bluuebunny/crossref_metadata_2025_split huggingface dataset:
157-OR: Cystatin C Predicts Major Cardiovascular Events in Patients with Coronary Artery Disease Both among Patients With and among Those Without the Metabolic Syndrome
Authors: MADER ARTHUR , MAECHLER MAXIMILIAN , LARCHER BARBARA , SPRENGER LUKAS , LEIHERER ANDREAS , MUENDLEIN AXEL , VONBANK ALEXANDER , PLATTNER THOMAS , DREXEL HEINZ , SAELY CHRISTOPH H. 
Published: June 2023

Cystatin C is an established biomarker for renal function, and, given the close association of chronic kidney disease and cardiovascular disease might indicate new-onset or deteriorating cardiovascular disease. However, evidence for cystatin C as a predictor of cardiovascular events is limited and controversial. We therefore aimed at investigating the role of cystatin C as a predictor of future major adverse cardiovascular events (MACE) in a high risk-cohort of patients with established coronary artery disease (CAD). We prospectively recorded cardiovascular events in 1481 patients with angiographically verified CAD over a mean follow-up of 10.0±5.2 years. At baseline, 684 patients had the metabolic syndrome (MetS) and 797 did not have the MetS. During follow-up, 578 (39%) of our patients suffered MACE. Cystatin C proved to be a strong and independent predictor for MACE in the total study cohort (standardized adjusted HR 1.56 [1.34-1.83], p&lt;0.001). When MetS status was taken into account, cystatin C significantly predicted major cardiovascular events both in patients with the MetS (HR 1.56 [1.28-1.90], p&lt;0.001) and in non-MetS patients (HR 1.44 [1.12-1.84], p=0.004). We conclude that cystatin C predicts major cardiovascular events in patients with coronary artery disease both among patients with the MetS and in non-MetS individuals.

Disclosure
A.Mader: None. C.H.Saely: None. M.Maechler: None. B.Larcher: None. L.Sprenger: None. A.Leiherer: None. A.Muendlein: None. A.Vonbank: None. T.Plattner: None. H.Drexel: None.
1571-P: Plasma FGF5 Concentration Correlates Better with Hepatic Steatosis, Blood Glucose, and Specific Plasma Free Fatty Acids than with Other Tissue Fat Accumulation
Authors: HO LEE DAE , BYUNG PARK IE 
Published: June 2023

A few studies reported an association between fibroblast growth factor-5 (FGF5) and NAFLD. We aimed to elucidate the physiologic implication of FGF5 in NAFLD and obesity. A total of 180 subjects [(24 healthy controls and 156 patients with biopsy-proven NAFLD and/or hepatic fat content (HFC) 5% or more on MRI-PDFF] were included to assess association between HFC and various metabolic factors including body fat and plasma levels of glucose, insulin, FGF5, FGF21, oxyntomodulin, incretins, and some free fatty acids (FFAs). Additionally, we analysed a subgroup of obese patients who would undergo laparoscopic sleeve gastrectomy (LSG) (n=50) to see correlation between changes in metabolic variables related to body weight (BW) and HFC before and 6 months after surgery. Plasma FGF5 correlated better with blood glucose and HFC than with total body fat, HOMR-IR, and visceral fat. In relation to plasma FFAs, both FGF5 and HFC together showed a positive correlation with plasma FFAs such as palmitic acid, linolenic acid, and arachidonic acid, but had an inverse correlation with nervonic acid, docosanoic acid, tetracosanoic acid, and hexacosanoic acid. FGF5 level showed an independent association with blood glucose and MRI-PDFF after adjusting for multiple factors. After LSG, BW decreased by an average of 24.6%, while HFC decreased from 19.5% ± 9.1% to 5.7 ± 2.9%, p &lt;0.01). Plasma FGF5 also decreased after LSG (1625.0 ± 656.8 pg/ml vs. 966.8 ± 339.9 pg/ml, p &lt;0.01). The amount of plasma FGF5 change showed a significant correlation with changes in HFC and blood glucose. In conclusion, our results showed that plasma FGF5 level correlated well with HFC, blood glucose, and specific plasma FFAs and also decreased with the improvement of hepatic steatosis after bariatric surgery. Further researches on the causal relationship between FGF5, glucose and lipid metabolism, and NAFLD are needed.

Disclosure
D.Lee: None. I.Park: None.

Funding
National Research Foundation of Korea (2021R1A5A2030333, 2019R1I1A2A02062305)
1574-P: FoxO1 Links Insulin Resistance to Hepatic Inflammation and Catalyzes the Evolution of Benign Steatosis to Nonalcoholic Steatohepatitis
Authors: LEE SOJIN , USMAN TAOFEEK , CHHETRI GOMA , WANG XINGCHUN , DONG H. HENRY 
Published: June 2023

Hepatic inflammation is intertwined with insulin resistance and is a causative factor for the transition of benign steatosis to nonalcoholic steatohepatitis (NASH). We found that FoxO1 was markedly upregulated in hepatic macrophages, coinciding with hepatic inflammation and steatosis in dietary obese mice. We generated myeloid-conditional FoxO1-transgenic and FoxO1-knockout mice, two complementary models for determining the effect of FoxO1 gain- vs. loss-of-function on macrophage activation in response to insulin resistance. We found that myeloid FoxO1 gain-of-function aggravated hepatic inflammation in mice in response to overnutrition or endotoxin. In contrast, myeloid FoxO1 loss-of-function skewed macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotypes, accompanied by the reduction of macrophage infiltration in liver. This effect contributed to the suppression of hepatic inflammation and improvement of insulin sensitivity. Despite fat-induced obesity, myeloid-conditional FoxO1-deficient mice were protected from developing hyperglycemia, hyperinsulinemia and glucose intolerance. Furthermore, the improvement in hepatic inflammation and insulin resistance translated into a significant beneficial effect on NASH, culminating in the reduction of hepatic steatosis and fibrosis in myeloid FoxO1-deficient mice on NASH-inducing diet. Human FOXO1 expression was upregulated in inflammatory macrophages in liver, correlating with hepatic inflammation, steatosis and fibrosis in patients with NASH. Mechanistically, FoxO1 counteracts Stat6 to skew macrophage polarization from M2 toward M1 signatures with pro-inflammatory profiles. We concluded that myeloid FoxO1 dysregulation is culpable for linking insulin resistance to abnormal macrophage activation. This effect perpetuates hepatic inflammation and catalyzes the evolution of simple steatosis to NASH.

Disclosure
S.Lee: None. T.Usman: None. G.Chhetri: None. X.Wang: None. H.Dong: None.
1575-P: Glycerol Metabolism and Gluconeogenesis in Mice Lacking the Mitochondrial Pyruvate Carrier in Hepatocytes
Authors: YIEW NICOLE , FERGUSON DANIEL , CHO KEVIN , DEJA STANISLAW , JARASVARAPARN CHAOWAPONG , FU XIAORONG , LUTKEWITTE ANDREW J. , MUKHERJEE SANDIP , SINGER JASON M. , PATTI GARY J. , BURGESS SHAWN C. , FINCK BRIAN N. 
Published: June 2023

Hepatic glucose production from glycogen breakdown and gluconeogenic substrates is an important physiologic adaptation, but uncontrolled glucose release by the liver contributes to hyperglycemia in diabetes. The liver can produce glucose from several substrates, including amino acids, lactate/pyruvate, and glycerol. Mitochondrial import of pyruvate by the mitochondrial pyruvate carrier (MPC) plays an important role in gluconeogenesis from lactate/pyruvate, but its role in gluconeogenesis from other substrates is less clear. For example, glycerol can be converted to glucose by two pathways; [1] a direct pathway involving the reversal of several steps in glycolysis and [2] a mitochondrial pathway requiring the import of pyruvate via the MPC. While prior work has shown that compared to wild-type (WT) mice, hepatocyte MPC-/- mice exhibit lower blood glucose concentrations after fasting 24 h, concentrations after fasting 18 h were not different between genotypes in the present study. To determine whether gluconeogenesis from glycerol was affected by MPC deficiency, we administered 13C-glycerol to overnight fasted WT and MPC knockout mice and found that loss of the MPC increased the incorporation of 13C into new glucose. Further analysis determined that MPC deletion reduced the incorporation of 13C into glucose derived from the mitochondrial pathway and hepatic TCA cycle metabolites, but actually increased glycerol-mediated gluconeogenesis via the direct pathway. Suppression of glycerol kinase or overexpression of glycerol-3-phosphate phosphatase markedly reduced glycerol-mediated glucose production from both the direct and mitochondrial pathways, but did not reduce glucose concentrations in fasted MPC knockout mice. These findings indicate that glycerol-mediated gluconeogenesis is not impaired in MPC-deficient hepatocytes and suggest that gluconeogenesis from other organs, likely kidney or intestine, compensates for loss of the hepatic MPC.

Disclosure
N.Yiew: None. G.J.Patti: None. S.C.Burgess: None. B.N.Finck: Advisory Panel; Cirius Therapeutics, Inc., Stock/Shareholder; Cirius Therapeutics, Inc. D.Ferguson: None. K.Cho: None. S.Deja: None. C.Jarasvaraparn: None. X.Fu: None. A.J.Lutkewitte: None. S.Mukherjee: None. J.M.Singer: None.

Funding
National Institutes of Health (R01DK104735, R01DK117657, T32DK007120, R35ES028365)
1582-P: Association of Low eGFR with Novel Liver Fibrosis Biomarker Mac-2 Binding Protein Glycosylation Isomer in Type 2 Diabetes Patients
Authors: SUZUKI EIICHIRO , SHINYA YUMI , KANARI BUNPEI , KAMBARA MISA , TAKAHASHI HIDEO 
Published: June 2023

Objective: Advanced liver fibrosis, which leads to liver cirrhosis and cancer, has been one of the major causes of death in type 2 diabetes (T2D). Efficient screening system is needed to detect liver fibrosis early and prevent its progression. A novel serum fibrosis biomarker Mac-2 binding protein glycan isomer (M2BPGi) has high sensitivity plus specificity, and can be used in combination with FIB-4 screening index (aspartate aminotransferase [AST]/alanine aminotransferase [ALT]/platelet ratio). This study aimed to investigate the predictive factors for the early detection of liver fibrosis using a combination of these two approaches.
Methods: This cross-sectional study consisted of T2D patients, with negative results for hepatitis viruses and no history of heavy drinking. FIB-4 high patients were divided into two groups based on M2BPGi (high, M2BPGi &gt; 1.00; normal level, M2BPGi &lt; 1.00. The levels of clinical biomarkers were measured among two groups and predictive factors were calculated for M2BPGi high patients.
Results: From July to December 2021, a total of 311 FIB-4 high T2D patients (male/female, 202/109; age, 71.1 + 9.8; Body Mass Index, 24.5 + 3.9; HbA1c 7.4 + 3.3 %) were enrolled in this study. The M2BPGi high group (44,3%, n=138) showed a significantly longer duration of diabetes, high alkaline phosphatase (ALP), AST, ALT, and low eGFR than M2BPGi normal group (55.7%, n=173). In multiple logistic regression analysis, eGFR &lt; 60 mL/min/1.73m2 was independently identified as a predictive factor for M2BPGi high (Odds Ratio [OR] 2.61, 95% C.I. 1.55-4.39 P &lt; 0.01) as well as AST &gt; 30 IU/ml (OR, 3.37) and ALP &gt; 113 IU/ml (OR, 1.88).
Conclusions: low eGFR is associated with liver fibrosis in type 2 diabetes patients, and requires more careful attention to liver related disease.

Disclosure
E.Suzuki: None. Y.Shinya: None. B.Kanari: None. M.Kambara: None. H.Takahashi: None.
1600-P: Duration of Morning Hyperinsulinemia Is Key to the Enhancement of Hepatic Glucose Uptake Later in the Day
Authors: WATERMAN HANNAH L. , SMITH MARTA S. , FARMER BEN , KRAFT GUILLAUME , SCOTT MELANIE , EDGERTON DALE S. , CHERRINGTON ALAN D. , MOORE MARY C. 
Published: June 2023

The second meal phenomenon, which occurs in normal and diabetic individuals, refers to the improvement in glucose tolerance seen following a second identical meal. We previously showed that 4h of morning (AM) hyperinsulinemia, but not hyperglycemia, enhanced hepatic glucose uptake (HGU) and glycogen storage during a PM hyperinsulinemic hyperglycemic clamp (HIHG) later that day. Our aim was to determine if the duration of morning hyperinsulinemia is important for the PM response to a HIHG clamp. To determine this, we administered the same amount of insulin over 2h in the first half of the morning (Ins2h-A), over 2h in the 2nd half of the morning (Ins2h-B), or over the entire 4h (Ins4h) of the morning. We then assessed the impact of the AM insulin duration on HGU during a PM HIHG clamp in conscious dogs. The dogs underwent an AM hyperinsulinemic euglycemic clamp from 0-120 min, 120-240 min, or 0-240 min (Ins2h-A, Ins2h-B, or Ins4h; n=6/group). The insulin infusion rates used in the Ins4h were selected to mimic the rise in endogenous insulin secretion previously observed during a 4h AM duodenal glucose infusion (2.1 mU/kg/min (0-30 min), 2.4 mU/kg/min (30-60 min), and 1.5 mU/kg/min (60-240 min)). These rates were doubled in both 2h groups to match the total amount of insulin being infused in the 4h AM clamp. In the PM, all groups had 4x basal insulin, 2x basal glycemia, and portal glucose infusion to simulate a 2nd meal. During the 4h PM clamp, there were no significant differences between the two 2h groups. However, there was a marked effect on the mean HGU in the Ins4h group compared to the Ins2h-A and Ins2h-B groups (HGU of 6.3±0.9 vs 3.8±0.3 and 4.4±0.4 mg/kg/min; AUC of 1393±199 vs 822±68 and 971±93 mg/kg/4hr, P&lt;0.05), respectively, despite matched hepatic glucose loads. The longer duration (Ins4h) of AM hyperinsulinemia allowed for a 41% and 66% greater uptake of glucose in the PM clamp (vs Ins2hA + B). Thus, the duration of AM hyperinsulinemia is an important determinant of hepatic metabolism later in the day.

Disclosure
H.L.Waterman: None. M.S.Smith: None. B.Farmer: None. G.Kraft: None. M.Scott: 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. M.C.Moore: None.

Funding
National Institutes of Health (5T32DK007563-34, 5R01DK131082-02)
161-LB: Diagnosis and Treatment of Diabetes Mellitus in Pediatric Patients with Pancreatitis Followed in a Multidisciplinary Clinic
Authors: VARGAS ELIZABETH , MARK JACOB , FORLENZA GREGORY P. , TRIOLO TAYLOR M. 
Published: June 2023

Children with recurring acute or chronic pancreatitis are at risk for pancreatitis related diabetes mellitus (DM). Pancreatic endocrine and exocrine concerns are managed by different subspecialists. Our center has a unique pediatric pancreatitis multidisciplinary clinic (MDC) with pediatric gastroenterology, endocrinology, pain, and nutrition experts. We obtain point-of-care (POC) HbA1c during clinic check-in for immediate DM screening. Our study describes the utility of POC HbA1c testing in our MDC. We analyzed a retrospective chart review of MDC patients from 2018-2023 with a diagnosis of pancreatitis and DM (n=27). Twelve were diagnosed with DM prior to presentation and 2 presented after total pancreatectomy with islet autotransplantation (TPIAT). Eight patients eventually developed DM and 5 later underwent TPIAT resulting in DM. We evaluated baseline characteristics at presentation to our MDC and longitudinal follow up. Of the 12 patients with previously diagnosed DM, 42% were Hispanic/Latino, 50% were female. On presentation to the MDC, patients were 15.4±2.1 years old with BMI 23.2±4.0 kg/m2 and HbA1c 9.6±2.9%. Eight patients developed DM within 1.1±1.2 years of follow up. Six were diagnosed by POC HbA1c in our MDC. Of all whom developed DM, 88% were Hispanic/Latino, 88% were female. DM was diagnosed at 14.3±1.6 years old with BMI 34.5±4.8 kg/m2 and HbA1c 8.5±2.5%. Of our 27 patients with DM, 4 had type 1 DM autoantibodies. At most recent visit HbA1c was 8.9±3.2%. DM treatment involved oral agents (15%), insulin (85%) and nutrition counseling for all patients. Total daily dose of insulin was 0.75±0.53 u/kg/day and 48% of patients used continuous glucose monitors. Instituting POC HbA1c screening in pancreatitis clinic identifies patients with new onset DM, supporting multidisciplinary care. Despite intensive care, HbA1c for these patients remains above guideline goals. More research is needed in providing DM care for children with pancreatitis.

Disclosure
E. Vargas: None. J. Mark: None. G. P. Forlenza: Advisory Panel; Medtronic, Consultant; Dexcom, Inc., Insulet Corporation, Tandem Diabetes Care, Inc., Lilly Diabetes, Research Support; Medtronic, Abbott, Dexcom, Inc., Insulet Corporation, Tandem Diabetes Care, Inc. T. M. Triolo: None.
1612-P: Energetic Contributions of GLP1 and GCGR Activity in GLP1/GIP/GCGR Triagonism
Authors: NASON SHELLY , ANTIPENKO JESSICA , HABEGGER KIRK M. 
Published: June 2023

Glucagon has been implicated as a key diabetogenic factor. However, agonists that couple the lipolytic and thermogenic properties of Glucagon Receptor (GCGR) activity with the antidiabetic actions of incretins (GLP1, GIP), lack hyperglycemic side effects associated with GCGR activity. GCGR agonism stimulates energy expenditure (EE) that contributes to weight loss. Interestingly, we also identified that the anti-obesity effects of GCGR agonism persisted for 50d after treatment cessation. Thus, we hypothesized that GCGR activity paired with incretin action (GGG) will result in increased EE during treatment and prolonged weight loss after cessation. Diet-induced obese mice were treated for 14d with vehicle, GGG, or single receptor agonism via IUB288 (GCGR), Semagutide (Sema;GLP1R), or GIP-FA 085 (GIPR). Indirect calorimetry was conducted for d 2-4 of treatment and d 16-18 after cessation. Congruent with our prior studies, IUB288 increased EE compared to vehicle controls. Conversely, Sema-treated mice displayed decreased EE (d 2 and 3) while EE following GIP treatment was similar to vehicle controls. Intriguingly, GGG reduced EE on d 2, had similar EE to vehicle controls on d 3, with a trend towards increased EE on d 4, suggesting GGG treatment stimulates characteristics of both GLP1 and GCGR activity. Nutrient utilization, measured via Respiratory Quotient (RQ), was reduced during the light period with IUB288 treatment. GIP, Sema, and GGG reduced RQ, regardless of time of day. Interestingly, GGG regulation of RQ appeared most like Sema. After treatment cessation, Sema mice gained significantly more weight than IUB288 or GGG mice, despite similar food intake during rebound. Surprisingly, EE was not elevated in mice that formerly received IUB288 or GGG, suggesting another mechanism may be driving this effect. RQ was similar in all groups, except IUB288 mice, which exhibited increased RQ across the day. These data suggest that GGG exhibits effects of both GLP1R and GCGR agonism with respect to EE and RQ.

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

Funding
Eli Lilly and Company
1613-P: Feasibility of Time-Restricted Eating in the Treatment of Type 2 Diabetes—The RESET2 Pilot Study
Authors: TERMANNSEN ANNE-DITTE , VARMING ANNEMARIE R. , STAGE HANSEN GITTE S.H. , BJERRE NATASJA , PERSSON FREDERIK , BAGGER JONATAN I. , JØRGENSEN NILS B. , HEMPLER NANA F. , FAERCH KRISTINE , QUIST JONAS S. 
Published: June 2023

Background: Time-restricted eating (TRE) is a type of intermittent fasting reducing the interval for eating and drinking without other dietary restrictions.
Aim: To investigate the feasibility of a 12-week 10-h TRE-based intervention targeting people with type 2 diabetes (T2D), including the participants’ needs and barriers when following TRE.
Methods: In this single-arm pilot study, 10 men and 10 women with T2D (mean HbA1c: 59 mmol/mol (7.8 %DCCT) and T2D duration: 15 years) followed a 12-week intervention co-created with people with T2D, their relatives and healthcare professionals (HCP). First, participants followed 8 weeks of strict TRE with a self-selected, fixed 10-h eating window (EW) to obtain lived experiences with TRE. This was followed by a 4-week TRE period with individually selected adjustments such as occasional rescheduling of EW, calorie-free beverages outside the EW, peer-support sessions, and phone calls with HCP. The individual EW and adjustments were planned during 1-hour meetings with an HCP at baseline and after 8 weeks. Body weight and HbA1c were measured at baseline and after 12 weeks. Qualitative interviews were conducted at baseline, after 8 and 12 weeks.
Results: Nineteen participants (median age: 68 years, mean body weight: 102.8 kg, and BMI: 34.6 kg/m2) completed the study. Body weight (-2.0 kg (95% CI: -2.9, -1.1), p&lt;0.001) and HbA1c (-4.1 mmol/mol (-6.7, -1.4), -0.38 %DCCT (-0.62, -0.13), p=0.005) were reduced after 12 weeks compared to baseline. Most participants were positive and found TRE easier to follow than expected, but many experienced barriers in relation to social activities and holidays. The adherence was impacted by a variety of factors and differed among participants, who emphasized the importance of support from HCPs, relatives, peers, and adjustments such as morning coffee and ‘days off’ TRE.
Conclusions: We found that 12-weeks of TRE was feasible and well-tolerated and may improve glycemic control and body weight in individuals with T2D.

Disclosure
A.Termannsen: None. J.S.Quist: Research Support; Novo Nordisk A/S. A.R.Varming: None. G.S.H.Stage hansen: None. N.Bjerre: Research Support; Novo Nordisk Foundation. F.Persson: Advisory Panel; AstraZeneca, Bayer Consumer Care AG, Boehringer-Ingelheim, Novo Nordisk A/S, Consultant; AstraZeneca, Boehringer-Ingelheim, Novo Nordisk A/S, Research Support; Boehringer-Ingelheim, Novo Nordisk A/S, Speaker's Bureau; AstraZeneca, Bayer Consumer Care AG, Boehringer-Ingelheim, Novo Nordisk A/S, Sanofi. J.I.Bagger: Speaker's Bureau; Novo Nordisk A/S. N.B.Jørgensen: None. N.F.Hempler: None. K.Faerch: Board Member; ChemoMetec A/S, Consultant; Novo Nordisk A/S, Research Support; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S, Novozymes, ChemoMetec A/S.