bluuebunny/crossref_metadata_2025_split huggingface dataset:
1541-P: Sympathetic Nervous System Activity in Response to Food Ingestion Is Impacted by Obesity
Authors: CHUNG TAMMY J. , DEAJON-JACKSON JELANI , BINI JASON , SONG HUIJIA , SANCHEZ RANGEL ELIZABETH , YECKEL CATHERINE W. , HWANG JANICE J. , STACHENFELD NINA , BELFORT-DEAGUIAR RENATA 
Published: June 2023

Studies have shown that sympathetic nervous system activity (SNSA) may differ in obese (OB) compared to lean individuals. In addition, increased (SNSA) has been observed after ingestion of food. However, it remains unclear whether obesity alters post-meal (SNSA). We tested the hypothesis that (SNSA) is increased post-meal in OB individuals. We used a dual strategy to assess SNSA: i) a whole-body PET radiotracer ([11C]MRB) in combination with CT imaging (PET-CT). [11C]MRB binds to norepinephrine (NE) transporter allowing measurement of NE release from SNS. ii) Skeletal muscle microneurography to measure muscle sympathetic nerve activity (MSNA). Participants underwent two PET-CT and MSNA visits: fasting and mixed meal test (MMT). We ​​examined 5 subjects, 3F/2M, age 41±7 years (2 OB) and 3 normal weight (NW). During the MSNA fasting visit, RR intervals were longer at 15 minutes (P=0.03), while opposite findings were observed with MMT, which diminished between 15 until 60 minutes indicating increased heart rate (HR). We also observed increased total MSNA area/burst at 60 min after MMT (P&lt;0.02). No statistically significant differences in MSNA were observed between OB and NW. PET-CT of deltoid muscle (n=4, 2 OB and 2 NW) showed changes in distribution volume ratio (DVR) between days (MMT - fasting) were correlated with BMI (R2=0.71, P=0.16). DVR changes in both NW were reduced, while both OB were increased (P=0.01), suggesting that OB had less endogenous NE competing with [11C]MRB to bind at the NE transporter compared to NW. These preliminary data suggest that MSNA increases following MMT in both NW and OB subjects which may be further impacted by obesity.

Disclosure
T.J.Chung: None. J.Deajon-jackson: None. J.Bini: None. H.Song: None. E.Sanchez rangel: None. C.W.Yeckel: None. J.J.Hwang: None. N.Stachenfeld: None. R.Belfort-deaguiar: Research Support; Fractyl Health, Inc., Silver Palate Kitchens.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (1R56DK129344)
1542-P: Commercially Available Aspartame-Based Sweetener Damages Morphology of Major Organs Both in Normal and Type 2 Diabetic Rats
Authors: DLAMINI SIPHIWE N. , ISLAM SHAHIDUL 
Published: June 2023

Non-nutritive sweeteners (NNS) such as aspartame have become highly popular as sugar substitutes for diabetics. Majority of studies have reported controversial results and used aspartame in its pure form, which is not consumed by people practically. Hence, the present study was aimed at investigating the effects of commercially available aspartame-based sweetener on diabetes related parameters and its associated complications in both normal and type 2 diabetic rats. Seven-week-old male Sprague-Dawley rats were randomly divided into four groups, namely: Normal Control (NC), Toxicological Aspartame (TASP), Diabetic Control (DBC) and Diabetic Aspartame (DASP). Type 2 diabetes was induced experimentally in the DBC and DASP groups only and animals with non-fasting blood glucose levels &gt;300 mg/dL were considered as diabetic. During 13 weeks experimental period, the control groups received normal drinking water, whilst TASP and DASP groups were given aspartame-containing NNS solutions, ad libitum, at concentrations equivalent to the sweetness of 20% and 10% sucrose solution, respectively. Treatment with toxicological aspartame resulted in significantly reduced serum fructosamine and creatinine levels in normal rats, when brain, heart, liver, kidney and pancreatic tissue morphologies were significantly damaged in both normal and diabetic rats. The data of this study suggest that although aspartame-based NNS may not have higher degree of detrimental effects on diabetes associated parameters, the significantly damaged morphology of the major organ tissues as well as deterioration of related serum biomarkers both in normal and diabetic conditions raises a concern of its use as a NNS in various food and food products.

Disclosure
S.N.Dlamini: None. S.Islam: None.

Funding
South African Sugar Association (Project 233)
1546-P: Gut-Specific Neprilysin Deletion Increases Insulin Secretion in High-Fat–Fed Mice
Authors: ESSER NATHALIE , MONGOVIN STEVE M. , BARROW BREANNE , ZRAIKA SAKENEH 
Published: June 2023

Global deletion of the ubiquitous peptidase neprilysin (NEP) protects against high fat diet (HFD)-induced insulin secretory dysfunction. Since NEP is expressed in the gut, it can cleave locally produced insulinotropic peptides. We previously found that under physiological conditions, acute inhibition of gut NEP enhances glucose-stimulated insulin secretion (GSIS) in mice. Thus, we determined whether this beneficial effect on GSIS also occurs in mice with gut-specific NEP deletion that are fed HFD. Mice with conditional deletion of NEP in enterocytes (NEPGut-/-) were generated by crossing Vil1-cre and floxed NEP mice. NEP activity was almost abolished throughout the gut in NEPGut-/- vs control mice (5±2 vs 164±20 vs 120±20 pmol MNA/h/μg, NEP Gut-/- vs Vil1-cre vs NEPfl/fl mice; n=5-6/group; p&lt;0.0001), and was similar in plasma, pancreas and kidney among all mice. At 11 weeks of age, mice were fed HFD for 14 weeks, after which an OGTT was performed and GSIS assessed as ∆insulin/∆glucose from 0 to 10 min. Despite similar body weights in NEP Gut-/- and control mice, fasting plasma glucose was lower and GSIS higher in NEP Gut-/- vs controls (Table). In sum, gut-specific NEP deletion decreases fasting plasma glucose and increases GSIS in HFD-fed mice, suggesting gut NEP impairs ß-cell function under conditions of HFD. Thus, strategies to inhibit NEP specifically in the gut may protect against fat-induced ß-cell dysfunction.

Disclosure
N.Esser: None. S.M.Mongovin: None. B.Barrow: None. S.Zraika: None.

Funding
National Institutes of Health (DK098506, (P30DK017047)
1549-P: scEMC10 Promotes Glucose Intolerance via the Inhibition of PKA-Mediated Insulin Secretion
Authors: DAI JIARONG , LIU SHAN , CHEN KUANGYANG , JIN SHUOSHUO , WANG YAHAO , CHEN LIJIAO , WANG XUANCHUN 
Published: June 2023

It has been shown recently that overexpression of the secreted isoform of endoplasmic reticulum membrane complex subunit 10 (scEMC10) impairs, whereas Emc10 knockout (KO) or antibody neutralization of circulating scEMC10 improves glucose tolerance in mice fed with high fat diet. In humans, serum scEMC10 levels correlate positively with fasting plasma glucose and HbA1c. The mechanism underlying the regulation of glucose metabolism by scEMC10 remains largely unknown. In this study, alation of EMC10 significantly improved glucose tolerance in chow diet-fed mice, which was attributed to increased glucose-stimulated insulin secretion (GSIS), but not improved insulin sensitivity evaluated by euglycemic-hyperinsulinemic clamp. Using an adeno-associated virus, either reconstitution of scEMC10 in Emc10 KO mice or overexpression of scEMC10 in wildtype mice significantly decreased glucose tolerance accompanied by blunted GSIS. Recombinant scEMC10 inhibited GSIS in both INS-1 cells and isolated primary islets in vitro. Mechanistically, we presented evidence that extracellular scEMC10 can be transported into beta cells where it binds to the catalytic subunit of PKA and inhibits phosphorylations of PKA substrates including phosphorylated CREB, along with reduced PDX-1 expression. Furthermore, antibody neutralization of circulating scEMC10 alleviated hyperglycemia in both STZ-treated mice and ob/ob mice. This work identifies scEMC10 as a suppressor of insulin secretion via the inhibition of PKA signaling in islet beta cells and suggests scEMC10 neutralizing antibody as a promising pharmaceutical agent to treat diabetes.

Disclosure
J.Dai: None. S.Liu: None. K.Chen: None. S.Jin: None. Y.Wang: None. L.Chen: None. X.Wang: None.

Funding
National Natural Science Foundation of China (81873645); Science and Technology Commission of Shanghai Municipality (22140902700)
1556-P: Hepatic AMP-Activated Protein Kinase Governs Adaptations in Liver Glucose Fluxes and Lipid Homeostasis in Response to Exercise Training in Mice
Authors: HUGHEY CURTIS C. , BRACY DEANNA , LANTIER LOUISE , FORETZ MARC , VIOLLET BENOIT , WASSERMAN DAVID 
Published: June 2023

During acute exercise the liver increases glycogenolysis and the energetically costly process of gluconeogenesis to supply glucose to the working muscle. In response to exercise training, the liver undergoes adaptations in glucose and lipid metabolic pathways to more effectively meet the ATP demand of the next exercise bout. We tested the hypothesis that the energy sensor and master regulator of ATP provision, AMP-activated protein kinase (AMPK), is necessary for liver glucose and lipid adaptations to exercise training. This was accomplished by studying mice with liver-specific deletion of AMPK α1 and α2 subunits (KO) and wild type (WT) littermates undergoing sedentary and exercise training protocols. In vivo isotope infusions combined with 2H/13C metabolic flux analysis quantified liver nutrient fluxes at rest and during treadmill running. Liver metabolite concentrations and the expression of molecular regulators of liver nutrient metabolism were evaluated. The results of this study showed that liver glycogen deposition in response to exercise training was impaired in KO compared to WT mice and that this lower glycogen availability resulted in diminished glycogenolysis, glucose production, and circulating glucose during acute exercise. Exercise training decreased liver diacylglycerides (DAGs) in both genotypes, however, the response was less pronounced in KO mice. Moreover, exercise training led to higher liver triacylglycerides (TAGs) in KO mice. A lack of AMPK action prevented exercise training from promoting the desaturation of DAG fatty acyl chains as evidenced by higher 16:1/16:0 and 18:1/18:0 ratios in KO mice. Unexpectedly, the differences in DAG fatty acyl chain composition between genotypes were not observed in TAGs. Together, these results suggest that AMPK is a critical regulator of the liver glycogen and lipid availability and selectively remodels DAG fatty acyl chain composition in response to exercise training.

Disclosure
C.C.Hughey: None. D.Bracy: None. L.Lantier: None. M.Foretz: None. B.Viollet: None. D.Wasserman: None.

Funding
National Institutes of Health (DK050277, DK054902, DK059637, DK020593)
1559-P: Glucagon Receptor–Mediated Improvements in Glycemia Are Dependent on Agonist Pharmacodynamics
Authors: NASON SHELLY , KIM TEAYOUN , ANTIPENKO JESSICA , YANG BIN , DIMARCHI RICHARD , HABEGGER KIRK M. 
Published: June 2023

Glucagon is considered the main glucose counter-regulatory hormone to insulin. Although, chronic glucagon receptor (GCGR) agonism induces hyperglycemia and glucose intolerance, it also improves insulin secretion and action. Surprisingly, we found chronic treatment with the selective, long-acting GCGR agonist, IUB288, improves ad libitum glycemia and glucose tolerance 4h after treatment. These glycemic improvements were associated with enhanced AKT phosphorylation, despite control-like insulin levels. We next tested if these results could be replicated with a short acting GCGR agonist. IUB94 displays improved aqueous solubility but maintains the short half-life and potency of native glucagon. 4h glucose excursion was monitored in lean mice after injection of IUB288, IUB94, or vehicle. We observed a transient rise in blood glucose (BG) 15min after either IUB288 or IUB94 compared to vehicle. Intriguingly, IUB288-treated mice exhibited improved BG from 120-240min, while BG in IUB94-treated mice was similar to vehicle controls. These data suggest that acute BG regulation is agonist-dependent yet, it remains unclear if pharmacodynamics or some inherent difference in potency is influencing the 4h BG. We next treated lean mice for 4d with vehicle or IUB288, measuring ad libitum glycemia over the final 24h period. IUB288-treated mice displayed improved glycemia 4h after the last injection and hyperglycemia after 12h, compared to vehicle-treated controls, suggesting chronic GCGR agonism is not exclusively hyperglycemic. Surprisingly, 4d IUB288 treatment in diet-induced obese (DIO) mice reduced ad libitum glycemia for a longer duration than observed in chow IUB288-treated mice. IUB288 treatment also increased glucose infusion rate, suppression of endogenous glucose production, and AKT phosphorylation during hyperinsulinemic-euglycemic clamps. These data provide insight into the potential therapeutic use of sustained-acting GCGR agonists against diabetes and obesity.

Disclosure
S.Nason: None. T.Kim: None. J.Antipenko: None. B.Yang: None. R.Dimarchi: None. K.M.Habegger: Consultant; Glyscend Inc., Research Support; Eli Lilly and Company, Novo Nordisk, Glyscend Inc., Stock/Shareholder; Glyscend Inc.

Funding
National Institutes of Health
156-LB: Nursing Burden Administering/Monitoring Complex Insulin Regimens vs. Basal Insulin/GLP-1 RA Fixed-Ratio Combinations (FRCs) for People with Type 2 Diabetes (PWT2D) in Long-Term Care (LTC)
Authors: DAVIDSON HARLEY E. , NELSON ASHLEY , HAN LISA F. , LAMANTIA MELISSA , DESAI KERRY , LI XUAN , DEX TERRY A. , VANCE JACQUELINE F. , OVERBECK KEVIN 
Published: June 2023

Aim: Management of older PWT2D in LTC is challenging due to comorbidity, functional dependence, and hypoglycemia risk, and is further complicated by nurse shortages. This cross-sectional survey emailed to LTC nurses assessed perceived nursing burden associated with complex insulin regimens (basal-bolus [BB], sliding scale insulin [SSI]) vs FRCs.
Methods: The survey comprised 3 hypothetical cases of PWT2D receiving BB, SSI, or FRC. Perceived burden was assessed using the unweighted NASA-Task Load Index (TLX). Responses for the 6 TLX subscales (mental, physical, and temporal demand; effort, frustration, performance) and perceived frequency of fingerstick use were summarized descriptively.
Results: 10,982 nurses received the survey. Of the 250 who qualified (administered BB/SSI/FRC in past 90 days), 87% were female, 51% were ≥45 y, 49% had ≥11 y experience in LTC. TLX scores (max 20 higher = worse) were lower for FRCs vs BB or SSI (Table). Nurses perceived FRCs to require fewer fingersticks vs BB or SSI (Table).
Conclusions: FRCs were perceived to reduce nursing burden and fingerstick use compared with complex insulin regimens. These findings, coupled with the lower hypoglycemia risk for FRCs vs complex insulin regimens reported in clinical trials suggest that use of FRCs in LTC has potential to reduce nursing workload.

Disclosure
H. E. Davidson: Research Support; Sanofi-Aventis U. S. A. Nelson: Research Support; Sanofi-Aventis U. S. L. F. Han: Research Support; Sanofi-Aventis U. S. M. Lamantia: Research Support; Sanofi-Aventis U. S. K. Desai: Employee; Sanofi. X. Li: Employee; Sanofi-Aventis U. S. T. A. Dex: Employee; Sanofi-Aventis U. S., Stock/Shareholder; Pfizer Inc., Viatris Inc., Teva Pharmaceutical Industries Ltd. J. F. Vance: None. K. Overbeck: None.

Funding
Sanofi
1560-P: Combining Glucagon with Insulin Can Lessen the Hypoglycemic Potential of Insulin
Authors: KRAFT GUILLAUME , SCOTT MELANIE , SMITH MARTA S. , FARMER BEN , EDGERTON DALE S. , CHERRINGTON ALAN D. 
Published: June 2023

We showed previously in people with T1D that by infusing glucagon along with insulin can buffer insulin’s hypoglycemic effect without worsening its ability to limit hyperglycemia. Our aim was to determine in the conscious dog the mechanisms by which glucagon limits the insulin driven fall in glucose. Somatostatin was infused to disable the endocrine pancreas and insulin and glucagon were infused into a leg vein at basal rates. After a 140 min control period, the insulin infusion rate was increased 4-7-fold for 3h to induce hypoglycemia. Glucagon was also infused into a leg vein, then was either increased proportionately to insulin (constant I/G molar ratio, HiGGN), or in a second study on the same dog, it was kept at its basal rate (Ba GGN). Hepatic sinusoidal insulin levels rose from 11±2 to 65±17 μU/ml regardless of the glucagon level, which remained basal in BaGGN (50±10pg/mL) but rose from 52±8 pg/ml to 238±50pg/ml in HiGGN. Plasma glucose fell over the first hour, reaching a nadir of 45±2 mg/dl when glucagon was basal, and fell more slowly when glucagon was elevated (nadir of 50±2 mg/dl). This difference was due to a greater increase in net hepatic glucose output in the HiGGN group (1.4 ± 0.2 vs 2.4 ± 0.2 mg/kg/min in BaGGN and HiGGN respectively). Interestingly the rise in plasma cortisol and epinephrine were reduced by 33 and 39%, respectively, in the group with elevated glucagon. Further, this lessening in the counterregulatory response was associated with reductions in lipolysis and lactate production by muscle. Thus, by maintaining a fixed I/G molar ratio the hypoglycemic potential of insulin is buffered. This could allow more aggressive insulin treatment which would in turn increase time in range for glucose.

Disclosure
G.Kraft: None. M.Scott: None. M.S.Smith: None. B.Farmer: None. D.S.Edgerton: None. A.D.Cherrington: Advisory Panel; Metavention, vTv Therapeutics, Diakard, Sekkei Bio, Sensulin Labs, LLC, Other Relationship; Fractyl Health, Inc., Novo Nordisk, Abvance Therapeutics, Research Support; Cellular Longevity, Inc, dba Loyal, Senda Biosciences.
1562-P: Hepatic ChREBP-ß Overexpression Enhances Peripheral Glucose and Lipid Homeostasis Independently of FGF21
Authors: HANNOU SARAH , SARGSYAN ASHOT , TONG WENXIN , AN JIE , NEWGARD CHRISTOPHER B. , ASTAPOVA INNA , HERMAN MARK A. 
Published: June 2023

Carbohydrate Response Element-Binding Protein (ChREBP) is a key transcription factor activated by carbohydrate metabolites which transactivates metabolic gene programs involved in the glycolytic and lipogenic response to dietary and circulating sugars. Genetic variants in the ChREBP locus associate with multiple aspects of cardiometabolic disease including dyslipidemia and risk of type 2 diabetes (T2D). Studies overexpressing ChREBP in the liver suggest that ChREBP can play a protective role in preserving glucose and lipid homeostasis. We hypothesized that this protective effect may be mediated through ChREBP’s effect to increase hepatic expression and circulating levels of the beneficial hepatokine, FGF21. To test this hypothesis, we transduced male mice with liver-specific knockout of FGF21 (L-FGF21KO) and lox/lox controls with adenovirus (ADV) containing the constitutively active isoform of murine ChREBP, ChREBP-β, versus ADV-GFP control (N = 4-7 / group). ADV-ChREBP-β transduction induced a 5-fold increase in hepatic (p&lt;0.001) and circulating FGF21 (p&lt;0.0001) in control mice and this was fully abrogated in L-FGF21KO mice. While no significant changes in body weight were detected, ADV-ChREBP-β transduction reduced fasting glycemia and enhanced glucose tolerance in both controls and L-FGF21KO mice. ADV-ChREBP-β transduction induced glycolytic and lipogenic genes similarly in L-FGF21KO and control mice, increased hepatic triglyceride content (3-fold, p&lt;0.005) and induced steatosis, while reducing circulating triglycerides and increasing browning of white adipose tissue. In conclusion, hepatic FGF21 does not mediate the beneficial effect of hepatic ChREBP-β overexpression on peripheral glucose and lipid homeostasis.

Disclosure
S.Hannou: None. A.Sargsyan: Employee; AstraZeneca. W.Tong: None. J.An: None. C.B.Newgard: Advisory Panel; Eli Lilly and Company, Novo Nordisk, AstraZeneca. I.Astapova: None. M.A.Herman: Research Support; Eli Lilly and Company.

Funding
National Institutes of Health (R01DK100425)
1564-P: Impaired Insulin Secretion Increases Glucagon Action on the Liver
Authors: TONELLO ALESSIO , LAURENTI MARCELLO C. , COBELLI CLAUDIO , VELLA ADRIAN , DALLA MAN CHIARA 
Published: June 2023

The transition from prediabetes to diabetes is characterized by defects in insulin secretion and glucagon suppression in response to glucose. However, simultaneous estimation of both hormones actions on endogenous glucose production (EGP) remains a challenge. To address this, we studied 36 nondiabetic subjects on 2 occasions when endogenous hormone secretion was inhibited by somatostatin. Glucagon was infused at 0.65 ng/kg/min, at 0 min to prevent a fall in its concentration (non-suppressed - NS) or at 120 min to create a transient fall (suppressed - S). [3-3H]-glucose was infused to mimic an oral glucose challenge together with a prandial insulin infusion - one group received the full dose (100%), another 80% and another 60%. We tested models describing EGP as a function of glucose, insulin and glucagon concentrations. The optimal model assumes that EGP is suppressed by the actions of glucose, its rate of change and insulin in a remote compartment, while plasma glucagon stimulated EGP (through parameter SGn), with an effect that is evanescent. With 60% replacement (corresponding to severely impaired insulin secretion), SGn was significantly higher than with 80% (moderately impaired) and 100% replacement (p=0.02, Fig.1). This demonstrates that glucagon action on EGP is modulated by insulin concentrations, emphasizing the need to quantify secretion and action of both hormones when measuring postprandial islet function.

Disclosure
A. Tonello: None. M.C. Laurenti: None. C. Cobelli: None. A. Vella: Other Relationship; Novo Nordisk. Advisory Panel; Rezolute, Inc. Consultant; Crinetics Pharmaceuticals, Inc., Hanmi Pharm. Co., Ltd., Zealand Pharma A/S. C. Dalla Man: Research Support; Sanofi-Aventis Deutschland GmbH, Becton, Dickinson and Company.

Funding
Italian Minister for Education; National Institutes of Health (DK116723)