bluuebunny/crossref_metadata_2025 huggingface dataset:
1410-P: Impacts of COVID-19 on Underserved Communities with Diabetes
Authors: MAIZEL JENNIFER , HALLER MICHAEL J. , MAAHS DAVID M. , ADDALA ANANTA , LAL RAYHAN , FILIPP STEPHANIE L. , GURKA MATTHEW J. , WESTEN SARAH C. , DIXON BRITTNEY , FIGG LAUREN , HECHAVARRIA MELANIE , MALDEN KEILECIA G. , WALKER ASHBY F.
Published: June 2023

People with diabetes have higher COVID-19 morbidity and mortality. These risks are amplified for racial minorities and people living in rural areas or with low income, who are more likely to experience severe COVID-19 illness, vaccine hesitancy, and unemployment. A survey of adults with type 1, type 2, and other forms of diabetes (n=450, µ age= 52.7 years) receiving care at 41 federally qualified and community health centers in FL and CA examined COVID-19 illness, prevention, and financial and healthcare impacts. Surveys were completed from fall 2021 to summer 2022; all outcomes were self-reported. Descriptive statistics were computed for key outcomes (n, %). Logistic regression assessed independent associations of COVID-19 vaccine receipt. Between-group comparisons were evaluated via Chi-Squared, Fisher’s Exact, and Cochran-Mantel-Haenszel tests. Overall, 29.7% of participants contracted COVID-19; of those, 45.3% sought medical care or were hospitalized. Most (81.3%) received at least 1 COVID-19 vaccine; of those, 97.5% were fully vaccinated. Hispanics had the highest vaccination rate while Non-Hispanic Blacks (NHB) had the lowest (91.1%, 73.9%, p=.0281). Hispanics had 4.63x greater odds of vaccination than Non-Hispanic Whites (NHW) [95% CI=(1.81, 11.89)]. A majority “always” or “very often” wore masks (53.2%). Participants reported income loss (64.9%), more frequently in FL (76.1%, CA: 52.2%, p<.001). NHB had the highest rate of severe income loss (26.4%, p=.0124). Loss of health insurance was greater among NHB (13.3%) than other races (<8%, p=.0422) and in FL (9.7%, CA: 4.5%, p=.039). Participants reported healthcare access changes (62%) and higher diabetes medication costs (41%). These findings demonstrate underserved communities with diabetes suffered significant health and financial challenges from COVID-19, which were especially disparate for NHB and FL residents. Further research, interventions, and policy changes are needed to promote health equity for underserved communities with diabetes.

Disclosure

J.Maizel: None. L.Figg: None. M.Hechavarria: None. K.G.Malden: None. A.F.Walker: None. M.J.Haller: Board Member; SAB Biotherapeutics, Inc., Consultant; Sanofi, MannKind Corporation. D.M.Maahs: Advisory Panel; Medtronic, LifeScan Diabetes Institute, MannKind Corporation, Consultant; Abbott, Research Support; Dexcom, Inc. A.Addala: None. R.Lal: Advisory Panel; Provention Bio, Inc., Consultant; Abbott Diabetes, Biolinq, Capillary Biomedical, Inc., Deep Valley Labs, Gluroo, Tidepool, PhysioLogic Devices, Morgan Stanley. S.L.Filipp: None. M.J.Gurka: None. S.C.Westen: None. B.Dixon: None.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust (G-2005-03934)
1425-P: C-Peptide and Islet Autoantibodies at Diagnosis Predict Long-Term ß-Cell Function and Insulin Dependence in Pediatric Diabetes
Authors: TOSUR MUSTAFA , HUANG XIAOFAN C. , DEEN SAIMA , UYSAL SERIFE , ASTUDILLO MARCELA , HAGOPIAN WILLIAM , ORAM RICHARD A. , JAHOOR FAROOK , REDONDO MARIA J. , BALASUBRAMANYAM ASHOK
Published: June 2023

We asked if assessment of islet autoimmunity and β cell function in children at diabetes diagnosis is useful for prognosis, using the “Aβ” system, [“A” representing autoimmunity (A+ = ≥1 autoantibody; A- = no antibodies), “β” representing β cell function (β+ = random serum C-peptide ≥0.6 ng/mL; β- = C-peptide <0.6 ng/mL)]. We followed β cell function longitudinally with 2h post-prandial urinary C-peptide-creatinine ratio (UCPCR) at 3-12 wk (V1) and 6-12 m (V2). We compared clinical characteristics, glycemia and β cell function at baseline and clinical outcomes at V2 between the groups. The cohort (n=74) was 50% female, 76% White, 22% non-Hispanic Black, 2% Other, 47% Hispanic. Median age (25p-75p) was 12.6 (8.5-14.6) years, median BMI 70.7 (16.7-96.1) %ile. Phenotypic frequencies were A+β- (36.5%), A-β+ (29.7%), A+β+ (31.1%) and A-β- (2.7%). Baseline serum C-peptide correlated with UCPCR at V1 (r=0.37, p=0.03). Adjusting for age, sex, race/ethnicity, and BMI, UCPCR at V2 was higher in A-β+ than A+β- (β=1.18, 95% CI:0.31-2.07, p=0.009). Fully 36% of A-β+ but none of A+β+ and A+β- were insulin-independent at V2 (p<0.001). The remaining results are shown in Table 1. The A-β+ phenotype at diagnosis predicts sustained β cell function and potential insulin-independence after 6-12 months. Random serum C-peptide at diagnosis correlates with 2h post-prandial UCPCR at 3-12 weeks.

Disclosure

M.Tosur: Advisory Panel; Provention Bio, Inc. A.Balasubramanyam: None. X.C.Huang: None. S.Deen: None. S.Uysal: None. M.Astudillo: None. W.Hagopian: Research Support; Janssen Research & Development, LLC, Provention Bio, Inc., Randox R & D. R.A.Oram: Consultant; Janssen Research & Development, LLC, Research Support; Randox R & D. F.Jahoor: None. M.J.Redondo: None.

Funding

Texas Children's Hospital (to M.T.); Rutherford Fund (to A.B.); National Institutes of Health (K23DK129821 to M.T.)
1431-P: Exocrine Pancreatic Insufficiency Is Both a Risk Factor for and Comorbidity of Diabetes Mellitus
Authors: ROMO KARINA G. , SHU SHARON , NOOR ABDULLAH A. , WEST WILLIAM A. , BHAMRE SNEHA , UWAIFO GABRIEL I.
Published: June 2023

Introduction: Exocrine Pancreatic Insufficiency (EPI) is an uncommon but important disease of the exocrine pancreas. Its relationship to endocrine pancreas function and diabetes (DM) remains poorly characterized. To better understand this relationship, a retrospective chart review was performed in a large statewide multispecialty practice.

Methods: A retrospective review of the entire 1.3 million patient-practice of Ochsner Health system in Louisiana was performed to cover the period of January 2017 to January 2020. All cases of documented EPI and patients on pancreatic enzyme replacement therapy (PERT) were identified and underwent individual chart review to identify etiologic factors and cardiometabolic, demographic, vital sign data, and clinical course information.

Results: 677 EPI patients were identified with DM being the most prevalent etiologic risk factor (44.6% T2DM, 9.6% T1DM and 11.5% secondary DM). EPI patients without DM had a 10.9% prevalence of pre-DM, and 127 new DM cases developed over the observation period among EPI patients initially without DM with an 18.7% incidence rate. EPI patients, compared to the general DM population, were significantly younger with more diverse DM etiology. They also had greater LFT and serum lipase elevations. EPI patients had lower BMIs; 25.6 ± 7.5 vs 32.8 ± 46.9 kg/m2 with greater alcohol use. EPI patients also had better glycemic control (HBAC 6.83 ± 2.1 vs 7.2 ± 1.9) and triglycerides (125.7 ± 104.7 vs 140.6 ± 118.9) though other lipids were similar. Discussion and

Conclusions: EPI, though uncommon, is both an important risk factor for onset of DM and comorbidity of diabetes. DM patients with EPI have distinctive etiologic, metabolic, and anthropometric features from DM patients in the general population. Further study of EPI patients to better understand predictors of onset of EPI in DM patients and DM onset in non-DM EPI patients are needed to guide evidence based screening. This would in turn enable early EPI recognition and management.

Disclosure

K.G.Romo: None. S.Shu: None. A.A.Noor: None. W.A.West: None. S.Bhamre: None. G.I.Uwaifo: None.
1456-P: 2022 State of Type 1 Diabetes in the U.S.—Real World T1D Exchange Multicenter Data from over 60,000 People
Authors: EBEKOZIEN OSAGIE , NOOR NUDRAT , DIMEGLIO LINDA , YAU MABEL , RAPAPORT ROBERT , WEISSBERG-BENCHELL JILL , HANNON TAMARA S. , MCNAMARA KIMBERLY , MILLER KELLEE , MAAHS DAVID M. ,   T1D EXCHANGE QUALITY IMPROVEMENT COLLABORATIVE (T1DX-QI)
Published: June 2023

Background: In response to sub-optimal type 1 diabetes (T1D) care data in the US, intensive quality improvement (QI) programs were implemented in the T1D Exchange QI collaborative (T1DX-QI) to improve outcomes for individuals with T1D. The aim of this analyses is to characterize the T1DX-QI patient population consisting of over 60,000 individuals with T1D

Method: This cross-sectional analysis included 2022 electronic medical record (EMR) data of 60,915 individuals with T1D from 26 diabetes centers. Population attributes analyzed included demographics, duration of diabetes, glycemic outcomes and diabetes technology use.

Result: In this population described in table 1, more adults ≥ 26 years of age were at A1c target goal (<7%) (34%), compared to children and adolescents (22%). Diabetes technology use was higher in the 6-13y age group (CGM: 64%, insulin pump: 53%) relative to adults 26-50y (CGM: 46%, insulin pump: 48%); whereas Hybrid Closed Loop System (HCLS) use was higher in adults 26-65y (13%) relative to children and younger adults 6-26y (6%). Self-reported Diabetes Ketoacidosis events were also higher in the younger age groups.

Conclusion: This study reports characteristics of persons with T1D from a multi-center database and demonstrates that efforts are still needed to improve optimal management of diabetes.

Table 1: T1DX-QI EMR T1D Data Distribution 2022 (N=60915)

Disclosure

O.Ebekozien: Advisory Panel; Medtronic, Research Support; Eli Lilly and Company, Dexcom, Inc. D.M.Maahs: Advisory Panel; Medtronic, LifeScan Diabetes Institute, MannKind Corporation, Consultant; Abbott, Research Support; Dexcom, Inc. .T1d exchange quality improvement collaborative (t1: n/a. N.Noor: None. L.Dimeglio: Advisory Panel; Merck & Co., Inc., Consultant; Abata Therapeutics, Vertex Pharmaceuticals Incorporated. M.Yau: None. R.Rapaport: None. J.Weissberg-benchell: Advisory Panel; Beta Bionics, Inc., Research Support; Beta Bionics, Inc. T.S.Hannon: Advisory Panel; Eli Lilly and Company. K.Mcnamara: None. K.Miller: Consultant; Dexcom, Inc.

Funding

The Leona M. and Harry B. Helmsley Charitable Trust
1465-P: Identification of GCK Gene Variants and Clinical Characterization in Japanese Pediatric MODY2 Cases
Authors: KATASHIMA RUMI , YOSHIDA SUMIKO , WATANABE YUKA , MORITANI MAKI , YOKOTA ICHIRO
Published: June 2023

Maturity-onset diabetes of the young (MODY) is traditionally characterized by early onset and a heterogeneous autosomal dominant form of inheritance. MODY2 may be common in the Japanese, but the difference in clinical characteristics compared to Europeans and Americans remains unclear. Here, we examined the characteristics in Japanese pediatric patients diagnosed with MODY2. We retrospectively reviewed the diagnostic data of Japanese MODY2 patients diagnosed at our hospital between 2009 and 2022. Genetic screening for MODY2 was performed by direct sequencing followed by multiplex ligation amplification assays. We identified 20 missense mutations in 25 patients and 2 nonsense mutations in 2 patients. We detected 5 deletions in 6 patients. The mean age at diagnosis was 10 years (range 2-14 years), the mean BMI percentile was 46.2%, with none being obese. Mean HbA1c was 6.54%. A glucose tolerance test was performed on 29 patients, 15 of whom were diabetic (7 were diabetic at fasting, 5 were diabetic at 120 min, 3 were diabetic at both) and 14 of borderline diabetes (IFG + IGT: 11, IFG: 2, and IGT: 1). The average glucose tolerance test values were 121.6 mg/dL at 0 min and 182.2 mg/dL at 120 min. No correlation was found between age at onset and plasma glucose value at 0 and 120 min. Reportedly, MODY2 causes a slight increase in post-load blood glucose levels, however the difference between 120 min and 0 min was 56.0 mg/dL (−32 to 140). A negative correlation was observed between 0 min and 120 min blood glucose levels. HOMAIR average was 1.85, 27% of which patients were 2.5 or higher; HOMA-β average was 37.0%, 39% of which showed <30%; and insulinogenic index averaged 0.63, 25% of which showed <0.4, indicating decreased initial insulin secretion. In this study, it is suggested that in Japanese MODY2 cases, glucose sensor dysfunction due to GCK gene mutation causes decreased initial insulin secretion.

Disclosure

R.Katashima: None. S.Yoshida: None. Y.Watanabe: None. M.Moritani: None. I.Yokota: None.
1544-P: Circadian Timing of SGLT2 Inhibitor Administration Modulates Therapeutic Effects on Pancreatic Islet Function, Composition, and Gene Expression
Authors: DHANASEKARAN MAHESWARAN , RAKSHIT KUNTOL , HER TRACY K. , MATVEYENKO ALEKSEY
Published: June 2023

Timing of drug administration based on endogenous circadian cycles (i.e., chronotherapy) has been shown to enhance treatment efficacy and improve outcomes in type 2 diabetes (T2DM). Sodium-Glucose Co-transporter 2 inhibitors (SGLT2i) are potent glucose lowering agents which improve cardiovascular health and exert systemic benefits on metabolic organs (e.g., pancreatic islets). Systemic benefits of SGLT2i are attributed to their ability to mimic a fasting state thus raising a question whether chronotherapeutic exposure to SGLT2i timed to the fasting vs. feeding circadian cycle will produce divergent benefits in T2DM. To address this, we generated a diet-induced T2DM mouse model by exposing male C57BL/6 mice to 14 weeks of high fat/high sucrose (HFHS) diet. Following induction of diabetes, mice were assigned into 3 groups for 4 weeks: 1) DAPAFAST: mice with daily Dapagliflozin (DAPA) oral gavage (1 mg/kg) given at the onset of the fasting (FAST) circadian cycle; 2) DAPAFED: daily DAPA oral gavage at the onset of the feeding (FED) cycle; 3) DAPAVEH: daily vehicle (VEH) gavage. DAPAFAST and DAPAFED groups demonstrated comparable lowering of basal and OGTT glucose versus DAPAVEH (~30%, p<0.05). In contrast, whereas improved glucose tolerance in DAPAFAST was associated with enhanced insulin secretion (p<0.05 vs. DAPAVEH), no changes in β-cell function was noted in DAPAFED mice. Consistently, RNAseq analysis of DAPAFAST isolated islets revealed attenuated expression of genes enriched for key pathways regulating β-cell failure such as p53, FOXO, and TGFβ signaling (all p<0.05). We also noted divergent effects on islet morphology with DAPAFAST group uniquely characterized by increased α-cell mass compared to DAPAFED and DAPAVEH (~70% increase, p<0.05). These data demonstrate divergent metabolic and islet effects of SGLT2i therapy highlighting the importance of chronotherapeutic approaches for optimal treatment of T2DM.

Disclosure

M.Dhanasekaran: None. K.Rakshit: None. T.K.Her: None. A.Matveyenko: None.
1553-P: Postprandial C-Peptide–to–Glucose Ratio Is Valuable in Assessing Beta-Cell Function in Japanese Patients with Type 2 Diabetes
Authors: MATSUHASHI YUKI , ABE TAKAHIRO , FUJITA TOMOYUKI , MIZUSHIRI SATORU , CHIKAZAWA SHINJI , DAIMON MAKOTO
Published: June 2023

Onset of type 2 diabetes (T2D) is based on the insulin secretion (loss of β-cell function) and resistance. Residual β-cell function is a key factor in achieving optimal glycemic control in T2D patients. Glucagon stimulates insulin, therefore glucagon stimulation test (GST) is a reliable marker for β-cell function. Fasting C-peptide (CPR) to glucose ratio (CPR[ng/ml] to glucose[mg/dl] x100; F-CPR-index) is used as a marker of insulin secretion. We evaluated the efficacy of postprandial CPR to glucose ratio (P-CPR-index) for evaluating β-cell function in T2D. Japanese T2D patients with inadequate glycemic control (HbA1c>7.0) were enrolled in the study (n=500, insulin therapy=283). HbA1c, fasting CPR and glucose, postprandial (120 min after breakfast) CPR and glucose were measured, and F-CPR-index and P-CPR-index were calculated. GST was performed as follows: 1mg of glucagon was injected intravenously, CPR was determined before and 6 min after injection, GSTΔCPR (CPR[6 min] - CPR[0 min]) was calculated. Factors correlated with GSTΔCPR were analyzed using simple and multiple stepwise regression analysis. P value<0.05 was defined as statistically different. F-CPR-index, P-CPR-index and GSTΔCPR were 1.60±0.95, 2.67±1.92 and 1.93±1.21, respectively. Simple regression analysis showed that GSTΔCPR was significantly correlated with age, height, body weight (BW), BMI, waist circumference, duration of diabetes, retinopathy, insulin therapy, urinary CPR, F-CPR-index and P-CPR-index. Multiple stepwise regression analysis revealed that independent factors contributing to GSTΔCPR were BW (β=0.336), duration of diabetes (β= −0.107), presence of retinopathy (β= −0.121), use of DPP-4i (β= −0.099), metformin (β= −0.109), SGLT2i (β= −0.108, p=0.002) and P-CPR-index (β=0.432)(R2=0.453). Our date demonstrated that P-CPR-index was valuable and simple method in assessing residual β-cell function with/without insulin therapy in daily clinical practice.

Disclosure

Y.Matsuhashi: None. T.Abe: None. T.Fujita: None. S.Mizushiri: None. S.Chikazawa: None. M.Daimon: None.
1573-P: Association of Thyroid Hormone Levels with NAFLD in Recent-Onset Diabetes
Authors: SAATMANN NINA , SCHÖN MARTIN , ZAHARIA OANA P. , HUTTASCH MAXIMILIAN , STRASSBURGER KLAUS , TRENKAMP SANDRA , KUPRIYANOVA YULIYA , SCHRAUWEN-HINDERLING VERA , KAHL SABINE , BURKART VOLKER , WAGNER ROBERT , RODEN MICHAEL
Published: June 2023

Nonalcoholic fatty liver disease (NAFLD) is a growing health concern associated with obesity and type 2 diabetes (T2D). Thyroid hormones are important regulators of lipid homeostasis. Indeed, people with hypothyroidism are at greater risk for NAFLD and it has been suggested that humans with T2D are more likely to develop hypothyroidism. However, little is known about the relationship of thyroid function with NAFLD in type 1 diabetes (T1D) and T2D.

We hypothesized that (i) low free thyroxin (fT4) and high thyroid-stimulating hormone (TSH) levels are associated with increased hepatocellular lipid content (HCL) and (ii) that fT4 and TSH can identify persons at high-risk for hepatic steatosis in people with recent-onset diabetes. We examined people with T1D (n=358) or T2D (n=596) and 175 healthy participants of the German Diabetes Study (GDS). First, validation of the fatty liver index (FLI) against quantification of HCL by 1H-magnetic resonance spectroscopy revealed a close correlation (ß=0.715, p<0.001; n=446). Second, FLI negatively correlated with fT4 in males (ß=−0.139, p<0.01), but not in females with T2D (ß=−0.086, p=0.26). Likewise, TSH associated positively with FLI in males (ß=0.116, p<0.05), but not in females with T2D (ß=−0.057, p=0.45). TSH and FLI were differently associated between males and females before (p<0.05), but not after (p=0.82) adjustment for BMI. Finally, fT4 had a low diagnostic precision for steatosis (by FLI) as derived from the respective area under the receiver operating curve (0.57, 95% CI [0.53;0.62]; p<0.001) in T2D and was not significant in other groups. TSH had no diagnostic precision for steatosis in any groups.

In conclusion, FLI can be used as a surrogate measure of HCL in recent-onset diabetes. The correlation of FLI with lower thyroid function in male T2D suggests a sex-specific interaction between thyroid and liver lipid metabolism, which is mainly driven by body mass. Both, fT4 and TSH offer no relevant efficacy to detect steatosis at least in recent-onset diabetes.

Disclosure

N. Saatmann: None. M. Schön: None. O.P. Zaharia: None. M. Huttasch: None. K. Strassburger: None. S. Trenkamp: None. Y. Kupriyanova: None. V. Schrauwen-Hinderling: None. S. Kahl: None. V. Burkart: None. R. Wagner: Speaker's Bureau; Novo Nordisk, Sanofi. Advisory Panel; Daiichi Sankyo. M. Roden: Advisory Panel; Eli Lilly and Company. Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis. Consultant; TARGET PharmaSolutions, Inc. Research Support; Sanofi.
1590-P: Post-Oral Glucose Load Hyperinsulinemia in Individuals with Metabolic Syndrome and Metabolic-Associated Fatty Liver Disease—First Steps toward the Development of Type 2 Diabetes?
Authors: TRÉPANIER GABRIELLE , GIGNAC THEO , PRADEAU MARION , MORISSETTE ARIANNE , AGRINIER ANNE-LAURE , GAGNON CLAUDIA , VOHL MARIE-CLAUDE , MARETTE ANDRE , CARREAU ANNE-MARIE
Published: June 2023

Introduction: Metabolic associated fatty liver disease (MAFLD) increases the risk of incident type 2 diabetes (T2D), but mechanisms involved have not been clearly elucidated.

Objective: To assess post-oral glucose tolerance test (OGTT) glucose metabolism, insulin resistance, secretion and clearance in individuals with metabolic alterations, with or without increased liver fat.

Methods: Individuals with a BMI >25 kg/m2 and at least 1 criteria for metabolic syndrome were included in this analysis. Liver fat was quantified using MRI and participants were assigned to 2 groups according to > 5% liver fat (MAFLD group) or ≤ 5%. A 3h frequently-sampled OGTT was performed and oral minimal model was used to measure insulin sensitivity, secretion and disposition index.

Results: Fifty participants were included in this analysis and 50% had a liver fat > 5%. Post-OGTT glucose concentrations and iAUC glucose were not different between groups (p -≥ 0.50), whereas post-OGTT insulin concentrations and iAUC were significantly higher in the MAFLD group (p < 0.03) and significantly associated with liver fat. The components of insulin secretion (dynamic, static and total) were not different between groups (p -≥ 0.27). Insulin sensitivity and dynamic disposition indices were lower in the MAFLD group and significantly associated with liver fat. but in a multivariable regression model including sex and BMI, liver fat was not statistically associated with these indices. Insulin clearance indices were significantly lower in the MAFLD group, and liver fat statistically explained most of the variance in the multivariate model (p< 0.02).

Conclusion: Among individuals with metabolic alterations, the presence of MAFLD is associated with impaired insulin clearance and post-oral glucose load hyperinsulinemia. Insulin sensitivity and dynamic beta-cell function are also altered, features of the early pathophysiology of T2D.

Disclosure

G.Trépanier: None. T.Gignac: None. M.Pradeau: None. A.Morissette: None. A.Agrinier: None. C.Gagnon: Advisory Panel; Novo Nordisk, Other Relationship; Ascendis Pharma A/S, Research Support; Novo Nordisk. M.Vohl: None. A.Marette: Advisory Panel; Valbiotis, Amancia, Plexus, Acasti. A.Carreau: Advisory Panel; Novartis, Consultant; Valbiotis, Speaker's Bureau; Novo Nordisk Canada Inc.
1596-P: Homozygous Mutations in MFN2 Aggravated Fat Deposition in Mouse Hepatocytes
Authors: YU YUE , LUO YINGYING , ZHOU XIANGHAI , JI LINONG
Published: June 2023

Objective: Studies had found that homozygous mutations at p.R707W in the mitofusin-2 (MFN2) gene cause severe lipids metabolic abnormalities, and the mechanism has not been elucidated. In this study, we aim to explore the effect of the mutant protein on hepatocyte lipids deposition.

Methods: Primary hepatocytes of wild-type (WT), heterozygous and homozygous mutation were isolated from 8 weeks old mice. Hepatocytes were treated with 600μmol/L free fat acid (FFA) of oleic acid/palmitic acid (2︰1) mixture for 12 hours to establish a NAFLD model in vitro. The lipid accumulation of hepatocytes was observed by Oil red O staining and the contents of triglyceride (TG).

Results: Mutant mice carrying a novel p.R707W (CGA to TGG) mutation and silent mutation (p.D708=(GAT to GAC)) were identified (Fig. 1A). The results of Oil Red O staining and TG content measurement before FFA treating showed that more lipid was deposited in the homozygous hepatocyte than in WT cells (Fig. 1B, Fig. 1C) (*P<0.05), revealing that different genotypes of mice already have varied liver lipid contents at 8 weeks. After stimulation with FFA, TG content and lipidosis area in homozygous hepatocytes were significantly higher than those in WT (**P<0.01). And there was no significant difference between heterozygote and WT hepatocytes with or without FFA stimulation.

Conclusion: Homozygous mutation at p.R707W in MFN2 aggravated lipid deposition in mouse.

Disclosure

Y.Yu: None. Y.Luo: None. X.Zhou: None. L.Ji: Other Relationship; Eli Lilly and Company, Novo Nordisk, Merck & Co., Inc., Bayer Inc., Sanofi-Aventis U.S., Roche Pharmaceuticals, MSD Life Science Foundation, AstraZeneca, Boehringer Ingelheim Inc., Abbott, Metronics.

Funding

China International Medical Foundation (2021-N-03)
1602-P: Galectin-3 Inhibition Protects ApoE Knockout Mice against Western Diet–Induced Nonalcoholic Steatohepatitis and Glucose Intolerance
Authors: ARAUJO LAYANNE , SUCUPIRA FELIPE , DIAS CAROLINA C.B. , AMARAL ANDRESSA , PAULO CAMPOREZ JOAO
Published: June 2023

Nonalcoholic Fatty Liver Disease represents a broad spectrum of histological abnormalities ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis or hepatocellular carcinoma. NASH is characterized by steatosis, hepatic inflammation, hepatocellular ballooning, and fibrosis. Therefore, the aim of this work was to evaluate the effect of modified citrus pectin (MCP), inhibitor of galectin-3, in ApoE KO mice fed a western diet (WD). ApoE KO mice were divided into 3 groups: standard diet-fed (SD) group, WD-fed group, and WD-fed + MCP-treated group (WD+MCP). WD-fed mice displayed increased hepatic triacylglycerides (TAG-290%), and plasma ALT (115%) and AST (130%) compared with SD group. MCP treatment decreased hepatic TAG (30%) in WD-fed mice, plasma ALT and AST were reverted. WD-fed mice also displayed increased hepatic collagen deposition (18%), and MCP treatment inhibited this increase. These results were similar with hydroxyproline concentration in liver. WD-fed mice showed an impaired glucose tolerance compared with SD-fed mice, while MCP treatment improved glucose tolerance in WD-fed mice. Also, WD-fed mice presented increased fasting insulin (140%) compared with SD-fed mice, and MCP treatment reverted this increase by 100%. Gene expression of F4/80 was increased by 76% in the WD group compared with SD group, however had not significant difference between WD+MCP and SD group. Gene expression of matrix metalloproteinase 2 was increased by 5-fold in WD group compared with SD group, while this increase was inhibited with MCP treatment. Also, it was observed an increase in JNK phosphorylation by 3-fold in WD group, and MCP treatment inhibited this increase. Taken together, we confirm WD-fed ApoE KO mice as a suitable experimental model of NASH, and the inhibition of galectin-3 by the treatment with MCP protects ApoE KO mice against the development of NASH and glucose intolerance.

Disclosure

L. Araujo: None. F. Sucupira: None. C.C.B. Dias: None. A. Amaral: None. J. Camporez: None.

Funding

São Paulo Research Foundation (FAPESP)
1629-P: Association between Dyslipidemia and Myosteatosis Evaluated by Abdominal Computed Tomography
Authors: SEUNG KIM HWI , NA JUNG HAN , KYUNG CHO YUN , JE LEE WOO , HEE JUNG CHANG
Published: June 2023

Introduction: The association between dyslipidemia and myosteatosis measured using muscular quality map in abdominal computed tomography(CT) was analyzed in a large population.

Methods: Abdominal CT of 20,210 subjects were evaluated to measure total abdominal muscle area (TAMA) at L3 level. TAMA was segmented into intramuscular adipose tissue and skeletal muscle area (SMA), which was further classified into normal attenuation muscle area (NAMA: good quality muscle) and low attenuation muscle area (LAMA: poor quality muscle). Myosteatosis indices used were SMA/body mass index(BMI), NAMA/BMI, NAMA/TAMA, and LAMA/BMI. Dyslipidemia was defined as high-density lipoprotein cholesterol(HDL-C) less than 40mg/dL in men and 50mg/dL in women, low-density lipoprotein cholesterol(LDL-C) greater than 160mg/dL, or triglycerides(TG) greater than 150mg/dL.

Results: According to multiple logistic regression analyses, the odds ratios (ORs) of dyslipidemia according to HDL and LDL definitions showed a decreasing trend with increasing quartiles for SMA/BMI, NAMA/BMI, and NAMA/TAMA (P for trend < 0.001 for all). The adjusted ORs (95% confidence intervals[CIs]) for dyslipidemia in Q2, Q3, and Q4 for NAMA/TAMA compared with Q1 were 0.87 (0.79-0.96), 0.76 (0.69-0.85) and 0.55 (0.49-0.61) according to the HDL definition and 0.93 (0.83-1.05), 0.95 (0.84-1.07), and 0.69 (0.60-0.79) according to the LDL definition. Conversely, the ORs of dyslipidemia according to HDL and LDL showed an increasing trend according to increasing LAMA/BMI quartiles (P for trend < 0.001 for all). Dyslipidemia according to TG did not show a significant association after adjustment.

Conclusion: Dyslipidemia according to HDL-C and LDL-C definitions is associated with myosteatosis, positively with bad quality (unhealthy) muscle and negatively with good quality (healthy) muscle. Muscle quality may be an important risk factor for dyslipidemia and ensuing cardiometabolic diseases.

Disclosure

H.Kim: None. H.Jung: None. Y.Cho: None. W.Lee: None. C.Jung: None.
1635-P: Sex Differences in Skeletal Muscle Mitochondrial Function in Rats Fed a High-Fat/High-Sucrose Diet
Authors: KNAUB LESLIE , HULL SARA , HULETT NICHOLAS A. , KELLER AMY C. , REUSCH JANE E.B. , SCALZO REBECCA L.
Published: June 2023

Women maintain their metabolic health at greater body mass indexes compared with men, delaying the onset of type 2 diabetes (T2D). Skeletal muscle is responsible for the bulk of glucose uptake and oxidation; these functions are impaired in T2D. Skeletal muscle mitochondria support muscle bioenergetics balancing oxidative phosphorylation of ATP with the production of reactive oxygen species. We hypothesized that skeletal muscle mitochondria in females would be protected from the oxidative metabolic stress of high-fat/high-sucrose (HFHS) diet compared with males. Wistar rats fed a chow or HFHS diet for 14 weeks were sacrificed at 18 weeks. HFHS fed males gained more body weight compared with females (P < 0.0001), yet fat mass was greater with HFHS diet in both sexes when controlled for body mass (P < 0.0001). Glucose was greater in males and HFHS fed rats (P < 0.001). Insulin resistance (HOMA-IR) was greater in males (P = 0.01) but unaffected by diet. HFHS fed males had greater mitochondrial respiration compared with females (P < 0.01 diet by sex interaction). Nutrient stress can induce reactive oxygen species. Hydrogen peroxide (H2O2) production measured with Amplex Red at this respiration steady state was 34% greater in HFHS fed males compared with 11% in females. ADP titration revealed a greater area under the curve for HFHS fed males for both oxygen (P = 0.02) and H2O2 flux (P = 0.07). Protein content of mitochondrial complexes I and III, the sites of electron leak and generation of mitochondrial reactive oxygen species, were greater in males (P < 0.02), and complex V, the site of ATP production, was greater in females (P = 0.01). These data suggest that males respond to an obesogenic challenge with greater mitochondrial respiration and accompanying oxidant production whereas females with similar fat mass accrual are protected from excess oxidant production in this setting. Sex-specific adaptation to nutrient excess may play a role in a higher obesity threshold for women compared to men at risk for T2D.

Disclosure

L.Knaub: None. S.Hull: None. N.A.Hulett: None. A.C.Keller: None. J.E.B.Reusch: Advisory Panel; Medtronic. R.L.Scalzo: None.

Funding

U.S. Department of Veterans Affairs (BX004533-01, BX002046); National Institutes of Health (5T32AG000279-20)
1638-P: Oxidized Lipids Cause Ceramide Accumulation and Insulin Resistance in Skeletal Muscle
Authors: ZEMSKI BERRY KARIN , BERGMAN BRYAN C.
Published: June 2023

Accumulation of muscle lipids promotes insulin resistance and type 2 diabetes (T2D). Ceramides are important muscle lipids that decrease insulin sensitivity and it was previously shown that accumulation of ceramides in the sarcolemma negatively impacts insulin sensitivity in humans. The mechanisms explaining accumulation of lipids in specific compartments in skeletal muscle are unknown, but one possibility is through circulating oxidized lipids. POVPC, a major circulating oxidized phospholipid, was exposed to rat myotubes (1-50 μM) for 4h and the total cellular ceramide levels in myotubes measured by LC-MS/MS. Total ceramide content increased dose dependently at POVPC doses in the physiological range (5 μM, p <0.05). To determine the mechanism of POVPC induced ceramide accumulation, ceramide was measured in myotubes after treatment with POVPC (25 μM) in the presence of inhibitors of neutral and acid sphingomyelinase (GW4869 and ARC39), ceramide synthase (fumonisin B1) and serine palmitoyltransferase (myriocin). The individually administered inhibitors in the presence of POVPC each showed a decrease (41-55%) in ceramide accumulation. When all of inhibitors were administered together along with POVPC, an almost complete inhibition of ceramide accumulation (95%) was observed indicating that the sphingomyelinase, de novo, and salvage pathways of ceramide synthesis are activated by POVPC. The role of oxidized lipids on insulin sensitivity was examined after treatment of rat myotubes with 1-25 μM POVPC. Increasing doses of POVPC at doses as low as 1 μM significantly decreased insulin sensitivity in vitro (p <0.05). These results reveal circulating oxidized lipids promote ceramide accumulation and insulin resistance in muscle cells and may help explain variability in total and localized muscle ceramide levels between individuals. These data also suggest that therapies designed to lower circulating oxidized lipids could be beneficial for the treatment and prevention of T2D.

Disclosure

K.Zemski berry: None. B.C.Bergman: Research Support; Eli Lilly and Company.

Funding

National Institutes of Health (P30DK048520); University of Colorado (25N0350)
1639-P: Meroterpenoid-Rich Fraction of the Ethanol Extract from Sargassum Serratifolium Suppressed Muscle Atrophy Induced by Dexamethasone in C2C12 Myotubes and C57BL/6 Mice
Authors: LEE MIN-KYEONG , RYU HEEYEON , HAK JEONG HYEON , LEE BONGGI
Published: June 2023

Decline in muscle mass and strength impairs the ability to perform normal daily functions and increases the risk of falls and fractures, significantly reducing the quality of life. In addition, as the muscle is considered a major regulator of systemic glucose homeostasis, maintaining muscle mass is important for glycemic control. Although dexamethasone (DEX), a synthetic glucocorticoid, is a well-known anti-inflammatory drug, high doses or long-term use induces side effects such as skeletal muscle atrophy. Sargassum serratifolium is a brown alga that contains high concentrations of meroterpenoids and exhibits antioxidant, anti-inflammatory, anti-obesity, anti-atherosclerosis, and hepatoprotective activities. However, its effects on DEX-induced muscle atrophy remain unknown. Here, we investigated the beneficial effects of the meroterpenoid-rich fraction of the ethanol extract from S. serratifolium (MES) on DEX-induced muscle atrophy in C2C12 myotubes and C57BL/6 mice. In the in vitro study using C2C12 myotubes, DEX (5 μM) treatment reduced cell viability, myotube diameter, and glucose uptake, whereas MES treatment reversed these effects. In addition, in DEX-stimulated C2C12 myotubes, MES treatment not only increased the phosphorylation of Akt and p706SK but also decreased the mRNA and protein expression of protein degradation factors such as MAFbx/Atrogin-1, MuRF1, and FoxO3a. In the in vivo study, MES suppressed DEX-induced decrease in body weight, ability to exercise, lean body mass, calf thickness, muscle weight, and cross-sectional area of the gastrocnemius muscle. Taken together, MES ameliorated DEX-induced muscle atrophy and maintained glucose homeostasis. Therefore, MES can be used as a potential therapeutic agent for the treatment of muscle atrophy.

Disclosure

M.Lee: None. H.Ryu: None. H.Jeong: None. B.Lee: None.
1640-P: Meroterpenoid-Rich Ethanolic Extract of Sargassum serratifolium (MES) Alters Macrophage Transcriptome and Secretion Profile toward Improving Muscle Atrophy and Glucose Intolerance
Authors: RYU HEEYEON , LEE BONGGI
Published: June 2023

Skeletal muscle plays an essential role in glucose homeostasis. Of many cell types in the skeletal muscle, recent studies indicate that secretion factors derived from macrophages are important for glucose metabolism in the skeletal muscle. Here, RNA Sequencing analysis showed that Lipopolysaccharide (LPS) treatment broadly altered the transcriptome of macrophages, of which signaling related to secretion factors was markedly altered toward elevating unfavorable cytokines to maintain skeletal muscle metabolism. On the other hand, the treatment of the Meroterpenoid-Rich Extract of Sargassum Serratifolium (MES), a strong anti-inflammatory and antioxidant extract found in our previous studies, reversed the LPS-induced signaling pathways. We further tested whether the treatment of conditioned media (CM) derived from LPS-macrophage (LPS-CM) or CM derived from LPS-macrophage treated with MES (MES-CM) affects glucose homeostasis in differentiated C2C12 myotube cells. LPS-CM treatment notably increased mRNA levels of muscle atrophy-associated genes including MuRF1, MAFbx, and Myostatin, and decreased glucose uptake, and MES-CM treatment reversed these characteristics, indicating that secretion factors induced by LPS or MES either impair or improve muscle glucose homeostasis, respectively. We further analyzed secretion factors inside by proteome array and data showed that LPS-CM includes GDF-15, IL-1 α/β, RAGE, etc related to muscle atrophy and glucose intolerance, which were significantly reduced in MES-CM. These data indicate that LPS- or MES-induced changes in the transcriptome in macrophages are closely related to the alteration in secretion factors toward either impairing or improving glucose metabolism in the skeletal muscle respectively. Of many, the decrease in macrophage-derived cytokine mentioned above may be important for glucose homeostasis in the skeletal muscle.

Disclosure

H.Ryu: None. B.Lee: None.
1668-P: Differentiated Metabolic Effects of DA-1726, a Balanced GLP1R/GCGR Dual Agonist
Authors: CHAE YUNA , JUNG IL-HUN , KIM TAE-HYOUNG , JIN LEE SU , KIM MI-KYUNG , HEON KIM HYUNG
Published: June 2023

DA-1726 is a novel oxyntomodulin analogue preparing for phase I clinical trials for obesity. In this study, the pharmacological effect of DA-1726 compared to other competitor peptides was evaluated. DA-1726 showed superior efficacy compared to other glucagon-like peptide-1 receptor (GLP1R)/glucagon receptor (GCGR) dual agonist (Cotadutide; COTA) in reducing body weight (14.4% for DA-1726 and 6.4% for COTA vs. DIO control at 30 nmol/kg, p<0.05) and improving plasma glucose, insulin, and HOMA-IR (-91% for DA-1726 vs. -52% for COTA) in diet-induced obese mice. In addition, superior plasma triglyceride (TG) reduction and similar reduction of total cholesterol (T-CHO) compared to COTA were confirmed by DA-1726. These data suggested that the balanced dual agonist DA-1726 was superior to a GLP1R-biased dual agonist in metabolic effects. Meanwhile, enhanced glucagon action of GLP1R/GCGR dual agonists may increase the risk of hyperglycemia when GLP1R agonism is reduced. Thus, DA-1726 was injected for 3 weeks and glucose tolerance test was performed at 72-h after the last dosing. DA-1726 did not impair glucose tolerance even at minimal plasma concentrations during repeated dosing up to 100 nmol/kg. In the case of repeated dosing of 100 nmol/kg, the plasma drug concentration at 72-h after the final injection is similar to the concentration that induces about 50% activation of receptors under 4% human albumin condition. In a comparative study with a GLP1R/glucose-dependent insulinotropic polypeptide receptor (GIPR) dual agonist (Tirzepatide; TIR), DA-1726 showed a similar maximum efficacy on weight loss (31.2% for DA-1726 and 31.3% for TIR vs. DIO control, p<0.05). However, DA-1726 was more efficacious in improving plasma metabolic parameters such as glucose, TG, and T-CHO compared to TIR, indicating differential metabolic effects caused by GCGR agonism. Taken together, these data suggest that DA-1726 is a well-balanced GLP1R/GCGR dual agonist that effectively reduces body weight and glycemic control.

Disclosure

Y.Chae: None. I.Jung: None. T.Kim: None. S.Lee: None. M.Kim: Employee; Dong-A ST. H.Kim: None.
167-LB: Knowledge Retention and Glycemic Control in Participants of Kids in Control of Food (KICk OFF) Program—Virtual vs. On-Site
Authors: ALMATROOK REEM , TAHA NEHAD , RAHME ZAHRAA , ALQABANDI ALGHALIA
Published: June 2023

Introduction: Kids In Control Of Food (KICk OFF) is a structured educational program for children with T1D from ages 11 to 16 years old. Due to the COVID-19 pandemic, the program was adapted and delivered virtually to accommodate regulations. It is unclear whether the virtual adaptation provides the same learning experience and effect on glycemic control as the original on-site version.

Objectives: To compare both HbA1c and knowledge retention between participants who completed the program virtually versus on-site.

Methods: A knowledge retention test of 15 questions was developed addressing the main diabetes concepts explained during KICk OFF: diabetes, insulin, carbohydrate counting, etc. This test was distributed to all the participants (virtual/on-site) 6 months after the completion of the course. Their knowledge retention tests were scored as a percentage of correct answers to total questions. HbA1c was recorded at baseline and 6 months. A t-test was used for statistical analysis.

Results: A total of 43 participants attended KICk OFF (23 on-site, 20 virtual). A significantly higher knowledge retention test score was achieved in the on-site group (p-value=0.015) (Table 1). An insignificant reduction of HbA1c of 0.3% was observed in the on-site group after 6 months, and no reduction in the virtual group (Table 2). Table 1: Mean retention test scores for the on-site and virtual participants.

Table 2: Mean HbA1c for the on-site and virtual participants.

Discussion: Although virtual KICk OFF was necessary during COVID-19, the results indicated a superiority in the on-site KICk OFF course in terms of knowledge retention, as well as HbA1c reduction. Further research is recommended.

Disclosure

R. Almatrook: None. N. Taha: None. Z. Rahme: None. A. Alqabandi: None.
1670-P: Sex-Dependent Effects of PERK Deletion in Thermogenic Adipocytes
Authors: JENA JAYASHREE , GARCÍA-PEÑA LUIS M. , PEREIRA RENATA
Published: June 2023

Brown and beige adipocytes dissipate chemical energy as heat through thermogenic respiration, thereby playing important roles in adaptive thermogenesis and energy homeostasis in mice. The Protein Kinase R (PKR)-Like Endoplasmic Reticulum Kinase (PERK) has been shown to be required for mitochondrial thermogenesis in cultured brown adipocytes, and in mice lacking PERK in white and brown adipose tissues. Here, we tested the hypothesis that PERK expression specifically in thermogenic adipocytes is required for adaptive thermogenesis and to regulate energy homeostasis in mice, by selectively deleting PERK in Ucp1-expressing cells (brown and beige adipocytes) of male and female mice. At baseline conditions, mitochondria oxygen consumption rates (OCR) were significantly reduced in brown adipocytes isolated from male, but not from female KO mice. After being housed at thermoneutrality for 7 days (30 °C), wild type (WT) and KO mice were exposed to 4 °C for 3 days. Surprisingly, both male and female KO mice were able to properly adapt to cold exposure, as demonstrated by preserved core body temperatures relative to WT mice. Interestingly, age-induced weight gain, fat mass expansion and impairments in glucose homeostasis were all attenuated in KO males, while weight gain was exacerbated in KO females. This correlated with increased energy expenditure (EE) in male mice, while EE was reduced in female mice. We, next, tested the hypothesis that male KO mice would be resistant to diet-induced obesity. After 12 weeks of high-fat feeding (60% calories from fat), male KO mice became as obese, glucose intolerant and insulin resistant as WT mice. In conclusion, our data suggest that PERK expression in thermogenic adipocytes reduces mitochondrial OCR in male mice, but is dispensable for thermoregulation after short-term cold exposure in both male and female mice. Furthermore, our data reveal a sex-dependent effect of PERK in thermogenic adipocytes in the regulation of energy homeostasis, which is dependent on changes in EE.

Disclosure

J.Jena: None. L.M.García-peña: None. R.Pereira: None.

Funding

National Institutes of Health (DK125405, 2T32DK112751-06)
1672-P: Isoxanthohumol Improves Obesity and Glucose Metabolism via Regulation of Gut Barrier and Intestinal Lipid Absorption with a Bloom of Akkermansia muciniphila
Authors: WATANABE YOSHIYUKI , FUJISAKA SHIHO , WATANABE SHIRO , NISHIMURA AYUMI , KADO TOMONOBU , RAHIL ASLAM MUHAMMAD , BILAL MUHAMMAD , MORINAGA YOSHITOMO , TOBE KAZUYUKI
Published: June 2023

Dysbiosis is an important factor that leads to metabolic disorders via disruption of the gut barrier function. A decrease in Akkermansia muciniphila (AM) is a phenotype of obesity-induced disruption of the gut barrier. Although interventions to increase AM have been reported to improve glucose metabolism, the underlying mechanism has not been fully understood. The administration of IX suppressed weight gain and steatohepatitis and improved glucose metabolism in diet-induced obese mice. Mechanistically, IX inhibited pancreatic lipase activity and lipid absorption via decreased expression of the lipid absorption transporter, CD36, in the jejunum. Moreover, IX administration improved the gut barrier function and reduced metabolic endotoxemia. In contrast, the observed effects of IX were cancelled by antibiotics and reproduced by fecal microbiota transplantation to GF mice. 16S rRNA sequencing revealed that the microbial community structure changed with a significant increase in AM in the IX-administration group. An anaerobic chamber study showed that IX promoted the growth of AM, while exhibiting antimicrobial activity against some Bacteroides and Clostridium species. To further explore the direct impact of AM on lipid and glucose metabolism in monocolonized mice, we transplanted either AM or Bacteroides thetaiotaomicron to GF mice. AM monocolonization decreased CD36 expression in the jejunum and improved glucose metabolism with decreased multiple classes of fatty acids in plasma metabolomics analysis. In summary, IX contributes to metabolic improvement by decreasing CD36 and lipid absorption in the small intestine which is associated with a bloom of AM, suggesting an important interaction between food ingredients and AM abundance in controlling metabolism.

Disclosure

Y.Watanabe: None. S.Fujisaka: None. S.Watanabe: None. A.Nishimura: None. T.Kado: None. M.Aslam: None. M.Bilal: None. Y.Morinaga: 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.

Funding

Japan Society for the Promotion of Science (21K20896, 22K16424); Lotte Foundation; Yakult Bio-Science Foundation