bluuebunny/crossref_metadata_2025_split huggingface dataset:
1628-P: Role of CD38 in the Regulation of Muscle Stem Cell Functions in Aged Mice
Authors: NAWAZ ALLAH , YAKU KEISUKE , JEELANI ISHTIAQ , TOBE KAZUYUKI , NAKAGAWA TAKASHI 
Published: June 2023

Skeletal muscle repair and regeneration is a complex process and is known to be delayed with aging, diabetes and obesity. This is in part due to infiltration of inflammatory macrophages which can delay the recovery process. Both macrophages and satellite cells require nicotinamide adenine dinucleotide (NAD+) for their biological functions. Aging-induced decline in NAD+ have been shown to worsen insulin resistance and muscle dysfunction. CD38 is an ectoenzyme that degrades NAD+ and is increased in inflammatory macrophages in aging, obesity and other insulin-resistant states. However, how inhibition of CD38 affects satellite cell functions in aged or obese mice, remains unknown. Here, we utilized aged CD38 knockout mice to assess the role of this protein and NAD+ in the recovery process in injured muscle. CD38 KO mice were found to be resistant to diet-induced obesity and had improved insulin sensitivity. Our data show that genetic deletion of CD38 in aged mice increased NAD+ levels and thus enhanced muscle stem/satellite cells differentiation and promote myogenesis. Deletion of CD38 also resulted in an enhanced number of regenerating myofibers. Furthermore, we found that deletion of CD38 significantly reduces fibrosis of muscle and also improved limb grip strength. Pharmacological inhibition of CD38 in C2C12 myoblasts and ex-vivo primary myoblasts significantly increased NAD+ levels and also enhanced the differentiation of satellite cells into myoblasts and myofibers. We, therefore, examined the rescue effects of 78c (CD38i) on human recombinant CD38 (hCD38) inhibition of muscle stem cells. Administration of hCD38 inhibited expression of MyoD and MyoG in primary myoblasts, while this effect was rescued through 78c treatment. Taken together, these data demonstrate that restoration of NAD+ levels either through genetic deletion/pharmacological inhibition of CD38 can improve muscle stem cell functions and muscle regeneration and might promote muscle regeneration in obesity, type 2 diabetes, and aging.

Disclosure
A.Nawaz: None. K.Yaku: None. I.Jeelani: 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. T.Nakagawa: None.
164-LB: Durable Improvement in HbA1c in Youth-Onset T2D—A Post Hoc Analysis of the DINAMO Trial of Empagliflozin and Linagliptin vs. Placebo
Authors: LAFFEL LORI M. , DANNE THOMAS , TAMBORLANE WILLIAM V. , KLINGENSMITH GEORGEANNA J. , NEUBACHER DIETMAR , TARTAKOVSKY IGOR , MARQUARD JAN , ZEITLER PHILIP , WILLI STEVEN M. 
Published: June 2023

The increasing prevalence of childhood overweight and obesity has led to a substantial increase in T2D in youth. The clinical course of youth-onset T2D is more aggressive than in adults, with a faster decline in beta‑cell function leading to worse glycemic control and an early onset of complications. The DINAMO trial compared the efficacy and safety of empagliflozin and linagliptin with placebo in 157 participants aged 10-17 years. Participants were randomized (1:1:1) to linagliptin 5 mg, empagliflozin 10 mg, or placebo. At Week 12, those in the empagliflozin group who did not attain HbA1c &lt;7.0% were re‑randomized (1:1) to empagliflozin 10 or 25 mg. Responders were defined as having no rescue medication and a HbA1c change from baseline ≤-0.5% or attained HbA1c &lt;7.0% at Week 26. Empagliflozin results were pooled. Significantly more participants responded to empagliflozin vs placebo (rate difference 23.6, 95% CI 4.3-41.4; p=0.01); this response was maintained to Week 52 by 40% of the group. Results for linagliptin vs placebo were not significant. Empagliflozin provided a clinically meaningful response even at higher HbA1c and FPG levels (Table). These results show that empagliflozin provides a clinically relevant, statistically significant, and durable improvement in glycemic control, suggesting SGLT2 inhibitors could be a new therapy for T2D in youth.

Disclosure
L. M. Laffel: Advisory Panel; Medtronic, Lilly Diabetes, Novo Nordisk, Vertex Pharmaceuticals Incorporated, Roche Diagnostics, Provention Bio, Inc., Consultant; Dexcom, Inc., Janssen Pharmaceuticals, Inc., Medscape. T. Danne: Research Support; Abbott Diabetes, AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk A/S, Sanofi, Medtronic, Stock/Shareholder; DreaMed Diabetes, Ltd. W. V. Tamborlane: None. G. J. Klingensmith: Advisory Panel; Boehringer Ingelheim Inc., Consultant; AstraZeneca, Boehringer Ingelheim Inc., Novo Nordisk, Takeda Pharmaceutical Co., Ltd. D. Neubacher: Employee; Boehringer Ingelheim Pharma GmbH&Co. KG. I. Tartakovsky: Employee; Boehringer Ingelheim International GmbH. J. Marquard: Employee; Boehringer Ingelheim Inc. P. Zeitler: Consultant; Eli Lilly and Company, Boehringer Ingelheim Inc., Johnson & Johnson. S. M. Willi: Advisory Panel; Boehringer Ingelheim International GmbH, Medtronic.

Funding
Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance
1644-P: Exercise and Caloric Restriction Exert Different Benefits on Metabolism and Mechanical Function of Skeletal Muscle in Aging Condition
Authors: THONUSIN CHANISA , PANTIYA PATCHARAPONG , NAWARA WICHWARA , ARUNSAK BUSARIN , SRIWICHAIIN SIRAWIT , CHATTIPAKORN NIPON , CHATTIPAKORN SIRIPORN C. 
Published: June 2023

Exercise and caloric restriction improve skeletal muscle metabolism. However, the benefits of exercise and caloric restriction on metabolism and mechanical function of skeletal muscle in aging condition have never been compared. Seven-week-old male Wistar rats (n = 24) were divided into 4 groups (n = 6 per group) to receive subcutaneous injection with either 1) normal saline solution as a vehicle for 28 weeks, 2) 150 mg/kg/day of D-galactose [D-gal] for 28 weeks to induce premature aging, 3) D-gal for 28 weeks and exercise for 16 weeks (week 13-28), and 4) D-gal for 28 weeks and 30% caloric restriction for 16 weeks (week 13-28). The 17-month-old male Wistar rats (n = 6) were subcutaneously injected with the vehicle for 28 weeks as the naturally aged control. At the end of week 28, whole-body substrate oxidation during vigorous physical activity, total walking distance, and fitness level were determined. Then, all rats were sacrificed to collect the tibialis anterior muscle for protein expression analyses and mass spectrometry-based metabolomics study. We found that skeletal muscle of D-gal successfully mimicked that of natural aging. Exercise and caloric restriction equally improved whole-body carbohydrate oxidation during vigorous physical activity, myogenesis, and amino acid metabolism in skeletal muscle. However, exercise was superior to caloric restriction in terms of improving fatty acid oxidation, oxidative phosphorylation, and mechanical function of skeletal muscle. Interestingly, caloric restriction decreased oxidative stress, whereas exercise increased oxidative stress in skeletal muscle. These findings suggested that the benefits of exercise and caloric restriction on metabolism and mechanical function of skeletal muscle in aging were different. Hence, either combined exercise and caloric restriction, exercise with antioxidant supplement, or caloric restriction with fatty acid oxidation enhancement is highly recommended.

Disclosure
C.Thonusin: None. P.Pantiya: None. W.Nawara: None. B.Arunsak: None. S.Sriwichaiin: None. N.Chattipakorn: None. S.C.Chattipakorn: None.
1654-P: Hepatic FGF21 Is Required for Curcumin and Resveratrol to Exert Their Metabolic Beneficial Effect in Male Mice
Authors: SHAO WEIJUAN , NUO FENG JIA , JIN TIANRU 
Published: June 2023

Intensive investigations have shown the profound metabolic beneficial effect of dietary intervention with plant polyphenols including curcumin and resveratrol. Recent studies have also shown that hepatic FGF21 is among the targets of dietary polyphenol intervention as well as intermittent fasting or nutritional restriction. Here we assessed whether hepatic FGF21 is required for dietary polyphenol intervention on metabolic homeostasis in mice on high fat high fructose diet (HFHF) challenge. Liver specific FGF21 null mice (Lfgf21-/-) were generated by mating Alb-Cre mice with Fgf21fl/fl mice. No appreciable defect on glucose disposal was observed in male or female Lfgf21-/- mice when they were fed with regular chow diet. In chow diet fed male but not female Lfgf21-/- mice, fat tolerance was impaired, associated with elevated fasting plasma TG level and reduced hepatic expression of Ehhadh and Ppargc1 (two downstream targets of FGF21). Following HFHF challenge, the control Fgf21fl/fl male mice exhibited response to 12-week curcumin intervention on reducing body weight, serum and hepatic TG elevation, and on improving fat tolerance. Those beneficial effects were absent in male Lfgf21-/- mice. In high fat diet challenged wild type mice, concomitant resveratrol intervention exhibited anticipated metabolic beneficial effect, associated with increased hepatic FGF21 mRNA and protein expression. Importantly, the metabolic beneficial effects of resveratrol intervention were observed in HFHF challenged Fgf21fl/fl mice but not in Lfgf21-/- mice. In wild type or transgenic female mice, we did not see appreciable beneficial effect with resveratrol intervention. Together we introduced a transgenic mouse model into the investigation of metabolic function of dietary intervention. We conclude that hepatic FGF21 is required for curcumin or resveratrol to exert its beneficial effect in male mice.

Disclosure
W.Shao: None. J.Feng: None. T.Jin: None.

Funding
Canadian Institutes of Health Research
1655-P: GLP-1R Is Required for Resveratrol in Exerting Its Metabolic Beneficial Effect in HFD-Challenged Male Mice
Authors: NUO FENG JIA , SHAO WEIJUAN , JIN TIANRU 
Published: June 2023

The beneficial effects of dietary polyphenols including resveratrol have been elucidated during the past 2-3 decades, yet the mechanism underlying their metabolic functions remains elusive or even controversial. Recent investigations revealed that hepatic hormone FGF21 is the common target for both GLP-1RAs and dietary polyphenol intervention. Here we utilized wild type (WT) and GLP-1R-/- mice to access whether GLP-1R is required for resveratrol to exert its beneficial effects. In WT male mice with HFD challenge, concomitant resveratrol intervention (REV-I) for 12 weeks reduced body weight gain and improved glucose tolerance, while in male GLP-1R-/- mice, such metabolic effects were lost. In WT mouse liver and epididymal white adipose tissue (eWAT), REV-I ameliorated HFD-induced FGF21 resistant and stimulated a battery of genes that are involved in lipid homeostasis. In addition, HFD-induced alterations on expressions of a battery of adipose tissue specific genes including those encode for leptin and adiponectin were reversed by concomitant REV-I. REV-I was also shown to exert anti-inflammatory effects in the ileum of WT mice fed with HFD. Specifically, genes that encode for a battery of pro-inflammatory markers including IL-1β and IFN-γ were significantly elevated by HFD challenge, while REV-I attenuated their expression. HFD challenge also reduced IL-10 mRNA level in the WT mouse ileum, while REV-I restored the expression. Together, we bring a novel player GLP-1R to explore the mechanism underlying the metabolic functions of resveratrol. Collectively, we conclude that the metabolic beneficial effects of resveratrol on reducing body weight gain and improving glucose disposal require GLP-1R.

Disclosure
J.Feng: None. W.Shao: None. T.Jin: None.

Funding
Canadian Institutes of Health Research
1658-P: Rectal Hyposensitivity, a Potential Marker of Enteric Autonomic Nerve Dysfunction, Is Significantly Associated with Gastrointestinally Mediated Glucose Disposal in Persons with Type 2 Diabetes
Authors: MELING SONDRE , TJORA ERLING , EJSKJAER NIELS , CARLSEN SIRI , KNOP FILIP K. , RASMUS NJØLSTAD PÅL , BROCK CHRISTINA , NEDERGAARD RASMUS B. , SØFTELAND EIRIK 
Published: June 2023

The incretin effect in type 2 diabetes is reduced, but the mechanisms behind are uncertain. We hypothesized that the incretin effect associates with degree of enteric autonomic nerve dysfunction and evaluated gastrointestinally mediated glucose disposal (GIGD), as a proxy for the incretin effect, and rectal sensitivity to mechanical distension representing afferent gut signalling. Sixty-six participants with either 1) longstanding type 2 diabetes, 2) newly onset (&lt;1 year), medically untreated diabetes, or 3) healthy controls, underwent a 75 g oral glucose tolerance test (OGTT) and an intravenous isoglycemic glucose infusion to determine GIGD. Earliest sensation to rectal rapid balloon distention was determined as a proxy for autonomic neuropathy. Compared to controls (59.3±14.4%), GIGD was reduced in both early (36.4±14.7%) and longstanding diabetes (17.4±22.3%), with significant difference between all three groups (P&lt;0.01). Both groups of diabetes needed higher pressure during rapid rectal balloon distention (3.7±1.1 kPa for longstanding diabetes, 4.0±1.3 for early diabetes), compared to controls (3.0±0.9 kPa, P&lt;0.01), with no significant difference between the two diabetes groups. GIGD was inversely correlated with pressure at earliest sensation (rho 0.341, P&lt;0.01). For those needing a pressure between 1 and 3 kPa and between 4 and 7 kPa, respectively, GIGD was 46.2%±24.9 and 34.4±23.9% (P=0.05). GIGD was inversely and significantly correlated with glucose values during OGTT, with strongest correlation to the 90-minute value (rho 0.873, P&lt;0.01), and HbA1c (rho 0.653, P&lt;0.01). We show that the degree of rectal hyposensitivity correlates with reduced GIGD and confirm that GIGD correlates with the degree of dysglycemia. These results warrant further studies on the potential role of gut autonomic dysfunction in the reduced incretin effect characterizing type 2 diabetes.

Disclosure
S.Meling: Consultant; Novo Nordisk, Lilly, AstraZeneca, Boehringer-Ingelheim, Sanofi. E.Tjora: None. N.Ejskjaer: None. S.Carlsen: None. F.K.Knop: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Research Support; Novo Nordisk, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Lundbeck. P.Njølstad: None. C.Brock: Research Support; Abbott, ElectroCore. R.B.Nedergaard: Other Relationship; Grünenthal Group. E.Søfteland: None.

Funding
Helse Vest, Norway (F-11637/4800002072); Johan Selmer Kvanes Legat (Legacy)
1662-P: The Bidirectional Relationship of Fibroblast Growth Factor 23 and Glucose Homeostasis
Authors: VAN DER VAART AMARENS , EELDERINK COBY , VAN BEEK ANDRÉ , BAKKER STEPHAN J. , VAN DIJK PR , DE BORST MARTIN 
Published: June 2023

Objective: To investigate potential cross-talk between the phosphate-regulating hormone fibroblast growth factor 23 (FGF23) and glucose homeostasis.
Research Design and Methods: First, we investigated the effect of glucose loading on plasma FGF23 and its temporal relationship with changes in plasma phosphate (0-15-30-45-60-75-90-120-150-180-240-300-360-420-480 minutes) in 45 overweight (BMI 25-30) subjects using time-lag analyses. Second, we studied cross-sectional associations of plasma FGF23 with glucose homeostasis using multivariable linear regression in a population-based cohort. We also investigated associations of FGF23 with incident diabetes and obesity (BMI &gt;30 kg/m2) in individuals without diabetes or obesity at baseline, respectively, using multivariable Cox regression analyses. Finally, we explored whether the association between FGF23 and diabetes depends on BMI.
Results: After glucose loading, changes in FGF23 preceded changes in plasma phosphate (Ptime-lag=0.04). In the population-based cohort (N=5482; mean age 52 yrs, 52% women, median FGF23 69 RU/mL), FGF23 was associated with plasma glucose (est. β 0.13[0.03-0.23], P=0.01), insulin (est. β 0.10[0.03-0.17], P&lt;0.001), and proinsulin (est. β 0.06[0.02-0.10], P=0.01) at baseline. Upon longitudinal analyses, a higher baseline FGF23 was independently associated with the development of diabetes (199 events (4%); fully adjusted HR 1.66[95% CI 1.06-2.60], P=0.03) and development of obesity (241 events (6%); fully adjusted HR 1.84[1.34-2.50], P&lt;0.001). The association between FGF23 and incident diabetes lost significance after additional adjustment for BMI.
Conclusions: Glucose loading has phosphate-independent effects on FGF23; vice versa, FGF23 is associated with glucose, insulin, proinsulin levels and obesity. These findings suggest deleterious cross-talk between FGF23 and glucose homeostasis, which may promote susceptibility to incident diabetes.

Disclosure
A.Van der vaart: None. C.Eelderink: None. A.Van beek: Advisory Panel; Novo Nordisk, Consultant; Novo Nordisk. S.J.Bakker: None. P.Van dijk: None. M.De borst: None.
167-OR: Significant Differences in DKA Outcomes across Hospitals Despite Same Guidelines Highlights the Need for Better Implementation Strategies—Results from DEKODE Initiative
Authors: KEMPEGOWDA PUNITH , RENGARAJAN LAKSHMI , NARENDRAN PARTH , TEAM DEKODE 
Published: June 2023

Aim: To measure differences in DKA care and outcomes between hospitals having same guidelines.
Method: The data was gathered as part of the DEKODE (Digital Evaluation of Ketosis and Other Diabetes-related Emergencies) initiative from October 2021 to September 2022 in six hospitals (anonymised as A to F) in the UK which has guidelines based on Joint British Diabetes Societies-Inpatient (JBDS-IP) recommendations. We collected data on adherence to Fixed Rate Intravenous Insulin Infusion (FRIII), fluids administration, glucose monitoring, and ketones monitoring. Pseudonymised data on dates and times of admission, discharge, DKA diagnosis and resolution was collected. Independent-Samples Kruskal-Wallis test was performed to assess differences in various parameters of DKA care and outcomes.
Results: A total of 442 DKA episodes were analysed. There were differences between hospitals in fluids administration (median: A-92.1%, B-101.3%, C-89.7%, D-76.0%, E-98.3%, F-115.5%; p&lt;0.001), glucose monitoring (median: A-103.1%, B-86.1%, C-88.9%, D-106.4%, E-99.2%, F-95.7%; p&lt;0.001), and ketone monitoring (median: A-71.5%, B-85.1%, C-70.0%, D-59.3%, E-65.0%, F-85.7%; p&lt;0.001). There was no significant difference in FRIII (median: A- 99.5%, B- 100.0%, C- 100.0%, D- 100.0%, E- 93.9%, F- 99.8%; p=0.064). We found inter-hospital differences in DKA duration (median in hours; A-13.3, B-13.4, C-18.5, D-15.1, E-17.1, F-16.3; p=0.002), and length of stay (median in days; A-2.1, B-2.5, C-3.5, D-3.6, E-2.5, F-3.0; p&lt;0.001).
Conclusion: Despite similar guidelines, significant variations in DKA outcomes exist between hospitals. Variations in various components of DKA highlight there may be differences in guidelines implementation. A centralised data collection system can identify and share best practices between centres, which may help minimise inter-hospital variations and facilitate uniform patient care.

Disclosure
P.Kempegowda: None. L.Rengarajan: None. P.Narendran: Advisory Panel; Omnipod, Speaker's Bureau; Abbott Diabetes, Lilly Diabetes. Dekode team: n/a.
1674-P: Increased Glucose Uptake in Brown Fat Promotes Energy Expenditure
Authors: REZAYAT FARID , RESNICK JULIE A. , FARAH ISABELLA M. , SKOROBOGATKO YULIYA , SALTIEL ALAN 
Published: June 2023

Brown and beige fat dissipate energy as heat in response to β3-adrenergic receptor (β3AR) stimulation. Strategies to facilitate this response may be employed to promote weight loss and improve health in patients with metabolic disease. Previously, we discovered that GTPase RalA and its GAP complex RalGAP regulate exocytosis of glucose transporter GLUT4. We demonstrated in vivo, that adipose-tissue specific knockout of RalGAP subunit RalGAPB activates RalA and increases glucose uptake 7 times in brown fat (BAT), leading to improved glucose handling on high fat diet (HFD). Here we seek to test the effect of increased glucose uptake in BAT on energy expenditure (EE), using mice with BAT-specific knockout of RalGAPB (the KO mice).
After 8 weeks on 45% HFD, the KO mice and control littermates (Ctr) were injected with β3AR agonist CL-316,243 (CL) or PBS for 8 days. Mice assigned to CL were placed in metabolic cages. Respiratory quotient was increased in the KO mice, indicating increased glucose oxidation (likely by BAT, due to increased glucose uptake). EE at room temperature was elevated in the KO mice. This was compensated by increased food uptake, explaining similar body weights between the KO and Ctr mice. CL injections, as expected, induced spikes in EE. Acute response to CL (arbitrarily defined as EE during 2 hours after CL injection) was consistent between daily CL injections in Ctr mice, and was increased twice in the KO mice compared to Ctr. In Ctr mice, 1st CL injection increased average day and night EE; this response gradually declined with consecutive CL injections. In the KO mice, 1st CL injection elicited similar to Ctr mice increase in average day and night EE; and the response to consecutive CL injections was preserved. As anticipated, CL reduced adiposity in Ctr mice, which was further augmented in the KO mice, consistent with finding on EE. We will further test the role of increased glucose uptake by BAT in EE of the KO mice, and will determine the mechanism of sustained CL responsiveness in the KO mice.

Disclosure
F.Rezayat: None. J.A.Resnick: None. I.M.Farah: None. Y.Skorobogatko: None. A.Saltiel: Board Member; Elgia Therapeutics.

Funding
National Institutes of Health (P30DK063491)