bluuebunny/crossref_metadata_2025_split huggingface dataset:
159-LB: Circulating MicroRNAs as Predictors of ß-Cell Function in Youth Onset Type 2 Diabetes—The TODAY Study
Authors: TRYGGESTAD JEANIE B. , BIALEK SHANNAN , REDLING DAKOTA , CHERNAUSEK STEVEN , EL GHORMLI LAURE 
Published: June 2023

In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, half the participants reached the primary outcome (HbA1c≥8% for at least 6 months) within 4 years which was associated with a decrease in C-peptide oral disposition index (oDI). We aimed to identify circulating miRNA species associated with β cell function decline. Following a preliminary survey of select participants using nCounter Human v3 miRNA Panel (NanoString Technologies), polymerase chain reaction validations were carried out for 17 miRNAs from 365 participants with samples at baseline, 24, 60, 96, and 120 months. During the first 6 months in TODAY, 150 (43%) of the participants (mean age 14 years at baseline and diabetes duration &lt;2 years) had a ≥20% decrease in C-peptide oDI. Using backward elimination modeling and adjusting for demographic characteristics, three baseline miRNA log2 fold changes remained significant predictors of this C-peptide oDI decline ≥20% (p&lt;0.05). Increased levels of miR-155 (OR:1.21, 95%CI:1.07-1.38) and miR-130b (OR:1.32, 95%CI: 1.02-1.70) were associated with oDI decline, while decreased levels of miRNA-126 (OR:0.60, 95%CI: 0.44-0.81) were associated with oDI decline. miR-122 was negatively correlated with C-peptide oDI at baseline and 24-months (R=0.22, p&lt;0.01 and R=0.19, p&lt;0.01, respectively), and positively correlated with proinsulin, at baseline, 24-, and 60-months (R=0.26, p&lt;0.01, R=0.26, p&lt;0.01, R=0.18, p&lt;0.01, respectively). These miRNA species are associated with alterations in β cell insulin secretion and apoptosis targeting pyruvate dehydrogenase, glucokinase, and GLI-similar zinc finger proteins, suggesting that differences in baseline abundance may serve as circulating markers of β cell dysfunction, providing potential mechanistic insights into the aggressive nature of youth-onset type 2 diabetes.

Disclosure
J. B. Tryggestad: None. S. Bialek: None. D. Redling: None. S. Chernausek: Advisory Panel; Ascendis Pharma A/S. L. El ghormli: None.

Funding
National Institutes of Health (5U01DK061230-16)
159-OR: Greater Sleep Variability Is Associated with Less Time in Range of Glucose Levels in Patients with Type 1 Diabetes
Authors: MARTYN-NEMETH PAMELA , ABU IRSHEED GHADA , PARK MINSUN , STEFFEN ALANA D. , BURKE LARISA , PRATUANGTHAM SARIDA , BARON KELLY , DUFFECY JENNIFER , PEREZ ROSANNE , QUINN LAURIE T. , CLARK WITHINGTON MEG , SALEH ADAM H. , LOIACONO BERNARDO , MIHAILESCU DAN , REUTRAKUL SIRIMON 
Published: June 2023

Background: Sleep and circadian disturbances emerge as novel factors influencing glycemic control in type 1 diabetes (T1D). We aimed to explore the associations between sleep, behavioral circadian parameters, self-care, and glycemic parameters in T1D.
Methods: Baseline data of 76 non-shift working adult T1D patients participating in a randomized study to optimize sleep health (NCT04506151) were analyzed. Glycemic assessments were derived from blinded 7-day continuous glucose monitoring (CGM) and A1C. Percentages of time-in-range (TIR of glucose levels between 70-180 mg/dL) and %CV were calculated from CGM. Sleep was recorded using 7-day actigraphy, yielding sleep duration and efficiency. Variability (SD) of mid-sleep time (MST) was used to represent sleep variability. Non-parametric behavioral circadian variables were derived from actigraphy activity recordings. Self-care was measured by the Diabetes Self-Management Questionnaire (DSMQ-R). Multiple regression analyses were performed to identify independent predictors of glycemic parameters.
Results: Mean (SD) age was 36.3 (11) years, 48 (63.2%) female, and median (IQR) A1C 6.8% (6.2, 7.4). Sleep duration, efficiency, and non-parametric behavioral circadian variables were not associated with glycemic parameters. After adjusting for age, sex, insulin delivery mode/CGM use, and ethnicity, each hour increase in SD of MST was associated with 9.64 % less TIR (B= -9.64, 95% (CI) [-16.29, -2.99], p=&lt;0.001). Higher DSMQ score was an independent predictor of lower A1C (B = -0.18, 95% CI -0.32, -0.04).
Conclusion: Greater sleep variability is independently associated with less time spent in desirable glucose range in this modern T1D cohort, with clinically important effect sizes. Sleep optimization to reduce variable sleep schedule could potentially lead to improved metabolic control and should be explored in future research.

Disclosure
P.Martyn-nemeth: None. L.T.Quinn: None. M.Clark withington: None. A.H.Saleh: None. B.Loiacono: None. D.Mihailescu: None. S.Reutrakul: Speaker's Bureau; Eli Lilly and Company. G.Abu irsheed: None. M.Park: None. A.D.Steffen: None. L.Burke: None. S.Pratuangtham: None. K.Baron: Other Relationship; National Sleep Foundation, Research Support; Google. J.Duffecy: Consultant; Chorus Health, K Health, Stock/Shareholder; Healent Health, My Alloy. R.Perez: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK121726)
1592-P: Evaluating Metabolic Effects of Nicotinamide Riboside on Hepatic Substrate Metabolism in CDAA-Induced NAFLD Mice
Authors: SHEN QINGYANG , PUGMIRE JACKSON K. , SUWANNASUAL USA , MAPTUE NESMINE R. , KHEMTONG CHALERMCHAI 
Published: June 2023

Nonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance and altered hepatic energy metabolism, with imbalanced glucose and lipid metabolism. Nicotinamide riboside (NR) has recently emerged as a potential therapeutic for a broad range of metabolic abnormalities. Here, we evaluate the effect of NR treatment on hepatic substrate metabolism in mice with NAFLD. NAFLD was induced by feeding the animals with a choline-deficient, amino acid-define (CDAA) diet for 4 weeks. Mice (C57BL/6) in the NR treatment group (CDAA+NR) were then put on a NR-containing CDAA diet for 10 weeks while the non-treated animals remained on CDAA. Both groups of animals had similar food consumption and weight gain rates, with comparable liver-to-body weight ratios. At the conclusion of the treatment, isolated livers were perfused via the portal vein with 13C metabolic tracers, i.e. 5.5 mM [1,6-13C]glucose + 0.4 mM [U-13C]long chain fatty acids (LCFA) suspended in bovine serum albumin. Fractional substrate oxidations and flux analyses were done using 13C nuclear magnetic resonance (NMR) spectroscopy. An increasing trend of oxygen consumption rates was observed as a result of NR treatment (1.50±0.43 µmol/min/liver) compared to the CDAA-treated group (0.68±0.15 µmol/min/liver). However, the increase is not statistically different. 13C NMR isotopomer flux analyses revealed that pyruvate dehydrogenase flux relative to citrate synthase flux are comparable across the 2 groups (CDAA: 30±4%; CDAA+NR: 33±10%). No changes in fractional oxidation of 13C-long-chain fatty acids and 13C-glucose were observed as a result of nicotinamide riboside treatment, with 44±2% and 48±3% of Ac-CoA derived from 13C-LCFA in CDAA and CDAA+NR livers, respectively. 13C-glucose contributed as a minor source of Ac-CoA (~4-5%) in both groups. These findings suggest that nicotinamide riboside treatment did not affect substrate, fats vs glucose, utilization in CDAA-induced NAFLD mouse livers.

Disclosure
Q. Shen: None. J.K. Pugmire: None. U. Suwannasual: None. N.R. Maptue: None. C. Khemtong: None.

Funding
University of Florida
1594-P: Interorgan Insulin-Leptin Signal Cross Talk Originating in the Liver Enhances Survival under Food-Shortage Conditions
Authors: TAKAHASHI KEI , YAMADA TETSUYA , KATAGIRI HIDEKI 
Published: June 2023

The liver can store energy and distribute it to other tissues/organs, according to the energy states involving hepatic insulin action. In addition, we and others have shown that the liver transmits metabolic information to other organs, via neuronal and humoral mechanisms. Herein, we demonstrate a novel form of inter-organ crosstalk originating in the liver, which links hepatic insulin action with hypothalamic leptin signaling and promotes survival during food shortage. We first observed that tamoxifen-inducible liver insulin receptor (IR) knockout (iLIRKO) mice ate more and consumed less oxygen with decreased hypothalamic leptin action, thereby gaining body weight. Circulating soluble leptin receptor (sLepR) levels were elevated in iLIRKO mice. We then produced tamoxifen-inducible liver leptin receptor (LepR) and IR double-knockout (iLLepRIRKO) mice. In iLLepRIRKO mice, sLepR elevations were not seen. Moreover, increased body weights, hyperphagia and decreased whole-body oxygen consumption seen in iLIRKO mice were reversed, indicating the importance of hepatic sLepR production in the liver-hypothalamus crosstalk. Human hepatic lepr and circulating sLepR levels also correlated negatively with hepatic insulin action indices. Additionally, we restricted food intake in wild type mice. Food restriction decreased hepatic insulin action and whole-body oxygen consumption with increased circulating sLepR. We furthermore performed food restriction in tamoxifen-inducible liver LepR knockout (iLLepRKO) mice. Notably, in iLLepRKO mice, the decreases in basal metabolic rates were blunted and mortality was markedly increased during food restriction. Collectively, the liver translates metabolic cues regarding energy-deficient status, which is reflected by decreased hepatic insulin action, into sLepR, thereby suppressing energy dissipation. This novel inter-organ crosstalk may assure survival of individuals facing food shortages in nature.

Disclosure
K.Takahashi: Speaker's Bureau; Taisho Pharmaceutical Holdings Co., Ltd. T.Yamada: Speaker's Bureau; MSD, Mitsubishi Tanabe Pharma Corporation, Eli Lilly Japan K.K., Boehringer Ingelheim Japan, Inc., Novo Nordisk, Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Abbott Japan Co., Ltd. H.Katagiri: None.

Funding
Japan Society for the Promotion of Science (21K08522, 22H03126, 20H05694); Japan Science and Technology Agency (JPMJPS2023)
1595-P: Empagliflozin Improves Nephropathy and Heart Failure with Preserved Ejection Fraction Despite Limited Effects on NASH in a Novel Obese Diabetic Hamster Model
Authors: BRIAND FRANCOIS , DUBROCA CAROLINE , SULPICE THIERRY 
Published: June 2023

Introduction: Sodium-glucose cotransporter 2 inhibitor empagliflozin (EMPA) has shown significant benefits for patients with diabetic nephropathy and heart failure with preserved ejection fraction (HFpEF), but the effects on nonalcoholic steatohepatitis (NASH) and liver fibrosis remain unclear. To further investigate the benefits of EMPA on these comorbidities, we established a novel diet-induced obese diabetic hamster model with human-like NASH and lipoprotein cholesterol metabolism, that also develops nephropathy and HFpEF.
Methods: Obesity, NASH, and HFpEF were induced with a 20-week free choice diet, which presents hamsters with a choice between control chow or high fat/cholesterol diet, and normal water or 10% fructose water. After 20 weeks of diet, obese hamsters were intraperitoneally injected with streptozotocin (STZ) to induce diabetes and were then treated orally once daily for 5 weeks with vehicle or EMPA 30mg/kg.
Results: Compared with vehicle, EMPA reduced hyperglycemia (vehicle: 373 +/- 43 mg/dL; EMPA: 182 +/- 30 mg/dL, p&lt;0.01), increased pancreatic insulin content (+146%, p&lt;0.05), significantly reduced plasma triglycerides and moderately raised LDL-cholesterol levels, as expected. However, EMPA did not improve NASH (including hepatocyte ballooning score) and liver fibrosis. EMPA reduced glomerular filtration rate and proteinuria (p=0.06 for both vs. vehicle), and significantly reduced urine albumin-to-creatinine ratio (-35%, p&lt;0.01). In addition, EMPA showed significant improvement in HFpEF with reduced E/A and E’/E ratios with no alteration in ejection fraction, as measured by echocardiography.
Conclusion: EMPA improves kidney parameters and HFpEF despite limited effects on NASH in obese diabetic hamsters. This preclinical model with multiple comorbidities will be useful to evaluate the combination of EMPA or other antidiabetic therapies with drugs targeting NASH.

Disclosure
F. Briand: Employee; PHYSIOGENEX. Stock/Shareholder; PHYSIOGENEX. C. Dubroca: Employee; CARDIOMEDEX. T. Sulpice: Employee; PHYSIOGENEX. Stock/Shareholder; PHYSIOGENEX. Employee; CARDIOMEDEX. Stock/Shareholder; CARDIOMEDEX.
1597-P: KCNH6 Regulates Hepatic Mitochondrial Function and Glucose Metabolism via NF-κB Pathway
Authors: ZHAO RUXUAN , LU JING , XIONG FENGRAN 
Published: June 2023

KCN, a human ether-a-go-go-related gene, encodes KCN ion channel in the Kv11 family, which ranks 11th in abundance among different ion channel families. KCNH6, a subfamily of KCN potassium channel family, has been proven to affect glucose metabolism and insulin secretion both in humans and mice. However, the precise function of KCNH6 in the liver remains unknown. In this study, we showed that knockout (KO) of Kcnh6 impairs mitochondrial function and insulin tolerance as well as promotes high-fat-diet-induced insulin resistance. In line, overexpression of Kcnh6 in hepatocytes ameliorates fatty acid oxidation, mitochondrial respiration, and the abundance of mitochondrial respiratory complexes ameliorating insulin resistance. Similarly, induction of Kcnh6 by tail vein injection into KO mice decreased insulin tolerance. Mechanistically, Kcnh6 improved mitochondrial function and insulin secretion via the the NFκB-IκB kinase (IKK) pathway both in vitro and in vivo. Therefore, we suggest Kcnh6 as a potential novel therapeutic target to treat hepatic energy metabolism and mitochondrial dysfunction and insulin resistance.

Disclosure
R.Zhao: None. J.Lu: None. F.Xiong: None.
1598-P: MIF-upregulated CD74 in Liver Contributes to the Development of NAFLD
Authors: CHEN LIUJUN , LI LISHA , HUANG YIHENG , CHEN XI , QI YADAN , TONG HAIBIN , WU HONG , QI DAKE 
Published: June 2023

Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic dysfunctions, such as obesity. Macrophage migration inhibitory factor (MIF), a pro-cytokine, was also identified to regulate NAFLD, but the molecular mechanisms remain unclear. We presently indicated that MIF has a non-inflammatory effect on triggering NAFLD through upregulating its cell membrane receptor, CD74. MIF increased CD74 protein rather than gene expression in liver cells in a time-dependent manner. That was not associated with any changes in the expression of pro-inflammatory factors, such as TNF-α, IL-6 and IL-1β. In a MIF overexpressed animal model (Mif lung Tg), high circulating MIF levels increased hepatic CD74 proteins but not genes in the absence of inflammation in the liver. High fat diet also increased circulating MIF levels leading to an upregulation of hepatic CD74. All these animal models with high circulating MIF and hepatic CD74 were accompanied with steatosis and fibrosis in the liver. These alterations could be reversed by either MIF neutralization or MIF knockout. Caspase 4 facilitates the degradation of CD74. MIF endocytosis inhibited caspase 4 cleavage and activation. Thus, inhibition of MIF upregulated cleaved caspase 4 leading to a degradation in CD74. Overall, our findings indicate that MIF stabilizes CD74 through suppressing caspase 4 and this may be an important mechanism in regulating NAFLD in the absence of inflammation.

Disclosure
L. Chen: None. L. Li: None. Y. Huang: None. X. Chen: None. Y. Qi: None. H. Tong: None. H. Wu: None. D. Qi: None.

Funding
Canadian Institutes of Health Research (PJT156116); Research and Development Corporation; National Sciences and Engineering Research Council of Canada (RGPIN-2017-04542); National Institutes of Health (AR-078334); China Scholarship Council (to L.C., Y.H., L.L.)
16-LB: Teneligliptin Observational Retrospective Real-World Study to Evaluate Its Effect on Renal Parameters and Safety in Indian Type 2 Diabetes Mellitus Patients with Chronic Kidney Disease (TOP RENAL)
Authors: SURYAWANSHI SACHIN , JADHAO VIBHUTI , BRID MANASI , BHUSHAN SUMIT , BARKATE HANMANT V. 
Published: June 2023

Background and Aim: Teneliglitpin, approved in India since 2015, is the most commonly prescribed DPP4i in India. Due to lack of evidence, this study was planned in real world setting to evaluate effects of teneligliptin on renal parameters and safety in Indian T2DM patients with CKD.
Methodology: TOP RENAL real world study enrolled T2DM patients with eGFR ≤60 to ≥15 ml/min/1.73m2 and were started on teneligliptin (20/40 mg OD) and continued it for next six months. Those patients prescribed any antidiabetic medication along with teneligliptin or those with change in antidiabetic prescription in the following six months were excluded.
Results: 377 patients data was collected during August'22-October'22 and grouped according to baseline eGFR (ml/min/1.73m2): G3a: 45-59 (n=102); G3b: 30-44 (n=124); G4: 15-29 (n=151). The mean age was 59.86±9.58 years and 47% were females. Renal parameters: eGFR, Sr creatinine and BUN were assessed at baseline, 3 months and 6 months. Results showed non-significant changes in eGFR (Table1), Sr. creatinine and BUN at 3 and 6 months in all three groups. No safety concerns or hypoglycemia were reported during the study.
Conclusion: Teneligliptin initiation in Indian T2DM patients with mild-severe renal impairment did not show any safety concerns and was well tolerated.

Disclosure
S. Suryawanshi: Employee; Glenmark Pharmaceuticals. V. Jadhao: Employee; Glenmark Pharmaceuticals. M. Brid: Employee; Glenmark Pharmaceuticals. S. Bhushan: None. H. V. Barkate: None.

Funding
Glenmark Pharmaceuticals Limited
160-LB: Circulating MicroRNAs as Predictors of Microvascular Complications in Youth Onset Type 2 Diabetes—The TODAY Study
Authors: REDLING DAKOTA , BIALEK SHANNAN , CHERNAUSEK STEVEN , EL GHORMLI LAURE , TRYGGESTAD JEANIE B. 
Published: June 2023

From the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, 60% of the participants demonstrated diabetes-related complications by 10 years. We aimed to identify circulating microRNA (miRNA) species associated with microvascular disease in TODAY participants with youth-onset type 2 diabetes. Using nCounter Human v3 miRNA Panel (NanoString Technologies) to identify relevant miRNAs in two groups of participants who lost glycemic control and either developed microvascular complications during follow-up (n=6) or not (n=11), 53 miRNA species were differentially expressed at baseline (p&lt;0.05) and 2 at the end of study visit (p&lt;0.05). Polymerase chain reaction validations were carried out for 17 miRNAs from 365 participants with samples obtained at baseline, 24, 60, 96, and 120 months. During follow-up, 250 (68%) of the participants (mean 14 years old and diabetes duration &lt;2 years at entry) developed at least one microvascular complication. Using backward elimination modeling and adjusting for demographic characteristics, a set of four baseline miRNA log2 fold changes remained significant predictors of microvascular complications (p&lt;0.05). Increased levels of miR-122 (OR:1.17, 95%CI:1.03-1.32) and miR-221 (OR:1.51, 95%CI: 1.51-1.98) were associated with higher risk of complication, while increased levels of miRNA-let 7g (OR:0.75, 95%CI: 0.60-0.94) and miRNA-130a (OR:0.82, 95%CI: 0.68-0.99) were associated with lower risk of complication. miR-122 abundance was also positively correlated with urine albumin/creatinine ratio at baseline and 24-months (R=0.11, p=0.041 and R=0.16, p=0.005, respectively). The alterations in miR-122, 221, 130a, and let 7g in circulation are all consistent with in vitro alterations that promote endothelial dysfunction suggesting that these early alterations in circulation may predict those at highest risk of microvascular disease in the future.

Disclosure
D. Redling: None. S. Bialek: None. S. Chernausek: Advisory Panel; Ascendis Pharma A/S. L. El ghormli: None. J. B. Tryggestad: None.

Funding
National Institutes of Health (5U01DK061230-16)
1608-P: Phenotype of Liver-Specific MC3R Knockout Mice
Authors: CHEN JOCELYN , PATEL TUSHAR P. , JAIN ARAD , ELIZONDO DIANA , ALTMAN ELIZABETH K. , TUGARINOV NICOL , HOLLIS MELANIE , ROBERSON ROBIN , CARON ALEXANDRE , ELMQUIST JOEL K. , YANOVSKI JACK A. 
Published: June 2023

The melanocortin 3 receptor (MC3R) is a key regulator of energy homeostasis and feeding behavior. Global Mc3r knockout mice exhibit greater fat mass and reduced lean mass. Our previous research has found that Mc3r transcripts can be detected in liver and the MC3R deficiency phenotype is partially reversed in liver-specific MC3R recovery mice on a chow diet, in both male and female mice, and high fat diet, in females only. To further examine the role of hepatic MC3R, we produced a liver-specific Mc3r knockout model by crossing mice expressing albumin-Cre recombinase (Alb-Cre+/+) to mice with a floxed Mc3r gene (LoxP+/+), and placed them on a 45 kcal% energy from fat diet for 12 weeks. Female liver-specific Mc3r-deficient mice with diet-induced obesity displayed nonsignificant trends towards worsened glucose tolerance during a glucose tolerance test (glucose AUC Lox+/+, Alb-Cre+/+: n=10, 24036±1644; Alb-Cre+/+: n=10, 19745±1364; BL/6: n=11, 21072±1152 min*mg/dL, p=0.059) and insulin resistance during a glucose tolerance test (glucose AUC LoxP+/+, Alb-Cre+/+: n=10, 14938±812.2;Alb-Cre+/+: n=14, 13062±850; BL/6: n=11, 11725±1024 min*mg/dL, p=0.12), but no differences in morning serum C-peptide (LoxP+/+, Alb-Cre+/+: n=8, 0.74±0.07; Alb-Cre+/+: n=4, 0.55±0.15; BL/6: n=8, 0.29±0.05 ng/mL, p=0.32). Similar patterns were observed for total food consumption (LoxP+/+, Alb-Cre+/+: n=10, 37.2±1.2; Alb-Cre+/+: n=15, 34.5±0.7; BL/6: n=10, 35.7±1.4 g/15 days, p=0.082), with no differences in feeding efficiency (LoxP+/+, Alb-Cre+/+: n=10, 0.027±0.008; Alb-Cre+/+: n=15, 0.009±0.011; BL/6: n=10, 0.017±0.025 g/kcal, p=0.19). No notable trends were observed in male mice. These data suggest that hepatic Mc3r deficiency alone is at most a minor contributor to the obesity phenotypes associated with HFD-treated Mc3r-deficient mice. Additional analysis of tissue samples from these mice and future studies examining Mc3r function in the liver will further elucidate the role of hepatic MC3R.

Disclosure
J.Chen: None. J.K.Elmquist: Research Support; Regeneron Pharmaceuticals Inc. J.A.Yanovski: Research Support; Hikma Pharmaceuticals, Rhythm Pharmaceuticals, Inc., Soleno Therapeutics, Inc., Versanis Bio Inc. T.P.Patel: None. A.Jain: None. D.Elizondo: None. E.K.Altman: None. N.Tugarinov: None. M.Hollis: None. R.Roberson: None. A.Caron: None.