bluuebunny/crossref_metadata_2025_split huggingface dataset:
227-OR: Increasing Quarterly Use of Intermittent CGM among Individuals with T2D Is Associated with Improved Glycemic Control over a One-Year Time Frame
Authors: ELLIS ROBERT J. , KOMPALA TEJASWI , BROOKS ROBERT J. , HONE JENNIFER , SALEHI ATOUSA , JAMES ROBERTA 
Published: June 2023

Introduction: Continuous glucose monitoring (CGM) is an important tool for biofeedback in diabetes self-management. Intermittent use CGM for T2D users is one approach to address cost and access limitations, but to date only limited evidence supports intermittent use. The objective of this study was to understand the impact of intermittent use CGM in T2D non-intensive insulin users in a real-world setting.
Methods: As part of an ongoing implementation study within the Livongo whole person digital health program, a select population of individuals living with T2D who had not previously used CGM and either used no insulin or basal insulin only were mailed and asked to wear Dexcom G6 CGM sensors for 7-10 days per quarter for 4 consecutive quarters. In this analysis, we examined data from 227 individuals who adhered to wearing CGM for at least 7 days in 2 or more quarters. A multiple linear regression design quantified the impact of the primary variable of interest - the number of quarters with CGM wear (2, 3, or 4) - on changes in glycemic control between the first and latest available sensors, while including additional variables (potential confounds) associated with demographic traits, medication use, and temporal aspects of CGM wear.
Results: Glycemic control at baseline varied widely; 54% of individuals had a Time In Range (TIR) less than the target of 70%. Among the full sample (N = 227), each additional quarter of CGM use (beyond 2) resulted in clinically meaningful average improvements (and significant partial correlations, all p &lt; .05) in mean sensor glucose (11.8 mg/dL decrease), TIR (7.7 point increase), Time Above Range (7.9 point decrease), and the Glycemia Risk Index (9.3 point decrease).
Conclusion: Type 2 non-intensive insulin users who were adherent to quarterly use of intermittent CGM over one year saw meaningful improvements in glycemic control. Providing access to CGM technology may facilitate improvement in outcomes and disease management.

Disclosure
R.J.Ellis: Employee; Teladoc Health. T.Kompala: Employee; Teladoc Health, Stock/Shareholder; Teladoc Health. R.J.Brooks: Employee; Teladoc Health, Stock/Shareholder; Dexcom, Inc. J.Hone: Employee; Teladoc Health, UnitedHealth Group. A.Salehi: Employee; Teladoc Health. R.James: Employee; Teladoc Health.
236-LB: FHL2-/- Perivascular Adipose Tissue Improves Vessel Tone and Insulin-Stimulated Vasodilation by Inhibiting ERK1/2
Authors: HABIBE JAYRON , VAN RAALTE DANIËL , NIEUWDORP MAX , DE VRIES CARLIE , ERINGA ETTO C. 
Published: June 2023

Background: Type 2 diabetes, obesity and aging increase risk of developing cardiovascular diseases. Perivascular adipose tissue (PVAT) is a crucial regulator of vascular function. Four and Half Lim domains 2 (FHL2) is a protein upregulated in aging which targets various proteins with established links to adipose tissue growth, potentially regulating metabolic signaling.
Objective: we hypothesized that FHL2 regulates adipose tissue regulation of vascular function.
Methods: Femoral arteries were isolated from Wild type (WT) and FHL2-/- mice and vasoreactivity to insulin and acetylcholine was studied with and without perivascular adipose tissue.
Results: FHL2-/- vessels with PVAT had increased tone compared to WT vessels with PVAT as well as improved insulin-stimulated vasodilation. Exchange experiments using vessels with PVAT from the opposite genotype showed that FHL2-PVAT enhanced tone and insulin-stimulated vasodilatation compared to WT-PVAT. Gene expression analysis showed downregulation of adiponectin in FHL2-PVAT. Western blot analysis of insulin-stimulated phosphorylation of ERK and Akt in human microvascular endothelial cells (HMECs) stimulated with PVAT-conditioned medium revealed that FHL2-PVAT but not WT-PVAT reduced insulin-stimulated phosphorylation of ERK but not activation of Akt. In line with the effect of FHL2 on insulin-induced vasodilatation and activation of ERK1/2, analysis of publicly available RNA sequencing data of peri-aortic PVAT showed that FHL2 expression in PVAT positively correlates with expression of the endothelial vasoconstrictor peptide endothelin-1 (edn1).
Conclusion: FHL2 regulates vascular function through enhancement of smooth muscle tone, regulation of adipokine secretion affecting insulin-stimulated ERK1/2 activation and Edn1 expression in endothelial cells. These finding provide a new mechanism for vascular dysfunction in type 2 diabetes.

Disclosure
J. Habibe: None. D. van Raalte: Consultant; Boehringer Ingelheim and Eli Lilly Alliance, AstraZeneca, Merck & Co., Inc. Research Support; Boehringer Ingelheim and Eli Lilly Alliance, AstraZeneca, Merck & Co., Inc. M. Nieuwdorp: Advisory Panel; caelus health. C. de Vries: None. E. C. Eringa: None.

Funding
Amsterdam Cardiovascular Sciences (ACS201703)
236-OR: Pancreatic ß-Cell TRAPδ Deficiency Reduces Insulin Production but Improves Insulin Sensitivity
Authors: GUO JIYUN , YANG YANSHU , XU NING , YANG YING , FENG WENLI , YE YUANYUAN , LI XIN , XU XIAOXI , CUI JINGQIU , HUANG YUMENG , LIU MING 
Published: June 2023

The endoplasmic reticulum (ER) membrane protein translocon-associated protein-δ (TRAPδ, also known as SSR4) is involved in insulin biosynthesis in pancreatic β cell lines. However, its pathophysiological significance for the maintenance of islet β cell function and glucose homeostasis is unclear. Herein, we generated a mouse line with pancreatic β cell-specific deletion of TRAPδ (TRAPδ βKO), and found that TRAPδ βKO led to decreased circulating insulin in mice fed with either normal chow diet or high fat diet. Multiple independent experiments confirmed that, although TRAPδ deletion decreased insulin content in the islets, it did not affect composition of islet cells, insulin gene expression, insulin/proinsulin ratio, nor the expression and glycosylation of the prohormone enzymes involved in proinsulin processing. These data suggest that TRAPδ does not play a critical role in the transcription of insulin gene and processing of proinsulin. Importantly, untranslocated preproinsulin was significantly increased when the islets were treated with a proteasomal inhibitor, suggesting that TRAPδ deficiency impaired preproinsulin translocation, resulting in a rapid degradation of untranslocated preproinsulin that accounts for the decreased insulin production. Interestingly, the moderate decrease in the circulating insulin level in TRAPδ βKO mice did not cause impaired glucose tolerance and elevated fasting blood glucose, suggesting that compensatory mechanisms may account for maintaining glucose homeostasis. The insulin tolerance tests confirmed improvement of insulin sensitivity accompanied with upregulation of phosphorylated AKT in the peripheral insulin target tissues of TRAPδ βKO mice. Together, these data uncover a critical role of TRAPδ in preproinsulin translocation and insulin biosynthesis. The moderately decreased circulating insulin promotes insulin sensitivity in the insulin target tissues.

Disclosure
J.Guo: None. Y.Huang: None. M.Liu: None. Y.Yang: None. N.Xu: None. Y.Yang: None. W.Feng: None. Y.Ye: None. X.Li: None. X.Xu: None. J.Cui: None.

Funding
National Natural Science Foundation of China (81830025, 82220108014, 82270864, 82070854); National Key R&D Program of China (2019YFA0802502, 2022YFE0131400); Tianjin Municipal Health and Health Committee (TJWJ2021ZD00); Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-030A)
239-OR: Glycemic Control after Total Pancreatectomy with Islet Autotransplantation—Results from a Single Center with Large Cohort of Patients
Authors: RUB HAKIM MOHAMMED ABDUL , DARDEN CARLY , KIRKLAND JEFFREY , KUNCHA JAYACHANDRA , MATTKE JORDAN D. , LAWRENCE MICHAEL C. , NAZIRUDDIN BASHOO 
Published: June 2023

Total pancreatectomy and islet autotransplantation (TPIAT) for refractory chronic pancreatitis has been performed at our center from 2006. We employed anti-inflammatory treatment using IL-1β and TNF-α blockers to improve graft outcomes. We present results on islet characteristics and glycemic control post-TPIAT from this large cohort of patients. Our database of 200 consecutive TPIAT procedures performed were retrospectively reviewed. We collected demographics, pancreas and islet characteristics. Patient follow-ups were performed at 3, 6, 12 m and then annually. Outcomes measures included glycemic control, pain relief and narcotic use. Baseline patient characteristics (age, sex, BMI, etiology, C-peptide and HbA1c, duration of symptoms) and isolation results were shown in Table 1A and post-TPIAT fasting glucose, HbA1c, C-peptide and daily insulin use in Table 1B. The insulin independence rate at 3, 6 and 12 months increased with time from 15%, 24 % and 27%, respectively). At 1 year, pain score was significantly improved (p&lt;0.0001). Narcotic free rate also increased to 47% at 6 months and 56% at 1 year. Most post-TPIAT patients preserved hypoglycemic awareness and good pain relief. A cohort of patients remained normoglycemic without insulin and this group can be further studied to identify the factors that prevent the incidence of T3cDM after TPIAT.

Disclosure
A.Hakim mohammed: None. C.Darden: None. J.Kirkland: None. J.Kuncha: None. J.D.Mattke: None. M.C.Lawrence: None. B.Naziruddin: None.
24-OR: Augmented Heparanase Secretion in Diabetes Regulates Development of Cardiac Hypertrophy
Authors: SYNG LEE CHAE , SHANG RUI , HUSSEIN BAHIRA , RODRIGUES BRIAN 
Published: June 2023

HSPG consist of a core protein to which several linear heparan sulphate (HS) side chains are linked. Heparanase (Hpa) is exceptional in its ability to degrade HS. This property is used to regulate cardiac metabolism by releasing LPL, for its onward movement to the vascular lumen to hydrolyze lipoprotein-TG for FA provision to the heart. We hypothesized that another function of Hpa is its ability to promote cardiac hypertrophy. Hearts from mice with global overexpression of Hpa appeared larger, had higher heart weight/tibia length ratios, and exhibited posterior wall thickening. This evidence of cardiac hypertrophy was not reflected in alterations in cardiac function; ejection fraction, fractional shortening, and stroke volume were largely unaffected. This suggested a physiological rather than pathological hypertrophy, and is linked to a role for Hpa in regulation of arterial structure and mechanics. Hearts from animals with cardiac-specific overexpression of VEGFB also released greater amounts of Hpa, and this coincided with a hypertrophic phenotype. Heart function in these VEGFB-Tg rats remained similar to wild-type, and was likely a consequence of the expanded coronary vasculature and metabolic reprogramming that favoured glucose utilization. Rats made diabetic with STZ did not show any changes in cardiac Hpa gene or protein expression. Nevertheless, immediately after retrograde perfusion, the diabetic hearts released significantly greater amounts of Hpa with evidence of relative cardiac hypertrophy. This cardiac hypertrophy in diabetic rats was pathological with ventricular wall thinning and reduced cardiac function. Our data imply that Hpa can stimulate cardiac hypertrophy that remains physiological when there is associated development of coronary vasculature with metabolic flexibility. With diabetes and the occurrence of microangiopathy along with metabolic inflexibility, hypertrophy progresses towards being pathological, leading to heart failure.

Disclosure
C.Lee: None. R.Shang: None. B.Hussein: None. B.Rodrigues: None.

Funding
Canadian Institutes of Health Research (PJT178134); Heart and Stroke Foundation of Canada (G190026493)
243-OR: A Novel Platform for Genetic Screening of NAFLD-Associated Genes Identifies UBE2G2 and Other Genes That Alter Hepatic Lipid Accumulation
Authors: HU SIQI , ADITI SRI VAISHNAVI KHANDAVILLI SESHA , DIAO RACHEL Y. , RAUM JEFFREY , AZHAR NABIL , BAKAJ IVONA , COWLEY GLENN , RADY BRIAN , REILLY DERMOT F. , MAJITHIA AMIT R. 
Published: June 2023

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver failure that is prevalent in 70% of people with diabetes. Human genetic studies (i.e. GWAS) have identified dozens of potentially causal genes/loci increasing NAFLD susceptibility but translation into actionable drug targets has been impeded by a lack of cellular and molecular mechanistic studies. To address this knowledge gap, we developed a platform for high-throughput genetic perturbation and assessment of fatty acid-triggered lipid accumulation (i.e. hepatic steatosis) in human hepatocytes by combining mechanized cell culture in multi-well plates with high-content microscopy and automated image analysis. We then deployed this platform to screen 106 genes nominated by NAFLD biomarker GWAS, knocking out each gene via CRISPR and scoring the phenotypic changes of the resulting engineered cells in response to oleate treatment. Analysis of over 24,000 images across all gene knockouts revealed 32 genes whose deletion caused significant alterations in cellular lipid droplet (LD) numbers and/or droplet size distribution. Here, we highlight ubiquitin-conjugating enzyme E2 G2 (UBE2G2), whose knockout robustly increases the size of cellular LDs that form in response to oleate stimulation in both the primary screen and subsequent validation. UBE2G2 localizes to the LD surface and is essential for the sterol-induced degradation of HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. Thus we propose that deletion of UBE2G2 may increase cholesterol derivative content in LDs, thereby increasing LD size. In summary, we demonstrate the successful development and use of a platform for genetic screening of hepatocyte steatosis in vitro and identify multiple NAFLD-associated genes of previously unknown function that likely operate during this early stage of NAFLD pathogenesis. We acknowledge input: Seunghan Lee, Lifeng Wang, David Frederick, Alessandro Pocai

Disclosure
S. Hu: None. S. Khandavilli: None. R.Y. Diao: None. J. Raum: Employee; Janssen Research & Development, LLC. N. Azhar: Employee; Janssen Research & Development, LLC. I. Bakaj: Employee; Janssen Research & Development, LLC. G. Cowley: Employee; Janssen Research & Development, LLC. B. Rady: Employee; Janssen Research & Development, LLC. D.F. Reilly: Employee; Janssen Research & Development, LLC. A.R. Majithia: None.

Funding
National Institutes of Health (RDK01DK123422)
245-LB: Glucagon Infusion into the Mediobasal Hypothalamus Lowers Hepatic Triglyceride Secretion
Authors: GREWAL MANTASH S. , VASILEV BOYAN , SOLTYS CARRIE-LYNN M. , LUM BRYAN , YUE JESSICA T. 
Published: June 2023

Diabetes and obesity are associated with dysregulated liver lipid metabolism. Glucagon has an essential role in lipid metabolism, in addition to regulating glucose homeostasis. The brain is a key coordinator of whole-body metabolism. Glucagon signalling in the mediobasal hypothalamus (MBH), a forebrain region that senses hormones and nutrients to regulate metabolism, lowers hepatic glucose production and appetite. However, whether glucagon action in the MBH affects lipid homeostasis in healthy and high-fat diet (HFD)-fed animals remains unknown. We assessed glucagon signaling in the MBH in regulating hepatic TG secretion in chow-fed normolipidemic and HFD-induced hyperlipidemic rats.
Stereotaxic MBH cannulation and vascular catheterizations in Sprague-Dawley rats allowed for direct MBH infusions, intravenous (IV) injections, and blood sampling. Plasma TGs were measured in 10h-fasted rats after IV poloxamer injection with concurrent MBH infusions. MBH glucagon decreased TG secretion compared to MBH vehicle control animals. This hypothalamic effect of glucagon was blocked by a simultaneous MBH co-infusion of an antagonist to the glucagon receptor (GCGR) and by protein kinase A (PKA) inhibition in the MBH in chow-fed rats. Direct MBH infusion of a PKA activator recapitulated the TG-lowering effects of MBH glucagon. Together, this suggests that MBH glucagon signals via a MBH GCGR-PKA pathway. Interestingly, both MBH glucagon and MBH PKA activation lowered TG secretion and plasma FFAs in HFD-induced hyperlipidemic animals. However, MBH glucagon did not affect hepatic TG content or liver lipogenic protein levels of MTP, FAS, or pACC:ACC of RC and HFD rats compared to their MBH vehicle controls.
We demonstrate that hypothalamic glucagon modulates hepatic TG secretion via a MBH GCGR-PKA signalling pathway, and activating MBH glucagon signalling improves lipid metabolism in hyperlipidemic rats. These findings may provide therapeutic insight on lowering lipids in hyperlipidemia.

Disclosure
M. S. Grewal: None. B. Vasilev: None. C. M. Soltys: None. B. Lum: None. J. T. Yue: None.

Funding
Canadian Institutes of Health Research (PJT-378765); Canada Foundation for Innovation (37267); Canada Research Chairs Tier 2 in Brain Regulation of Metabolism
252-OR: Continuous Glucose Monitoring in Patients with Post-bariatric Hypoglycemia Reduces Hypoglycemia and Glycemic Variability
Authors: CUMMINGS CAMERON J. , JIANG ALEX , SHEEHAN AMANDA L. , FERRAZ-BANNITZ RAFAEL , PULEIO ALEXA , SIMONSON DONALD C. , DREYFUSS JONATHAN , PATTI MARY-ELIZABETH 
Published: June 2023

Post-bariatric hypoglycemia (PBH) is an increasingly recognized complication of bariatric surgery, with prevalence of up to 36% after gastric bypass. Hypoglycemia typically follows postprandial glycemic spikes. Continuous glucose monitors (CGM) can alert patients to high or low sensor glucose (SG), allowing treatment and prevention of severe hypoglycemia. The aim of this study (NCT03353415) was to determine whether CGM, currently indicated only for diabetes, could reduce hypoglycemia in PBH. In an open label, nonrandomized, pre-post design, sensor glucose data were collected using Dexcom CGM in two sequential phases: (1) masked (no access to SG or alarms); and (2) unmasked (access to SG and alarms for low or rapidly declining SG). Data were available for paired analysis for 22 individuals with PBH (mean±SD age 51.1±13.0 yrs, 20F/2M, BMI 30.6±6.2 kg/m2, 82% with level 3 hypoglycemia and 100% with neuroglycopenia). Participants with PBH spent a lower percentage of time in hypoglycemia with unmasked vs masked CGM (&lt;60 mg/dL, median [MAD]: 0.7 [0.8] vs 1.4 [1.7]%, p=0.03; &lt;70 mg/dL: 2.9 [2.5] vs 4.7 [4.8]%, p=0.04), with similar trends overnight. Likewise, there was more time between 70-180 mg/dL (94.8 [3.9] vs 90.8 [5.2]%, p=0.004), and lower glycemic variability (mean amplitude of glycemic excursion: 74.0 [17.7] vs 79.6 [17.8] mg/dL, p=0.04) during unmasked wear. During the day (6:00 AM-11:59 PM), participants spent more time in normoglycemia with unmasked CGM (94.2 [4.8] vs 90.9 [6.2]%, p=0.005), largely due to reduced hyperglycemia (&gt;180 mg/dL: 1.9 [2.2] vs 3.9 [3.6]%, p=0.02). Availability of real-time CGM data and alarms is associated with reductions in low SG, elevated SG, and glycemic variability. This suggests CGM helps patients detect hyperglycemic peaks and imminent hypoglycemia, allowing dietary modification and self-treatment to reduce hypoglycemia. CGM may thus improve safety in PBH, particularly for patients with hypoglycemia unawareness.

Disclosure
C.J.Cummings: None. A.Jiang: None. A.L.Sheehan: None. R.Ferraz-bannitz: None. A.Puleio: None. D.C.Simonson: Stock/Shareholder; Phase V Technologies, Inc., GI Windows. J.Dreyfuss: None. M.Patti: Consultant; MBX Biosciences, AstraZeneca, Hanmi Pharm. Co., Ltd., Other Relationship; Fractyl Health, Inc.

Funding
Diabetes Research Center (P30DK036836)
253-LB: Characterization of Korean Type 2 Diabetes as Hyperinsulinemic, Insulin-Resistant, and miR-10a/b-5p-Deficient Hyperglycemia
Authors: YANG YU TAE , KIM MIN-SEOB , EUN HA SE , SINGH RAJAN , SEON DAHYUN , WOO JEONG JIN , YOUNG LEE MOON , RO SEUNGIL 
Published: June 2023

Background: We previously reported that miR-10a-5p and miR-10b-5p are key regulators in the development of type 2 diabetes (T2D). Deficiency of miR-10a-5p or miR-10b-5p triggers the onset of T2D in mice while restoration of their miRNAs remarkably rescues the diabetic symptoms including hyperglycemia by restoration of insulin production and sensitivity. Deficiency of the antidiabetic miR-10a-5p and miR-10b-5p was also observed in T2D patients in the United States. However, the miRNA levels have not been examined in Korean T2D patients.
Method: Plasma samples were obtained from 54 (32 males and 22 females) patients with T2D, 24 (17 males and 7 females) patients with prediabetes, and 38 (21 males and 17 females) healthy donors in South Korea. T2D patients were selected based on the criteria of elevated both fasting glucose (&gt;125 mg/dL), and A1C (&gt;6.5). We examined levels of miR-10a/b-5p and metabolic panels including insulin (INS) and its receptor (INSR) using qPCR, ELISA, and Western blot. For statistics, we used a one-way analysis of variance or the Kruskal-Wallis test.
Results: Plasma samples were grouped into T2D, prediabetes, and healthy controls by levels of both fasting glucose and A1C. Fasting glucose, A1C, C-peptide, and insulin were significantly elevated in the T2D patient group while miR-10a/b-5p and INSR were noticeably reduced compared to the prediabetic group and the healthy control group. The Spearman rank correlation analysis showed significant correlations between miR-10a/b-5p levels and metabolic parameters in T2D patients and. healthy controls. miR-10a/b-5p levels were positively correlated with INSR, but negatively correlated with glucose, INS, C-peptide, BMI, and age in T2D patients.
Conclusion: Korean T2D was defined as miR-10a/b-5p deficiency as well as increased insulin production and resistance through reduction of insulin receptor.

Disclosure
T. Yu: None. M. Kim: None. S. Ha: None. R. Singh: None. D. Seon: None. J. Jeong: None. M. Lee: None. S. Ro: None.