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Weight Loss-Independent Effect of Liraglutide on Insulin Sensitivity in Individuals With Obesity and Prediabetes

Mashayekhi, Mona; Nian, Hui; Mayfield, Dustin; Devin, Jessica K; Gamboa, Jorge L; Yu, Chang; Silver, Heidi J; Niswender, Kevin; Luther, James M; Brown, Nancy J
UNLABELLED:Metabolic effects of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and not fully recapitulated by increasing endogenous GLP-1. We tested the hypothesis that GLP-1 receptor (GLP-1R) agonists exert weight loss-independent, GLP-1R-dependent effects that differ from effects of increasing endogenous GLP-1. Individuals with obesity and prediabetes were randomized to receive for 14 weeks the GLP-1R agonist liraglutide, a hypocaloric diet, or the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin. The GLP-1R antagonist exendin(9-39) and placebo were administered in a two-by-two crossover study during mixed-meal tests. Liraglutide and diet, but not sitagliptin, caused weight loss. Liraglutide improved insulin sensitivity measured by HOMA for insulin resistance (HOMA-IR), the updated HOMA model (HOMA2), and the Matsuda index after 2 weeks, prior to weight loss. Liraglutide decreased fasting and postprandial glucose levels, and decreased insulin, C-peptide, and fasting glucagon levels. In contrast, diet-induced weight loss improved insulin sensitivity by HOMA-IR and HOMA2, but not the Matsuda index, and did not decrease glucose levels. Sitagliptin increased endogenous GLP-1 and GIP values without altering insulin sensitivity or fasting glucose levels, but decreased postprandial glucose and glucagon levels. Notably, sitagliptin increased GIP without altering weight. Acute GLP-1R antagonism increased glucose levels in all groups, increased the Matsuda index and fasting glucagon level during liraglutide treatment, and increased endogenous GLP-1 values during liraglutide and sitagliptin treatments. Thus, liraglutide exerts rapid, weight loss-independent, GLP-1R-dependent effects on insulin sensitivity that are not achieved by increasing endogenous GLP-1. ARTICLE HIGHLIGHTS/UNASSIGNED:Metabolic benefits of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and are not fully achieved by increasing endogenous GLP-1 through dipeptidyl peptidase 4 (DPP-4) inhibition. We investigated weight loss-independent, GLP-1 receptor (GLP-1R)-dependent metabolic effects of liraglutide versus a hypocaloric diet or the DPP-4 inhibitor sitagliptin. GLP-1R antagonism with exendin(9-39) was used to assess GLP-1R-dependent effects during mixed meals. Liraglutide improved insulin sensitivity and decreased fasting and postprandial glucose prior to weight loss, and these benefits were reversed by exendin(9-39). GLP-1R agonists exert rapid, weight loss-independent, GLP-1R-dependent effects on insulin sensitivity not achieved by increasing endogenous GLP-1.
PMID: 37874653
ISSN: 1939-327x
CID: 5612992

Associations between traditional Chinese medicine body constitution and obesity risk among US adults

Zhu, Xiangzhu; Yin, Xiaolin; Deng, Xinqing; Shubin, Yevheniy Eugene; Murff, Harvey J; Ness, Reid M; Yu, Chang; Shrubsole, Martha J; Dai, Qi
BACKGROUND/UNASSIGNED:Traditional Chinese medicine (TCM) body constitution (BC), primarily determined by physiological and clinical characteristics, is an important process for clinical diagnosis and treatment and play a critical role in precision medicine in TCM. The purpose of the study was to explore whether the distributions of BC types differed by obesity status. METHODS/UNASSIGNED:We conducted a study to evaluate BC type in US population during 2012-2016. A total of 191 White participants from Personalized Prevention of Colorectal Cancer Trial (PPCCT) completed a self-administered Traditional Chinese Medicine Questionnaire (TCMQ, English version). In this study, we further compared the distribution of major types of TCM BC in the PPCCT to those Chinese populations stratified by obesity status. RESULTS/UNASSIGNED:We found the Blood-stasis frequency was higher in US White adults, 22.6% for individuals with BMI <30 and 11.2% for obese individuals, compared to 1.4% and 1.8%, respectively, in Chinese populations. We also found the percentages Inherited-special and Qi-stagnation were higher in US White adults than those in Chinese populations regardless of obesity status. However, the proportions of Yang-deficiency were higher in Chinese populations than those in our study conducted in US White adults regardless of obesity status. CONCLUSIONS/UNASSIGNED:These new findings indicate the difference in distribution of BC types we observed between US and Chinese populations cannot be explained by the differences in prevalence of obesity. Further studies are needed to confirm our findings and understand the potential mechanism including genetic background and/or environmental factors.
PMID: 38827360
ISSN: 2616-2806
CID: 5664862

Comparative effects of weight loss and incretin-based therapies on vascular endothelial function, fibrinolysis and inflammation in individuals with obesity and prediabetes: A randomized controlled trial

Mashayekhi, Mona; Beckman, Joshua A; Nian, Hui; Garner, Erica M; Mayfield, Dustin; Devin, Jessica K; Koethe, John R; Brown, Jonathan D; Cahill, Katherine N; Yu, Chang; Silver, Heidi; Niswender, Kevin; Luther, James M; Brown, Nancy J
AIM/OBJECTIVE:To test the hypothesis that glucagon-like peptide-1 receptor (GLP-1R) agonists have beneficial effects on vascular endothelial function, fibrinolysis and inflammation through weight loss-independent mechanisms. MATERIALS AND METHODS/METHODS:Individuals with obesity and prediabetes were randomized to 14 weeks of the GLP-1R agonist liraglutide, hypocaloric diet or the dipeptidyl peptidase-4 inhibitor sitagliptin in a 2:1:1 ratio. Treatment with drug was double blind and placebo-controlled. Measurements were made at baseline, after 2 weeks prior to significant weight loss and after 14 weeks. The primary outcomes were measures of endothelial function: flow-mediated vasodilation (FMD), plasminogen activator inhibitor-1 (PAI-1) and urine albumin-to-creatinine ratio (UACR). RESULTS:Eighty-eight individuals were studied (liraglutide N = 44, diet N = 22, sitagliptin N = 22). Liraglutide and diet reduced weight, insulin resistance and PAI-1, while sitagliptin did not. There was no significant effect of any treatment on endothelial vasodilator function measured by FMD. Post hoc subgroup analyses in individuals with baseline FMD below the median, indicative of greater endothelial dysfunction, showed an improvement in FMD by all three treatments. GLP-1R antagonism with exendin (9-39) increased fasting blood glucose but did not change FMD or PAI-1. There was no effect of treatment on UACR. Finally, liraglutide, but not sitagliptin or diet, reduced the chemokine monocyte chemoattractant protein-1 (MCP-1). CONCLUSION/CONCLUSIONS:Liraglutide and diet reduce weight, insulin resistance and PAI-1. Liraglutide, sitagliptin and diet do not change FMD in obese individuals with prediabetes with normal endothelial function. Liraglutide alone lowers the pro-inflammatory and pro-atherosclerotic chemokine MCP-1, indicating that this beneficial effect is independent of weight loss.
PMID: 36306151
ISSN: 1463-1326
CID: 5359672

Electronic cigarette use during pregnancy and the risk of adverse birth outcomes: A cross-sectional surveillance study of the US Pregnancy Risk Assessment Monitoring System (PRAMS) population

Ammar, Lin; Tindle, Hilary A; Miller, Angela M; Adgent, Margaret A; Nian, Hui; Ryckman, Kelli K; Mogos, Mulubrhan; Piano, Mariann R; Xie, Ethan; Snyder, Brittney M; Ramesh, Abhismitha; Yu, Chang; Hartert, Tina V; Wu, Pingsheng
BACKGROUND:Research on health effects and potential harms of electronic cigarette (EC) use during pregnancy is limited. We sought to determine the risks of pregnancy EC use on pregnancy-related adverse birth outcomes and assess whether quitting ECs reduces the risks. METHODS:Women with singleton live births who participated in the US Pregnancy Risk Assessment Monitoring System (PRAMS) survey study 2016-2020 were classified into four mutually exclusive groups, by their use of ECs and combustible cigarettes (CCs) during pregnancy: non-use, EC only use, CC only use, and dual use. We determined the risk of preterm birth, low birth weight, and small-for-gestational-age (SGA) by comparing cigarette users to non-users with a modified Poisson regression model adjusting for covariates. In a subset of women who all used ECs prior to pregnancy, we determined whether quitting EC use reduces the risk of preterm birth, low birth weight, and SGA by comparing to those who continued its use. All analyses were weighted to account for the PRAMS survey design and non-response rate. RESULTS:Of the 190,707 women (weighted N = 10,202,413) included, 92.1% reported cigarette non-use, 0.5% EC only use, 6.7% CC only use, and 0.7% dual use during pregnancy. Compared with non-use, EC only use was associated with a significantly increased risk of preterm birth (adjusted risk ratio [aRR]: 1.29, 95% confidence interval [CI]: 1.00, 1.65) and low birth weight (aRR: 1.38, 95%CI: 1.09, 1.75), but not SGA (aRR: 1.04, 95%CI: 0.76, 1.44). Among 7,877 (weighted N = 422,533) women EC users, quitting use was associated with a significantly reduced risk of low birth weight (aRR: 0.76, 95%CI: 0.62, 0.94) and SGA (aRR: 0.77, 95%CI: 0.62, 0.94) compared to those who continued to use ECs during pregnancy. CONCLUSIONS:Pregnancy EC use, by itself or dual use with CC, is associated with preterm birth and low birth weight. Quitting use reduces that risk. ECs should not be considered as a safe alternative nor a viable gestational smoking cessation strategy.
PMID: 37874824
ISSN: 1932-6203
CID: 5614302

Regression methods for the appearances of extremes in climate data

Yu, Chang; Blaha, Ondrej; Kane, Michael; Wei, Wei; Esserman, Denise; Zelterman, Daniel
For any given city, on any calendar day, there will be record high and low temperatures. Which record occurred earlier? If there is a trend towards warming then, intuitively, there should be a preponderance of record highs occurring more recently than the record lows for each of the 365 calendar days. We are interested in modeling the joint distribution of appearances of the extremes but not these values themselves. We develop a bivariate discrete distribution modeling the joint indices of maximum and minimum in a sequence of independent random variables sampled from different distributions. We assume these distributions share a proportional hazard rate and develop regression methods for these paired values. This approach has reasonable power to detect a small mean change over a decade. Using readily available public data, we examine the daily calendar extreme values of five US cities for the decade 2011"“2020. We develop linear regression models for these data, describe models to account for calendar-date dependence, and use diagnostic measures to detect remarkable observations.
ISSN: 1180-4009
CID: 5330802

Factors influencing intent to receive COVID-19 vaccination among Black and White adults in the southeastern United States, October - December 2020

Cunningham-Erves, Jennifer; Mayer, Carol S; Han, Xijing; Fike, Landon; Yu, Chang; Tousey, Phyllis M; Schlundt, David G; Gupta, Deepak K; Mumma, Michael T; Walkley, David; Steinwandel, Mark D; Edwards, Kathryn M; Lipworth, Loren; Sanderson, Maureen; Shu, Xiao-Ou; Shrubsole, Martha J
Vaccination intent is foundational for effective COVID-19 vaccine campaigns. To understand factors and attitudes influencing COVID-19 vaccination intent in Black and White adults in the US south, we conducted a mixed-methods cross-sectional survey of 4512 adults enrolled in the Southern Community Cohort Study (SCCS), an ongoing study of racial and economic health disparities. Vaccination intent was measured as "If a vaccine to prevent COVID-19 became available to you, how likely are you to choose to get the COVID-19 vaccination?" with options of "very unlikely," "somewhat unlikely," "neither unlikely nor likely," "somewhat likely," and "very likely." Reasons for intent, socio-demographic factors, preventive behaviors, and other factors were collected. 46% of participants had uncertain or low intent. Lower intent was associated with female gender, younger age, Black race, more spiritual/religious, lower perceived COVID-19 susceptibility, living in a greater deprivation area, lower reading ability, and lack of confidence in childhood vaccine safety or COVID-19 vaccine effectiveness or safety (p < .05 for all). Most factors were present in all racial/gender groups. Contextual influences, vaccine/vaccination specific issues, and personal/group influences were identified as reasons for low intent. Reasons for higher intent included preventing serious illness, life returning to normal, and recommendation of trusted messengers. Hesitancy was complex, suggesting tailored interventions may be required to address low intent.
PMID: 34847822
ISSN: 2164-554x
CID: 5162862

Impact of renin-angiotensin-aldosterone system inhibition on morbidity and mortality during long-term continuous-flow left ventricular assist device support: An IMACS report

Brinkley, D Marshall; Wang, Li; Yu, Chang; Grandin, E Wilson; Kiernan, Michael S
BACKGROUND:Inhibition of the renin angiotensin aldosterone system (RAAS) improves survival and reduces adverse cardiac events in heart failure with reduced ejection fraction, but the benefit is not well-defined following left ventricular assist device (LVAD). METHODS:We analyzed the ISHLT IMACS registry for adults with a primary, continuous-flow LVAD from January 2013 to September 2017 who were alive at postoperative month 3 without a major adverse event, and categorized patients according to treatment an angiotensin converting enzyme inhibitor (ACEI/ARB) or mineralocorticoid receptor antagonist (MRA). Propensity score matching was performed separately for ACEI/ARB vs none (n = 4,118 each) and MRA vs none (n = 3,892 each). RESULTS:Of 11,494 patients included, 50% were treated with ACEI/ARB and 38% with MRA. Kaplan-Meier survival was significantly better for patients receiving ACEI/ARB (p < 0.001) but not MRA (p = 0.31). In Cox proportional hazards analyses adjusted for known predictors of mortality following LVAD, ACEI/ARB use (hazard ratio 0.81 [95% confidence interval 0.71-0.93], p < 0.0001) but not MRA use (hazard ratio 1.03 [95% confidence interval 0.88-1.21], p = 0.69) was independently associated with lower mortality. Among patients treated with an ACEI/ARB, there was a significantly lower unadjusted risk of cardiovascular death (p < 0.001), risk of gastrointestinal bleeding (p = 0.01), and creatinine level (p < 0.001). MRA therapy was associated with lower risk of gastrointestinal bleeding (p = 0.01) but higher risk of hemolysis (p < 0.01). Potential limitations include residual confounding and therapy crossover. CONCLUSION:These findings suggest a benefit for ACEI/ARB therapy in patients with heart failure after LVAD implantation.
PMID: 34663529
ISSN: 1557-3117
CID: 5162882

A Mobile Health Intervention to Increase Physical Activity in Pulmonary Arterial Hypertension

Hemnes, Anna R; Silverman-Lloyd, Luke G; Huang, Shi; MacKinnon, Grant; Annis, Jeffrey; Whitmore, Carolyn S; Mallugari, Ravinder; Oggs, Rashundra N; Hekmat, Rezzan; Shan, Rongzi; Huynh, Pauline P; Yu, Chang; Martin, Seth S; Blaha, Michael J; Brittain, Evan L
BACKGROUND:Supervised exercise training improves outcomes in patients with pulmonary arterial hypertension (PAH). The effect of an unsupervised activity intervention has not been tested. RESEARCH QUESTION:Can a text-based mobile health intervention increase step counts in patients with PAH? STUDY DESIGN AND METHODS:We performed a randomized, parallel arm, single-blind clinical trial. We randomized patients to usual care or a text message-based intervention for 12 weeks. The intervention arm received three automated text messages per day with real-time step count updates and encouraging messages rooted in behavioral change theory. Individual step targets increased by 20% every 4 weeks. The primary end point was mean week 12 step counts. Secondary end points included the 6-min walk test, quality of life, right ventricular function, and body composition. RESULTS:Among 42 randomized participants, the change in raw steps between baseline and week 12 was higher in the intervention group (1,409 steps [interquartile range, -32 to 2,220] vs -149 steps [interquartile range, -1,010 to 735]; P = .02), which persisted after adjustment for age, sex, baseline step counts, and functional class (model estimated difference, 1,250 steps; P = .03). The intervention arm took a higher average number of steps on all days between days 9 and 84 (P < .05, all days). There was no difference in week 12 six-minute walk distance. Analysis of secondary end points suggested improvements in the emPHasis-10 score (adjusted change, -4.2; P = .046), a reduction in visceral fat volume (adjusted change, -170 mL; P = .023), and nearly significant improvement in tricuspid annular plane systolic excursion (model estimated difference, 1.2 mm; P = .051). INTERPRETATION:This study demonstrated the feasibility of an automated text message-based intervention to increase physical activity in patients with PAH. Additional studies are warranted to examine the effect of the intervention on clinical outcomes. CLINICAL TRIAL; No. NCT03069716; URL:
PMID: 33878341
ISSN: 1931-3543
CID: 5161672

GSK2256294 Decreases sEH (Soluble Epoxide Hydrolase) Activity in Plasma, Muscle, and Adipose and Reduces F2-Isoprostanes but Does Not Alter Insulin Sensitivity in Humans

Luther, James M; Ray, Justina; Wei, Dawei; Koethe, John R; Hannah, Latoya; DeMatteo, Anthony; Manning, Robert; Terker, Andrew S; Peng, Dungeng; Nian, Hui; Yu, Chang; Mashayekhi, Mona; Gamboa, Jorge; Brown, Nancy J
[Figure: see text].
PMID: 34455816
ISSN: 1524-4563
CID: 5161922

Magnesium treatment on methylation changes of transmembrane serine protease 2 (TMPRSS2)

Fan, Lei; Zhu, Xiangzhu; Zheng, Yinan; Zhang, Wei; Seidner, Douglas L; Ness, Reid; Murff, Harvey J; Yu, Chang; Huang, Xiang; Shrubsole, Martha J; Hou, Lifang; Dai, Qi
OBJECTIVES:The viral entry of SARS-CoV-2 requires host-expressed TMPRSS2 to facilitate the viral spike protein priming. This study aims to test the hypothesis that magnesium (Mg) treatment leads to DNA methylation changes in TMPRSS2. METHODS:This study is nested within the Personalized Prevention of Colorectal Cancer Trial, a double-blind 2 × 2 factorial randomized controlled trial, which enrolled 250 participants from Vanderbilt University Medical Center. RESULTS:We found that 12 wk of personalized Mg treatment significantly increased 5-methylcytosine methylation at cg16371860 (TSS1500, promoter) by 7.2% compared to the placebo arm (decreased by 0.1%) in those ages < 65 y. The difference remained statistically significant after adjusting for age, sex, and baseline methylation as well as correction for false discovery rate (adjusted P = 0.014). Additionally, Mg treatment significantly reduced 5-hydroxymethylcytosine levels at cg26337277 (close proximity to TSS200 and the 5' untranslated region, promoter) by 2.3% compared to an increase of 7.1% in the placebo arm after adjusting for covariates in those ages < 65 y (P = 0.003). The effect remained significant at a false discovery rate of 0.10 (adjusted P = 0.088). CONCLUSIONS:Among individuals ages < 65 y with calcium-to-magnesium intake ratios equal to or over 2.6, reducing the ratio to around 2.3 increased 5-methylcytosine modifications (i.e., cg16371860) and reduced 5-hydroxymethylcytosine modifications (i.e., cg26337277) in the TMPRSS2 gene. These findings, if confirmed, provide another mechanism for the role of Mg intervention in the prevention of COVID-19 and treatment of early and mild disease by modifying the phenotype of the TMPRSS2 genotype.
PMID: 34116393
ISSN: 1873-1244
CID: 5162842