bluuebunny/crossref_metadata_2025_split huggingface dataset:
129-LB: The Impact of a Passive Alert on Screening for Euglycemic Diabetic Ketoacidosis in Hospitalized Patients Using an Sodium–Glucose Cotransporter 2 Inhibitor
Authors: SOLIMAN DIANA , MUSSER R. CLAYTON , JACKSON JASON P. , GERMAN JASHALYNN , CARLSON SCOTT , ODONNELL KATHRYN H. , SETJI TRACY 
Published: May 2022

The use of sodium-glucose cotransporter-2 (SGLT2) inhibitors has recently been associated with euglycemic diabetic ketoacidosis (euDKA) . The absence of hyperglycemia can delay recognition of euDKA. We aimed to increase screening rates for euDKA by implementing a passive alert to providers in the EHR (built as a BestPractice Advisory [BPA] on the Epic Storyboard) if an emergency department or hospitalized patient taking an SGLT2 inhibitor was at risk for euDKA. Criteria were blood glucose &lt;250 mg/dL, SGLT2 inhibitor on the home medication list or initiated in the hospital, lack of an insulin infusion, and one of the following labs indicating acidosis: 1) anion gap &gt;12 with serum bicarbonate &lt;18 mmol/L, 2) urine ketones ≥ 3+, or 3) serum ketones ≥ 2 mmol/L. We conducted a retrospective review of the alert from implementation on 5/15/2021 until 12/13/2021. Of the 76 patients who triggered the alert, 13 (18%) had euDKA confirmed and 5 (7%) may have had it but were not evaluated for it. The alert introduced in the electronic health record successfully identified patients taking an SGLT2 inhibitor who were at risk for euDKA and may serve as a safety net to reduce delayed recognition of this serious condition.

Disclosure
D. Soliman: None. R. Musser: None. J. P. Jackson: None. J. German: None. S. Carlson: None. K. H. Odonnell: None. T. Setji: None.
129-OR: Catastrophic Health Expenditures: A Disproportionate Risk in Uninsured Ethnic Minorities with Diabetes
Authors: LINDE SEBASTIAN , EGEDE LEONARD E. 
Published: May 2022

Background: Chargemaster prices are the list prices that providers and health systems assign to each of their medical services in the US. These charges are often several factors of magnitude higher than those extended to individuals with either private or public insurance, however, these list prices are billed in full to uninsured patients, putting them at increased risk of catastrophic medical expenditures (CHE) .
Methods: We perform a retrospective observational study on a nationally representative cohort of adult patients from the Medical Expenditure Panel Survey for the years 2002-2017. Using logistic regression models we estimate the risk of CHE across insurance status, diabetes diagnosis and explore disparity gaps across race/ethnicity.
Results: Our fully adjusted results show that the relative odds of having CHE if uninsured is 5.9 (p&lt;0.01) compared to if insured, and 1.1 (p&lt;0.01) for patients with a diabetes diagnosis (compared to those without one) . We note significant interactions between insurance status and diabetes diagnosis, with uninsured patients with a diabetes diagnosis being 9.5 (p&lt;0.01) more likely to experience CHE than insured patients without a diabetes diagnosis. In terms of racial/ethnic disparities, we find that among the uninsured, non-Hispanic blacks are 13% (p&lt;0.05) , and Hispanics 14.2% (p&lt;0.05) , more likely to experience CHE than non-Hispanic whites. Among uninsured patients with diabetes, we further find that Hispanic patients are 39.3% (p&lt;0.05) more likely to have CHE than non-Hispanic white patients.
Conclusions: Our findings indicate that uninsured patients with diabetes are at significantly elevated risks for CHE. These risks are further found to be disproportionately higher among uninsured racial/ethnic minorities, suggesting that CHE may present a channel through which structural economic and health disparities are perpetuated.

Disclosure
S.Linde: None. L.E.Egede: None.

Funding
National Institute of Diabetes and Digestive Kidney Disease (K24DK093699, R01DK118038, R01DK120861, PI: Egede) National Institute for Minority Health and Health Disparities (R01MD013826, PI: Egede/Walker)
1303-P: Decreased Hepatic HMGB1 in Type 2 Diabetes Increases Mitochondrial Glucose Uptake by Regulating Insulin/AKT Signaling
Authors: LIU ZEYU , KALTENMEIER CHRISTOF , MOTA ALVIDREZ ROBERTO I. 
Published: May 2022

Introduction: High Mobility Group Box-1 (HMGB1) is strongly associated with Type 2 Diabetes (T2D) and hepatocyte function. HMGB1 can regulate mitochondrial function under high glucose conditions. Our group has shown that knockdown of HMGB1 reduces hyperglycemia with decrease insulin activity. We want to further understand the role of HMGB1 in hepatocyte mitochondrial function and the insulin/AKT signaling, a vital pathway in glucose hemostasis. We hypothesize that by decreasing HMGB1, hepatocytes increase glucose uptake by regulating mitochondrial function with more effective Insulin/AKT signaling.
Methods: Primary hepatocytes and liver lysates were isolated from inducible HMGB1 KO (iHMGB1 KO) and HMGB1 Flox (wildtype) mice after Tamoxifen and Streptozotocin IP injections for HMGB1 knockout and T2D-10-weeks development. HMGB1 knockdown and insulin/AKT signaling were assessed by RT-PCR and immunoblot. Flow cytometry was performed on primary hepatocyte cell suspension for mitochondrial function/mass (TMRE, Mitotracker) and glucose uptake (NDBG) cellular markers.
Results: Liver lysates showed significant decreased expression/activity of HMGB1, Insulin Receptor-B, phosphorylated AKT, PDK and SIRT3 in iHMGB1 KO T2D mice. A counter regulator of metabolic and glucose activity, phosphorylated PDH, was found increased in iHMGB1 KO mice. Flow cytometry of isolated hepatocytes showed that iHMGB1 KO T2D animals had significantly less mitochondrial mass and functioning mitochondria, however showed increased glucose uptake.
Conclusion: We found a potential mechanism by which HMGB1 regulates glucose uptake by regulating mitochondrial function and mass potentially by regulating the effectiveness of the Insulin/Akt signaling in T2D. Future studies will be directed to test glucose transport/metabolism in HMGB1 KO hepatocytes guided by more effective Insulin activity in the mediation of mitochondria function at the different stages of T2D progression.

Disclosure
Z.Liu: None. C.Kaltenmeier: None. R.I.Mota alvidrez: None.

Funding
This work was funded by department of surgery support for RIMA
1305-P: Insulin Receptor Condensates in Insulin Sensitivity and Resistance
Authors: DALL’AGNESE ALESSANDRA , PLATT JESSE , LEE TONG IHN , JEPPESEN JACOB F. , YOUNG RICHARD A. 
Published: May 2022

Insulin receptor (IR) signaling is central to normal metabolic control and is dysregulated in metabolic diseases such as type 2 diabetes. We have found that IR is incorporated into biomolecular condensates during the response to insulin stimulation and that the activity of IR in these condensates is altered in insulin resistance. In normal cells, insulin stimulation results in accumulation of IR in bodies that display dynamic molecular characteristics expected of liquid-like condensates. In insulin-resistant cells, both IR accumulation in condensates and the normal dynamic behavior of these condensates are reduced, suggesting a physico-mechanical link between insulin response and the dynamic molecular behavior of IR condensates. The observed defects in IR condensate behaviors are caused, at least in part, by an increase in oxidative stress in insulin-resistant cells, which is known to interfere with normal condensate dynamics. Treatment of insulin-resistant cells with metformin, a first-line drug used to treat type 2 diabetes, can rescue accumulation and dynamic behavior of IR condensates. This rescue corresponds with metformin’s effect of reducing the levels of reactive oxygen species. The observation that IR is incorporated into biomolecular condensates during the response to insulin stimulation, and evidence that changes in the physico-mechanical features of IR condensates contribute to insulin resistance, have implications for improved therapeutic approaches for patients.

Disclosure
A.Dall’agnese: Consultant; Dewpoint Therapeutics. J.Platt: None. T.Lee: None. J.F.Jeppesen: Employee; Novo Nordisk A/S. R.A.Young: Research Support; Novo Nordisk.
1317-P: Intermittent Hypoxia Increased the Expression of DBH and PNMT in Neuronal Cells via MicroRNA-Mediated Mechanism
Authors: TAKASAWA SHIN , SHOBATAKE RYOGO , TAKEDA YOSHINORI , UCHIYAMA TOMOKO , YAMAUCHI AKIYO , MAKINO MAI , ASAI KEITO , OTA HIROYO 
Published: May 2022

Sleep apnea syndrome (SAS) , characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]) , is a risk factor for hypertension and insulin resistance. We have reported correlation between IH and insulin resistance. However, why hypertension is induced by IH has been elusive. Here, we investigated the effect of IH on the expression of catecholamine metabolizing enzymes using in vitro IH system. Human and mouse neuronal cells, NB-1 and Neuro-2a, were exposed to IH (70 cycles of 5 min hypoxia [1% O2] and min normoxia [21% O2]) or normoxia for 24 hours. Real-time RT-PCR revealed that IH significantly increased the mRNA levels of dopamine β-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT) in both NB-1 (P=0.0271 and P&lt;0.0001, respectively) and Neuro-2a (P=0.0135 and P=0.0341, respectively) . Western blot showed that the expression of DBH and PNMT in the NB-1 cells significantly increased by IH (P=0.0296 and P=0.0007, respectively) . We next prepared reporter plasmids containing human DBH (-1018˜+10) and PNMT (-600˜+67) upstream of luciferase reporter gene and transfected them into NB-1 cells. The promoter activities of these genes were not increased by IH. Target mRNA search of microRNA (miR) s using MicroRNA.org program revealed that the mRNAs have a potential target sequence for miR-375. The miR-375 level of IH-treated cells was significantly decreased than that of normoxia-treated cells (P=0.0222) . To clarify the role of miR-375, miR-375 mimic and non-specific control RNA (miR-375 mimic NC) were introduced into NB-1 cells. The IH-induced up-regulation of mRNAs of DBH and PNMT was abolished by introduction of miR-375 mimic but not by miR-375 mimic NC. Theses results strongly suggest that IH stress down-regulates the miR-375 in neuronal cells, resulting in the increased levels of DBH and PNMT via the inhibition of the miR-375-mediated mRNA degradation, leading SAS patients to hypertension.

Disclosure
S.Takasawa: None. R.Shobatake: None. Y.Takeda: None. T.Uchiyama: None. A.Yamauchi: None. M.Makino: None. K.Asai: None. H.Ota: None.
1321-P: Reproductive Experience Impairs Warm Sensing in Female Mice
Authors: ZHANG NAN , HE YANLIN , XU YONG 
Published: May 2022

The maternal body experiences drastic alterations in energy balance during pregnancy and lactation, but little is known about the long-term metabolic changes after this reproductive experience. Here we systemically compared the metabolic phenotypes in reproductive experienced (RE) female mice vs. virgin females, and found that RE mice showed a chronic hypothermia when housed at the room temperature (24°C) . In a warm sensing test, virgin females show clear preference to 30 °C ambient temperature vs. the room temperature, while RE mice lose this preference. In a cold sensing test, both virgin and RE females showed similar preference to the room temperature vs. 15 °C ambient temperature. Immunofluorescence staining revealed that expression of estrogen receptor alpha (ERα) in the medial preoptic area (MPA) was significantly decreased in the RE mice compared to virgins. Electrophysiological recordings demonstrated that the warm-sensing property of ERα neurons in the MPA were impaired in RE mice. Our results indicate that reproductive experience impairs the thermoregulation in female mice, associated with defective warm sensing of ERα neurons in the MPA.

Disclosure
N.Zhang: None. Y.He: None. Y.Xu: None.
1327-P: Loss of Exocrine Pancreas Improves Glucose Tolerance and Insulin Secretion in Diet-Induced Hyperglycemia
Authors: ABI RAAD SARAH , SALEH MOHAMED , GITTES GEORGE 
Published: May 2022

There are two intra-pancreatic axes of communication between the endocrine and exocrine pancreas (insular-acinar & acinar-insular axes) yet the study of the endocrine and exocrine pancreas have generally been conducted separately. We previously showed that loss of acinar cells improved glucose homeostasis in wild type mice. Here, we examined the effect of loss of acinar cells on diet-induced hyperglycemia.We used a genetic mouse model (ElaCreERT2; R26DTR) , wherein diphtheria toxin (DT) ablates acinar cells, allowing for the study of β-cell function in the absence of acinar cells. We included 3 groups [ElaCreERT2; R26DTR + high fat diet (HFD) ], [R26DTR + HFD], and [R26DTR + regular diet (RD) ]. These groups were on their respective diets for 12 weeks, then underwent glucose tolerance testing (GTT) and glucose stimulated insulin secretion (GSIS) after DT injection. Four days post-DT, the ElaCreERT2; R26DTR+HFD mice had a significantly improved glucose tolerance compared to R26DTR + HFD (AUC p=0.0003) . Importantly, the ElaCreERT2; R26DTR + HFD were not different from R26DTR+RD, indicating complete reversal of the hyperglycemia. GSIS done during GTT showed significantly lower insulin secretion in ElaCreERT2; R26DTR + HFD compared to R26DTR + HFD (AUC p=0.0388) , but similar to R26DTR+ RD, again indicating normalization. Islets were isolated from the 3 groups for in vitro GSIS, which showed no difference in the insulin secretion between ElaCreERT2; R26DTR + HFD and R26DTR + RD, but both had increased insulin secretion compared to R26DTR + HFD. Four weeks post-DT, when full regeneration of acinar cells from duct cells takes place, repeat GTT in the same animals showed that HFD groups had worse glucose tolerance compared to the RD group, suggesting that it was specifically the loss of the acinar cells that improved glucose tolerance. We conclude that the acute ablation of exocrine pancreas improves glucose tolerance and reverses HFD-induced hyperglycemia by enhancing insulin secretion.

Disclosure
S.Abi raad: None. M.Saleh: None. G.Gittes: None.
1328-P: COVID Associated Insulitis in Type 1 Diabetes
Authors: UWAIFO GABRIEL I. 
Published: May 2022

Recent reports suggest a potential relationship between COVID-and onset of diabetes (DM) . We present the case of a 35 yr old female with type 1 DM (T1DM) who following COVID-pneumonia (COVP) developed worsening insulitis suggesting a potential direct effect of COVID-on beta cell function. The patient is a 35 yr old Caucasian female with T1DM first diagnosed 5 yrs ago. She had some residual beta cell secretory function with fasting C-peptide; 0.51 (0-8-3.85ng/ml) . She also has hemochromatosis, thyroiditis with thyroid nodular disease and +ve history of T1DM in her older brother and maternal cousin. Since diagnosis she has been on insulin pump therapy and a CGMS device with excellent glycemic control and HBA1c of 6.7-7.1. She had not received the COVID-vaccine and had COVP in July 2021 requiring inpatient care but not intubation. She received oral steroids and Remdesivir with salutary response. She has not had post-acute sequelae of SARS-CoV (PASC) but ˜ 2 months post discharge had acute thyroiditis with no thyroid abscess, elevated sed rate, leucocytosis and peak thyroglobulin; 158 (3-40ng/ml) . Since discharge she noted persistent global hyperglycemia requiring increased basal and bolus insulin therapy with peak HBA1c of 8.3. Further evaluation showed active insulitis with reduced C-peptide 0.and increase in islet related antibodies compared to titers obtained at the time of initial diagnosis 5 yrs prior. The clinical presentation of our patient suggests a potential role of COVID-in inducing insulitis with significant implications for at risk patients including T1DM patients with preserved islet function but also type 2 DM and LADA patients. This case provides another compelling reason for advocating COVID-vaccination in at risk patients. The duration of this effect on islet function and whether beta cell functional recovery is possible over time remains to be seen. The insulitis manifests with worsening glycemic profiles as well as possibly impacting islet mediated counterregulatory glycemic responses.

Disclosure
G.I.Uwaifo: None.
133-OR: Increasing Economic Returns of Structured Lifestyle Intervention Associated with Rising Costs of Treating Diabetes: 2010–2018
Authors: HUANG WENXI , GUAN DAWEI , NIU SHU , ALI MOHAMMED K. , ZHANG YONGKANG , GUO JINGCHUAN , SHAO HUI 
Published: May 2022

The medical costs of treating type 2 diabetes (T2D) can be considered a counterfactual to measure the value for preventing T2D. This study examined changes in the cost-effectiveness of the structured lifestyle intervention (SLI) to prevent T2D, attributable to the sharp increase in the costs of T2D between 20 and 2018. We developed a patient-level discrete-time microsimulation model for diabetes progression and mortality in people eligible for SLI as specified in the National Diabetes Prevention Program (NDPP) using data from the 2009-20 National Health and Nutrition Examination Survey (NHANES) with linked National Death Index, and published literature. We used the Medical Expenditure Panel Survey to develop a health utility equation (2018 data) and two cost equations (20 and 2018 data) . We simulated the long-term health and economic consequences of SLI using the simulation model based on 20 and 2018 cost equations, respectively. We took a payers’ perspective, and all costs were standardized to 2018 USD. The incremental net benefit (INB) was estimated using a $50,000/QALY. The SLI achieved cost-saving over a 20-year time horizon in a scenario using 2010’s costs but only 9 years under 2018’s costs. Based on 20 costs, SLI costs below $997 and $2,153 would make the SLI cost-saving and cost-effective, respectively, over a 20-year window. Based on 2018 costs, if SLI costs were below $1,479 and $2,635, respectively, it would be cost-saving and cost-effective over 20 years. Subgroup analysis suggested the SLI was more cost-effective in the Hispanic adults (INB:$5,383) than non-Hispanic white (INB: $2,192) and black (INB:$2,364) adults. From 20 to 2018, the increasing medical costs for treating T2D has led to a higher likelihood and shorter time horizon for SLI to be cost-saving. This suggests that payers can raise reimbursements for SLI programs to make the adoption of these programs more feasible for delivery systems while maintaining economic value.

Disclosure
W.Huang: None. D.Guan: None. S.Niu: None. M.K.Ali: Advisory Panel; Bayer AG, Research Support; Merck & Co., Inc. Y.Zhang: None. J.Guo: None. H.Shao: Board Member; BRAVO4HEALTH, LLC.
1333-P: Therapeutic Potential of DA-1726, a Novel Oxyntomodulin Analogue, in a Diet-Induced NASH Mouse Model
Authors: JUNG IL-HUN , KIM TAE-HYOUNG , GOO MOON-JUNG , KIM MI-KYUNG , CHAE YUNA 
Published: May 2022

DA-1726 is a novel balanced long-acting GLP-1/glucagon receptor dual agonist, which is under preclinical development for the treatment of obesity. DA-1726 represented a superior efficacy to semaglutide (SEMA) in weight loss in various animal studies. In this study, we evaluated the therapeutic potential of DA-1726 for the treatment of nonalcoholic steatohepatitis (NASH) . To induce NASH, male mice were given a diet containing 40% total fat, 20% fructose, and 2% cholesterol for 30-week. After then DA-1726 and SEMA were subcutaneously injected every three days for 8-week. At the end of treatment, vehicle control, DA-1726 (100 or 200 nmol/kg) and SEMA (250 nmol/kg) significantly reduced body weight compared to baseline (+10.4%, -8.9%, -17.2%, and -12.9%, respectively) . Plasma clinical chemistry parameters (ALT, AST, ALP and T-BIL) and hepatic fat accumulation were significantly decreased by DA-1726. The reduction of plasma glucose and total cholesterol induced by DA-1726 200 nmol/kg was superior to that of SEMA. In a histopathological analysis of steatosis, lobular inflammation, and ballooning in the liver, DA-1726 showed an excellent improvement in NAFLD Activity Score compared to SEMA (NAS: 6.75 for vehicle control, 3.88 and 3.63 for DA-1726, and 5.00 for SEMA) . Liver fibrosis was assessed by Masson Trichrome stain. Improvement of hepatic fibrosis by DA-1726 was also observed (fibrosis score: 1.88 for vehicle control, 1.25 and 1.13 for DA-1726, and 1.50 for SEMA) . In the liver tissue, the expression of inflammatory (Tnfa, Il-1β, and Ccl2) and fibrotic (Acta2, Timp1, Col1a1, Col3a1, and Mmp9) genes were significantly decreased by DA-1726 treatment. In particular, the DA-1726 low-dose group showed a higher efficacy despite lower weight loss compared to SEMA. This is thought to be a result of the dual actions of DA-1726 to GLP-1 and glucagon receptors. Taken together, our findings suggest that DA-1726 has a therapeutic potential for NASH in addition to obesity and type 2 diabetes.

Disclosure
I.Jung: None. T.Kim: None. M.Goo: None. M.Kim: None. Y.Chae: None.
1337-P: Sex-Specific Variation in Lipid Metabolism in Response to Nutritional Stress Is Associated with Differences in NASH Progression
Authors: MOON MACKENZIE , MURALI ANJANA , BELLO FIONA , WANG JIEBIAO , JURCZAK MICHAEL J. 
Published: May 2022

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the US, encompassing a disease spectrum defined by steatosis, inflammation (NASH) , and fibrosis. Although the incidence of NASH is less in women compared with men, the mechanistic basis for this phenomenon is unclear. The aim of this study was to use high-resolution LC-MS/MS proteomics to determine sex-specific differences in liver protein abundance in healthy mice and in response to NASH that may contribute to protection in females. Male and female C57BL6J mice were fed regular chow (RC) or fast food (FF) diet (40% fat, 0.15% cholesterol, 42 g/L high-fructose corn syrup drinking water; n=18-20/g) to induce NASH. Liver weight and steatosis were significantly increased in male and female FF mice compared to RC counterparts, and the effects were more pronounced in males versus females. Plasma insulin and ALT followed similar patterns. Label-free differential mass spectrometry identified 2,917 proteins, where 314 and 445 proteins exhibited statistically significant changes in expression associated with sex and diet, and 2proteins showed a significant sex x diet interaction. Unsupervised hierarchical clustering of the 2proteins identified four groups of proteins defined by sex-specific differences in baseline abundance or response to FF-diet. Enrichment analysis of proteins within the four groups identified biological process related to 1) lipid catabolism and synthesis that were upregulated in FF males compared with females; 2) catabolism and oxidation-reduction reactions that were suppressed by FF diet in males but not females and 3) acyl-CoA hydrolase activity and fatty acid oxidation that were higher in RC females than males and induced by FF in males but not females. These data suggest that sex-specific differences in liver lipid metabolism at baseline and in response to nutritional stress may contribute to sexual dimorphism in NASH susceptibility.

Disclosure
M.Moon: None. A.Murali: None. F.Bello: None. J.Wang: None. M.J.Jurczak: None.

Funding
National Institutes of Health (DK114012)