bluuebunny/crossref_metadata_2025 huggingface dataset:
1551-P: Association between Short-Term Postprandial C-Peptide Index Recovery during Hospitalization and Future Glycemic Control in Patients with Type 2 Diabetes
Authors: ENKAKU ASAKO , CHUJO DAISUKE , KAMIGISHI MIKI , INAGAWA SHINYA , SAKAI WAKA , MATSUKOSHI SHINNOSUKE , TAKIKAWA AKIKO , FUJISAKA SHIHO , TOBE KAZUYUKI
Published: June 2023

Endogenous insulin secretion could be recovered by improving hyperglycemia in patients with type 2 diabetes (T2D). However, no reports have showed the associations between short-term insulin secretion recovery and future glycemic control. In this study, we investigated whether short-term C-peptide index (CPI) recovery during hospitalization could predict future glycemic control. In this study, 117 patients with T2D were included. The recovery of fasting and postprandial CPI were defined as (fasting CPI at discharge - fasting CPI at admission [index-A]) and (postprandial CPI at discharge - postprandial CPI at admission [index-B]). We compared the clinical background between the low-recovery and high-recovery groups of each index and assessed the association between the indices and metabolic parameters after discharge. Using index-A, age was significantly younger (P = 0.017) and body mass index (BMI) was significantly higher (P = 0.004) in the high-recovery group than that in low-recovery group. Using index-B, the age was significantly younger (P = 0.019) and BMI was significantly higher (P = 0.004) in the high-recovery group. Additionally, visceral fat area (P = 0.043), serum TG (P < 0.001), and γ-GTP levels (P = 0.009) were significantly higher in the high-recovery group. Regarding the association between CPI recovery and future glycemic control, GA levels were significantly lower in the high-recovery group than that in low-recovery group at 6 months (16.7 vs 21.1%, P = 0.045) and 12 months (16.8 vs 21.7%, P = 0.033) after discharge in the analysis using index-B. Furthermore, postprandial CPI (cut-off; 3.79 [AUC 0.698, P = 0.007]) at discharge and index-B (cut-off; 1.66 [AUC 0.657, P = 0.018]) were identified as indicators to predict HbA1c ≤ 7.0% at 6 months after discharge. In conclusion, short-term postprandial CPI recovery during hospitalization may predict future glycemic control.

Disclosure

A.Enkaku: None. D.Chujo: None. M.Kamigishi: None. S.Inagawa: None. W.Sakai: None. S.Matsukoshi: None. A.Takikawa: None. S.Fujisaka: 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.
1557-P: Ctcfl Is a Fasting-Induced Epigenetic Regulator of Lipid Metabolism and Ketogenesis in the Liver
Authors: EFTHYMIOU VISSARION , POULOS LINDSAY , STRAUB LEON , NAVARRETE VALERIE , OZTURK BERKCAN , OSATAPHAN SORAVIS , CHIMENE-WEISS JEREMY I. , PATTI MARY-ELIZABETH
Published: June 2023

Engaging regulatory mechanisms mediating physiologic adaptations to fasting may be a potential tool for obesity and T2D. We previously demonstrated SGLT2i induce a fasting-like transcriptional program in liver, and identified Ctcfl (CCTC-binding factor (CTCF)-like) as a top-ranking transcript upregulated in SGLT2i-treated C57BL/6J mice (↑1.5-fold, p=0.01). Ctcfl was also upregulated 2.5-fold with fasting vs. fed littermates. We hypothesize Ctcfl mediates fasting-related transcriptional modulation via dynamic epigenetic regulation of chromatin accessibility. To identify drivers of Ctcfl expression, we studied AML12 hepatocytes, demonstrating key roles for AMPK activation and mTOR inhibition as upstream regulators. Moreover, in vivo inhibition of mTOR or insulin receptor increased hepatic Ctcfl expression (~2-fold), while insulin suppressed Ctcfl by ~50% within 3h. siRNA knockdown (KD) of Ctcfl indicates Ctcfl regulates transcriptional mediators of fasting (e.g. Hnf4, Srebf, Chrebp, Pgc1α), lipid/carbohydrate metabolism, and mitochondrial biogenesis. Single-cell RNAseq in Ctcfl-KD cells revealed distinct populations, enriched in mTOR, insulin signaling and Tfeb targets. Conversely, human CTCFL overexpression resulted in repression of regulators of lipid metabolism (Fas) and ketogenesis (Hmgcs2). In vivo liver-specific knockdown of Ctcfl, using N-acetyl galactosamine-conjugated siRNA, did not modulate body weight but increased circulating β-hydroxybutyrate and reduced respiratory quotient in the fasted state, suggesting shift to increased lipid utilization. Thus, we demonstrate Ctcfl is upregulated with fasting and fasting-like stimuli, including SGLT2i and AMPK activation, and repressed by refeeding, insulin signaling, and mTor pathways. Ctcfl can mediate a transcriptional program which may regulate lipid and ketone metabolism while acting as a “brake” to limit aberrant ketogenesis, potentially via alterations in chromatin accessibility.

Disclosure

V.Efthymiou: None. L.Poulos: None. L.Straub: None. V.Navarrete: None. B.Ozturk: None. S.Osataphan: None. J.I.Chimene-weiss: None. M.Patti: Consultant; MBX Biosciences, AstraZeneca, Hanmi Pharm. Co., Ltd., Other Relationship; Fractyl Health, Inc.

Funding

Swiss National Foundation; National Institutes of Health (R01DK106193)
156-OR: Apolipoprotein C-II Posttranslational Truncation Is Associated with Reduced Incident Cardiovascular Risk in Multiethnic Study of Atherosclerosis (MESA)
Authors: KOSKA JURAJ , FURTADO JEREMY , HU YUEMING , NEDELKOV DOBRIN , BILLHEIMER DEAN , BUDOFF MATTHEW , ALLISON MATTHEW , MCCLELLAND ROBYN , REAVEN PETER
Published: June 2023

Higher truncated-to-native proteoform ratios of apolipoproteins (apo) C-I (C-I’/C-I) and C-II (C-II’/C-II) are associated with lower triglycerides (TG) and higher HDL levels. Here we examined the relationships of C-I’/C-II and C-II’/C-II, and total apo C-I and C-II concentrations with atherosclerotic cardiovascular disease (ASCVD) and coronary heart disease (CHD). Apo C-I and C-II proteoforms were measured by mass spectrometry immunoassay at baseline in 5,765 MESA participants followed for CHD (definite myocardial infarction, resuscitated cardiac arrest or fatal CHD) and ASCVD (CHD or stroke) for up to 17 years. Baseline total apo C-I and C-II levels were measured in a subgroup of 3,848 participants. After adjusting for age, gender, and race/ethnicity, lower C-II’/C-II was associated with both ASCVD and CHD (Figure). The association of C-II’/C-II with CHD remained significant after further adjusting for BMI, diabetes, systolic BP, eGFR, use of tobacco, statins, antihypertensive medications, total apoC-II, and plasma TG, but was abolished after adjusting for HDL. Neither ASCVD nor CHD were related to total apo C-I and C-II or CI’/CI. In conclusion, increased posttranslational apoC-II truncation (but not total apo C-I or C-II) is associated with reduced cardiovascular risk, possibly explained by differences in HDL cholesterol metabolism.

Disclosure

J.Koska: None. J.Furtado: Employee; Biogen. Y.Hu: None. D.Nedelkov: None. D.Billheimer: Advisory Panel; AstraZeneca. M.Budoff: Research Support; Novo Nordisk, Novartis, Boehringer Ingelheim Inc., Speaker's Bureau; Boehringer Ingelheim and Eli Lilly Alliance. M.Allison: None. R.Mcclelland: None. P.Reaven: Research Support; Dexcom, Inc.

Funding

National Heart, Lung, and Blood Institute (R01HL138969, 75N92020D00001, HHSN268201500003I, N01HC95159, 75N92020D00005, N01HC95160, 75N92020D00002, N01HC95161, 75N92020D00003, N01HC95162, 75N92020D00006, N01HC95163, 75N92020D00004, N01HC95164, 75N92020D00007, N01HC95165, N01HC95166, N01HC95167, N01HC95168, N01HC95169); National Center for Advancing Translational Sciences (UL1TR000040, UL1TR001079, UL1TR001420)
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<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<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 <0.01). Plasma FGF5 also decreased after LSG (1625.0 ± 656.8 pg/ml vs. 966.8 ± 339.9 pg/ml, p <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 > 1.00; normal level, M2BPGi < 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 < 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 < 0.01) as well as AST > 30 IU/ml (OR, 3.37) and ALP > 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<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<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.
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 <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 <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 (<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<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<0.01), with no significant difference between the two diabetes groups. GIGD was inversely correlated with pressure at earliest sensation (rho 0.341, P<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<0.01), and HbA1c (rho 0.653, P<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 >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<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<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.