bluuebunny/crossref_metadata_2025_split huggingface dataset:
332-OR: Pharmacological Inhibition of CREBZF Improves Insulin Resistance by Altering Activation of Macrophage in Adipose Tissue of Diet-Induced Obese Mice
Authors: LIU YUXIAO , HU ZHIMIN , LIU ZHENGSHUAI , SU WEITONG , ZHENG ZENGPENG , DING DONG , MA FENGGUANG , XUE YAQIAN , CAI GENXIANG , WEI SHUANG , WANG ZIXUAN , SUN XIAOYANG , JIANG YANG , DAI XIAOZHEN , LI YU , CUI AOYUAN 
Published: June 2021

Obesity and type 2 diabetes are associated with chronic inflammation response in adipose tissue, in which macrophage activation and infiltration are hallmark characteristics. However, the molecular mechanism of this association remains largely unknown. Here, we report that CREBZF, a newly characterized transcription factor for insulin-induced lipogenesis, functions as a key regulator in adipose tissue macrophage and couples inflammatory signals to systemic insulin resistance in obesity. Myeloid cell-specific CREBZF knockout (CREBZF MKO) mice were generated by crossing floxed CREBZF mice with LysM-Cre transgenic mice. A small molecule (LIC902) was identified as a CREBZF inhibitor using a luciferase reporter-based high-throughput screening, which is shown to repress expression levels of CREBZF in the macrophage, such as J774. We found that ablation of CREBZF in myeloid cells or administration of LIC902 attenuates insulin resistance and hyperglycemia in mice fed with high-fat high-sucrose (HFHS) diet. Intriguingly, myeloid CREBZF deficiency or LIC902 treatment causes a profound reduction of infiltrated macrophages and reverses M1/M2 imbalance in white adipose tissue of mice fed with HFHS diet, suggesting important roles of CREBZF in regulating macrophage polarization in adipose tissue. CREBZF is capable of potentiating NF-κB signaling in the macrophage as evidenced by increased phosphorylation of p65, whereas CREBZF deficiency or inhibition of CREBZF activity results in the opposite effect. These data indicate that CREBZF plays a critical role in the regulation of innate immune response in the macrophage and maintains whole-body glucose homeostasis. Pharmacological manipulation of CREBZF may provide novel opportunities for treating metabolic diseases such as insulin resistance and type 2 diabetes.

Disclosure
Y. Liu: None. S. Wei: None. Z. Wang: None. X. Sun: None. Y. Jiang: None. X. Dai: None. Y. Li: None. A. Cui: None. Z. Hu: None. Z. Liu: None. W. Su: None. Z. Zheng: None. D. Ding: None. F. Ma: None. Y. Xue: None. G. Cai: None.

Funding
National Key Research and Development Program of China (2019YFA0802502); National Natural Science Foundation of China (81925008); Shanghai Science and Technology Commission (19140903300)
34-LB: Vitamin D Supplementation and Risk of Type 2 Diabetes in Patients with Prediabetes: A Meta-analysis of Individual Participant Data from Randomized, Placebo-Controlled Trials
Authors: PITTAS ANASTASSIOS G. , KAWAHARA TETSUYA , JORDE ROLF , NELSON JASON P. , ANGELLOTTI EDITH , VICKERY ELLEN , DAWSON-HUGHES BESS , TRIKALINOS THOMAS , BALK ETHAN M. 
Published: June 2021

Background: Individual randomized clinical trials have not shown conclusively that taking vitamin D can prevent type 2 diabetes.
Methods: We conducted a systematic review and meta-analysis of individual participant-level data to determine whether vitamin D supplementation lowers the risk of diabetes in people with prediabetes. Trials published through February 12, 2021, that compared oral vitamin D supplementation (alone) with placebo over a minimum 2-year follow up, and had new-onset diabetes as a primary outcome were included. Proportional hazards models were used to analyze individual participant data, with pre-specified intention-to-treat (ITT) and per-protocol analyses, without and after adjustment for baseline age, gender, BMI, race and hemoglobin A1c. Safety was also assessed.
Results: Three trials were eligible (testing D3 20,000 IU/week [Tromsø], D3 4,000 IU/day [D2d], and eldecalcitol 0.75 μg/day [DPVD] vs. matching placebos) and contributed data from 4190 randomized participants (mean age 60.4 years, 44.2% women). After a median 3.0 years of follow-up, new-onset diabetes occurred in 475/2097 participants assigned to vitamin D and 524/2093 assigned to placebo (8.42 and 9.50 events per 100 person-years, respectively). The unadjusted hazard ratio (95% CI) for vitamin D was 0.88 (0.77 to 0.99) in the ITT and 0.85 (0.75 to 0.97) in the per-protocol analyses. Adjusted hazard ratios were 0.85 (0.75 to 0.96) in the ITT and 0.83 (0.73 to 0.94) in the per-protocol analyses. There was no evidence of heterogeneity of treatment effect among the three trials. The incidence of hypercalcemia, hypercalciuria, or kidney stones did not differ between the vitamin D and placebo groups.
Conclusion: In adult patients with prediabetes, vitamin D supplementation is safe and effective for lowering the risk of diabetes by about 15%.

Disclosure
A. G. Pittas: None. T. Kawahara: None. R. Jorde: None. J. P. Nelson: None. E. Angellotti: None. E. Vickery: None. B. Dawson-hughes: None. T. Trikalinos: None. E. M. Balk: None.

Funding
American Diabetes Association (1-14-D2D-01 to A.G.P.); National Institutes of Health (U01DK098245)
366-P: Cystatin C Predicts Incident Diabetes in Angiographied Coronary Patients
Authors: MADER ARTHUR , SPRENGER LUKAS , VONBANK ALEXANDER , LARCHER BARBARA , MAECHLER MAXIMILIAN , MUTSCHLECHNER BEATRIX , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H. 
Published: June 2021

Cystatin C is an established marker of renal function, and has also been found to be associated with cardiovascular disease. There is substantial overlap between risk factors for cardiovascular disease and type 2 diabetes; however, it is unclear whether cystatin C predicts new onset diabetes. This issue is addressed in the present study. We prospectively followed 481 consecutive nondiabetic patients undergoing coronary angiography for the evaluation of established or suspected stable coronary artery disease over a follow-up period of 5.5 ± 3.5 years. Overall, 135 patients (28.1%) newly developed diabetes. Cystatin C proved to be a strong predictor of incident diabetes univariately (standardized HR=1.80 [1.14-2.28], p=0.011) and after adjustment for age, gender, hypertension, smoking, LDL cholesterol, HDL cholesterol and fasting glucose (HR=1.86 [1.07-3.21], p=0.027). We conclude that cystatin C is a strong predictor of incident diabetes in angiographied coronary patients.

Disclosure
A. Mader: None. C. H. Saely: None. L. Sprenger: None. A. Vonbank: None. B. Larcher: None. M. Maechler: None. B. Mutschlechner: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
37-OR: Mitofusins 1 and 2 Collaborate to Fuel Pancreatic Beta-Cell Insulin Release via Regulation of Both Mitochondrial Structure and DNA Content
Authors: SIDARALA VAIBHAV , ZHU JIE , PEARSON GEMMA , SOLEIMANPOUR SCOTT 
Published: June 2021

Mitochondrial health and function are critical for coupling glucose metabolism to insulin secretion in pancreatic β-cells. Mitochondria are highly dynamic organelles, and mitochondrial fusion is essential for regulating mitochondrial architecture. To decipher the role of mitochondrial fusion in β-cell function, we investigated the roles of dynamin-like GTPases mitofusins 1 and 2 (Mfn1 and Mfn2) in the maintenance of functional mitochondria. We observe that while loss of Mfn1 or Mfn2 is dispensable for β-cell function, combined loss of both Mfn1 and Mfn2 (Mfn1/2) in β-cells results in impaired glucose tolerance and glucose-stimulated insulin secretion (GSIS). Our assessments indicate decreased respiratory capacity in Mfn1/2-deficient β-cells, coupled with increased mitochondrial fragmentation, loss of mtDNA content, and decreased expression of subunits comprising the electron transport chain. Gene dosage studies suggest that a single allele of Mfn2 is sufficient to maintain mtDNA content and glucose homeostasis, independent of maintenance of mitochondrial structure and reticular network. Further investigations revealed that Mfn1/2-deficiency reduced mtDNA copy number through decreased levels of Tfam, a critical regulator of mitochondrial nucleoid packaging and maintenance. Overexpression of Tfam rescued mtDNA levels and GSIS in Mfn1/2 deficient β-cells. Lastly, Mfn1/2 agonists restored mtDNA levels and β-cell function in db/db mouse islets, a model for type 2 diabetes. Together, our studies demonstrate concerted roles of Mfn1 and 2 in the maintenance of mitochondrial structure and mtDNA in β-cells, and therefore propose novel therapeutic targets to restore glucose homeostasis in diabetes.

Disclosure
V. Sidarala: None. J. Zhu: None. G. Pearson: None. S. Soleimanpour: None.
38-LB: Reduced Carbohydrate and Increased Protein and Fat during Weight Loss Improve the Atherogenic Lipid Profile in Type 2 Diabetes
Authors: THOMSEN MADS N. , SKYTTE MADS J. , SAMKANI AMIRSALAR , ASTRUP ARNE , FRYSTYK JAN , CHABANOVA ELIZAVETA , HARTMANN BOLETTE , HOLST JENS J. , LARSEN THOMAS M. , MADSBAD STEN , MAGKOS FAIDON , THOMSEN HENRIK S. , WALZEM ROSEMARY , HAUGAARD STEEN B. , KRARUP THURE 
Published: June 2021

Objective: Elevated triglyceride-rich lipoproteins (TRL), excess small dense LDL particles (LDL5) and decreased HDL2/HDL3 ratio promote atherogenesis in type 2 diabetes (T2D). Carbohydrate restriction reduced intrahepatic triglyceride (IHTG) content beyond the positive effect of weight loss in a group of T2D patients, the present study sought to determine whether parallel improvements in lipoprotein density profiles occurred in these same patients.
Research Design and Methods: Seventy-two adult T2D patients with a mean BMI of 33 kg/m2 were assigned to 6 weeks of fully-provided hypocaloric dietary treatment aimed at ~6% weight loss, either with a carbohydrate-reduced high-protein (CRHP, C30E%/P30E%/F40E%) diet or a conventional diabetes (CD, C50E%/P17E%/F33E%) diet. Density profiles of lipoproteins were determined by ultracentrifugation of fluorescently labelled plasma. Magnetic resonance spectroscopy was used to assess IHTG.
Results: Body weight decreased by 5.8 kg (~6%) in both groups. Compared with the CD diet, the CRHP diet reduced TRL (mean [95% CI]) by -16 [-30;1]% (p=0.07) and LDL5 by -13 [-22;-3]% (p=0.01), and increased HDL2/HDL3 by 11 [1;22]% (p=0.04). The CRHP diet also decreased IHTG more than the CD diet (-26 [-45;0]%, p=0.05), and changes in IHTG including both groups correlated significantly with changes in TRL and LDL5 (Spearman’s ρ 0.39 and 0.38, p&lt;0.01).
Conclusions: Carbohydrate restriction adds to the positive effect of weight loss in T2D patients by inducing greater improvements in atherogenic lipid profile, maybe facilitated by a reduction in intrahepatic fat.

Disclosure
M. N. Thomsen: None. S. Madsbad: Advisory Panel; Self; AstraZeneca; Boehringer Ingelheim; Eli Lilly; Merck Sharp & Dohme; Novo Nordisk; Sanofi, Research Support; Self; Novo Nordisk, Boehringer Ingelheim, Speaker’s Bureau; Self; AstraZeneca; Boehringer Ingelheim; Merck Sharp & Dohme; Novo Nordisk; Sanofi. F. Magkos: None. H. S. Thomsen: None. R. Walzem: None. S. B. Haugaard: None. T. Krarup: None. M. J. Skytte: None. A. Samkani: None. A. Astrup: Consultant; Self; Groupe Éthique et Santé, France, Employee; Self; Novo Nordisk Foundation, Other Relationship; Self; Flaxslim ApS, Denmark, Gelesis, Personalized Weight Management Research Consortium ApS (Gluco-Diet. dk). J. Frystyk: None. E. Chabanova: None. B. Hartmann: None. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. T. M. Larsen: None.

Funding
Arla Foods; Danish Dairy Research Foundation
39-LB: Estimating Basal Metabolic Rate in People with Diabetes
Authors: WEXLER YDO , GOLDNER DAN 
Published: June 2021

Objective: Health care settings and self-care programs use Basal Metabolic Rate (BMR) to determine caloric need. BMR is difficult to measure directly, so many formulas have been published to estimate BMR, each derived from relatively small samples. We fit two regressions to a large sample of BMR estimates from the Apple Watch for people with diabetes and prediabetes, and compared the results to 10 common BMR formulas.
Method: Data included self-reported height, age, sex, weight, diabetes type, and over 500,000 daily values of BMR and caloric expenditures from Apple Watch, from 3,071 people (56% male, 14.5% female; 29.5% unreported; 11.4% type 1, 58.9% type 2, 15.3% prediabetes, 14.4% other diabetes). We regressed to Apple Watch BMR using 5-fold cross-validation, first with height, weight, age and sex only, then adding 30-day calorie expenditure, and measured the hold-out accuracy.
Results: The 10 published formulas we evaluated predicted Apple Watch BMR with an average RMSE of 354 ± 67 calories and an average R2 of 0.726 ± 0.074. The Harris-Benedict equation showed the closest correspondence to Apple Watch BMR, with RMSE 287 calories and R2 0.760. Our regression without energy expenditure yielded BMR = -112.2 + 1.08w + 3.89h - 51.6g + 0.13w2 + 0.0467h2 - 0.00041w3 - 0.00017h3, and with energy expenditure, BMR = -232 + 1.66w + 4.01h - 46.9g + 0.13w2 + 0.045h2 - 0.000417w3 - 0.00017h3 + 0.0091e, where w=weight (kg), h=height (cm), g=gender(-1=male, 1=female, 0=unreported) and e = 30-day energy burn (kcal). The accuracies were RMSE 280 calories, R2 0.766; without energy expenditure and RMSE 274 calories, R2 0.780 with energy expenditure.
Conclusion: Regressions to more than a half-million samples from over 3,000 people with diabetes predicted Apple Watch BMR estimates with lower error than common published formulas. The most accurate regression included 30-day energy burn, reducing RMSE by 13 calories (4.5%) and increasing R2 by .02 vs. the closest common formula. These results recommend consideration of activity measures when estimating BMR.

Disclosure
Y. Wexler: None. D. Goldner: Employee; Self; One Drop.
39-OR: Pancreatic Beta Cell SERCA2 Deficiency Impacts ER-Golgi Vesicle Trafficking and Ceramide Metabolism
Authors: KONO TATSUYOSHI , IIDA HITOSHI , LEE CHIH-CHUN , KRISHNAN PREETHI , ARVAN PETER , LINDBERG IRIS , EVANS-MOLINA CARMELLA 
Published: June 2021

Alterations in endoplasmic reticulum (ER) calcium (Ca2+) levels arising from reduced activity of the Sarcoendoplasmic Reticulum Ca2+ ATPase (SERCA) pump are associated with impaired insulin secretion and reduce β-cell survival in both major forms of diabetes. However, at present, the mechanisms of how reduced ER Ca2+ impairs β-cell function remain incompletely understood. To test this, we analyzed mice with β-cell specific SERCA2 deletion (βS2KO mice) and S2KO INS1 cells. βS2KO mice exhibited age-dependent glucose intolerance, reduced glucose-stimulated insulin secretion, and increased proinsulin secretion without evidence of impaired insulin sensitivity. Immunoblot analysis of βS2KO islets and S2KO INS-1 cells revealed reduced active forms of the proinsulin processing enzymes, PC1/3, PC2, and CPE, while immunofluorescence analysis suggested impaired ER-Golgi trafficking of the convertase enzymes and proinsulin. Because the ER serves as the main site of cellular lipid synthesis and changes in the β-cell lipidome have been linked with diabetes pathophysiology, we hypothesized that ER Ca2+ loss may alter protein trafficking in the secretory pathway through changes in ER lipid content. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed on the ER fractions of control and S2KO INS1 cells and revealed increased levels of 16:0, 24:0, 24:1, and total ceramides in S2KO cells. SERCA2 restoration partially rescued convertase enzyme expression, proinsulin processing, and ceramide content. Consistent with these findings, RNA sequencing analysis of βS2KO islets revealed changes in pathways related to vesicle transport, protein processing, and lipid metabolism. We conclude that SERCA2 in the β-cell plays a central role in the maintenance of insulin biosynthesis as well as ceramide metabolism.

Disclosure
T. Kono: None. H. Iida: None. C. Lee: None. P. Krishnan: None. P. Arvan: None. I. Lindberg: None. C. Evans-molina: Advisory Panel; Self; Provention Bio, Inc., Consultant; Self; Dompe, Other Relationship; Self; Bristol-Myers Squibb Company, Nimbus Pharmaceuticals, Pfizer Inc.

Funding
National Institutes of Health (R01DK093954)
397-P: Insulin Dosing Adjustments in Patients with Diabetes on Peritoneal Dialysis or Hemodialysis: A Systematic Review of the Literature
Authors: TUMLINSON ROBIN , BLAINE EMILY , COLVIN MARION , HAYNES TYLER G. , WHITLEY HEATHER P. 
Published: June 2021

Chronically uncontrolled hyperglycemia is the leading cause of end-stage renal disease (ESRD) necessitating dialysis. During times of transition to hemodialysis (HD) or peritoneal dialysis (PD), considerations must be given to insulin dosing adjustments for persons with diabetes (PWD) in efforts to maintain glycemic control. However, literature is sparse with few clear and direct practical clinical recommendations for therapeutic adjustments. The objective of this systematic review was to identify and report the evidence and gaps in the literature for adjustments in therapeutic insulin recommendations when initiating HD or PD in patients with ESRD and diabetes mellitus. A literature search using PubMed, CENTRAL, MEDLINE, CINAHL, Google Scholar, and ClinicalTrials.gov revealed 184 results. After removing duplicates and articles not reaching pre-specified criteria, 29 relevant articles remained for further analysis. The most common recommendation regarding HD was to reduce the basal insulin dose up to 25% on HD days to prevent hypoglycemia, although a lack of consensus exists on the percent reduction. Little information was found as to insulin management with continuous ambulatory PD (CAPD) or automated PD (APD). During PD, insulin may be administered subcutaneously, intraperitoneally, or with the dialysis fluid. Administration of insulin with dialysate may necessitate a dose increase of up to 30% due to a loss to tubing and dilution. Furthermore, the use of dextrose-based dialysate may require additional insulin to mitigate systemic impact of dextrose absorption on blood glucose. Overall, a gap exists in the primary literature regarding recommendations for prophylactically adjusting insulin therapy when initiating HD or PD, or when switching between the two. Greater research is needed to clarify ideal alterations in insulin dosing, administration techniques, and product selections for this patient population.

Disclosure
R. Tumlinson: None. E. Blaine: None. M. Colvin: None. T. G. Haynes: None. H. P. Whitley: None.
426-P: Sudomotor Dysfunction Is Associated with Decreased Cardiac Diastolic Function in Patients with Type 2 Diabetes
Authors: CHEN XUEYAN , YANG XUBIN , XU WEN , DENG HONGRONG , WU JINPING , YAN JINHUA , YAO BIN 
Published: June 2021

Diabetic autonomic neuropathy has been proved to be associated with onset of heart failure in patients with diabetes. However, relationship between sudomotor dysfunction, the early manifestation of autonomic neuropathy, and cardiac diastolic function has not yet been investigated. This study aimed to explore the association between sudomotor function and cardiac diastolic function in patients with type 2 diabetes mellitus (T2DM).
A total of 63 patients (65% male, 50±13 years old) with T2DM were enrolled and divided into two groups according to mean feet electrochemical skin conductance (ESC) assessed by sudoscan device: sudomotor dysfunction group(SDF group: ESC≤60 μS) and normal sudomotor function group (NSF group: ESC&gt;60 μS). Impaired cardiac diastolic function detected by tissue Doppler imaging echocardiography manifested as elevations of late atrial (A) transmitral peak flow velocity (LgA) and the early (E) transmitral peak flow velocity/early diastolic velocity (e’) (E/e’ratio).
The prevalence of sudomotor dysfunction was 30.2%. In SDF group, LgA and E/e’ ratio were significantly higher than those in NSF group (-0.2±0.2 m/s vs. -0.4±0.3 m/s, P=0.011 and 11.0±3.8 vs. 8.8±2.7, P=0.013, respectively). Pearson correlation analysis revealed that LgA was negatively correlated with mean feet ESC(r=-0.3, P=0.017). In logistic regression analyse, LgA (OR=0.05, 95%CI 0.004-0.585, P=0.017) and E/e‘ ratio (OR=0.79, 95%CI 0.641-0.970, P=0.025) were found to be independently associated with presence of sudomotor dysfunction.
Cardiac diastolic function significantly decreased in type 2 diabetic patients with sudomotor dysfunction.

Disclosure
X. Chen: None. X. Yang: None. W. Xu: None. H. Deng: None. J. Wu: None. J. Yan: None. B. Yao: None.

Funding
Natural Science Foundation of Guangdong Province (2018A030313915); Medical Scientific Research Foundation of Guangdong Province (A2018286)
451-P: Participants’ Satisfaction with the Support Online Self-Guided Educational Platform for Type 1 Diabetes Management: A Proof-of-Concept Study, Preliminary Results
Authors: XIE LI FENG , LEROUX CATHERINE , ROY-FLEMING AMÉLIE , RABASA-LHORET RÉMI , BRAZEAU ANNE-SOPHIE 
Published: June 2021

Introduction: The development of the SUPPORT self-guided online educational platform was guided by the behavioral wheel framework and built by healthcare professionals specialized in type 1 diabetes (T1D) and patient-partners. It has 4 learning paths that are based on the mode of insulin delivering and blood glucose monitoring of the patient. The learning modules are divided into 6 groups (e.g., medication, nutrition) and have 3 levels of complexity. Features (e.g., quiz, glossary) are included. This proof-of-concept study aims to evaluate the satisfaction of adults with T1D using the SUPPORT platform after 6 months.
Methods: Adults (≥18 years old) living with T1D for ≥ 1 year, using ≥ 4 insulin injections per day or an insulin pump, and having access to the Internet were recruited from the BETTER registry in Quebec. People with ongoing pregnancy or illness limiting diabetes care were excluded. Usage data were collected with Google Analytics. A face-validated 10-item questionnaire was sent after 6 months of access to SUPPORT to evaluate participants’ satisfaction and feedback (e.g., top 3 preferred features).
Results: A total of 61 participants (38% men; age 50.3±13.3 years; T1D duration 24.3±14.6 years; mean viewing time per connected session: 12min56sec) completed the 6-month questionnaire. The mean satisfaction score was 39.6±7.8 (out of 49; higher score for a greater satisfaction). The most preferred features were access to downloadable PDF summaries, quizzes, and blogs on scientific updates. Providing certificates, virtual points, and glossary were the least appreciated. More than half reported being more confident to prevent (53%) and manage (53%) hypoglycemia.
Conclusion: The SUPPORT platform received a high level of satisfaction. Although further validation is needed, this platform may be a useful resource for widely and timely diabetes education and for reducing the hypoglycemia burden faced by patients.

Disclosure
L. Xie: None. C. Leroux: None. A. Roy-fleming: None. R. Rabasa-lhoret: Advisory Panel; Self; Bayer Inc., Covance Inc., Insulet Corporation, Pfizer Inc., Other Relationship; Self; Abbott, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Dexcom, Inc., Eli Lilly and Company, HLS Therapeutics Inc., Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Novo Nordisk, Sanofi-Aventis, Research Support; Self; Canadian Institutes of Health Research, Cystic Fibrosis Canada, Diabetes Canada, JDRF, National Institutes of Health, Prometic, Société Francophone du Diabète, Speaker’s Bureau; Self; CMS Canadian Medical&Surgical Knowledge Translation Research Group, CPD Network. A. Brazeau: None.

Funding
Canadian Institutes of Health Research (JT1-157204); JDRF (4-SRA-2018-651-Q-R)