bluuebunny/crossref_metadata_2025_split huggingface dataset:
1400-P: Endothelial Cell Autophagy Contributes to HFD-Induced Obesity and Insulin Resistance in Mice
Authors: REN GUANG , KIM JEONGA 
Published: May 2022

Autophagy is a catabolic process and plays crucial roles in cellular physiology, including energy homeostasis, cell survival, and inflammation. Autophagy-related gene 7 (ATG7) is an essential regulator of autophagosome formation. Although endothelial cell ATG7 (EC-ATG7) plays a critical role in atherosclerosis, thrombosis, and injuries from ischemia/reperfusion, the role of EC-ATG7 in obesity and insulin resistance is not known. Because endothelial function contributes to insulin resistance by regulating blood flow and delivery of nutrients and hormones to metabolic tissues, EC autophagy may affect metabolism and insulin resistance. Thus, we hypothesize that EC-ATG7 contributes to high-fat diet (HFD) -induced obesity and insulin resistance. To examine the role of EC-ATG7 in obesity and insulin resistance, we generated an EC-specific ATG7 knockout mouse (ATG7Δ EC) by breeding Cdh5-CRE mouse with ATG7flox/flox mouse. ATG7Δ EC mice were fed a normal chow diet (NCD) or HFD for twelve weeks. HFD-fed ATG7Δ EC mice gained less body weight compared with HFD-fed wild-type (WT) mice, while body weight was not different when the mice were fed NCD. HFD-fed ATG7Δ EC mice demonstrated lower food intake. Interestingly, intraperitoneal injection of low dose 2-arachidonoyl glycerol (2AG) , a cannabinoid receptor agonist, restored the food intake in ATG7Δ EC mice but not in WT mice. This indicates that the EC-ATG7 affects food intake by stimulating endogenous cannabinoid receptor (s) in the brain. Furthermore, HFD-fed ATG7Δ EC mice were more insulin sensitive than HFD-fed WT mice.
In conclusion, our findings demonstrate a novel function of EC-ATG7 in regulating food intake and insulin resistance.

Disclosure
G.Ren: None. J.Kim: None.

Funding
National Institutes of Health (R01-HL128695, R03-AG058078, P30-DK079626)
1411-P: Increased 24-Hour Plasma Free Fatty Acids in People with Obesity and Prediabetes
Authors: PETERSEN MAX C. , FARABI SARAH S. , SMITH GORDON , KLEIN SAMUEL 
Published: May 2022

The importance of increased plasma free fatty acids (FFAs) in the pathogenesis of insulin resistance in people with prediabetes is unclear. It has been proposed that the increase in plasma insulin associated with obesity should be adequate to suppress adipose tissue lipolytic rates and maintain normal plasma FFA levels. We evaluated serial plasma FFA concentrations for 24 h in 20 adults with obesity and normal fasting glucose and glucose tolerance (metabolically healthy obesity [MHO]) and 20 adults with prediabetes, matched on age, sex, BMI and percent body fat with the MHO group. Insulin sensitivity, assessed as the glucose infusion rate during an insulin clamp, was greater in the MHO than the prediabetes group (48.1 ± 3.0 vs. 23.5 ± 1.3 μmol/kg fat-free mass/min, respectively, P &lt; 0.0001) . Plasma FFA were greater throughout 24 h in the prediabetes group than the MHO group (Figure) . The 24-h areas under the curve were greater for plasma FFA (5.59 ± 0.37 vs. 4.58 ± 0.30 mmol/L x hour, P = 0.04) and plasma insulin (13,5± 1720 vs. 6,541 ± 558 pmol/L x hour, P = 0.0004) in the prediabetes group than the MHO group. We conclude that plasma FFA concentrations are greater throughout the day in people with prediabetes than those with MHO, despite a marked increase in plasma insulin concentration in those with prediabetes. These data support the notion that increased 24-h plasma FFAs contribute to insulin resistance associated with obesity.

Disclosure
M.C.Petersen: None. S.S.Farabi: n/a. G.Smith: None. S.Klein: Advisory Panel; Altimmune, Consultant; Janssen Research & Development, LLC, ProSciento, Research Support; Janssen Research & Development, LLC.

Funding
NIH T32DK007120Endocrine Fellows Foundation
1430-P: Association of Obesity and Diabetes with SARS-Cov-2 Infection and Symptoms
Authors: MONGRAW-CHAFFIN MORGANA , TJADEN ASHLEY H. , SEALS AUSTIN , MILLER KRISTEN , AHMED NAHEED , ESPELAND MARK , GIBBS MICHAEL A. , USCHNER DIANE , WEINTRAUB WILLIAM S. , EDELSTEIN SHARON 
Published: May 2022

Background: Obesity and T2D are risk factors for SARS-CoV-2 outcomes, but less is known about non-hospitalized cases. We hypothesized that those with obesity or T2D are more likely to have a positive Covid test, and among those with a positive test, to have symptoms.
Methods: Among 31,117 North Carolina Covid Community Research Partnership participants with EHR data, we evaluated the association of self-reported and EHR obesity and T2D with a self-reported positive Covid test at any time. Among 2,418 participants with a positive test during the study, we evaluated the association of obesity and T2D with self-report of symptoms. Logistic regression models were adjusted for age, sex, race/ethnicity, socioeconomic status, and healthcare worker status.
Results: We found a positive graded association between BMI category and positive Covid test, and a similar but weaker association with Covid symptoms among those with a positive test (Table) . T2D was associated with Covid infection but not symptoms.
Conclusions: While the limitations of this health system convenience sample include generalizability and test seeking selection bias, the strong graded association of BMI and T2D with self-reported Covid infection suggests that obesity and T2D may play a role in risk for symptomatic SARS-CoV-2 beyond co-occurrence with socioeconomic risk factors.

Disclosure
M.Mongraw-chaffin: None. S.Edelstein: None. A.H.Tjaden: None. A.Seals: None. K.Miller: None. N.Ahmed: None. M.Espeland: None. M.A.Gibbs: None. D.Uschner: None. W.S.Weintraub: None.

Funding
The CARES Act of the U.S. Department of Health and Human Services (HHS) [Contract # NC DHHS GTS #49927].
1453-P: Possible Delta- to Beta-Cell Transdifferentiation in Aged Diabetic Mutant CRY1 Transgenic Mice
Authors: OKANO SATOSHI , YASUI AKIRA , SATOH KENNICHI , KANNO SHIN-ICHIRO , IGARASHI MASAHIKO , NAKAJIMA OSAMU 
Published: May 2022

Cysteine414 (zinc-binding site of mCRY1) -alanine mutant mCRY1 transgenic mice (TG) show diabetes characterized by the reduction of β-cell proliferation due to the characters of senescence-associated secretory phenotype (SASP) in β-cells as we have reported at ADA Scientific Sessions in 2015. We also showed that various structural remodeling progresses in the islets of TG age-dependently: the increase of the population ratios of α-cell to β-cell and of ∂-cell to β-cell as well as fibrillation, angiogenesis and also the generation of mucin-producing atypical intra-islet ducts. Also, we revealed that trefoil factor family 2 (TFF2) is up-regulated in the β-cell of aged TG (Okano S. et al., ADA Scientific Sessions in 2020). To explore the mechanisms of keeping of the amount of β-cells under hyperglycemia for prolonged period in TG, we further conducted detailed double immune-staining experiments in the pancreatic sections of various ages (approximately 1, 10, and 19 months) of TG. The results demonstrated that, somatostatin and insulin double-positive cells were observed exclusively in aged TG (19 months of age). In wild-type mice (WT) of all stages, the double-positive cells were not observed. No glucagon and insulin double-positive cell was observed in islets of both TG and WT of all stages. In addition, scrutinized analyses demonstrated that not only β-cells but also small portion of somatostatin-positive cells express TFF2 in islets of aged TG. Taken together, these results suggest the possible ∂-cell to β-cell transdifferentiation in aged TG, that is, ∂-cells may play some role as the source for β-cells to supply new β-cells for islets in TG.

Disclosure
S.Okano: None. A.Yasui: None. K.Satoh: None. S.Kanno: None. M.Igarashi: None. O.Nakajima: None.

Funding
Grants-in-Aid for Scientific Research (19K07498). The Joint Research Program of IDAC, Tohoku University (38).
1457-P: Cholesterol Accumulation in Islets Increases Steroidogenic Acute Regulatory (StAR) Protein Expression and Decreases Islet Cell Viability and ß-Cell Function
Authors: AKTER REHANA , HOGAN MEGHAN F. , ESSER NATHALIE , CASTILLO JOSEPH J. , HULL-MEICHLE REBECCA L. , ZRAIKA SAKENEH , KAHN STEVEN E. 
Published: May 2022

Diabetes is associated with elevated plasma cholesterol (Chol) , with its intracellular accumulation resulting in β-cell dysfunction. In steroidogenic tissues, StAR facilitates Chol transport from the outer to inner mitochondrial membrane for subsequent metabolism. We have shown that StAR is expressed in β cells and its upregulation increases mitochondrial Chol content and decreases mitochondrial function. To determine whether excess Chol per se increases StAR expression and reduces islet viability, we cultured mouse islets for 24 hours in Chol and quantified mRNA levels of Star and genes involved in Chol synthesis (Hmgcr) , uptake (Ldlr) and efflux (Abca1) , cell viability and glucose stimulated insulin secretion (GSIS) . Islet Chol content increased with increasing Chol concentrations (27.1±1.7, 55.3±0.5 and 72.7±5.2 µg/mg protein for 0, 0.25 and 0.5 mM respectively; n=3, p&lt;0.0by ANOVA) , with mitochondrial Chol increasing 2.4-fold in 0.5 mM (9.1±0.2 to 22.4±1.9 µg/mg protein; n=3, p&lt;0.005) . This was associated with increased Star mRNA expression (1.0±0.1, 3.0±0.9 and 7.0±1.5; n=3, p=0.014) . Further, mRNA expression of Hmgcr tended to decrease (1.0±0.2, 0.8±0.3 and 0.3±0.0; n=3, p=0.088) , whereas expression of Ldlr and Abca1 did not change (Ldlr: 1.7±0.8, 1.1±0.7 and 0.5±0.3; n=3, p=0.508; Abca1: 1.1±0.3, 1.9±0.7 and 1.1±0.1; n=3, p=0.413) . These changes were associated with reductions in cell viability (100±15.7%, 68.0±12.6% and 57.3±9.6%; n=2, p=0.025) and GSIS in response to 20 mM glucose (fold increase over 2.8 mM: 0 mM Chol 28.5±0.6, 0.25 mM Chol 8.9±0.5, 0.5 mM Chol 10.8±0.9; n=2, p&lt;0.0001) .
In summary, islet cholesterol accumulation is associated with increased StAR expression, decreased cell viability and reduced β-cell function. These data suggest that elevated cholesterol in diabetes may contribute to β-cell dysfunction by increasing StAR expression and mitochondrial cholesterol accumulation.

Disclosure
R.Akter: None. M.F.Hogan: Employee; NanoString. N.Esser: None. J.J.Castillo: None. R.L.Hull-meichle: Research Support; Casma Therapeutics. S.Zraika: None. S.E.Kahn: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc.

Funding
VA (I01BX001060) ,VA (IBX004063) ,NIDDK (P30 DK017047) ,NIDDK (T32 DK007247)
148-LB: Glomerular Filtration Rate Trajectories in Children with Type 1 Diabetes
Authors: FAVEL KRISTEN , MAMMEN CHERRY , PANAGIOTOPOULOS CONSTADINA 
Published: May 2022

Background: While children with type 1 diabetes (T1D) may be at risk for chronic kidney disease (CKD) , data describing changes in kidney function from diagnosis is lacking. Currently, Canadian guidelines do not recommend routine monitoring of serum creatinine in these children. As part of a quality improvement initiative, we implemented routine serum creatinine monitoring. In this study, we describe estimated glomerular filtration rate (eGFR) trajectories in children with T1D.
Methods: This longitudinal cohort study involved children with T1D followed in the Diabetes Clinic, who had ≥2 eGFR measurements. Data was collected from health records from 2016 to 2021. Annualized change in eGFR was calculated using the Bedside Schwartz equation, and a declining trajectory was defined a priori as &lt;-3 ml/min/1.73m2 per year. Latent class mixed models were used to categorize eGFR trajectories, and patient characteristics were compared between trajectories.
Results: Of the 307 participants, 46% were male; the median age at diagnosis and duration of T1D was 6.2 years and 6.9 years, respectively. Three eGFR trajectories were identified: stable-declining from normal baseline (93.8%) , rapidly declining from high baseline (4.5%) , and rapidly inclining from normal baseline (1.6%) . During their follow-up, 68 (22%) patients had an eGFR &lt;90 ml/min/1.73 m2. Increasing BMI and blood pressure were observed in patients with a declining trajectory (46.9% of all patients) .
Conclusion: Nearly half of children with T1D in this cohort had a declining eGFR trajectory. Notably, 22% of these children are at risk for CKD (eGFR &lt;90 ml/min/1.73 m2) early in their T1D course. These findings, along with the steady rise in blood pressure, are concerning given the increased risk of CKD and end-stage renal disease in adults with T1D. These data suggest that careful monitoring of serum creatinine and blood pressure at baseline and regular intervals is warranted in children with T1D.

Disclosure
K. Favel: None. C. Mammen: None. C. Panagiotopoulos: Speaker's Bureau; Eli Lilly and Company.

Funding
BC Children's Hospital Research Institute, Canucks for Kids Fund Diabetes Legacy Grant (FAS #: F21-02506)
149-OR: Genetic Modulation of HNF1A Activity via SGLT2 Deficiency Leads to Transient Intermittent Hyperglycemia: Consequences for HNF1A-MODY
Authors: ACOSTA-MONTALVO ANA , SAPONARO CHIARA , THEVENET JULIEN , CHIRAL MAGALI , PIRON ANTHONY , DELALLEAU NATHALIE , PASQUETTI GIANNI , CODDEVILLE ANAÏS , MORENO MARIA , GMYR VALERY , CNOP MIRIAM , KERR-CONTE JULIE A. , PATTOU FRANCOIS , PONTOGLIO MARCO , LISTON ADRIAN , BONNER CAROLINE 
Published: May 2022

Hepatocyte Nuclear Factor-1A (HNF1A) is a master regulator of key glucose-responsive genes in metabolic organs such as the intestine, liver, kidney, and pancreas. Heterozygous mutations in HNF1A cause Maturity-Onset-Diabetes-of-the-Young (HNF1A-MODY) . Mutant carriers are normoglycemic in childhood, but with age, they develop hyperglycemia. Although insulin secretory defects have been extensively studied, it is unclear whether HNF1A deficiency contributes to a progressive decline in alpha cell function. HNF1A-MODY patients display glycosuria and endogenous glucose production linked to reduced renal SGLT2 expression. Since SGLT2 is also expressed in alpha cells and is required for glucagon regulation, we hypothesized that HNF1A coordinates renal and alpha cell SGLT2 activity to maintain glucose homeostasis. Here, we studied Hnf1a regulation of renal Sglt2, Sglt1, and Glut2 in Hnf1a-/- mutant mice, glucagon expression and secretion in siHNF1A transfected human islets and we developed a novel Hnf1a mutant mouse model (Hnf1a+/Δe4-10) . Sglt2 protein was significantly reduced in the kidney of Hnf1a-/- mice, with no changes in Sglt1 or Glut2 protein expression. We observed that HNF1A is heterogeneously expressed in alpha, beta, and delta cells. siHNF1A islets displayed reduced insulin secretion and content, which was rescued by GLP1 treatment. HNF1A deficiency reduced SGLT2 levels, correlating with increased glucagon content and secretion. The Hnf1a+/Δe4-mice were born normoglycemic but became glucose intolerant at 12 weeks of age, mimicking the clinical characteristics of HNF1A-MODY patients. Collectively, these findings indicate that HNF1A deficiency downregulates renal and alpha cell SGLT2 expression, which is associated with an alteration in glucagon secretion in response to glucose stimulation. The new Hnf1a+/Δe4-mouse model may be a useful tool to study the progression of MODY with and without chronic drug treatment.

Disclosure
A.Acosta-montalvo: None. V.Gmyr: None. M.Cnop: None. J.A.Kerr-conte: None. F.Pattou: None. M.Pontoglio: None. A.Liston: None. C.Bonner: None. C.Saponaro: None. J.Thevenet: None. M.Chiral: None. A.Piron: None. N.Delalleau: None. G.Pasquetti: None. A.Coddeville: None. M.Moreno: None.

Funding
EFSD/Lilly (2017) awarded to Caroline Bonner, I-SITE ULNE awarded to Caroline Bonner, the European Genomic Institute for Diabetes (ANR-10-LABX-46) , the European Consortium for Islet Transplantation funded by the Juvenile Diabetes Research Foundation. TIGER was developed within the European Union’s Horizon 2020 research and innovation program project T2DSystems, under grant agreement 667191 (to Miriam Cnop) .
152-OR: Evidence Linking Loss of Hypothalamic Perineuronal Nets to Obesity Pathogenesis
Authors: ALONGE KIMBERLY M. , DORFMAN MAURICIO D. , SCARLETT JARRAD M. , MELHORN SUSAN J. , YE YUANCHAO , HU SHANNON J.W. , FRANCIS KENDRA L. , HENDRICKSON AARUN , CUI KATHERINE , MORTON GREGORY J. , SCHUR ELLEN , THALER JOSHUA , SCHWARTZ MICHAEL W. 
Published: May 2022

Defective neurocircuit activity within the hypothalamic arcuate nucleus (ARC) , a crucial brain area for the regulation of metabolism, is implicated in obesity pathogenesis. Perineuronal nets (PNNs) are extracellular matrix structures that regulate neurocircuit activity, and PNN loss can adversely influence the activity of the enmeshed neurons. To determine if defective ARC PNNs might contribute to obesity, we first quantified PNN abundance in obese mice induced by consuming a high-fat high-sucrose diet (HFHS; Bio-Serv #F4997) 12 wk. We found that compared to chow-fed controls, HFHS diet feeding caused an 84.3% decrease (p&lt;0.0001) in the abundance of PNNs enmeshing ARC neurons. This loss was also associated with increases of ARC microgliosis (1.5-fold; p=0.004) and astrogliosis (2.9-fold; p=0.006) , suggesting a link between ARC PNN loss and glial activation. To translate these findings to humans, we analyzed postmortem hypothalamic samples from 9 subjects (Sex, 7M/2F; Age, 22-71y) that had previously undergone quantitative T2 magnetic resonance imaging (MRI) to assess obesity-associated hypothalamic gliosis. Consistent with our findings in mice, ARC PNN content was strongly and inversely correlated with the hypothalamic gliosis score measured by T2-weighted MRI imaging (R2=0.63, p=0.01) . To assess whether this depletion of ARC PNNs might contribute to obesity, we microinjected either the PNN-digesting enzyme, ChABC, or heat-inactivated ChABC control, into the rat ARC at the onset of a 4 wk HFHS dietary intervention. We found that compared to controls, the magnitude of diet-induced hyperphagia (17%; p&lt;0.0001) , weight gain (41%; p&lt;0.0001) , and excess body fat accumulation (28%; p=0.01) increased following PNN digestion, driven largely by increased dark cycle food intake (24%; p=0.006) . These findings collectively identify ARC PNNs as novel participants in the central control of energy homeostasis, and implicate their loss as a potential contributor to obesity pathogenesis.

Disclosure
K.M.Alonge: None. G.J.Morton: Research Support; Novo Nordisk A/S. E.Schur: None. J.Thaler: None. M.W.Schwartz: None. M.D.Dorfman: None. J.M.Scarlett: None. S.J.Melhorn: None. Y.Ye: None. S.J.W.Hu: None. K.L.Francis: None. A.Hendrickson: None. K.Cui: None.

Funding
AG066509DK017047AG074152DK101997DK720269
154-OR: The Site Specific Role of GDF15 in Metformin Action
Authors: ZHANG SONG-YANG , LI ROSA J.W. , DANAEI ZAHRA , LIM YUMI , LAM TONY K. 
Published: May 2022

Metformin lowers glucose levels, appetite and body weight in rodents and humans, but the mechanisms on energy balance regulation have been rarely studied. Metformin increases plasma growth/differentiation factor 15 (GDF15) levels in humans and rodents, while elevating GDF15 via GDF15 infusion in rodents lowers food intake and body weight via its receptor GDNF family receptor α-like (GFRAL) , which is expressed in the hindbrain nucleus area postrema (AP) . However, whether the GDF15-GFRAL axis in the AP mediates metformin effect is unknown. In this study, metformin (200 mg/kg) was infused into the upper small intestine (USI) of rats, while fasting-refeeding study or intravenous glucose tolerance test was performed. USI metformin infusion elevated plasma GDF15 levels (met 138 ± 25 vs. veh 59 ± 7 pg/ml, n = 8, p &lt; 0.01) in parallel to a lowering of food intake (met 30 ± 2 vs. veh 40 ± 2 kcal, n = 16, p &lt; 0.01) and an increase in glucose tolerance (AUC met 5243 ± 75 vs. veh 5674 ± 153, n = 7, p &lt; 0.05) . Further, metformin lowered not only food intake but also body weight gain by 12 h (met 14 ± 1 vs. veh 23 ± 3 g, n = 8, p &lt; 0.01) . Importantly, a knockdown of GFRAL achieved via an injection of lentivirus expressing shRNA GFRAL vs. mismatch into the AP by ∼40% (p &lt; 0.05) negated the ability of metformin to not only lower food intake and body weight, but also increase glucose tolerance independent of body weight. Finally, acute AP GDF15 infusion (2 pmol) decreased food intake (GDF15-25 ± 2 vs. veh-36 ± 3 kcal, n = 10, p &lt; 0.01) and weight gain (as early at 6 h, GDF15 3.6 ± 1.2 vs. vehicle 8.7 ± 1.6 g, n = 10, p &lt; 0.05) , and increased glucose tolerance independently from body weight (AUC, GDF15-5322 ± 94 vs. veh-5722 ± 169, n = 6, p &lt; 0.05) , and these metabolic effects of AP GDF15 infusion were prevented by GFRAL knockdown in the AP.
In summary, our findings indicate that the AP GDF15-GFRAL axis is sufficient and necessary for metformin to regulate energy and glucose homeostasis in rodents.

Disclosure
S.Zhang: None. R.Li: None. Z.Danaei: None. Y.Lim: None. T.K.Lam: None.

Funding
Canadian Institutes of Health Research (FDN-143204)
174-LB: Diabetes as a Risk Factor for Long-COVID-19—A Scoping Review
Authors: HARDING JESSICA L. , ALI MOHAMMED K. , GANDER JENNIFER C. , PATZER RACHEL E. 
Published: May 2022

Background: Diabetes is a key risk factor for severe COVID-19 (i.e., hospitalization, mortality) . Whether diabetes is also a risk factor for post-acute sequelae of COVID-19 (PASC) , also known as long COVID, is unknown.
Methods: We conducted a scoping literature review on January 27, 2022 using the keyword terms ‘long hauler’, ‘long COVID-19’, ‘post-acute sequalae’, and ‘persistent COVID-19’ combined with the operator OR, with AND ‘diabetes’, AND ‘COVID-19 [MeSH Term]’. We included all peer-reviewed full-text observational research studies published in English between January 1, 2020 and January 27, 2022 that reported on the risk of PASC in people with and without diabetes with a minimum of 4-weeks follow-up after COVID-19 diagnosis, and narratively synthesized results.
Results: Among 39 studies identified, seven were included in the review and are summarized in Table 1. Overall, we found that 43% of studies identified diabetes as a potent risk factor for PASC (all odds ratios were &gt;4) . However, this conclusion is limited by the heterogeneity of studies with regard to PASC definitions (e.g., ongoing symptoms of fatigue, cough, dyspnea etc.) , populations at risk (hospitalized vs. non-hospitalized populations) , and follow-up times (range 4 weeks to 7 months) .
Conclusions: More high-quality studies across multiple populations and settings are needed to determine if diabetes is indeed a risk factor for PASC. In the meantime, careful monitoring of people with diabetes for development of PASC may be advised.

Disclosure
J. L. Harding: None. M. K. Ali: Advisory Panel; Bayer AG, Research Support; Merck & Co., Inc. J. C. Gander: None. R. E. Patzer: None.