bluuebunny/crossref_metadata_2025_split huggingface dataset:
1618-P: Fasting Decreases Pyruvate Carboxylase Flux in the Perfused Exocrine Pancreas
Authors: RUSHIN ANNA , MCLEOD MARC , GLANZ MAX , GRAHAM DALTON S. , MERRITT MATTHEW 
Published: June 2023

The exocrine pancreas displays structural and functional abnormalities in type 1 diabetes, such as acinar atrophy and fibrosis. Metabolic dysfunction may occur alongside these changes. We established a method to investigate exocrine metabolism using nuclear magnetic resonance (NMR) and hyperpolarized (HP) substrates. This approach conserves the native environment while permitting analysis of metabolic flux in the living pancreas. Here, we compared exocrine pancreas metabolism in fed (n=4) and fasted (n=5) male C57BL/6J mice. Each pancreas was perfused for 30 minutes with oxygenated Krebs-Heinsleit buffer in a 14 T NMR instrument. NMR spectra were collected after injection of 4 mM HP [1-13C] pyruvate into the common bile duct. 13C signals from several central carbon metabolites were detected, such as alanine, malate, and fumarate. Pancreata from fasted mice produced less (p&lt;0.05) fumarate and aspartate compared to those from the fed mice. After perfusion, all pancreata were analyzed by gas chromatography - mass spectrometry for metabolite quantification. Malate was significantly enriched (p&lt;0.05) by 13C in the fed pancreas with similar total malate between groups. Overall, these results suggest that the exocrine pancreas displays higher pyruvate carboxylase (PC) flux in the fed state compared to the fasted state. The methodology presented here provides a unique avenue to assess pancreatic metabolism in real-time.

Disclosure
A.Rushin: None. M.Mcleod: None. M.Glanz: None. D.S.Graham: None. M.Merritt: None.

Funding
National Institutes of Health (T32DK10876); National Science Foundation (DMR-1644779)
1619-P: Creation of a Mouse Model That Phenocopies Human MODY8—A Valuable Tool to Interrogate Exocrine–Endocrine Cross Talk
Authors: EL JELLAS KHADIJA , KAHRAMAN SEVIM , LOWE MARK E. , MOLVEN ANDERS , KULKARNI ROHIT 
Published: June 2023

Despite the intimate anatomical relationship between the two compartments of the pancreas, little is known about the biological components mediating the exocrine-endocrine communication in regulating glucose homeostasis. Maturity-onset diabetes of the young, type 8 (MODY8) is a dominantly inherited autosomal form of monogenic diabetes, caused by heterozygous mutations in the carboxy ester lipase (CEL) gene expressed in acinar cells. MODY8 is characterized by chronic pancreatitis (CP) and exocrine dysfunction from childhood, followed by diabetes in adulthood. Heterozygous MODY8 mice develop CP but are normoglycemic. Here, we report a refined mouse model that bears the mutation present in MODY8 patients on one allele, and the humanized normal variable number of tandem repeat (VNTR) of CEL with 16 repeats (16R) on the other, mimicking the genetic make-up seen in MODY8 patients. This mouse model (MODY8/16R) acts as a unique tool to directly interrogate the dynamic communication between the exocrine and endocrine compartments by phenotyping longitudinally from weaning to age 2 yrs. Preliminary histopathological analyses of the pancreata reveal features of CP in some lobes, including inflammation, fibrosis and fat infiltration, mirroring the disease in humans. Moreover, confocal microscopy showed the presence of zymogen granules containing mutant CEL within beta cells. These data argue that the mutant CEL protein is transferred from acinar cells to beta cells in pathological conditions, with implications of directly impacting beta cell viability. Examination of glucose homeostasis revealed that inducing stress (e.g. a high-fat diet) leads to glucose intolerance in MODY8/16R mice compared to their control littermates. In conclusion, the availability of a MODY8/16R mouse model provides a unique opportunity to carefully characterize the endocrine-exocrine communication in the pancreas in a longitudinal manner that is otherwise not possible in humans.

Disclosure
K.El jellas: None. S.Kahraman: Employee; Boehringer Ingelheim Pharmaceuticals Inc. M.E.Lowe: Other Relationship; MilliporeSigma, Wolters Kluwer Health. A.Molven: None. R.Kulkarni: Advisory Panel; Novo Nordisk, Inversago, Biomea Fusion, Inc., REDD Pharma, Research Support; Inversago.

Funding
National Institutes of Health (U01135095)
1621-P: Commercially Available Stevia-Based Sweetener, Antidiabetic or Toxic—An Ad Libitum Feeding Study in a Type 2 Diabetes Model of Rat
Authors: ISLAM SHAHIDUL , DLAMINI SIPHIWE N. 
Published: June 2023

The use of non-nutritive sweeteners as sugar substitutes by overweight, obese and diabetic individuals has been increased rapidly in recent years, when Stevia is the most popular one not only due to its natural source of origin but also for it antidiabetic potential. However, the effects commercially available stevia-based NNS are not investigated at all. The present study was conducted to investigate the effects of ad libitum consumption of commercially available stevia-based non-nutritive sweetener (NNS) in an experimentally-induced rat model of type 2 diabetes (T2D). Seven-week-old male Sprague-Dawley rats were randomly divided into three groups, namely: Normal Control (NC), Diabetic Control (DBC) and Diabetic Stevia (DSTV). T2D was induced in the DBC and DSTV groups only. The control groups were received normal drinking water, whilst rats in the DSTV group were administered with stevia-containing NNS solution, at a concentration equivalent to the sweetness of 10% sucrose. After 13 week intervention, although food and fluid intake, body weight, weekly blood glucose, glucose tolerance, serum insulin, fructosamine, ALT, ALP, creatinine and brain, liver and pancreatic histopathology were not significantly affected; serum AST, LDH and CK-MB as well as heart and kidney histopathology were significantly deteriorated in stevia-based NNS consuming group compared to the DBC group. The data of this study suggest that uncontrolled consumption of stevia-based NNS has no significant antidiabetic effect but have some toxicological effects in an animal model of T2D. Hence, diabetic patients consuming stevia-based NNS should limit their daily intake.

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

Funding
South African Sugar Association (Project 233)
1624-P: Hudev-PRE, a Combination of Plant Extracts, Improves Glucose Homeostasis in Both High-Fat Diet C57Bl/6J and Ob/Ob Mice
Authors: LE MAY CEDRIC , BLUA JEAN-LOUIS , CARIOU BERTRAND 
Published: June 2023

Despite advances in the understanding of the pathogenesis of type 2 diabetes (T2D), new therapeutic & nutritional solutions are needed to delay its emergence and prevent the development of its associated complications. Here, we tested the effect of HUDEV-PRE, an original mixture of plant extracts, on glucose homeostasis in in two different mouse models of T2D. In a first experiment, 8 weeks old C57Bl/6J males were fed with high-fat diet during 8 weeks to induce insulin resistance. In a second set-up, we used 6 weeks old Ob/Ob males. In both experiments, mice received a double daily oral administration of vehicle, metformin (150mg/kg) or HUDEV-PRE for 30 days. Food intake, body weight change, random fed plasma glucose, cholesterol and triglyceride levels were measured once weekly. Finally, oral glucose tolerance tests (GTT) were performed after 7 and 21 days of treatment. In both models, HUDEV-PRE did not alter food intake and body weight. Interestingly, a rapid, sustainable and significant reduction of random fed blood glucose levels was observed in HFD fed C57Bl/6J and Ob/Ob mice receiving metformin or HUDEV-PRE administration. In HFD fed C57Bl/6J mice, GTT revealed no significant effects at day 7 but a strong improvement of glucose tolerance in mice treated for 21 days with metformin or HUDEV-PRE compared to control vehicle treated mice. In Ob/Ob mice, we observed similar results and the glucose tolerance was even improved after only 7 days of treatment. Finally, at day 21, we also measured a significant reduction of fasting plasma insulin levels and HOMA-IR in both mouse models treated with HUDEV-PRE. Together, our data demonstrate that HUDEV-PRE rapidly improve glucose homeostasis in two mouse models of T2D. Although additional studies are warranted to decipher the mechanisms of action, these findings indicate that HUDEV-PRE could represent a nutritional supplement of interest to delay the onset of insulin resistance and T2D in patients at metabolic risk.

Disclosure
C.Le may: None. J.Blua: None. B.Cariou: Board Member; Eli Lilly and Company, Novartis, Research Support; Sanofi, Speaker's Bureau; Abbott, AstraZeneca, Novo Nordisk, Sanofi.
1625-P: Osteoprotection by FNIP1 Signaling in Skeletal Muscle
Authors: YAN MAO , XU ZHISHENG , YIN YUJING , FU TINGTING , ZHOU ZHENG , YANG LIKUN , GAN ZHENJI 
Published: June 2023

Obesity is increasingly recognized to exert negative impact on bone mass. Skeletal muscle and bone are closely related throughout life, and muscle dysfunction can cause osteoporosis. Understanding of the crosstalk between muscle and bone could have implications for maintaining bone fitness in various disease states such as obesity. FNIP1 is emerging as key regulator of muscle metabolism acting via AMPK. However, the role of muscle FNIP1 in bone mass control is unknown. Using both gain- and loss-of function muscle-specific genetic models, we show that in addition to the known role in the regulation of mitochondrial function muscle fiber type, FNIP1 participates in muscle programs that govern bone homeostasis. FNIP1 KO mice showed a decrease in trabecular bone volume and bone mineral density, whereas muscle specific restoration of FNIP1 expression in KO mice (FNIP1Tg/KO) reversed the bone loss phenotypes. Femoral bending tests revealed a marked decrease in elastic modulus and maximum force in FNIP1 KO mice but increase in FNIP1 TgKO mice. Consistent with these findings, muscle cell-specific deletion of FNIP1 resulted in a pronounced bone structural and mechanical dysfunction. Using AMPKα1/α2 KO lines, we show that muscle FNIP1 exerts control actions upon bone homeostasis independently of AMPK. Through comprehensive RNA-seq and genomic analyses, we reveal that muscle FNIP1 deficiency induces IGF2 secretion, thereby driving an IGF2-depenent osteoclast program. Importantly, we also found that the muscle FNIP1-IGF2 regulatory circuit is associated with osteoporosis in humans. Thus, muscle FNIP1 is a critical safeguard of bone mass. These findings provide new therapeutic opportunities for enhancing muscle fitness to combat a variety of metabolic and musculoskeletal diseases.

Disclosure
M.Yan: None. Z.Xu: None. Y.Yin: None. T.Fu: None. Z.Zhou: None. L.Yang: None. Z.Gan: None.
163-LB: Youth with Delayed Sleep Phase Have Reduced Insulin Sensitivity
Authors: HITT TALIA A. , STEFANOVSKI DARKO , KELLY ANDREA , MALINA SARA , WANG CYNTHIA X.D. , SGAMBATI FRANCIS P. , ZEMEL BABETTE S. , JUN JONATHAN , MAGGE SHEELA N. 
Published: June 2023

Background: U.S. adolescents have short and delayed sleep, which may have metabolic consequences. We hypothesized that shorter sleep duration and later sleep phase are associated with decreased insulin sensitivity (SI) and worse glucose tolerance in overweight youth.
Methods: We enrolled healthy youth aged 12-21y with BMI ≥80%ile (or ≥23kg/m2 if ≥18y). We obtained 14 days of wrist actigraphy (ActiGraph GT3XP-BTLE), a frequently-sampled 180 min OGTT (fsOGTT) with 10 samples, and administered validated questionnaires to estimate obstructive sleep apnea (OSA) risk. From actigraphy, we derived average sleep duration (SLD), mid-sleep time (MST), and sleep onset (SO). From the fsOGTT, we estimated SI using the OGTT Minimal Model and the disposition index (DI = SI x incremental insulin AUC 180min). We used multivariable linear regression to examine associations between sleep patterns and glycemic outcomes adjusting for confounders.
Results: To date, we enrolled 24 youth (13F) with a median (IQR) age of 20.6y (19.2, 21.5), BMI of 25.2kg/m2 (24.3, 28.9), and fsOGTT glucoses of: fasting 91mg/dL (86, 95), 1h 141mg/dL (113, 179), and 2h 117mg/dL (78, 144). Participants had a median SLD of 7.3h (6.8, 8.1) per night, with SO of 1:13am (12:27am, 2:09am) and MST of 4:48am (4:23am, 6:01am). Age, race, and sex were not associated with sleep outcomes and not included in regressions. We found that (1) later MST [β=10.3, p=0.01] and SO [β=11.4, p=0.01] were each associated with higher fsOGTT 2h glucose, (2) later SO was associated with lower log-transformed SI [β= -0.27, p=0.04], and (3) later MST trended towards lower log-transformed DI [β= -0.1, p=0.055] adjusting for BMI and OSA risk. SLD was not related to any fsOGTT variables.
Conclusions: To our knowledge, this is the first study in overweight youth to show that delayed sleep phase (SO and MST), but not short SLD, was associated with lower SI using the rigorous OGTT minimal model. Further studies are needed to examine if delayed sleep is a modifiable risk factor for diabetes prevention in youth.

Disclosure
T. A. Hitt: None. D. Stefanovski: None. A. Kelly: None. S. Malina: None. C. X. D. Wang: None. F. P. Sgambati: None. B. S. Zemel: None. J. Jun: None. S. N. Magge: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK115648); National Institutes of Health (UL1TR001878, UL1TR001079)
163-OR: Association between Diabetes Distress and Suicide Risk in Emerging Adults with Type 1 Diabetes
Authors: MOSS ASHLEY , LOWRY SARAH J. , ROBERTS ALISSA J. , HUANG ALYSSA , PIHOKER CATHERINE , WEAVER KATHRYN , HIRSCH IRL B. , EHRHARDT NICOLE M. , ZENNO ANNA , MALIK FAISAL 
Published: June 2023

Aim: Emerging adults (EA) with type 1 diabetes (T1D) have higher rates of suicide risk compared to their peers without T1D. This is the first known study to examine the association between diabetes distress (DD) and suicide risk in EA with T1D.
Methods: EA completed measures of DD (Problem Areas in Diabetes-Teen; PAID-T), depressive symptoms (Patient Health Questionnaire-9; PHQ-9) and anxiety (General Anxiety Disorder-7) as part of routine clinical care. Suicide risk was assessed as a binary variable using PHQ-9 item 9, which queries about thoughts of suicide or self-harm. Mixed effects logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) to assess the relationship between DD and suicide risk. Analyses were adjusted for depression as measured by the PHQ-8 (first 8 PHQ-9 items), anxiety, sex, and BMI.
Results: Sample included 450 EA. Approximately 9% of participants reported suicide risk; endorsement of suicide risk was associated with elevated A1C and female sex (Table 1). Adjusted regression analyses show an additional 10 points on the PAID-T was associated with over doubled odds of endorsing suicide risk (OR 2.07, 95% CI 1.12-3.83).
Conclusion: DD may be a unique risk factor for suicide risk in EA with T1D. Routine screening of DD is critical for early identification and offers a potential intervention point for patients who may be at increased risk for suicide.

Disclosure
A.Moss: Other Relationship; American Diabetes Association. F.Malik: None. S.J.Lowry: None. A.J.Roberts: None. A.Huang: None. C.Pihoker: None. K.Weaver: None. I.B.Hirsch: Consultant; Abbott Diabetes, Lifecare, Inc., Hagar, Research Support; Beta Bionics, Inc., Insulet Corporation, Dexcom, Inc. N.M.Ehrhardt: Advisory Panel; Novo Nordisk, Dexcom, Inc., Consultant; Nestlé Health Science. A.Zenno: None.
1630-P: Reduced Fatty Acid Oxidation Does Not Prevent Intralipid-Induced Peripheral Insulin Resistance in Humans
Authors: GILLINGHAM MELANIE B. , GREGOR ASHLEY N. , VARLAMOV OLEG , ROBINO JACOB J. , MCCURDY CARRIE E. , GREYSLAK KEENAN T. , CHOI DONGSEOK , BAETSCHER ERIC , ROONEY WILLIAM , PURNELL JONATHAN Q. 
Published: June 2023

Mitochondrial handling of excess lipid substrate is thought to be an important determinant of insulin resistance. Evidence from animal models support insulin signaling defects resulting from either intra-cellular lipid accumulation or by mitochondrial dysfunction and altered fatty acid oxidation (FAO) flux. To explore the relationship between FAO and insulin sensitivity, we measured the change in peripheral glucose disposal (Rd) during a 5-hour hyperinsulinemic euglycemic clamp with co-infusion of a control glycerol solution versus a 20% intralipid solution in 18 subjects with an inherited defect in FAO (FAOD; including Carnitine Palmitoyltransferase 2, Very long-chain, medium-chain or long-chain 3-hydroxy AcylcoA Dehydrogenase Deficiencies) and 18 age, sex, and weight-matched normal healthy controls. Rd was similar between groups during the glycerol control clamp. Intramyocellular lipid (IMCL) content as measured by MRS increased after the 5 hour intralipid infusion in controls but not in participants with FAOD. Plasma free fatty acids during intralipid infusion were higher in FAOD compared to controls suggesting infused lipid remained in circulation. Muscle fiber type and expression of lipid transporters CD36 and FATP1 were similar in biopsy samples between groups and cannot explain decreased lipid uptake into muscle among FAOD subjects. However, intralipid suppressed Rd equally in subjects with FAOD and controls inducing peripheral insulin resistance in both groups. Impaired FAO decreased lipid accumulation in the muscle during intralipid infusion, but despite lower IMCL, subjects with FAOD developed peripheral insulin resistance similar to controls. Increased IMCL is not essential for, nor is reduced FAO flux protective against, the development of peripheral insulin resistance during intralipid infusion.

Disclosure
M.B.Gillingham: None. J.Q.Purnell: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk. A.N.Gregor: None. O.Varlamov: None. J.J.Robino: None. C.E.Mccurdy: None. K.T.Greyslak: None. D.Choi: None. E.Baetscher: Consultant; Biogen. W.Rooney: Consultant; Ultragenix, Research Support; Revalesio.

Funding
National Institutes of Health (DK102813)
1631-P: scEMC10 Suppresses Glucose Uptake in Skeletal Muscle via the Inhibition of AMPK Signaling
Authors: JIN SHUOSHUO , WANG YAHAO , CHEN KUANGYANG , DAI JIARONG , CHEN LIJIAO , LIU SHAN , WANG XUANCHUN 
Published: June 2023

Skeletal muscle is one of the most important organs involved in the glucose metabolism, and is mainly responsible for postprandial glucose uptake. We have previously shown that overexpression of the secreted isoform of endoplasmic reticulum protein complex subunit 10 (scEMC10) impairs, while Emc10 knockout (KO) or antibody neutralization of circulating scEMC10 improves glucose tolerance in mice. In this study, we presented evidence the regulation of glucose metabolism is achieved through the impacts of scEMC10 on skeletal muscle. PET-CT analyses showed Emc10 KO increased, whereas overexpression of scEMC10 decreased glucose uptake of skeletal muscle in mice, which can be accounted for by the corresponding changes in GLUT4 expression in their skeletal muscle tissues. Recombinant scEMC10 protein reduced both expression and membrane translocation of GLUT4, thus inhibiting glucose uptake in L6-GLUT4myc skeletal muscle cells. Mechanistically, scEMC10 decreased phosphorylations of both AMPK and its downstream target TBC1D1 in both skeletal muscle cells and tissues. Intraperitoneal administration of a scEMC10 neutralizing antibody increased both expression and membrane translocation of GLUT4 accompanied by increased uptake of glucose in gastrocnemius in mice. These data support scEMC10 as an inhibitor of glucose uptake in skeletal muscle and suggest the inhibition of scEMC10 will be a promising way to lower blood glucose in diabetes.

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

Funding
National Natural Science Foundation of China (81873645); Science and Technology Commission of Shanghai Municipality (22140902700)
1633-P: Type 1 Diabetes Induced Alterations in Motor Unit Discharge Rate
Authors: MINNOCK DEAN , VALLI GIACOMO , WU RUI 
Published: June 2023

Type 1 diabetes (T1D) is a contributing factor in alterations in skeletal muscle health. It has been attributed to accelerated muscle ageing (Monaco et al., 2019), and the molecular alterations in the muscle are also associated with impaired adaptations to physical exercise (Minnock et al., 2022). However, there is no evidence about the consequences of this condition on the behaviour of individual motor units (MUs), despite them being the effectors of the contractile stimulus coming from the nervous system via modulation of their recruitment and discharge activity. This study aimed to investigate whether MUs discharge rate (DR) differs between people living with T1D compared with a control (CON) group of people living without diabetes. Eight people with T1D (4M/4F, 30.50 ± 3.66 years, HbA1c of 8.31 ± 2.40%) without comorbidities and 8 age and sex-matched CON participants undertook the study. MUs DR was evaluated from the vastus lateralis muscle during trapezoidal submaximal isometric contractions with High-Density Electromyography at 20, and 40% of the maximum voluntary contraction (MVC) and DR modulation was defined as the difference between DR at recruitment (i.e., first 3 MUs firings) and DR during the steady-state phase of the contraction. Groups were compared for maximum torque (182.06 ± 47.65 Nm T1D and 171.99 ± 101.97 Nm Non-D). MUs DR was lower for those with T1D at recruitment and during the steady-state phase, both during contractions at 20 and 40% MVC (p&lt;0.05). MUs DR modulation was comparable between the two groups. In conclusion, reductions in MUs DR indicate initial alterations of MUs properties in people living with uncomplicated T1D when compared to CON counterparts. The reduced DR, however, was not accompanied by a reduced range of DR modulation (gain) and was not reflected in reduced force production. These findings suggest that initial alterations of MUs properties are present in people living with uncomplicated T1D and that these alterations are detectable before they become functionally manifest.

Disclosure
D.Minnock: Employee; Innovation Zed. G.Valli: None. R.Wu: None.