bluuebunny/crossref_metadata_2025_split huggingface dataset:
1523-P: A Leptin-Mediated Interoceptive Network between the Brain and Brown Adipose Tissue
Authors: MUNOZ MARCOS D. , YANG XIAOHUA , TORRES IRIZARRY VALERIA C. , LUO PEI , CARRILLO-SÁENZ LESLIE , ANTONY NIMISHA , WEE LIEW CHONG , XU PINGWEN 
Published: June 2023

Obesity is attributed to chronic disruption in energy homeostasis. This phenomenon is controlled by systemic and local signals such as leptin, a nutrient-sensitive signal secreted primarily by the white adipose tissue (WAT). Previously, interscapular brown adipose tissue (iBAT) has been shown to express undetectable or very low levels of leptin. Unexpectedly, in this study, we observed that iBAT leptin expression displayed a distinct circadian pattern and fluctuated with nutritional and ambient temperature. These observations suggest a vital role of iBAT leptin in the regulation of energy homeostasis. To explore this idea, we performed gain and loss of function experiments by overexpressing (LEPOE) or knocking down (LEPKD) leptin selectively in UCP1+ cells of iBAT, respectively. We found that LEPOE reduced food intake while LEPKD increased it in normal and fasting-induced feeding conditions. Notably, LEPOE/LEPKD selectively increased/decreased the mRNA expression of leptin in the iBAT without affecting circulating leptin levels, indicating a possible paracrine role of iBAT leptin. In supporting this point of view, we found that the leptin receptor is highly expressed in the iBAT-associated sensory nerve (iBAT-SN). Moreover, iBAT-specific leptin infusion activated leptin signaling in the iBAT-SN and subsequently stimulated proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus. Conversely, chemical ablation of iBAT-SN increased food intake and blunted hypothalamic POMC activation induced by iBAT-specific leptin infusion. These findings indicate that iBAT possesses a structural and functional basis for paracrine leptin signaling via iBAT-SN, which cross-talks with POMC neurons to modulate energy homeostasis. Our results support an unappreciated metabolic role of iBAT leptin in energy homeostasis.

Disclosure
M.D.Munoz: None. X.Yang: None. V.C.Torres irizarry: None. P.Luo: None. L.Carrillo-sáenz: None. N.Antony: None. C.Liew: None. P.Xu: None.

Funding
National Institutes of Health (R01DK123098); U.S. Department of Defense (W81XWH-19-PRMRP-DA); Diabetes Research and Training Center (DK020595)
1528-P: Hypothalamic SEL1L-HRD1 ER–Associated Degradation Is Indispensable for Leptin Signaling in Diet-Induced Obesity by Degrading Misfolded Leptin Receptor
Authors: MAO HANCHENG , QI LING 
Published: June 2023

It has been reported that endoplasmic reticulum (ER) stress, also known as unfolded protein response (UPR), is a contributor to the development of diet-induced leptin resistance in central nervous system. However, the evidence for this model remains circumstantial and controversial. Moreover, the importance of ER homeostasis in leptin signaling remains unexplored. Interestingly, our data suggested that neither acute nor chronic HFD feeding triggers any overt UPR in vivo though with the presence of the central and peripheral pathogenesis. Rather, we found that the SEL1L-HRD1 protein complex of ER-associated protein degradation (ERAD) - the principal protein degradation and quality control mechanism - in hypothalamic POMC neurons is indispensable for leptin signaling in diet-induced obesity. We found that SEL1L-HRD1 ERAD, ubiquitously expressed in hypothalamic neurons, can be transiently induced by acute HFD. Notably the deficiency of SEL1L-HRD1 ERAD in POMC neurons leads to striking hypothalamic leptin resistance, concomitant hyperphagia and diet-induced obesity and pathogenesis in mice of both sexes. Mechanistically, our data show that in ER, SEL1L-HRD1 interacts with leptin receptors long isoform (LepRb) and mediates the degradation of LepRb. The lack of SEL1L-HRD1 impairs the clearance of misfolded LepRb that forms high molecular aggregates. Further, the SEL1L-HRD1 deficient cells exhibit significantly less membrane display of lepRb. Hence, we hypothesize that leptin receptor is an endogenous substrate candidate of SEL1L-HRD1 ERAD and that SEL1L-HRD1 ERAD is required for the maturation of nascent leptin receptor in the ER in response to leptin signaling. Overall, this study challenges the current dogma by demonstrating a key role of hypothalamic SEL1L-HRD1 ERAD, not UPR, in the pathogenesis of diet-induced obesity and leptin resistance.

Disclosure
H.Mao: None. L.Qi: None.
153-LB: Early Impact of a Hybrid Chronic Care Model on A1C Levels among Underserved Patients with Diabetes in Primary Care
Authors: LEE JOYCE Y. , NGUYEN JENNY T. , SEO MINJONG , NGUYEN TAN , PATEL NISA , RODRIGUEZ VANESSA , MAYORGA JOSE 
Published: June 2023

Underserved populations are at higher risk of developing diabetes-related complications. This study aimed to evaluate changes in A1c among undeserved patients who received care through a hybrid Chronic Care Model (h-CCM).
This was a retrospective observational study conducted in two satellite clinics of a federally qualified health center. h-CCM was delivered collaboratively via in-person and telehealth visits conducted by family physicians, nurse practitioners and clinical pharmacists. Baseline sociodemographic of patients &gt;40 years old with diabetes who received care through h-CCM for ≥ 3 months between Oct 2020 and Nov 2022 were included. Patients with any missing data were excluded. Descriptive analysis and paired t-test were used accordingly.
A total of 104 (53.0%) patients were analyzed. The average age was 60.7± 9.8 years with the majority being Hispanic (72.1%), female (57.7%) and with a mean h-CCM visits of 2.2± 1.8 over 3 months. The average ASCVD risk at baseline was 20.0± 16.6% with hypertension (88.5%) being the most common comorbidity. Average A1c decreased from 9.4± 2.1% at baseline to 8.7±1.9 at 3 months (-0.7%, p &lt;0.001) with improvements observed in all levels of baseline A1c (p&lt;0.001, Figure 1).
h-CMM was effective in achieving timely A1c reduction among underserved patients with diabetes. Greater improvements were observed in patients with higher baseline A1c.

Disclosure
J. Y. Lee: None. J. T. Nguyen: None. M. Seo: None. T. Nguyen: None. N. Patel: None. V. Rodriguez: None. J. Mayorga: None.
1537-P: Regulation of Energy Balance by a Gut–Brain Axis Mediated by SCFAs and FFA2/3 in the Brain
Authors: YANG XIAOHUA , LUO PEI , FENG BING , YE HUI , ANTONY NIMISHA , CARRILLO-SÁENZ LESLIE , TORRES IRIZARRY VALERIA C. , LAYDEN BRIAN T. , HE YANLIN , XU PINGWEN 
Published: June 2023

Short-chain fatty acids (SCFAs) derived from gut microbiota fermentation have been shown to generate beneficial metabolic effects on energy and glucose homeostasis by binding with free fatty acid receptors 2 (FFA2) and 3 (FFA3). Accumulating evidence indicates that the gut microbiota/SCFAs interact with the central nervous system (CNS) to regulate central metabolic function. Interestingly, we found that a single bolus intracerebroventricular (ICV) injection of acetate (ACE), propionate (PRO), or butyrate (BUT) dose-dependently inhibited food intake in an FFA2/3-dependent manner. Notably, both in situ hybridization and RNAscope analysis showed that FFA3 but not FFA2 was expressed in the cerebellar granule neurons, which was inhibited by PRO or FFA3-selective agonists in a Gi/o-dependent mechanism. We also showed that high-fat diet (HFD)-induced hypothalamic inflammation is diminished by dietary fiber supplementation, which is associated with increased circulating SCFAs. Notably, these anti-inflammatory effects of dietary fiber supplementation were partially attenuated in FFA2/3 double-knockout mice, suggesting a beneficial effect of FFA2/3 on hypothalamic inflammation. Taking all these together, our results suggest a model that SCFAs act on the brain to regulate energy homeostasis and hypothalamic inflammation.

Disclosure
X.Yang: None. P.Xu: None. P.Luo: None. B.Feng: None. H.Ye: None. N.Antony: None. L.Carrillo-sáenz: None. V.C.Torres irizarry: None. B.T.Layden: Consultant; Bayer Inc. Y.He: None.

Funding
National Institutes of Health (R01DK123098, P30DK020595 to P.X.), (P20GM135002, R01DK129548 to Y.H.), (T32AA026577 to V.C.T.I.); American Heart Association (915789 to V.C.T.I.), (20POST35120600 to Y.H.); U.S. Department of Defense (W81XWH-20-1-0075 to P.X
154-LB: HEDIS Glycemic Goals Achieved by Control-IQ Technology Users across All Payer Types
Authors: PATEL BIMAL V. , ALENCAR GABRIEL , WANG SHARON M. , LEAS SCOTT , MESSER LAUREL H. , PINSKER JORDAN E. 
Published: June 2023

Background: The t:slim X2 with Control-IQ technology (“Control-IQ”) is an advanced hybrid closed-looped system. This analysis evaluated glycemic outcomes in Control-IQ users by payer type using Healthcare Effectiveness Data and Information Set (HEDIS) quality thresholds. HEDIS is used by &gt;90% of health plans to measure performance and includes a metric to identify A1c control (&lt;8.0%) and poor control (&gt;9.0%). Glucose management indicator (GMI) is a recognized surrogate for A1c when sufficient data are provided (≥14 days, 70% CGM use).
Methods: We retrospectively analyzed glycemic data for individuals with type 1 diabetes from 1/1/20 to 3/4/23 who used Control-IQ for ≥1 year (with ≥70% of CGM use in final 3 months) and had a recorded baseline A1c prior to Control-IQ initiation. Results were stratified by payer type, prior therapy, and baseline A1c. GMI was calculated for last 3 months and compared to baseline A1c.
Results: Analysis included 20,319 users, with 42% (n= 8,493) on multiple daily injections (MDI) and 58% (n=11,826) on pump therapy at baseline. Control-IQ use significantly improved glycemic outcomes and mean HEDIS thresholds were achieved for all payer types and strata (table).
Conclusion: Control-IQ use improved HEDIS A1c (GMI) outcomes across all payer types, with the largest glycemic improvement seen in those with the highest A1c at baseline and for prior MDI users.

Disclosure
B. V. Patel: Employee; Tandem Diabetes Care, Inc. Stock/Shareholder; Tandem Diabetes Care, Inc. G. Alencar: Employee; Tandem Diabetes Care, Inc. S. M. Wang: Employee; Tandem Diabetes Care, Inc. Stock/Shareholder; Tandem Diabetes Care, Inc. S. Leas: Employee; Tandem Diabetes Care, Inc. L. H. Messer: Employee; Tandem Diabetes Care, Inc. Consultant; Dexcom, Inc. Advisory Panel; Lilly. Consultant; Capillary Biomedical, Inc. Research Support; Beta Bionics, Inc., Medtronic, Insulet Corporation. J. E. Pinsker: Employee; Tandem Diabetes Care, Inc.
1543-P: The Effect of Insulin Resistance on Brain Glucose Uptake—A Systematic Review and Meta-analysis
Authors: JENSEN NICOLE J. , PORSE ANE J. , SPEYER HELENE , KROGH JESPER , GEJL MICHAEL , GJEDDE ALBERT H. , RUNGBY JØRGEN 
Published: June 2023

Objective: We investigated the association between peripheral insulin resistance (IR) and brain glucose uptake (BGU) and further determined if testing condition (fasting vs. hyperinsulinemic-euglycemic clamp) was a moderator of the association.
Methods: A systematic search was conducted in PubMed, Embase, Cochrane Library, and Web of Science, studies assessing an association between measures of or clinical proxies for IR (e.g. diabetes and obesity) and BGU were included. Effect sizes were standardized and transformed into correlation coefficients and a random effect meta-analysis performed. Further, a subgroup analysis on testing condition was conducted.
Results: Twenty-one studies (n = 3,620) were included in the meta-analysis. The pooled correlation (-0.13 [95% CI: -0.37; 0.12], p=0.3) showed a substantial heterogeneity (I2 = 98%). Subgroup analysis revealed that IR negatively correlated with BGU when subjects were examined at fasting conditions (-0.42 [95% CI: -0.59; -0.21], I2 = 99%) and positively correlated when subjects were examined during a hyperinsulinemic-euglycemic clamp (0.53 [ 0.38; 0.66], I2 = 47%)(figure 1). Test condition significantly moderated the association (p &lt;0.01) and explained 55% of the heterogeneity.
Conclusion: Across the studies IR results in abnormal BGU in both fasting and hyperinsulinemic states, clamp conditions reverse the low BGU in IR.

Disclosure
N.J.Jensen: None. A.J.Porse: None. H.Speyer: None. J.Krogh: None. M.Gejl: None. A.H.Gjedde: None. J.Rungby: Advisory Panel; Abbott, Consultant; Novo Nordisk, Speaker's Bureau; Boehringer-Ingelheim, AstraZeneca.
155-LB: Econsults—An Innovative Model for Diabetes Specialty Care Delivery
Authors: KARSLIOGLU-FRENCH ESRA , ZUPA MARGARET , QUAYTMAN JACOB 
Published: June 2023

Background: More than 10% of the US population has diabetes. However, a national shortage of endocrinologists limits access to diabetes specialty care, creating a delay of several weeks to months for a new patient appointment in endocrine clinic. Econsults, which are asynchronous provider-to-provider communications embedded in the electronic medical record, are a relatively new pathway to seek consultation from specialists. The most common reason for endocrine econsult is uncontrolled diabetes. However, there is little evidence on effectiveness of econsults in improving diabetes control.
Methods: We completed a retrospective chart review of all endocrine econsults that were completed for adults with diabetes within a large integrated health system in 2022. We compared HbA1c values before and 3, 6, 12 months after econsult to assess glycemic change. We also analyzed how many econsults were followed by an endocrinology office visit.
Results: Of 212 diabetes econsults completed in 2022, 8% (16/212) were for type 1 DM, and 92% (196/212) were for type 2 DM management. Follow-up HbA1c values were available in 189 patients. Eighty-eight percent (166/189) of patients had improvement in HbA1c 12 months following econsult. Only 15% (32/212) of all econsults were followed by a video or in-person visit with an endocrinologist, while 85% (180/212) did not require a follow-up endocrine appointment. Of the patients who only received econsult, mean HbA1c improved from 9.9% at baseline to 7.4% at 12 months (p&lt;0.05). Of the 31 patients with type 2 DM who required a follow-up appointment with endocrinologist, mean HbA1c improved from 10.4% at baseline to 7.1% post-visit (p&lt;0.05). Of note, 6 patients were diagnosed with new-onset type 1 DM during econsult process and were triaged to an immediate video visit to start appropriate insulin treatment and prevent DKA.
Conclusion: Econsult is an efficient and effective model which can expand access to diabetes specialty care for patients with uncontrolled diabetes.

Disclosure
E. Karslioglu-French: Research Support; Abbott. M. Zupa: None. J. Quaytman: None.

Funding
Pittsburgh Foundation Grant (MR2022-128717)
1551-P: Association between Short-Term Postprandial C-Peptide Index Recovery during Hospitalization and Future Glycemic Control in Patients with Type 2 Diabetes
Authors: ENKAKU ASAKO , CHUJO DAISUKE , KAMIGISHI MIKI , INAGAWA SHINYA , SAKAI WAKA , MATSUKOSHI SHINNOSUKE , TAKIKAWA AKIKO , FUJISAKA SHIHO , TOBE KAZUYUKI 
Published: June 2023

Endogenous insulin secretion could be recovered by improving hyperglycemia in patients with type 2 diabetes (T2D). However, no reports have showed the associations between short-term insulin secretion recovery and future glycemic control. In this study, we investigated whether short-term C-peptide index (CPI) recovery during hospitalization could predict future glycemic control. In this study, 117 patients with T2D were included. The recovery of fasting and postprandial CPI were defined as (fasting CPI at discharge - fasting CPI at admission [index-A]) and (postprandial CPI at discharge - postprandial CPI at admission [index-B]). We compared the clinical background between the low-recovery and high-recovery groups of each index and assessed the association between the indices and metabolic parameters after discharge. Using index-A, age was significantly younger (P = 0.017) and body mass index (BMI) was significantly higher (P = 0.004) in the high-recovery group than that in low-recovery group. Using index-B, the age was significantly younger (P = 0.019) and BMI was significantly higher (P = 0.004) in the high-recovery group. Additionally, visceral fat area (P = 0.043), serum TG (P &lt; 0.001), and γ-GTP levels (P = 0.009) were significantly higher in the high-recovery group. Regarding the association between CPI recovery and future glycemic control, GA levels were significantly lower in the high-recovery group than that in low-recovery group at 6 months (16.7 vs 21.1%, P = 0.045) and 12 months (16.8 vs 21.7%, P = 0.033) after discharge in the analysis using index-B. Furthermore, postprandial CPI (cut-off; 3.79 [AUC 0.698, P = 0.007]) at discharge and index-B (cut-off; 1.66 [AUC 0.657, P = 0.018]) were identified as indicators to predict HbA1c ≤ 7.0% at 6 months after discharge. In conclusion, short-term postprandial CPI recovery during hospitalization may predict future glycemic control.

Disclosure
A.Enkaku: None. D.Chujo: None. M.Kamigishi: None. S.Inagawa: None. W.Sakai: None. S.Matsukoshi: None. A.Takikawa: None. S.Fujisaka: None. K.Tobe: Other Relationship; MSD K.K., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Company Limited, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Suntory Global Corporation, Ltd.,, Taiho Pharmaceutical Co. Ltd., Japan Diabetes Foundation, Japan Association for Diabetes Education and Care.
1557-P: Ctcfl Is a Fasting-Induced Epigenetic Regulator of Lipid Metabolism and Ketogenesis in the Liver
Authors: EFTHYMIOU VISSARION , POULOS LINDSAY , STRAUB LEON , NAVARRETE VALERIE , OZTURK BERKCAN , OSATAPHAN SORAVIS , CHIMENE-WEISS JEREMY I. , PATTI MARY-ELIZABETH 
Published: June 2023

Engaging regulatory mechanisms mediating physiologic adaptations to fasting may be a potential tool for obesity and T2D. We previously demonstrated SGLT2i induce a fasting-like transcriptional program in liver, and identified Ctcfl (CCTC-binding factor (CTCF)-like) as a top-ranking transcript upregulated in SGLT2i-treated C57BL/6J mice (↑1.5-fold, p=0.01). Ctcfl was also upregulated 2.5-fold with fasting vs. fed littermates. We hypothesize Ctcfl mediates fasting-related transcriptional modulation via dynamic epigenetic regulation of chromatin accessibility. To identify drivers of Ctcfl expression, we studied AML12 hepatocytes, demonstrating key roles for AMPK activation and mTOR inhibition as upstream regulators. Moreover, in vivo inhibition of mTOR or insulin receptor increased hepatic Ctcfl expression (~2-fold), while insulin suppressed Ctcfl by ~50% within 3h. siRNA knockdown (KD) of Ctcfl indicates Ctcfl regulates transcriptional mediators of fasting (e.g. Hnf4, Srebf, Chrebp, Pgc1α), lipid/carbohydrate metabolism, and mitochondrial biogenesis. Single-cell RNAseq in Ctcfl-KD cells revealed distinct populations, enriched in mTOR, insulin signaling and Tfeb targets. Conversely, human CTCFL overexpression resulted in repression of regulators of lipid metabolism (Fas) and ketogenesis (Hmgcs2). In vivo liver-specific knockdown of Ctcfl, using N-acetyl galactosamine-conjugated siRNA, did not modulate body weight but increased circulating β-hydroxybutyrate and reduced respiratory quotient in the fasted state, suggesting shift to increased lipid utilization. Thus, we demonstrate Ctcfl is upregulated with fasting and fasting-like stimuli, including SGLT2i and AMPK activation, and repressed by refeeding, insulin signaling, and mTor pathways. Ctcfl can mediate a transcriptional program which may regulate lipid and ketone metabolism while acting as a “brake” to limit aberrant ketogenesis, potentially via alterations in chromatin accessibility.

Disclosure
V.Efthymiou: None. L.Poulos: None. L.Straub: None. V.Navarrete: None. B.Ozturk: None. S.Osataphan: None. J.I.Chimene-weiss: None. M.Patti: Consultant; MBX Biosciences, AstraZeneca, Hanmi Pharm. Co., Ltd., Other Relationship; Fractyl Health, Inc.

Funding
Swiss National Foundation; National Institutes of Health (R01DK106193)
156-OR: Apolipoprotein C-II Posttranslational Truncation Is Associated with Reduced Incident Cardiovascular Risk in Multiethnic Study of Atherosclerosis (MESA)
Authors: KOSKA JURAJ , FURTADO JEREMY , HU YUEMING , NEDELKOV DOBRIN , BILLHEIMER DEAN , BUDOFF MATTHEW , ALLISON MATTHEW , MCCLELLAND ROBYN , REAVEN PETER 
Published: June 2023

Higher truncated-to-native proteoform ratios of apolipoproteins (apo) C-I (C-I’/C-I) and C-II (C-II’/C-II) are associated with lower triglycerides (TG) and higher HDL levels. Here we examined the relationships of C-I’/C-II and C-II’/C-II, and total apo C-I and C-II concentrations with atherosclerotic cardiovascular disease (ASCVD) and coronary heart disease (CHD). Apo C-I and C-II proteoforms were measured by mass spectrometry immunoassay at baseline in 5,765 MESA participants followed for CHD (definite myocardial infarction, resuscitated cardiac arrest or fatal CHD) and ASCVD (CHD or stroke) for up to 17 years. Baseline total apo C-I and C-II levels were measured in a subgroup of 3,848 participants. After adjusting for age, gender, and race/ethnicity, lower C-II’/C-II was associated with both ASCVD and CHD (Figure). The association of C-II’/C-II with CHD remained significant after further adjusting for BMI, diabetes, systolic BP, eGFR, use of tobacco, statins, antihypertensive medications, total apoC-II, and plasma TG, but was abolished after adjusting for HDL. Neither ASCVD nor CHD were related to total apo C-I and C-II or CI’/CI. In conclusion, increased posttranslational apoC-II truncation (but not total apo C-I or C-II) is associated with reduced cardiovascular risk, possibly explained by differences in HDL cholesterol metabolism.

Disclosure
J.Koska: None. J.Furtado: Employee; Biogen. Y.Hu: None. D.Nedelkov: None. D.Billheimer: Advisory Panel; AstraZeneca. M.Budoff: Research Support; Novo Nordisk, Novartis, Boehringer Ingelheim Inc., Speaker's Bureau; Boehringer Ingelheim and Eli Lilly Alliance. M.Allison: None. R.Mcclelland: None. P.Reaven: Research Support; Dexcom, Inc.

Funding
National Heart, Lung, and Blood Institute (R01HL138969, 75N92020D00001, HHSN268201500003I, N01HC95159, 75N92020D00005, N01HC95160, 75N92020D00002, N01HC95161, 75N92020D00003, N01HC95162, 75N92020D00006, N01HC95163, 75N92020D00004, N01HC95164, 75N92020D00007, N01HC95165, N01HC95166, N01HC95167, N01HC95168, N01HC95169); National Center for Advancing Translational Sciences (UL1TR000040, UL1TR001079, UL1TR001420)