index (HR, 1.5 [95% CI, 1.2 to 1.9])., Conclusion: Although VAT and LF are each associated with cardiometabolic risk, these observations demonstrate the importance of separating their cardiometabolic implications when there is presence or absence of either or both in an individual., (Copyright © 2021 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: Visceral and ectopic fat are key drivers of adverse cardiometabolic outcomes in obesity. We aimed to evaluate the effects of injectable liraglutide 3·0 mg daily on body fat distribution in adults with overweight or obesity without type 2 diabetes at high cardiovascular disease risk., Methods: In this randomised, double-blind, placebo-controlled, phase 4, single centre trial, we enrolled community-dwelling adults, recruited from the University of Texas Southwestern Medical Center, with BMI of at least 30 kg/m 2 or BMI of at least 27 kg/m 2 with metabolic syndrome but without diabetes and randomly assigned them, in a 1:1 ratio, to 40 weeks of treatment with once-daily subcutaneous liraglutide 3·0 mg or placebo, in addition to a 500 kcal deficient diet and guideline-recommended physical activity counselling. The primary endpoint was percentage reduction in visceral adipose tissue (VAT) measured with MRI. All randomly assigned participants with a follow-up imaging assessment were included in efficacy analyses and all participants who received at least one dose of study drug were included in the safety analyses. The trial is registered on ClinicalTrials.gov: NCT03038620., Findings: Between July 20, 2017 and Feb 21, 2020 from 235 participants assessed for eligibility, 185 participants were randomly assigned (n=92 liraglutide, n=93 placebo) and 128 (n=73 liraglutide, n=55 placebo) were included in the final analysis (92% female participants, 37% Black participants, 24% Hispanic participants, mean age 50·2 years (SD 9·4), mean BMI 37·7 kg/m 2 ). Mean change in VAT over median 36·2 weeks was -12·49% (SD 9·3%) with liraglutide compared with -1·63% (SD 12·3%) with placebo, estimated treatment difference -10·86% (95% CI -6·97 to -14·75, p<0·0001). Effects seemed consistent across subgroups of age, sex, race-ethnicity, BMI, and baseline prediabetes. The most frequently reported adverse events were gastrointestinal-related (43 [47%] of 92 with liraglutide and 12 [13%] of 93 with placebo) and upper respiratory tract infections (10 [11%] of 92 with liraglutide and 14 [15%] of 93 with placebo)., Interpretation: In adults with overweight or obesity at high cardiovascular disease risk, once-daily liraglutide 3·0 mg plus lifestyle intervention significantly lowered visceral adipose tissue over 40 weeks of treatment. Visceral fat reduction may be one mechanism to explain the benefits seen on cardiovascular outcomes in previous trials with liraglutide among patients with type 2 diabetes., Funding: NovoNordisk., Competing Interests: Declaration of interests IJN has previously received consulting income from Merck, honoraria, consulting, speaking fees, and travel support from Boehringer-Ingelheim–Lilly Alliance, a research grant from Novo Nordisk, and has been a member of the scientific advisory board of AMRA Medical. PHJ has received consulting income from Regeneron and Bayer, reports equity in G3 Therapeutics, and grant support from AHA, NASA, Novo Nordisk, Amgen, GlaxoSmithKline, Sanofi, AstraZeneca, and Novartis. SPM has received consulting income from Novo Nordisk, Boston Scientific, Asahi Intec, and Abbott Vascular. All other authors have no potential competing interests to report. AP has served on the advisory board of Roche Diagnostics, has received non-financial support from Pfizer and Merck, has received research support from the Texas Health Resources Clinical Scholarship, the Gilead Sciences Research Scholar Program, the National Institute of Aging GEMSSTAR Grant (1R03AG067960-01), and Applied Therapeutics., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: The aim of this study was to determine the effects of empagliflozin on glycerol-derived hepatic gluconeogenesis in adults with obesity without type 2 diabetes mellitus (T2DM) using oral carbon 13 ( 13 C)-labeled glycerol., Methods: A randomized, double-blind, placebo-controlled trial was performed in participants with magnetic resonance imaging assessment of body fat and measurement of glycerol-derived 13 C enrichment in plasma glucose by nuclear magnetic resonance spectroscopy following ingestion of [U- 13 C 3 ]glycerol. Participants were randomized to oral empagliflozin 10 mg once daily or placebo for 3 months. Glycerol-derived 13 C enrichment studies were repeated, and treatment differences in the mean percentage of 13 C glycerol enrichment in glucose were compared using mixed linear models., Results: Thirty-five participants completed the study. Empagliflozin increased glycerol-derived 13 C enrichment between baseline and follow-up by 6.5% (P = 0.005), consistent with less glycerol from visceral adipose tissue (VAT). No difference was found with placebo. Glycerol-derived 13 C enrichment was lower in participants with high VAT compared with low VAT by 12.6% (P = 0.04), but there was no heterogeneity of the treatment effect by baseline VAT. Glycerol-derived 13 C enrichment was inversely correlated with VAT but was not correlated with weight loss., Conclusions: VAT is associated with endogenous glycerol-derived hepatic gluconeogenesis, and empagliflozin reduces endogenous glycerol gluconeogenesis in adults with obesity without T2DM. These findings suggest a mechanism by which sodium-glucose cotransporter 2 inhibitors may prevent T2DM in obesity., (© 2020 The Obesity Society.)

Objective: Lifestyle intervention remains the cornerstone of management of type 2 diabetes mellitus (T2DM). However, adherence to physical activity (PA) recommendations and the impact of that adherence on cardiorespiratory fitness in this population have been poorly described. We sought to investigate adherence to PA recommendations and its association with cardiorespiratory fitness in a population of patients with T2DM., Research Design and Methods: A cross-sectional analysis of baseline data from a randomized clinical trial (NCT00424762) was performed. A total of 150 individuals with medically treated T2DM and atherosclerotic cardiovascular disease (ASCVD) or risk factors for ASCVD were recruited from outpatient clinics at a single academic medical center. All individuals underwent a graded maximal exercise treadmill test to exhaustion with breath-by-breath gas exchange analysis to determine VO 2peak . PA was estimated using a structured 7-Day Physical Activity Recall interview., Results: Participants had a mean ± SD age of 54.9 ± 9.0 years; 41% were women, 40% were black, and 21% were Hispanic. The mean HbA 1c was 7.7 ± 1.8% and the mean BMI, 34.5 ± 7.2 kg/m 2 . A total of 72% had hypertension, 73% had hyperlipidemia, and 35% had prevalent ASCVD. The mean ± SD reported daily PA was 34.3 ± 4 kcal/kg, only 7% above a sedentary state; 47% of the cohort failed to achieve the minimum recommended PA. Mean ± SD VO 2peak was 27.4 ± 6.5 mL/kg fat-free mass/min (18.8 ± 5.0 mL/kg/min)., Conclusions: On average, patients with T2DM who have or are at risk for ASCVD report low levels of PA and have low measured cardiopulmonary fitness. This underscores the importance of continued efforts to close this therapeutic gap., (© 2019 by the American Diabetes Association.)

Objective: To assess the impact of intermediate-term treatment with rosiglitazone on high-sensitivity cardiac troponin T levels among patients with type 2 diabetes mellitus with or at high risk of coronary artery disease., Methods: High-sensitivity cardiac troponin T level was measured at baseline and after 6 months of study treatment in a randomized trial comparing rosiglitazone versus placebo in patients with type 2 diabetes and prevalent cardiovascular disease or multiple cardiovascular disease risk factors. Univariable and multivariable linear regression analyses were performed to assess the effect of rosiglitazone versus placebo on high-sensitivity cardiac troponin T levels., Results: The study included 150 randomized participants, of whom 106 had paired baseline and end-of-study blood samples for analysis (mean age: 56 ± 8 years, 42% women; 8.8 years average type 2 diabetes duration; mean haemoglobin A1c of 7.5). Almost all study participants (93%) had detectable high-sensitivity cardiac troponin T (⩾ 3 ng/L) at baseline, including 23% with high-sensitivity cardiac troponin T levels exceeding the threshold commonly used to diagnose myocardial infarction (⩾ 14 ng/L). Change in high-sensitivity cardiac troponin T levels from baseline to follow-up was not significantly different between rosiglitazone and placebo groups (p = 0.316)., Conclusion: Rosiglitazone did not impact high-sensitivity cardiac troponin T levels, adding to the growing body of literature suggesting that the incremental heart failure risk associated with rosiglitazone is not mediated by direct myocardial injury., (© The Author(s) 2015.)

Objective: To evaluate the impact of exercise training (ET) on metabolic parameters among participants with type 2 diabetes mellitus (T2DM) who do not improve their cardiorespiratory fitness (CRF) with training., Research Design and Methods: We studied participants with T2DM participating in the Health Benefits of Aerobic and Resistance Training in Individuals With Type 2 Diabetes (HART-D) trial who were randomized to a control group or one of three supervised ET groups for 9 months. Fitness response to ET was defined as a change in measured peak absolute oxygen uptake (ΔVO(2peak), in liters per minute) from baseline to follow-up. ET participants were classified based on ΔVO(2peak) into fitness responders (ΔVO(2peak) ≥5%) and nonresponders (ΔVO(2peak) <5%), and changes in metabolic profiles were compared across control, fitness responder, and fitness nonresponder groups., Results: A total of 202 participants (mean age 57.1 ± 7.9 years, 63% women) were included. Among the exercise groups (n = 161), there was substantial heterogeneity in ΔVO(2peak); 57% had some improvement in CRF (ΔVO(2peak) >0), with only 36.6% having a ≥5% increase in VO(2peak). Both fitness responders and nonresponders (respectively) had significant improvements in hemoglobin A1c and measures of adiposity (ΔHbA(1c): -0.26% [95% CI -0.5 to -0.01] and -0.26% [-0.45 to -0.08]; Δwaist circumference: -2.6 cm [-3.7 to -1.5] and -1.8 cm [-2.6 to -1.0]; Δbody fat: -1.07% [-1.5 to -0.62] and -0.75% [-1.09 to -0.41]). No significant differences were observed in the degree of change of these metabolic parameters between fitness responders and nonresponders. Control group participants had no significant changes in any of these metabolic parameters., Conclusions: ET is associated with significant improvements in metabolic parameters irrespective of improvement in cardiorespiratory fitness., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: The aim of this study was to determine whether high fitness attenuates the defects in left ventricular (LV) structure, function and triglyceride (TG) content in patients with type 2 diabetes mellitus (T2DM)., Materials and Methods: Patients (n = 74) with T2DM and ≥1 additional cardiac risk factor were recruited to participate in this cross-sectional study. Outcome measures of interest were LV structure and function by magnetic resonance imaging (MRI) and myocardial TG content by (1)H-magnetic resonance spectroscopy (MRS). The primary exposure variable was cardiorespiratory fitness defined by peak oxygen consumption scaled to fat-free mass (FFM; VO2peak-FFM)., Results: Mean age was 53.5 years; 42.9% were women and mean glycosylated haemoglobin (HbA1c) was 8.0% with the mean duration of T2DM 8.2 years. VO2peak-FFM was crudely associated with both LV end systolic (r = 0.35, p = 0.002) and diastolic volumes (r = 0.32, p = 0.004), but not with ejection fraction (r = -0.15, p = 0.206), myocardial TG (r = -0.04, p = 0.734) or early diastolic peak filling rate (PFR; r = -0.01, p = 0.887). In multiple linear regression analyses, among measures of LV structure/function, VO2peak-FFM was independently associated only with LV end-diastolic volume (EDV) (β = 1.037, p = 0.038)., Conclusion: In individuals with T2DM at increased cardiovascular (CV) risk, cardiorespiratory fitness is not associated with LV morphology, function or myocardial TG content., (© The Author(s) 2014.)

Context: The risk of type 2 diabetes mellitus is heterogeneous among obese individuals. Factors that discriminate prediabetes or diabetes risk within this population have not been well characterized. A dysfunctional adiposity phenotype, characterized by excess visceral fat and insulin resistance, may contribute to diabetes development in those with obesity., Objective: To investigate associations between adiposity phenotypes and risk for incident prediabetes and diabetes in a multiethnic, population-based cohort of obese adults., Design, Setting, and Participants: Among 732 obese participants (body mass index ≥30) aged 30 to 65 years without diabetes or cardiovascular disease enrolled between 2000 and 2002 in the Dallas Heart Study, we measured body composition by dual energy x-ray absorptiometry and magnetic resonance imaging (MRI); circulating adipokines and biomarkers of insulin resistance, dyslipidemia, and inflammation; and subclinical atherosclerosis and cardiac structure and function by computed tomography and MRI., Main Outcome Measures: Incidence of diabetes through a median 7.0 years (interquartile range, 6.6-7.6) of follow-up. In a subgroup of 512 participants with normal fasting glucose values at baseline, incidence of the composite of prediabetes or diabetes was determined., Results: Of the 732 participants (mean age, 43 years; 65% women; 71% nonwhite), 84 (11.5%) developed diabetes. In multivariable analysis, higher baseline visceral fat mass (odds ratio [OR] per 1 SD [1.4 kg], 2.4; 95% CI, 1.6-3.7), fructosamine level (OR per 1 SD [1.1 μmol/L], 2.0; 95% CI, 1.4-2.7), fasting glucose level (OR per 1 SD [1.1 μmol/L], 1.9; 95% CI, 1.4-2.6), family history of diabetes (OR, 2.3; 95% CI, 1.3-4.3), systolic blood pressure (OR per 10 mm Hg, 1.3; 95% CI, 1.1-1.5), and weight gain over follow-up (OR per 1 kg, 1.06; 95% CI, 1.02-1.10) were independently associated with diabetes, with no associations observed for body mass index, total body fat, or abdominal subcutaneous fat. Among the 512 participants with normal baseline glucose values, the composite outcome of prediabetes or diabetes occurred in 39.1% and was independently associated with baseline measurements of visceral fat mass; levels of fasting glucose, insulin, and fructosamine; older age; nonwhite race; family history of diabetes; and weight gain over follow-up (P < .05 for each) but not with measurements of general adiposity., Conclusion: Excess visceral fat and insulin resistance, but not general adiposity, were independently associated with incident prediabetes and type 2 diabetes mellitus in obese adults.

This was a nested sub-study of a randomised placebo-controlled trial of the effect of 6 months of treatment with rosiglitazone added to existing therapy on myocardial triglyceride (mTG) content in patients with type 2 diabetes (T2D) and prevalent cardiovascular disease (CVD) or at least one additional risk factor. The primary endpoint, mTG content, was measured with cardiac (1)H-magnetic resonance spectroscopy. Of the 99 randomised participants selected for the imaging sub-study, 49 (48%) had complete and interpretable spectroscopy data (age = 58 years, duration of T2D = 9.5 years; 57% women and 69% non-white). There was no significant change in mTG in either group (-0.1 ± 0.6% and -0.05 ± 0.8% respectively) and the changes in mTG were not associated with changes in left ventricular structure or function. Compared with placebo, treatment with rosiglitazone for 6 months had no discernible effect on mTG or left ventricular function in this population with long-standing diabetes and CVD.

Aims: Plasma levels of the adipokine adiponectin are accepted as excellent correlates to metabolic health. Here, we aim to characterise associations between circulating plasma adiponectin complexes and baseline parameters in a population of patients with type 2 diabetes mellitus (DM) with increased risk of cardiovascular disease., Methods: We measured levels of high molecular weight (HMW), low molecular weight (LMW) and trimeric adiponectin., Results: The study population comprised 53 subjects, mean age 57 years, 36% non-white and 44% women, with an average body mass index (BMI) of 34 and duration of DM of 8.5 years. There was an established history of cardiovascular disease in 36% of the patients. BMI was inversely associated with the proportion of HMW adiponectin compared with LMW and trimeric adiponectin. Longer duration of DM correlated with an increased proportion of trimeric adiponectin., Conclusions: Patients with elevated BMI, longer history of diabetes and cardiovascular disease have lower levels of the higher order adiponectin complex. In addition, we have measured for the first time levels of trimeric adiponectin in a diabetic population using high resolution fast protein liquid chromatography (FPLC) analysis and identified trimeric adiponectin as a promising new biomarker for cardiovascular disease with a stronger correlative relationship to cardiovascular disease than HMW adiponectin.

Background: Thiazolidinediones cause peripheral oedema, the aetiology of which remains poorly understood., Methods: In a sub-study of a 6-month trial comparing rosiglitazone (Rsg) versus placebo, we compared those with versus without oedema among the 74 subjects treated with Rsg with respect to peak oxygen consumption indexed to fat-free mass (VO(2peak-FFM) ), cardiac MRI and markers of plasma volume expansion., Results: Almost half (49%) of the Rsg-treated patients developed oedema. Baseline VO(2peak-FFM) was not different between those with versus without oedema (25.8 versus 28.2 ml/kg/min; p = 0.22) and declined 5% in the oedema group (Δ -1.3 ml/min/kg; p = 0.005) with no change in those without oedema. Stroke volume increased in both groups (Δ 8.7 and 8.8 ml; p < 0.001 for each); end-diastolic volume increased only in those with oedema (+13.1 ml; p = 0.001). No other cardiac function changes were observed. In both groups, weight increased (3.6 and 2.2 kg) and haematocrit decreased (-3.2% and -2.1%; p < 0.001 for each). In those with oedema, albumin decreased (-0.2 g/dl) and brain natriuretic peptide increased (11.9 pg/ml; p < 0.03 for each)., Conclusions: Oedema was associated with a small decline in VO(2peak FFM), no adverse effects on cardiac function, and changes in selected measures suggesting that volume expansion underpins Rsg oedema.

Aims: To assess the effect of rosiglitazone on cardiovascular performance and cardiac function., Methods and Results: One hundred and fifty type 2 diabetes patients with cardiovascular disease (CVD) or ≥ 1 other CVD risk factor were randomized to receive rosiglitazone vs. placebo for 6 months. The primary outcome was peak oxygen uptake indexed to fat-free mass (VO(2peak)-FFM) during maximum exercise. A subset of 102 subjects underwent cardiac magnetic resonance imaging (cMRI). On hundred and eight subjects completed the study, including 75 completing the cMRI substudy. No significant differences were observed in mean VO(2peak)-FFM between rosiglitazone and placebo (26.1 ± 7.0 vs. 27.6 ± 6.6 mL/kg-FFM/min; P = 0.26). Compared with placebo, the rosiglitazone group had lower hematocrit (38 vs. 41%; P < 0.001) and more peripheral oedema (53.7 vs. 33.3%; P = 0.03). In the cMRI substudy, compared with placebo, the rosiglitazone group had larger end-diastolic volume (128.1 vs. 112.0 mL; P = 0.01) and stroke volume (83.7 vs. 72.9 mL; P = 0.01), and a trend toward increased peak ventricular filling rate (79.4 vs. 60.5; P = 0.07)., Conclusion: Rosiglitazone increased peripheral oedema but had no pernicious effects on cardiovascular performance or cardiac function, with modest improvement in selected cMRI measures. Changes in indirect markers of plasma volume suggest expansion with rosiglitazone., Trial Registration: clinicaltrials.gov identifier: NCT00424762.

In previous studies, with up to 16 weeks of exposure to rosiglitazone or pioglitazone, circulating markers of bone formation [procollagen I N-terminal propeptide (P1NP), osteocalcin, and bone-specific alkaline phosphatase] decreased but no change in bone resorption markers was found. We examined the effect of rosiglitazone on bone resorption and formation markers when used for 24 weeks. This post-hoc analysis of a double-blind, placebo-controlled, randomized trial evaluated the effects of 6 months of rosiglitazone use versus placebo on circulating markers of bone turnover in 111 patients with type 2 diabetes and cardiovascular disease or additional cardiac risk factors. The principal end points for analysis were changes in bone formation and resorption markers, measured by P1NP and carboxy-terminal cross-links (CTX), respectively. There were 111 subjects who completed the study and had baseline and 6-month data; mean age was 56, including 41% women and 67% nonwhite (50 black, 18 Hispanic, and six other), and subjects were evenly distributed between placebo and rosiglitazone groups. Women treated with rosiglitazone had higher CTX levels (0.43 ng/mL) than those who received placebo (0.23 ng/mL) (P = 0.007), with no significant differences in P1NP or OPG. Overall, in stratified analyses of men and in stratified analyses among different ethnicities, there were no statistically significant differences observed in CTX, P1NP, OPG, PTH, or 25-OHD between the treatment groups. Women taking rosiglitazone had higher circulating markers of bone resorption, which is contrary to prior studies of shorter duration, where the principal observation was a decrease in markers of bone formation.

The thiazolidinedione (TZD) class of medications has been associated with increased risk for peripheral oedema, as well as incident and worsening heart failure (HF). The mechanism of these observed effects remains unclear. Here we present the rationale and study design for a randomised clinical trial designed to evaluate the cardiac effects of rosiglitazone on integrated cardiovascular performance, cardiac structure and function. The study is a randomised, single-centre, double-blind, placebo-controlled, parallel-group clinical trial to evaluate the effect of rosiglitazone on integrated cardiovascular performance in a cohort of patients with type 2 diabetes mellitus (T2DM) at increased risk for developing heart failure (HF). Participants will be randomised to receive rosiglitazone or matching placebo for six months. All subjects will undergo maximal treadmill cardiopulmonary exercise testing at baseline and after six months on study drug, with the primary trial end point of peak oxygen uptake indexed to fat-free mass (VO 2peak-FFM). Approximately two-thirds of the study cohort will undergo cardiac magnetic resonance imaging (MRI) and spectroscopy (MRS) at baseline and after six months of study therapy to assess cardiac structure, function and myocardial triglyceride content. While concerns for peripheral oedema and HF continue to confound clinical use of TZD medications, the direct cardiac effects of these drugs remain poorly understood and the clinical relevance of these clinical observations remains unclear. The present study will combine a series of state-of-the-art assessments to evaluate the cardiac effects of rosiglitazone treatment.