bluuebunny/crossref_metadata_2025_split huggingface dataset:
1695-P: Ablation of Adipose CREB3L3 Prevents Browning and Promotes Inflammation
Authors: MCCANN MAXIMILIAN A. , MUNOZ MARCOS D. , GIL VICTORIA , ZHANG KEZHONG , LIEW CHONG WEE 
Published: June 2020

The body contains two kinds of fat: white fat, which acts as an energy storage organ, and brown fat, which utilizes energy to generate heat. White fat consists of the subcutaneous and the visceral fat. Accumulation of visceral fat contributes more to metabolic dysfunction due to its increased rate of lipolysis, reduced ability to form brown-like adipocytes known as “beige” cells, and its more inflammatory nature. In this study, we investigated the role that cyclic-AMP Responsive Element Binding Protein 3-like-3 (CREB3L3) plays in adipose tissue. CREB3L3 is an ER-bound transcription factor that has previously been described as liver specific, and an important regulator of lipid metabolism. Upon discovering that CREB3L3 is not only expressed in adipose tissue, but selectively downregulated in the more “metabolically healthy” subcutaneous fat in both obese mice and humans, we investigated how ablating this transcription factor would affect adipose biology. To study this, we created a CREB3L3 fat-specific knockout (fKO) mouse. When challenged with high-fat diet, the fKO mice became 18% heavier than floxed controls. They had significant expansion of their epididymal and inguinal adipose depots, due to a reduction in whole-body energy expenditure and oxygen consumption as measured by indirect calorimetry. The fKO mice are also more resistant to browning during cold exposure and treatment with the β3-adrenergic receptor agonist CL316,243, suggesting impairment of adaptive thermogenesis in the subcutaneous fat. Expansion of the visceral epididymal fat caused the tissue to become more inflammatory as evidenced by an increase in the number of crown-like structures and expression of the macrophage marker F/480 in the fKO tissue. This led to the fKO mice becoming more insulin resistant following high-fat feeding. Together, ablation of CREB3L3 enhances adiposity and insulin resistance during obesity due to a reduction in browning potential and amplified visceral inflammation.

Disclosure
M.A. McCann: None. M.D. Munoz: None. V. Gil: None. K. Zhang: None. C. LIew: None.

Funding
National Institutes of Health (R01DK109015-01); American Heart Association (16PRE30190011)
170-OR: Association of Timing of Physical Activity Bouts with Cardiorespiratory Fitness in Adults with Type 2 Diabetes in the Look AHEAD Study
Authors: QIAN JINGYI , WALKUP MICHAEL P. , CHEN SHYH-HUEI , BRUBAKER PETER H. , BOND DALE , RICHEY PHYLLIS A. , JAKICIC JOHN M. , HU KUN , SCHEER FRANK A. , MIDDELBEEK ROELAND 
Published: June 2020

Background: Moderate-to-vigorous physical activity (MVPA) is an important treatment in type 2 diabetes (T2D). Few studies examine the timing of MVPA, as there are no established methods to characterize the MVPA bout timing throughout the day. We determined the timing of MVPA bouts in adults with T2D, and examined whether cardiorespiratory fitness and odds of cardiovascular disease (CVD) history relate to timing of MVPA bouts in men and women.
Methods: Baseline data from Look AHEAD participants (n=2153, 57% women) were analyzed. Cardiorespiratory fitness assessed by VO2max test was expressed as METs. MVPA bouts (≥3METs in ≥10mins bouts) were determined using the hip-worn RT3 accelerometer for 7 days. Participants were categorized into six groups based on the time of day with the major amount of MVPA bouts (MET-min): ≥50% of MVPA bouts during the same time window (Early morning, Late morning, Afternoon, or Evening, N=214-280/group), &lt;50% of MVPA bouts in any time category (Mixed; reference group, N=436), and ≤1 day with MVPA bouts per week (Inactive, N=624).
Results: Cardiorespiratory fitness differed by timing of MVPA bout category (P&lt;0.0001). In a multivariate adjusted model, the association of timing of MVPA bouts with fitness varied by sex (P=0.002). In women, the evening group had higher fitness (β 0.35 [0.04, 0.66] METs). After further adjustment for individual total bout-MVPA (MET-min) per week, in men, the early morning group was associated with higher fitness (β 0.46 [0.06, 0.85] METs). Interestingly, in men, but not in women, the early morning group also had higher odds of CVD history (OR 2.4 [1.38, 4.21]).
Conclusion: Higher cardiorespiratory fitness associated with evening MVPA bouts in women, and with early morning MVPA bouts in men independent of total amount of bout-MVPA. Prospective studies are needed to investigate the relationship between timing of MVPA and cardiovascular outcomes to optimize MVPA benefits in adults with T2D.

Disclosure
J. Qian: None. M.P. Walkup: None. S. Chen: None. P.H. Brubaker: None. D. Bond: None. P.A. Richey: None. J.M. Jakicic: Advisory Panel; Self; Weight Watchers International, Inc. K. Hu: None. F.A. Scheer: None. R. Middelbeek: None.
1718-P: Heme Oxygenase-1 Promotes Hepatic Glucose Production via Increasing the Intracellular Ferrous Iron
Authors: LIAO WANG , YANG WANBAO , PAN QUAN , SHEN ZHENG , AI WEIQI , GUO SHAODONG 
Published: June 2020

The heme oxygenase-1 (HO1) catalyzes the degradation of heme into biliverdin, ferrous iron and carbon monoxide (CO). Although HO1 has long been considered as an anti-inflammatory molecule, recent studies showed that HO1 disrupts the mitochondrial function in hepatocytes, as well as drives inflammation and insulin resistance in mice and humans. Such different findings from the historical view impelled us to further investigate the roles of HO1 in glucose metabolism. In the present study, we found that overexpression of HO1 promoted hepatic glucose production (HGP) in hepatocytes from the wild type (WT) mice, which was comparable to the treatment of glucagon. Since the regulatory roles of the transcription factor forkhead box O1 (Foxo1) in HGP have been well recognized, we then generated the liver-specific Foxo1 knockout (L-FKO) mice to study the contribution of Foxo1 in mediating the effects of HO1. We found that HO1 overexpression did not have a significant effect in promoting HGP in hepatocytes from the L-FKO mice, suggesting HO1 improved HGP dependent on Foxo1. Besides, HO1 overexpression improved the mRNA levels of Foxo1-targeted gluconeogenic genes and increased the phosphorylation of Foxo1 at Ser273, which is a phosphorylation site integrating into the glucagon signaling. We also found that HO1 overexpression activated p38α and p65/NF-κB in hepatocytes. Further study using siRNA or specific inhibitor demonstrated that p65/NF-κB, but not p38α, mediated the HO1-induced pFoxo1-S273 and HGP in hepatocytes. We then explored the role of HO1-induced ferrous iron in activating p65/NF-κB and promoting HGP. We found that HO1 overexpression in hepatocytes substantially increased the intracellular ferrous iron. The pretreatment of iron chelator deferoxamine mesylate diminished the effects of HO1 overexpression on p65/NF-κB, pFoxo1-S273, and HGP. Taken together, results from this study revealed the mechanisms of HO1 in driving HGP, which is through the generation of ferrous iron.

Disclosure
W. Liao: None. W. Yang: None. Q. Pan: None. Z. Shen: None. W. Ai: None. S. Guo: None.

Funding
National Institutes of Health (R01DK120968)
1729-P: Insulin Resistance Cutoff for High Probability of Blood Glucose Normalization in T2DM Patients with Obesity after Bariatric Surgery
Authors: SKLYANIK IGOR , SHESTAKOVA EKATERINA , STAFEEV IURII , MICHURINA SVETLANA , KARMADONOV ANDREY , VOROTNIKOV ALEXANDER V. , YAHYAEV KAMIL , YURASOV ANATOLIY , MENSHIKOV MIKHAIL , MAYOROV ALEXANDR , PARFYONOVA YELENA V. , SHESTAKOVA MARINA V. 
Published: June 2020

There are several models of T2DM remission after bariatric surgery (ABCD, DiaRem, DRS), but none of them includes insulin resistance. Moreover these models are not suitable for early prediction of T2DM remission (within several months after surgery).
Methods: We included 42 patients with T2DM and morbid obesity (BMI 42.3 [38.9; 48.1] kg/m2) after bariatric surgery (16 pts after restrictive procedures and 26 pts after bypass surgery). Insulin resistance was measured by hyperinsulienic euglycaemic test with M-index estimation (mg/kg/min) and HOMA-IR before the surgery. Glycaemia normalization was assessed by self-monitoring of blood glucose (FPG &lt; 110 mg/dl (6.1 mmol/l) and postprandial PG &lt; 140 mg/dl (7.8 mmol/l) in 1 month after surgery) as well as HbA1c &lt; 6.0% (42 mmol/mol) in 3 months after surgery. ROC-curve identified insulin resistance predictive value of blood glucose normalization after bariatric surgery. Statistical analysis was performed using SPSS v.23.0.
Results: All patients had severe insulin resistance at baseline (median M-index before surgery 1.535 mg/kg/min, HOMA-IR 10.0). Within 1 month after surgery 7 patients (16,7%) reached blood glucose normalization, within 3 months - 22 patients (52,4%), within 6 months - 31 patient (73,8%), in 12 months - 35 patients (83,3%). ROC-analysis showed that M-index within 1st month after surgery was predictive of blood glucose normalization; insulin resistance cut-off value was 1.876 mg/kg/min (Youden’s index). HOMA-IR and M-index in 3, 6 and 12 months after surgery didn’t predict glycaemia normalization.
Conclusion: Baseline insulin resistance value defined as M-index &gt; 1.876 mg/kg/min can be used to predict early blood glucose normalization within 1 month after bariatric surgery.

Disclosure
I. Sklyanik: None. E. Shestakova: Employee; Spouse/Partner; AstraZeneca. Speaker’s Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharma K.K., Novo Nordisk A/S, Sanofi-Aventis, Takeda Pharmaceutical Company Limited. I. Stafeev: None. S. Michurina: None. A. Karmadonov: None. A.V. Vorotnikov: None. K. Yahyaev: None. A. Yurasov: None. M. Menshikov: None. A. Mayorov: Speaker’s Bureau; Self; Abbott, LifeScan, Inc., Novo Nordisk A/S, Roche Diabetes Care, Sanofi-Aventis. Y.V. Parfyonova: None. M.V. Shestakova: None.

Funding
Russian Science Foundation (17-15-01435)
173-OR: High Out-of-Pocket Health Care Burden for Medicare Beneficiaries with Diabetes, 1999-2015
Authors: PARK JOOHYUN , WANG YU , LOOK KEVIN A. , LUMAN ELIZABETH , ZHANG PING 
Published: June 2020

People with diabetes face higher out-of-pocket (OOP) health care costs than those without diabetes. This burden can lead to low adherence to treatments and adverse health outcomes, particularly among older adults. The OOP burden in older adults with diabetes has not been studied in the U.S. We estimated the OOP burden from 1999-2015 in Medicare beneficiaries with diabetes aged ≥65 using the Medicare Current Beneficiary Survey. OOP costs included premiums, deductibles, copays, coinsurance, and payments not covered by insurance. High OOP burden was defined as a person’s OOP costs ≥ 10% of their income. We estimated the prevalence of high OOP burden in all beneficiaries, by income quartile, and by race/ethnicity. Average OOP costs ranged from $2,864 to $4,212 (2015 $) and the percentage of those with high OOP burden varied from 38% to 46%, with slight increases over time. By income quartile, the average OOP costs were $2,292, $3,661, $4,032, and $4,430 for &lt;25%, 25-50%, 50-75% and &gt;75% groups, with decreases only in &lt;25% group over time. There were large income-related disparities in prevalence of high OOP burden, with the highest in 25-50% group. Non-Hispanic whites had the highest prevalence of high OOP burden. In elderly Medicare beneficiaries with diabetes, OOP burden was high and increased over time, with large income-related disparities. Efforts to reduce both OOP burden and disparities in this population may be needed.

Disclosure
J. Park: None. Y. Wang: None. K.A. Look: None. E. Luman: None. P. Zhang: None.
1731-P: The Mechanism of the Protective Effect of GLP-1 on the Amelioration of Alzheimer’s Disease by Enhancing Brain Insulin Production
Authors: HUANG JIAOJIAO , YANG YAN 
Published: June 2020

Background: Growing evidence supported that type 2 diabetes mellitus (T2DM) patients had a greater risk of developing Alzheimer’s disease (AD). Insulin secreted by “β cells” in brain played a critical role in T2DM patients and in AD patients. GLP-1 could improve cognition in AD patients via enhancing brain insulin signaling. We hypothesize the therapeutic effect of GLP-1 in T2DM might be due to promoting the insulin secretion of “β cells” in the nervous system. However, the molecular mechanism is unclear.
Methods: The hippocampus cell- HT-22 cell line and T2DM rats were used in this study. The genes of insulin syntheses, animals’ cognitive function and the phosphorylation of tau protein in hippocampus of T2DM brain were examined.
Results: Firstly, HT22 cell line was intervened by GLP-1 or high glucose or GLP-1+ high glucose. When stimulated by GLP-1 combined with high glucose, IRS1/PI3K/AKT located in insulin signal pathway could be activated and the expression of neurod-1 and ngn3 (insulin synthesis genes) were notably increased. These results indicated that neuronal cell could secrete insulin under a certain condition.
Secondly, RAAV-sh- neurod-1 and RAAV-sh-ngn3 were icv to the T2DM rats to prevent the production of brain insulin. The Barnes Maze test indicated the T2DM rats with peripheral GLP-1 and icv RAAV-sh-nc injection had a more intelligence than those with peripheral GLP-1 and icv RAAV-sh- neurod-1 and RAAV-sh-ngn3.
Thirdly, the T2DM rats with peripheral GLP-1 and icv RAAV-sh- neurod-1 and RAAV-sh-ngn3 had a significantly hyperphsphorylation of tau protein than those rats with peripheral GLP-1 and icv RAAV-sh-nc injection. This result showed that brain insulin could improve cognition by GLP-1 in T2DM rats.
Conclusions: These results suggested that neuronal cells might synthesis and secrete insulin under the condition of high glucose and GLP-1. And GLP-1 could not improve cognitive ability in T2DM when brain insulin synthesized was prevented.

Disclosure
J. Huang: None. Y. Yang: None.

Funding
National Natural Science Foundation of China (81670754)
1733-P: Phosphoproteomic Analysis of Insulin Action Using Human IPS-Derived Myoblasts Reveals Important Interactions between Differences Based on Insulin Sensitivity and Sex
Authors: HAIDER NIDA , LEBASTCHI JASMIN , BATISTA THIAGO M. , KNOWLES JOSH , PAN HUI , DREYFUSS JONATHAN , KAHN C. RONALD 
Published: June 2020

To identify disease-specific indicators associated with insulin resistance by using human induced pluripotent stem cells (iPSCs) as a “disease-in-a-dish” model, iPSCs were derived from 20 nondiabetic individuals, with 10 each in the most insulin resistant (IR) or insulin sensitive (IS) quintiles as determined using SSPG measurements. Half of each group was male and half female. Given that muscle is the first site of insulin resistance in type 2 diabetes, iPSCs were differentiated into myoblasts, and global phosphoproteomics was performed without/with insulin stimulation to determine the full spectrum of signaling. Analysis of phosphoproteome revealed altered serine/threonine phosphorylation of the insulin-regulated sites on IRS2, Akt1, mTOR, RPS6 in the IR iPSC-myoblasts indicating defects related to insulin resistance. Unexpectedly, hierarchical clustering of the phosphosites (FDR&lt; 0.05) also revealed alterations in IR males as compared to IS males but not in females. Rather female cells demonstrated a drastically different overall phosphoproteome as compared to the males, indicating the existence of an important sexual dimorphism that dominated over differences in insulin resistance. The top up-regulated phosphosites in the males, such as SRRM1 S697, THRAP3 S535, PRRC2C T1244 (all p&lt;1x10-9 and fold change &gt;5 compared to females) belonged to mRNA splicing pathway and included many targets of mTOR. In contrast, some of the top up-regulated phosphosites in the females included LMNB1 S23, SKP2 S64, MARCKS S167 (p&lt;1x10-7 and fold change &gt;5 compared to males) belonged to cell cycle pathways. These findings indicate that iPSC-derived myoblasts provide a potent approach to understanding differences in phosphorylation networks. These studies have also uncovered previously unrecognized differences in signaling between males and females, which may play a major role in the pathogenesis of disease.

Disclosure
N. Haider: None. J. Lebastchi: None. T.M. Batista: None. J. Knowles: None. H. Pan: None. J. Dreyfuss: None. C. Kahn: Advisory Panel; Self; ERX Pharmaceuticals, Kaleido Biosciences. Consultant; Self; AntriaBio, Flagship Pioneering, Sana-Cobalt.
1734-P: High Dietary Fat Intake Exacerbates Insulin Resistance in a Type 2 Diabetes Genetic Mouse Model
Authors: REILLY AUSTIN , YAN SHIJUN , LONCHARICH ALEXA J. , REN HONGXIA 
Published: June 2020

GLUT4, an insulin-sensitive glucose transporter, plays a major role of postprandial glucose disposal. We previously reported that human GLUT4 promoter-driven insulin receptor knockout (GIRKO) mice have reduced insulin signaling in central and peripheral tissues and develop hyperglycemia, albeit at a lower rate in an age-dependent manner on normal chow diet. Long-term high fat diet (HFD) feeding is well established for causing adiposity gain, increased inflammation, and insulin resistance. We hypothesized that HFD feeding will exacerbate the insulin resistance and result in rapid progression to overt diabetes in GIRKO mice. To test this, we examined the physiological response of euglycemic GIRKO mice to HFD in a time course study. We used indirect calorimetry analysis and found that GIRKO mice showed differences in energy partitioning shortly after HFD feeding started. The majority of GIRKO mice cohorts had 5-fold higher circulating insulin and 1.5-fold elevated blood glucose after 1 month of HFD feeding. In addition to the hyperglycemia and hyperinsulinemia, GIRKO mice also exhibited impaired glucose tolerance and islet hyperplasia, suggesting extreme insulin resistance exceeded the compensatory increase of insulin production. After 3 months on HFD, GIRKO mice had increased relative liver size, elevated hepatic triglycerides, and reduced hepatic glycogen, demonstrating impaired hepatic insulin signaling to stimulate glycogen synthesis and inhibit gluconeogenesis. We also confirmed the increase of key hepatic gluconeogenic gene expression, which likely contributed to hyperglycemia. The rapid progression of metabolic defects of GIRKO mice on HFD is not due to excessive weight or adiposity gain.
In conclusion, our studies of HFD-fed GIRKO mouse will offer insights in the role of the dietary contribution to diabetes disease progression without the confounding factor of increased adiposity.

Disclosure
A. Reilly: None. S. Yan: None. A.J. Loncharich: None. H. Ren: None.

Funding
Indiana University Diabetes and Obesity Research Training Program (T32DK064466); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK120772, R00DK098294); Indiana Diabetes Center (P30DK097512); Indiana Clinical and Translational Sciences Institute (UL1TR002529)
1739-P: Insulin Rapidly Increases Skeletal Muscle Mitochondrial ADP Sensitivity, Mitigating HFD-Induced Mitochondrial Dysfunction
Authors: BRUNETTA HENVER , PETRICK HEATHER L. , NUNES EVERSON A. , HOLLOWAY GRAHAM 
Published: June 2020

Introduction: Causality of the association between impairments in mitochondrial function and insulin resistance remains debatable. We have previously demonstrated that mitochondrial ADP sensitivity is impaired in high-fat diet (HFD)-induced insulin resistance, which contributes to bioenergetic imbalance and higher reactive oxygen species (ROS) production. However, insulin regulates several metabolic processes within skeletal muscle, and we tested the hypothesis that insulin could rapidly improve mitochondrial ADP sensitivity, a phenomenon possibly lost in HFD-induced insulin resistance.
Methods: Male and female C57Bl/6 mice were fed a control diet (10% fat) or HFD (60% fat) for 8 weeks. At the end of treatment, insulin was injected intraperitoneally (3 U/kg) twice (0 and 30 minutes). At 60 minutes red gastrocnemius muscle was excised to evaluate mitochondrial bioenergetics, ADP sensitivity, and ROS production.
Results: In control mice, insulin increased respiration by ∼2-fold in the presence of submaximal (100-1000 μM ADP) but not maximal ADP-supported respiration. As a result, insulin decreased the apparent ADP Km from 700 to 380 μM ADP. Despite these respiratory changes, insulin had no effect on mitochondrial maximal succinate-supported ROS emission or the ability of ADP to suppress ROS emission. HFD consumption impaired whole-body glucose intolerance, skeletal muscle insulin resistance (decreased insulin-stimulated Akt Thr-308 and Ser-473 phosphorylation) and impaired mitochondrial submaximal ADP-supported respiration by ∼50% (ADP Km ∼1100 μM). However, despite the reduction in insulin signaling following HFD, insulin increased submaximal ADP-supported respiration by ∼2-fold, decreased the apparent ADP Km to ∼400 μM and improved the ability of ADP to suppress mitochondrial ROS emission.
Conclusion: Insulin rapidly improves mitochondrial ADP sensitivity, mitigating the apparent HFD-induced mitochondrial dysfunction.

Disclosure
H. Brunetta: None. H.L. Petrick: None. E.A. Nunes: None. G. Holloway: None.

Funding
Natural Sciences and Engineering Research Council of Canada (400360); Coordination for the Improvement of Higher Education Personnel
174-LB: Association between Metformin Treatment and Improved Symptoms of Post-Traumatic Stress Disorder
Authors: LIU SHUQIAN , RAINES AMANDA M. , YOSHIDA YILIN , TANG WAN , CONSTANS JOSEPH I. , FONSECA VIVIAN , SHI LIZHENG 
Published: June 2020

U.S. veterans have a high prevalence of post-traumatic stress disorder (PTSD), for which no effective psychotropic medications are indicated. Nearly 25% of veterans have diabetes, for which metformin is a first line treatment. Although metformin is associated with improved neurodegenerative outcomes, there is no evidence on the association between metformin and PTSD-related symptom relief. This study aimed to examine whether metformin was associated with a clinically meaningful reduction in PTSD symptoms (≥20 points reduction PTSD checklist for DSM-5 {PCL-5}) score)) among veterans with PTSD using data from Veterans Health Administration. The metformin cohort was defined as first metformin use after a recorded PTSD diagnosis with a PCL-5 score ≥33 (i.e., clinical cut-score). The control cohort (never used metformin) was selected by propensity score 1:1 matching on the likelihood of initiating metformin with the covariates of age, gender, race, durations of PTSD, diabetes, and depression, and baseline CCI, PCL-5, and PHQ-9 scores. Multivariable Cox proportional regression was used to assess the association between metformin exposure and improvement in the PCL-5 scores. A total of 7950 veterans (mean age: 51.9 ± 13.6 years, male: 85%, white: 61.4%, African American: 28.8%) with confirmed PTSD were comparable on the baseline demographics and medical conditions between metformin and control PSM-matched cohorts with a median follow-up 1.2 years in both cohorts. The baseline PCL-5 score was 56.2±11.6 and 56.5±11.7 in metformin and control cohort, respectively. The metformin-treated cohort was more likely to have a clinically meaningful reduction in PTSD symptoms (adjusted hazard ratio (aHR): 1.31, 95%CI: 1.16-1.48), compared the control cohort. Furthermore, patients on metformin ≥2 years were 22% more likely to reduce PTSD symptoms (aHR: 1.22, 95%CI: 1.04-1.43), compared with metformin exposure &lt;2 years. Metformin exposure may be beneficial to PTSD symptoms among veterans.

Disclosure
S. Liu: None. A.M. Raines: None. Y. Yoshida: None. W. Tang: None. J.I. Constans: None. V. Fonseca: Consultant; Self; Abbott, Asahi Kasei Corporation, AstraZeneca, Bayer Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Stock/Shareholder; Self; Amgen, Bravo4health. L. Shi: None.