bluuebunny/crossref_metadata_2025_split huggingface dataset:
255-LB: Liver Pyruvate Carboxylase Deletion in Mice Prevents Fibrosis from a NASH Diet
Authors: IÑIGO-VOLLMER MELISSA MAE R. , KUCEJOVA BLANKA , MIZERSKA MONIKA N. , KHAN SHAHANSHAH , SZWEDA PAMELA A. , ZAKI HASAN , SZWEDA LUKE I. , FU XIAORONG , BURGESS SHAWN C. 
Published: June 2023

Obesity and T2D are closely associated with Nonalcoholic Fatty Liver Disease, which can advance to Nonalcoholic Steatohepatitis (NASH) with fibrosis. We previously found that liver pyruvate carboxylase (PC) is required for hepatic gluconeogenesis and the concentration of metabolites essential to mediating redox state and antioxidant function. Liver PC knockout (LPCKO) mice are protected from HFD-induced hyperinsulinemia and glucose intolerance despite retaining excess liver fat and exhibiting reduced antioxidant capacity. Here, we report that despite impaired antioxidant markers and increased inflammatory markers on a HFD, PC loss protected the liver from fibrosis and other indices of liver damage induced by a long-term NASH diet. LPCKO and control mice were fed a high fat, high cholesterol Western Diet (WD) for 13-14 months. After 10 mos. of WD, markers of insulin resistance were assessed by lactate/pyruvate, glucose, and insulin tolerance tests. After sacrifice, liver damage was assessed by serum markers and histology. Oxidative stress and inflammation were evaluated by gene expression, MDA concentration, GSH/GSSG and NADPH/NADP+ redox states, and H2O2 emission potential in isolated mitochondria. LPCKO-WD mice were more sensitive to an insulin tolerance test and exhibited lower fasting blood glucose and better glycemic control during a lactate/pyruvate or glucose tolerance test than controls. Liver malate/pyruvate indicated substantially lower NADPH/NADP+ in LPCKO-WD mice, but there were no differences in MDA levels, GSH/GSSG, and H2O2 emission potential. Despite similar hepatic steatosis, inflammation, and ballooning between LPCKO-WD and controls, fibrosis and serum markers of liver injury were markedly lower in LPCKO-WD mice. The data suggest that liver PC deletion improves glycemia and insulin resistance during chronic Western Diet exposure by reducing hepatic gluconeogenesis and prevents fibrosis independent of steatosis, inflammation, ballooning, and oxidative stress.

Disclosure
M. R. Iñigo-Vollmer: None. B. Kucejova: None. M. N. Mizerska: None. S. Khan: None. P. A. Szweda: None. H. Zaki: None. L. I. Szweda: None. X. Fu: None. S. C. Burgess: None.
274-OR: Do-It-Yourself Automated Insulin Delivery (AID) Systems Are Noninferior to Commercial AID Systems in Glucose Management among Adults with Type 1 Diabetes
Authors: WU ZEKAI , LEBBAR MAHA , BONHOURE ANNE , RAFFRAY MARIE , DEVAUX MARIE , GROU CAROLINE , MESSIER VIRGINIE , BOUDREAU VALERIE , BRAZEAU ANNE-SOPHIE , RABASA-LHORET RÉMI 
Published: June 2023

AIM: We aim to compare commercial automated insulin delivery (C-AID) systems with open-source do-it-yourself (DIY)-AID systems for glucose management among adults with type 1 diabetes (T1D) in real-life conditions.
METHODS: A prospective observational, non-inferiority, parallel-cohort study involving 77 adults with T1D, having used an AID for ≥3 months and living in Canada (25 DIY-AID and 52 C-AID users): 59.7% females, mean age 44.0 ± 14.7 years old with mean diabetes duration of 26.9 ± 14.5 years and HbA1c of 6.7 ± 0.7%. A total of 30 days’ data from an additional blinded CGM (Dexcom G6) was used to assess effectiveness [Primary outcome: 24h time in range% (TIR%) for 30 days].
RESULTS: DIY-AIDs were non-inferior to C-AIDs regarding the TIR% [78.3±11.0% vs. 71.2±10.9%, mean difference 7.2% [95% CI 1.9% to 12.5%], P&lt;0.001 for non-inferiority (non-inferiority margin 5%)], even after adjusting for various confounding factors (age, sex, auto-mode%, duration of AID use, annual household income, and educational level). The percentage of time in hypoglycemia (&lt;70 mg/dL) was higher with DIY-AID (3.9±3.1%) than with C-AID (1.8±1.3%) but still below recommended threshold (Table). Differences between both systems are more pronounced during daytime.
CONCLUSION: DIY-AIDs are non-inferior to C-AIDs for TIR% among adults with T1D in real-world settings.

Disclosure
Z.Wu: Other Relationship; Eli Lilly and Company. R.Rabasa-lhoret: Consultant; Dexcom, Inc., Abbott, Janssen Pharmaceuticals, Inc., Novo Nordisk Canada Inc., Sanofi, Lilly, Tandem Diabetes Care, Inc., Insulet Corporation. M.Lebbar: None. A.Bonhoure: Consultant; Dexcom, Inc. M.Raffray: None. M.Devaux: None. C.Grou: None. V.Messier: None. V.Boudreau: None. A.Brazeau: Other Relationship; Dexcom, Inc., Diabète québec, Ordre des diététistes nutritionnistes du Québec, Research Support; Canadian Institutes of Health Research, Fonds de recherche du Québec en Santé.

Funding
Canadian Institutes of Health Research (148464)
339-OR: Timing of the Pre-exercise Temporary Target with Advanced Hybrid Closed-Loop (AHCL) and Hypoglycemia Risk
Authors: MORRISON DALE , KURTZ NATALIE , COHEN OHAD , VIGERSKY ROBERT A. , O'NEAL DAVID N. 
Published: June 2023

Aim: People with type 1 diabetes using hybrid closed loop (HCL) are advised to set a temporary elevated glucose target (TT) 1-2h pre-exercise. We aim to assess hypoglycemia risk with AHCL with TT set &lt; 1h pre-exercise.
Method: To date 7 adults with type 1 diabetes using MiniMedTM 780g AHCL have completed 16 exercise bouts, including 40 min moderate intensity (MIE) at 50% VO2max in the morning (mMIE40) and evening (eMIE40); 90 min MIE at 50% VO2max in the evening (eMIE90]; and 40 min high intensity with 5×4min intervals at 90% VO2max in the evening (eHIE40). A TT (150mg/dL) was set: i) 1h prior [t60]; ii) 20min prior [t20]; iii) onset [t0]; iv) no TT [tNil]. For eMIE90 up to 45g supplemental CHO was given during exercise as per guidelines for exercise &gt;60 min. CGM metrics were compared from exercise commencement to 2h post.
Results: For all TT conditions mean glucose with mMIE40 was higher than eMIE40 (7.9 [6.8, 9.3]mg/dL vs 6.5 [5.5, 7.2]mg/dL; p&lt;0.05) with less time spent below 70mg/dL (0.0 [0.0, 0.0]% vs 6.3 [0.0, 13.3]%; p&lt;0.001). Timing of initiating TT pre-exercise had minimal effect on glycemia with 40 min exercise while reducing hypoglycemia with 90min evening exercise (Table 1).
Conclusion: Supplemental CHO may be required for evening MIE of &lt;60 min duration, while a TT set prior to long duration MIE in the evening reduces the risk of hypoglycemia. Morning MIE results in less time spent in hypoglycemia than evening MIE.

Disclosure
D.Morrison: None. N.Kurtz: Employee; Medtronic. O.Cohen: Employee; Medtronic. R.A.Vigersky: Employee; Medtronic. D.N.O'neal: None.
353-OR: Cdkn2a Regulates Beige Fat Maintenance through BECN1-Mediated Autophagy
Authors: JIANG YUWEI 
Published: June 2023

Summary: A potential therapeutic target to curb the obesity and diabetes epidemic is thermogenic beige adipocytes. However, beige adipocytes quickly transition into white adipocytes upon removing stimuli. Here, we define the critical role of Cdkn2a as a molecular pedal for the beige-to-white transition. Beige adipocytes lacking Cdkn2a exhibit prolonged lifespan, and mice are more resistant to diet-induced obesity, along with enhanced energy expenditure and improved glucose tolerance. Mechanistic studies demonstrate that Cdkn2a promotes the expression and activity of BECN1 by directly binding to its mRNA and its negative regulator BCL2L1, activating autophagy and accelerating the beige-to-white transition. Notably, reactivating autophagy by pharmacological or genetic methods abolishes beige adipocyte maintenance induced by Cdkn2a-ablation. Furthermore, hyperactive BECN1 alone significantly accelerates the beige-to-white transition. Collectively, these findings show that Cdkn2a-mediated autophagy serves as a brake system for beige adipocyte maintenance and is a highly promising target for anti-obesity and antidiabetes therapy.
Keywords: Beige adipocyte, UCP1, Cdkn2a, BECN1, Autophagy, Obesity

Disclosure
Y. Jiang: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (K01DK11177, R03DK127149, R01DK132398); Diabetes Research and Training Center (P30DK020595)
370-OR: Optimized Weight Loss with Bimagrumab—Reduced Fat Mass with Increased Muscle Mass by Appetite-Independent Mechanisms
Authors: ATTIE KENNETH M. , HEYMSFIELD STEVEN B. , MINDEHOLM LINDA , SPRUILL SUSAN , PRUZANSKI MARK , KLICKSTEIN LLOYD 
Published: June 2023

Background: Obesity is managed with lifestyle changes or incretin Tx to produce wt loss that is challenging to maintain long-term, perhaps because lean mass loss accounts for 20-40% of total wt loss. Semaglutide Tx results in rapid wt loss with 35% lower caloric intake, no further wt loss after 1 yr and rapid wt regain post-Tx. Bimagrumab (bima), a mAb to ActRIIA/ActRIIB, blocks activin pathways, leading to increased lean mass/decreased fat mass in numerous clinical studies (N=1561). Effects of bima IV or SC on fat and muscle were evaluated by DXA and MRI.
Results: In a Ph2 study of bima 10 mg/kg IV q4wks vs placebo (respectively) in persons with overweight/obesity and T2DM (N=75), LS mean change at Wk 48 in body wt was −5.9 vs −0.8 kg (p&lt;0.001; −7.5% vs −1.1%), with minimal change in daily caloric intake. DXA: LS mean change at Wk48 in total body (TB) fat mass was −7.5 vs −0.2 kg (p&lt;0.001; −22.2% vs −0.3%), TB lean mass +1.7 vs −0.4 kg (p&lt;0.001; +3.6% vs -0.9%), and appendicular lean mass +0.5 vs −0.3 kg (p=0.009; +2.5% vs −1.1%); fat mass loss was maintained 12 wks post-last dose. MRI: LS mean change at Wk24 in visceral adipose tissue was −1.5 vs +0.2 L (p&lt;0.001; −36.1% vs +3.6%), absolute hepatic fat fraction (FF, %) −4.6 vs +0.2 (p=0.006; -23.6% vs +14.3%), and paravertebral muscle (PVM) mass +363.3 vs −331.0 mm2 (p=0.003; +6.4% vs -4.6%); a trend for decreased PVM fat fraction and intermuscular adipose tissue was observed (p=NS). Bima improved HbA1c (%) by -0.76 vs +0.04. AEs included diarrhea, muscle spasms. In a Ph1 study comparing bima 525 mg SC (N=12) and 700 mg IV (N=8), q4wks X3, fat mass loss and lean mass (total body and appendicular) increase were similar, with fat mass loss maintained 12 wks post-last dose; SC arm had fewer AEs than IV arm.
Conclusions: Bimagrumab Tx results in decreased fat deposition in tissues and increased muscle mass despite minimal change in caloric intake, which could lead to durable, high quality wt loss. A study of bima in obesity without T2DM is ongoing (NCT05616013).

Disclosure
K.M.Attie: Employee; Versanis Bio. S.B.Heymsfield: None. L.Mindeholm: Consultant; Versanis Bio, Novartis AG, Stock/Shareholder; Novartis AG, Alcon Research, LLC, Novo Nordisk A/S. S.Spruill: None. M.Pruzanski: None. L.Klickstein: None.
386-P: Inpatient Hypoglycemic Rate Reduction through the Implementation of Prescriber Targeted Decision Support Tools
Authors: GOLDSTEIN REBECCA , ODOM JESSICA M. 
Published: June 2023

Introduction: Hypoglycemia has been shown to increase mortality and length of hospital stay in patients with and without diabetes. The purpose of this study is to determine if the implementation of prescriber targeted decision support tools reduces the incidence of inpatient hypoglycemic events.
Methods: This pre-post intervention study included adult patients who experienced an inpatient hypoglycemic event within 24 hours of insulin administration from October 2018 to December 2019. Pregnant women and patients receiving insulin infusions were excluded. Best Practice Alerts (BPAs) and banners were implemented in January 2019 to alert providers of patients at risk for hypoglycemia. Triggers for the BPAs and banners include use of sulfonylureas with reduced renal function, high weight-based basal doses, a previous episode of hypoglycemia during the admission, or concomitant use of fluoroquinolones and scheduled insulin. The primary outcome was to measure the incidence of hypoglycemia per 1000 patient days in pre- vs. post-intervention groups.
Results: In total, 1186 hypoglycemic events in the pre-intervention group were compared to 5260 events in the post-intervention group. The implementation of EMR alerts significantly decreased hypoglycemia (glucose ≤ 70 mg/dL) from 22.91 events/1000 patient days to 18.27 events/1000 patient days (p&lt;0.001). Severe hypoglycemia (glucose &lt; 54 mg/dL) was not significantly reduced (1.65 events/1000 patient days vs. 1.79 events/1000 patient days (p=0.453)). The use of high weight-based basal insulin doses was reduced in the post-intervention patients with normal renal function, 23.0% vs. 16.7% (p&lt;0.001), and patients with impaired renal function, 7.1% vs. 4.9% (p=0.017).
Conclusion: The implementation of prescriber targeted decision support tools was successful in reducing the overall incidence of inpatient hypoglycemia.

Disclosure
R.Goldstein: None. J.M.Odom: None.
40-OR: Insulin Stabilized Arterial Plaque by Regulating Vascular Smooth Muscle Cell Metabolism and Differentiation
Authors: LI QIAN , FU JIALIN , PARK KYOUNGMIN , WU I-HSIEN , KING GEORGE L. 
Published: June 2023

The main pathology of cardiovascular diseases (CVD) in insulin resistance and diabetes is an acceleration of atherosclerosis and increased risk for the development of unstable plaques. Insulin’s effect on vascular smooth muscle cell (VSMC) has been attributed to be pro-atherogenic due to its actions to increase migration and proliferation. We reported that insulin receptors (IR) are responsible for increasing arterial intimal hyperplasia after wire injury. Surprisingly, mice with VSMC specific deletion of IR (Myh11IRKO/ApoE-/-), atherosclerosis was increased with plaques exhibited unstable pathologies of less VSMC and ECM, but more macrophages and necrosis than ApoE-/- mice. To characterize these unexpected findings in the arterial plaques of Myh11IRKO/ApoE-/- mice, we performed single cell RNA sequencing study of VSMC comparing 4 groups of mice including ApoE-/- and MyH11IRKO/ApoE-/- on normal chow or high fat diet (HFD). Bioinformatics analysis demonstrated that VSMC can be separated into 21 distinctive clusters with those expression enriched for contractile and mitochondrial genes separated from clusters which expressed heat shock protein (HSP) or inflammatory genes. Aorta of HFD insulin resistant WT ApoE-/- mice exhibited significantly increases of multiple clusters of inflammatory VSMCs and, surprisingly, also those clusters enriched for mitochondrial metabolism. However, in Myh11IRKO/ApoE-/- mice on HFD, aortic VMSC clusters with contractile and mitochondrial genes were significantly reduced, but distinct VMSC clusters with expressions of HSP or inflammatory genes were greatly increased. These novel findings, along with metabolic studies in cultured VSMC, indicated that insulin’s actions on VSMC metabolism to reduce the transition of VSMCs subsets from mitochondria enriched VSMCs to stressed and inflammatory VSMCs, which is critical to increase plaque stability and decrease CVD risks in people with insulin resistance and diabetes.

Disclosure
Q.Li: None. J.Fu: None. K.Park: None. I.Wu: None. G.L.King: Research Support; Janssen Research & Development, LLC.
410-P: Two-Year (2y) eGFR Slope in People with Type 2 Diabetes (T2D) Receiving a Very Low Carbohydrate Diet (VLCD) Intervention
Authors: ATHINARAYANAN SHAMINIE J. , ROBERTS CAROLINE G.P. , ADAMS REBECCA N. , VOLK BRITTANIE M. , PHINNEY STEPHEN D. , VOLEK JEFF , MCKENZIE AMY L. 
Published: June 2023

A VLCD including nutritional ketosis is an effective T2D intervention, but its use is cautioned in renal disease. We compared eGFR slope among people with T2D with varying renal function who received a VLCD intervention via continuous remote telemedicine care (CCI, n=262) or Usual Care without carbohydrate restriction (UC, n=87) over two years. Four ketosis trajectory classes (KTs) were identified within CCI using latent class trajectory modeling. We compared eGFR slopes for CCI KTs using a linear mixed effect model with UC as the reference. The eGFR slope was positive in all CCI KTs and negative in UC (Table 1). eGFR slope improved in CCI (p=0.045), in sustained nutritional ketosis (SNK) group (p=0.01), and in those with baseline eGFR &lt;90 (p&lt;0.001) compared with UC. KT with higher blood ketones (SNK and MDNK) had greater eGFR rise. These results show that eGFR slopes rose in people with T2D on CCI and declined in UC. Rise of eGFR slope appears to have a dose-dependent relationship with endogenous ketone concentration and duration of maintenance of ketosis, including those with stage 2 chronic kidney disease, suggesting nutritional ketosis VLCD may provide benefit rather than risk in early renal disease.

Disclosure
S.J.Athinarayanan: Employee; Virta Health Corp. C.G.P.Roberts: Employee; Virta Health Corp. R.N.Adams: Employee; Virta Health Corp. B.M.Volk: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. S.D.Phinney: Board Member; Virta Health Corp., Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp. J.Volek: Stock/Shareholder; Virta Health Corp. A.L.Mckenzie: Employee; Virta Health Corp., Stock/Shareholder; Virta Health Corp.
428-P: Diabetic Retinopathy Predicts Hemodialysis Induction in Subjects with Type 2 Diabetes with Normo- and Microalbuminuria and Normal Renal Function
Authors: MORIYA TATSUMI , SUZUKI AKIHIKO , HAYASHI AKINORI , MATSUBARA MADOKA , MIYATSUKA TAKESHI 
Published: June 2023

It is important to elucidate which factors are associated with the progression of diabetic nephropathy (DN) toward end-stage renal disease, i.e., hemodialysis (HD) as early stage of DN as possible. We hypothesized that different grades of diabetic retinopathy (DR) affect the progression toward HD in persons with type 2 diabetes with normoalbuminuria (NA) or microalbuminuria (MA), and normal renal function.278 NA and 170 MA persons with type 2 diabetes with normal renal function (GFR≥60 ml/min/1.73m2) whose GFRs had been measured by iohexol injection in 1995-2013 and followed for over 5 years were analyzed (n=448). At the baseline, HbA1c levels was divided into HbA1c≥7.0 (n=327) and &lt;7.0 (n=121) groups. 86 subjects had simple DR (SDR), and 65 had proliferative DR (PDR). 217 had hypertension. The subjects were followed up for 16 ± 6 years. During the study period, 7 subjects in NA and 11 subjects in MA started to receive HD. A Kaplan-Meier analysis revealed that DR (Wilcoxon 5.82, p=0.016), PDR (Wilcoxon 8.53, p=0.014) and MA (Wilcoxon 5.87, p=0.015) were associated with a significantly higher risk of HD induction than no DR, SDR, and NA, respectively while HbA1c and hypertension were not associated with the risk of HD induction in whole diabetic subjects. In the multivariate analysis, DR (p=0.042), but not MA, was significantly associated with the HD induction in all the subjects. As each group analysis, a Kaplan-Meier analysis demonstrated that PDR was associated with HD induction in NA. However, SDR and PDR were not associated with HD in MA. HbA1c or hypertension did not affect HD induction in each group. In conclusions, MA itself is a risk factor of HD induction, and DR is a more predominant predictor for HD induction at the early stage of DN. PDR is a risk factor for HD induction even in NA subjects with normal renal function.

Disclosure
T.Moriya: None. A.Suzuki: None. A.Hayashi: Research Support; Abbott Japan Co., Ltd., Roche Diabetes Care, Speaker's Bureau; Abbott Japan Co., Ltd., Medtronic, Terumo Corporation. M.Matsubara: None. T.Miyatsuka: Speaker's Bureau; Eli Lilly Japan K.K., Novo Nordisk, Sanofi K.K., Mitsubishi Tanabe Pharma Corporation, Sumitomo Dainippon Pharma Co., Ltd., Teijin Pharma Limited, Sanwa Kagaku Kenkyusho, Daiichi Sankyo.
46-LB: Effect of Nonnutritive Sweetener (Sucralose) on Gut Microbiome in Asian Indian adults with Type 2 Diabetes—A Randomized Clinical Trial
Authors: MOHAN VISWANATHAN , ABIRAMI KUZHANTHAIVELU , RAJAGOPAL GAYATHRI , SOUNDARARAJAN PADMAVATHI , UNNIKRISHNAN RANJIT , MOHAN ANJANA RANJIT , VASUDEVAN SUDHA , KAMALA KRISHNASWAMY 
Published: June 2023

Background: Non-Nutritive Sweeteners (NNS) can help reduce calorie intake when substituted for added sugar. Some studies have reported detrimental effect of NNS on gut microbiome when given at high doses in animal models. Clinical studies have been done mostly in small sample sizes. This study aims to evaluate the effect of using sucralose in coffee, tea and fruit juices on gut microbiome in Asian Indian adults with type 2 diabetes (T2D).
Method: A parallel arm, randomized trial was carried out for 12 weeks in adults with T2D aged 30-50 yrs and glycated haemoglobin between 7-11 %. Participants were randomized into Intervention group (sucralose added in beverages) and Control group (No sucralose). Both groups received standard of care for diabetes. Faecal samples were collected from participants, V3-V4 libraries were generated and sequenced using illumina Miseq NGS. Alpha and beta diversity were derived for both groups to assess within and between groups changes. Ratio of fermicutes to bacteroidetes was also computed.
Results: Interim data of 38 participants who completed the study (Control group, n=14 and Intervention group, n=24) was analysed for changes in operational taxonomical units (OTU) of gut microbiome. Major phyla detected across all samples were Fermicutes, Actinobacteria, Bacteroidetes, Proteobacteria and Verrucomicrobiota. Alpha and beta diversity analysis showed no significant changes between intervention and control groups. Fermicutes to bacteroidetes ratio did not show any significant difference between groups. At end of 12 weeks significant reduction in body weight (p&lt;0.004) and body fat % (p&lt;0.04) was observed in the intervention group.
Conclusion: Use of sucralose in beverages produced no significant change in gut microbiome in Asian Indian adults with T2D but helped in reduction of body weight and body fat.
Clinical trial registry: CTRI/2021/04/032686

Disclosure
V. Mohan: None. K. Abirami: None. G. Rajagopal: None. P. Soundararajan: None. R. Unnikrishnan: None. R. Anjana: None. S. Vasudevan: None. K. Kamala: None.

Funding
Zydus Wellness Products Ltd.