bluuebunny/crossref_metadata_2025 huggingface dataset:
1427-P: Factors Predicting Significant Improvement in Glycemic Control after Endocrinology Referral in Patients with Type 2 Diabetes Mellitus and Hemoglobin A1c ≥ 10%
Authors: WILLIAMS VANESSA , NAIR TRISHA P. , AYEGBUSI OLUBUKOLA , BOTCHWAY ALBERT , BUHNERKEMPE MICHAEL , JAKOBY MICHAEL G.
Published: June 2024

Endocrinology referral has been shown in several studies to significantly improve glycemic control in patients with uncontrolled type 2 diabetes mellitus (DM2). However, studies identifying factors that predict glycemic improvement are lacking. This is a retrospective study of adults (N =138, age ≥ 18 y) with DM2 who were referred to the Southern Illinois University Division of Endocrinology with initial HbA1c ≥ 10% and attended 6-month follow-up appointments. Patients who achieved HbA1c reduction ≥ 1% at 6-months were defined as the glycemic improvement group, while patients whose HbA1c fell by < 1% or increased were considered controls. There was no difference in mean initial HbA1c for the glycemic improvement (12.0 ± 1.6%) and control groups (12.0 ± 1.2%, P = 0.98). At the 6-month visit, 82% (113/138) of patients achieved glycemic improvement, with mean HbA1c 7.9 ± 1.7% for the improvement group and 12.2 ± 1.7% for the control group (P < 0.0001). There were no differences in demographics, insurance status, or comorbidities between the two groups. In a LASSO regression, factors that predicted glycemic improvement were proportion of endocrinologist appointments attended (OR 4.01, 95% CI 1.33-228.61), initiation of continuous glucose monitoring (OR 2.11, 1.11-45.86), proportion of dietitian and diabetes educator appointments attended (OR 1.91, 1.07-28.41), and initiation of a GLP-1 receptor agonist (OR 1.62, 1.04-11.71). Endocrinology referral significantly improves glycemic control for patient with DM2 and severe hyperglycemia, with compliance with appointments, initiation of CGM, and treatment with GLP-1 receptor agonists appearing to be key predictors of glycemic improvement.

Disclosure

V. Williams: None. T.P. Nair: None. O. Ayegbusi: None. A. Botchway: None. M. Buhnerkempe: None. M.G. Jakoby: None.
1428-P: Impact of Socioeconomic Inequalities on COVID-19 Mortality of People Living with Diabetes during the 2020 Epidemic Waves in France
Authors: GUION MARIE , GORIA SARAH , FOSSE-EDORH SANDRINE , COSSON EMMANUEL
Published: June 2024

Introduction & Objective: The aim was to describe the impact of socioeconomic inequalities (SEI) on COVID-19 mortality in people living with pharmacologically treated diabetes (TD) during the two 2020 epidemic waves (W1: March-May; W2: September-December) in European France.

Methods: TD were identified using a validated algorithm from the French National Health Data System. COVID-19 mortality in 2020 was obtained from medical causes of death for people alive on January 1, 2020. SEI were measured using the French Deprivation index (FDep, by population quintiles; Q1: corresponding to the least deprived municipalities). Annual average age-standardized (European standard population 2013) mortality rates (aMR) for each wave are presented with their 95% confidence intervals [IC95%] per 100,000 person-years.

Results: During W1, the highest aMR were observed in men with TD living in the least deprived municipalities (Q1: 398 [373-422]). Then, the aMR decreased until Q3 (234 [219-249]) before increasing again until Q5 to 309 [297-321]. The same trends were observed but less pronounced in women with TD (Q1: 257 [240-275]; Q3: 156 [143-169] Q5: 196 [187-206]); and in men and women without TD. During W2, aMR were stable from Q1 to Q4, at around 240/100,000, and significantly higher in Q5: 300 [286-314] in men with TD. In women with TD, no difference was observed according to deprivation level (Q1: 171 [156-186] and Q5: 171 [162-180]), whereas an increasing gradient was observed in men and women without TD (respectively Q1: 45 [42-49]; Q5: 70 [66-74] and Q1: 17 [15-19]; Q5: 28 [25-30]).

Conclusion: These first descriptive results show that the impact of SEI on COVID-19 mortality appeared to change between the two epidemic waves in France in 2020. They raise questions about the impact of barrier measures and non-pharmaceutical interventions in SEI.

Disclosure

M. Guion: None. S. Goria: None. S. Fosse-Edorh: None. E. Cosson: Advisory Panel; Abbott, AstraZeneca, Lilly Diabetes, Novo Nordisk, Sanofi, Roche Diagnostics, Novartis AG, Amgen Inc.
1434-P: Lower Insulin-Like Growth Factor-1 and Insulin-Like Growth Factor Binding Proteins Increase Ten-Year Diabetes Risk in Individuals with Obesity
Authors: MAURYA PRIYANSHI , YANEK LISA , YANG JUN , EVERETT ALLEN D. , BECKER LEWIS , VAIDYA DHANANJAY
Published: June 2024

Introduction: Obesity predisposes to Type 2 Diabetes, thus risk stratification among the nondiabetes people with obesity is important. Insulin-like Growth Factor-1 (IGF1) and Insulin-like Growth Factor Binding Proteins (IGFBPs), which modulate metabolism, may predict diabetes in such high-risk adults.

Methods: In this case cohort analysis nested within the GeneSTAR study, 40 incident diabetes cases and 40 in a random cohort sample with a BMI ≥ 30 kg/m2 at baseline (38% males, 50% African Americans, age range 22-69 years) were followed for incident diabetes during a follow up of ≥10 years. Sampling-weighted logistic regression assessed the relationship between baseline IGF/IGFBP biomarkers measured by ELISA and diabetes risk.

Results: Lower levels of IGF1, IGFBP1, IGFBP2, IGFBP3 and IGFBP6 predicted 10-year diabetes incidence adjusting for demographic factors (Table, Model 1). This association remained statistically significant for IGFBP2, IGFBP3 and IGFBP6 after adjusting for fasting glucose at baseline (Model 2).

Conclusions: IGF/IGFBP complex proteins may serve as early indicators for diabetes risk in people with obesity without current diabetes beyond fasting glucose levels. Future studies should investigate the functional role of the IGF/IGFBP system in glucose metabolism and diabetes prevention.

Disclosure

P. Maurya: None. L. Yanek: None. J. Yang: None. A.D. Everett: Advisory Panel; Merck & Co., Inc. L. Becker: None. D. Vaidya: None.

Funding

National Institutes of Health (HL092165 and HL099747)
1455-P: The Oral Disposition Index (ODI) and Its Components during the Progression of Autoantibody-Positive (Ab+) Individuals to Type 1 Diabetes (T1D)
Authors: ISMAIL HEBA M. , CUTHBERTSON DAVID D. , JACOBSEN LAURA M. , ATKINSON MARK A. , LIBMAN INGRID , REDONDO MARIA J. , SOSENKO JAY
Published: June 2024

Introduction and Objective: A lower ODI (secretion x sensitivity) has been shown to be predictive of T1D. In a longitudinal analysis, we assessed whether there is differential change during the progression to T1D between the two components of ODI, secretion and sensitivity.

Methods: TrialNet Pathway to Prevention progressors to T1D (n=336) were studied. All had OGTTs at baseline, 0.5 years before diagnosis, and at diagnosis. The mean (±SD) interval from baseline to 0.5 years before diagnosis was 3.6 (2.4) years. AUC C-peptide/AUC glucose (AUC Ratio) and 1/fasting insulin (1/FI) were used as proxies for secretion and sensitivity, respectively. Change/yr was calculated.

Results: Mean (±SD) baseline age and BMI were 13.3 (10.7) years and 23.0 (41.8) kg/m2, respectively. The majority were male (53.3%) and White (91.7%). The change/yr of both ODI and AUC Ratio was not significant from baseline to 0.5 years before diagnosis (table). However, from 0.5 years before to diagnosis, ODI and AUC Ratio declined appreciably (both p<0.001). In contrast, 1/FI did not change significantly in either interval.

Conclusion: In progressors to T1D, insulin secretion (measured by AUC Ratio) has an accelerated decline proximal to diagnosis of T1D, whereas insulin sensitivity (measured by 1/FI) changes minimally. These findings are relevant to the interpretation of the ODI in Ab+ individuals.

Disclosure

H.M. Ismail: Consultant; Sanofi, Rise Therapeutics. D.D. Cuthbertson: None. L.M. Jacobsen: Advisory Panel; Insulet Corporation. M.A. Atkinson: None. I. Libman: None. M.J. Redondo: None. J. Sosenko: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases
1457-P: Challenges in Detecting Immune Checkpoint Inhibitor-Induced Type 1 Diabetes Mellitus by Glucose Monitoring
Authors: SHARP JOHN , PASADYN CASSANDRA , ZHAO SONGZHU , WEI LAI , PRESLEY CAROLYN , OWEN DWIGHT , WYNE KATHLEEN , MEARA ALEXA A.
Published: June 2024

Introduction: Immune checkpoint inhibitor (ICI) induced type 1 diabetes (T1D) occurs in less than 1% of patients. It is unknown if glucose abnormalities prior to T1D diagnosis occur and in what fashion. We aimed to evaluate whether abnormal glucose trends precede ICI-T1D diagnosis.

Methods: We conducted a single-center retrospective study of patients with ICI-T1D after cancer treatment between 2010 and 2022. Characteristics assessed included serum glucose values at baseline, immediately prior to T1D, and at T1D diagnosis. Linear mixed model with random intercepts for each participant was used to examine glucose trend over time. To test effect modification of sex, age, BMI, autoantibodies, and DKA, interaction terms were added.

Results: Thirty-five patients had ICI-T1D. Median glucose levels were baseline=116 mg/dL (IQR 105-152), prior to T1D=170 mg/dL (IQR 130-298) and at T1D diagnosis=453 mg/dL (IQR 388-544) with median interval between of 16 days. Mixed model demonstrated significant increase in serum glucose of 6.02 mg/dL per day (95% CI 4.18, 7.85, p<0.001). Notably, females had larger increases in serum glucose per day than males (Figure 1).

Conclusion: Patients who develop ICI-T1D have abnormal serum glucose elevations prior to T1D diagnosis though rises were mild. Whether intervention utilizing continuous glucose monitoring could prevent morbidity requires further research.

Disclosure

J. Sharp: None. C. Pasadyn: None. S. Zhao: None. L. Wei: None. C. Presley: Advisory Panel; Regeneron Pharmaceuticals Inc. Other Relationship; Jazz Pharmaceuticals. D. Owen: Research Support; Merck & Co., Inc., Bristol-Myers Squibb Company, Palobiofarma, Genentech, Inc. Other Relationship; Genentech, Inc. Research Support; Pfizer Inc. K. Wyne: None. A.A. Meara: Consultant; AbbVie Inc., Sanofi, Amgen Inc., AstraZeneca.
1458-P: Cardiovascular Risk Is Higher in People with Type 1 Diabetes Living with Overweight or Obesity—Insights from the SFDT1 Cohort
Authors: SALLE LAURENCE , JULLA JEAN-BAPTISTE , AGUAYO GLORIA A. , TATULASHVILI SOPIO , SABLONE LAURA , JOUBERT MICHAEL , RENARD ERIC , LABLANCHE SANDRINE , COSSON EMMANUEL , FAGHERAZZI GUY , RIVELINE JEAN-PIERRE
Published: June 2024

Introduction and Objectives: Individuals with type 1 diabetes (T1D) are faced with a growing prevalence of obesity, a recognized determinant of cardiovascular (CV) risk. This study aims to evaluate the metabolic profile, CV risk, and diabetes-related complications across body mass index (BMI) classes in individuals with T1D.

Methods: Using data from SFDT1, a multicentric French cohort, individuals with T1D were stratified into four BMI classes: underweight (<18.5 kg/m²), normal weight (18.5-24.9 kg/m²), overweight (OW) (25-29.9 kg/m²), and obesity (OB) (BMI ≥30 kg/m²). Baseline statistical analyses were performed with mean ± SD or frequency (%), with group comparisons through Kruskall-Wallis, variance analysis, and Chi-squared tests. Spearman correlation and logistic regression were applied. CV risk was evaluated using the Steno T1 Risk Engine score (STRS) in people in primary prevention.

Results: Among 1,724 participants (age 38 years, diabetes duration 22 years, BMI 24.9kg/m2, Male 53%), 8% had a CV history and 31% were classified as OW or OB. Age and duration of diabetes (ranging from 17.5 to 25.0 years) increased with BMI class. The mean HbA1c remained comparable (7.5% overall, p=0.5975) but the proportion of participants with HbA1c≥6.9%, as well as those with high blood pressure and dyslipidemia increased with BMI class. BMI was associated with CV history (OR=1.044, CI95% 1.004-1.084), even after adjustments for age, sex, and diabetes duration. In the primary prevention population, compared to normal weight, those with OW and OB had an increase of STRS at 5 years (57% and 74%) and 10 years (50 and 60%) (p<0.001). BMI correlated with 5 and 10-year STRS (p<0.001) and Waist/Height ratio with 10-year risk (p<0.001). OW and OB were associated with retinopathy but not nephropathy.

Conclusion: T1D individuals with OW and OB had more CV history, higher STRS at 5 and 10 years, and more retinopathy. Visceral adiposity was associated with increased STRS.

Disclosure

L. Salle: Advisory Panel; Sanofi, Amarin Corporation. J. Julla: Board Member; Sanofi. Speaker's Bureau; Lilly Diabetes, Novo Nordisk. G.A. Aguayo: None. S. Tatulashvili: None. L. Sablone: None. M. Joubert: Consultant; Abbott, Medtronic, Dexcom, Inc. E. Renard: None. S. Lablanche: None. E. Cosson: Advisory Panel; Abbott, AstraZeneca, Lilly Diabetes, Novo Nordisk, Sanofi, Roche Diagnostics, Novartis AG, Amgen Inc. G. Fagherazzi: Speaker's Bureau; Sanofi. Advisory Panel; Timkl, SAB Biotherapeutics, Inc., Vitalaire, Roche Diabetes Care. J. Riveline: Board Member; Abbott, Novo Nordisk A/S, Sanofi, Eli Lilly and Company, Medtronic, Dexcom, Inc., Insulet Corporation, Air Liquide, AstraZeneca.
1466-P: Screening and Functional Analysis of Mutations and Variations in NEUROD1 Gene in Pedigrees of Maturity-Onset Diabetes of the Young
Authors: LIU LIMEI , ZHANG JUAN , GE XIAOXU , JIANG FUSONG , LI TIANTIAN , LIU CHANWEI , CHEN YATING
Published: June 2024

Introduction & Objective: To screen the mutations of NEUROD1 gene in maturity-onset diabetes of the young (MODY) families, and to investigate the association of mutations and variants with the onset of MODY6 in Chinese, and its potential pathogenesis.

Methods: PCR-direct sequencing was used for screening NEUROD1 mutations and variations from 96 MODY probands who were negative for mutations in the GCK/MODY2, HNF1A/MODY3, and HNF1B/MODY5 genes. A de novo modeling method was used to predict the three-dimensional (3D) structures of wild type (WT) and mutated NEUROD1 proteins. Transcriptional activities of both WT and mutant of NEUROD1 on insulin gene were detected using dual luciferase reporter gene system. Moreover, the genotypic frequency of NEUROD1 variations were compared between the 96 MODY probands and 100 nondiabetic control subjects.

Results: Glu59Gln (NM_002500.5, c.175G>C), a heterozygous missense mutation in the NEUROD1 gene, was identified in a MODY pedigree. 3D structural analysis showed that the mutation transformed the negatively charged Glu59 of WT into uncharged mutation Gln59, leading to the loss of Glu59-Arg54 and Glu59-Lys88, two salt bridge bonds, and the formation of Gln59-Arg54, one new hydrogen bond. Transcriptional activity of Glu59Gln mutant for insulin gene was reduced 36.3% when compared with that of WT (P<0.01). A common variation Ala45Thr (G-A) was identified, and AA+GA genotypic frequency of the variation was significantly elevated in the 96 MODY probands in comparison to 100 nondiabetic control subjects (P=0.002).

Conclusion: Glu59Gln mutation altered the N-terminal molecular conformation of NEUROD1 protein, resulting in decreased transcriptional activity of insulin gene, which was the cause of the defective insulin secretion in mutation carriers of the MODY6 pedigree. In addition, the Ala45Thr variation was associated with earlier age of onset of diabetes in MODY6 probands.

Disclosure

L. Liu: None. J. Zhang: None. X. Ge: None. F. Jiang: None. T. Li: None. C. Liu: None. Y. Chen: None.

Funding

National Science Foundation of China (81970686,81770791)
147-OR: Obesity Is Associated with Increased Clearance and Reduced Drug Exposure to Metformin in Youth with Type 2 Diabetes
Authors: SRINIVASAN SHYLAJA , YEN KEVIN , FLOREN ALEXANDER , SAVIC RADA
Published: June 2024

Introduction & Objectives: Youth have higher treatment failure rates on metformin when compared with adults. There is interpatient variability in metformin pharmacokinetics (PK) and the influence of obesity on metformin PK in youth remains unclear. Our objectives were to develop a population PK model for metformin in youth to examine current dosing strategies and to quantify the relationship between metformin PK and obesity in youth with T2D.

Methods: We performed semi-intensive PK sampling in 50 youth < 18 years with T2D on metformin. We measured metformin levels before, 1-2 and 3-6-hours after a supervised 1000 mg dose of immediate-release metformin. We used non-linear mixed effects modeling to develop a population PK model. Simulations were performed to estimate area under the 24-hour metformin concentration-time curve (AUC) values.

Results: Mean participant age was 15.0 (SD 1.6) years, 66% were male, mean body mass index (BMI), 35.9 (SD 6.8) kg/m2, and mean eGFR, 114.7 (SD 22.6) mL/min/1.73m2. A one-compartment model best described the data, with the following parameter estimates: clearance (CL), 110 L/h (7.8% CV); volume of distribution, 461 L (11.0% CV); absorption rate constant, 0.76 /h (9.8% CV). Estimated CL increased by 3% (21.4% CV) for every 1 kg/m2 increase in BMI, and by 6% (53.8% CV) for every 10 mL/min increase in eGFR. When comparing AUC estimates from our model with those from a model developed using data from 236 adults on metformin, median AUC for youth receiving 2000 mg metformin daily was lower than for adults on the same dose (18.47 mg*h/L vs. 27.49 mg*h/L). Simulations showed that in youth, higher doses of at least 2550 mg and up to 3000 mg daily were needed to achieve exposures similar to adults.

Conclusion: Obesity is associated with increased metformin CL and reduced AUC in youth and higher doses are needed to achieve comparable drug exposure to adults. As next steps, we are testing the tolerability and efficacy of higher doses of metformin in a clinical trial.

Disclosure

S. Srinivasan: None. K. Yen: None. A. Floren: None. R. Savic: None.

Funding

National Institutes of Health (K23DK120932)
1472-P: Low CRP Alleles in HNF1A Are Associated with Increased Risk of Cardiovascular Disease—A Meta-analysis
Authors: YANG CHAOCHAO , HAN XUEYAO , JI LINONG
Published: June 2024

Objective: Rare variants in HNF1A account for Maturity onset diabetes of the young 3 (MODY3). Common variants of HNF1A are associated with serum CRP, and MODY3 patients have greatly low CRP levels distinct from other types of diabetes. Low dose sulfonylureas are recommended for MODY3 patients in ADA guideline. However, available clinical trial showed liraglutide, an anti-diabetic drug protecting from cardiovascular disease (CVD), had similar effect and lower risk of hypoglycemia compared with glimepiride. Since the common variants of HNF1A are associated with higher risk of CVD, we aimed to perform the meta-analysis to investigate the association of the low CRP alleles in HNF1A with CVD and indirectly evaluate the CVD risk of MODY3.

Methods: A comprehensive literature search was conducted using PubMed, Embase and CNKI databases from inception to December 2023. Association studies concerning the association of HNF1A with CRP, CVD, blood lipid and diabetes were included. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using Review Manager 5.3.

Results: Three common variants in the coding region of HNF1A (rs1169288, rs2464196, rs1169289) were included in our study. The minor alleles of these variants were all associated with low CRP levels (OR 0.89, 95%Cl 0.86-0.91; OR 0.89, 95%Cl 0.88-0.91; OR 0.89, 95%Cl 0.88-0.91, respectively). Their low CRP alleles were associated with increased risk of CVD (OR 1.05, 95%CI 1.04-1.06), elevated LDL cholesterol levels (OR 1.05, 95%Cl 1.03-1.08) and increased risk of type 2 diabetes (OR 1.04, 95%Cl 1.01-1.08).

Conclusion: Our study has revealed an association between low CRP alleles in HNF1A and an elevated risk of CVD, possibly due to dyslipidemia or poor glycemic control. This suggests that for MODY3 patients, it may be more reasonable to prioritize anti-diabetic with cardiovascular protection such as GLP-1 receptor agonist, but not sulfonylureas.

Disclosure

C. Yang: None. X. Han: None. L. Ji: None.
1512-P: Brown Adipose NMNAT1 Is Necessary for Maintaining NAD+ Levels but Dispensable for Systemic Energy Metabolism
Authors: SHEN XIYU , SONG WON-SUK , CAO YANG , JIAO XINFENG , ZHU YUAN , JANG CHOLSOON , YANG QIN
Published: June 2024

Brown adipose tissue (BAT) is rich in mitochondria and expresses high levels of uncoupling protein 1 (UCP1), enabling it to regulate thermogenesis and system energy expenditure. NAD+ (nicotinamide adenine dinucleotide) is a key cofactor for maintaining mitochondrial function by serving as a redox carrier and signaling molecule. To investigate the regulation and function of NAD+ in BAT, we measured the expression of genes involved in NAD+ synthesis and catabolism in mice under room temperature, cold challenge, and thermoneutral conditions. We found that the expression of nicotinamide nucleotide adenylyltransferase 1 (NMNAT1), the final enzyme for NAD+ synthesis, was suppressed by thermoneutrality and increased by cold challenge in BAT. We, therefore, generated brown adipocyte-specific NMNAT1 knockout mice (NMNAT1-bKO) by crossing the NMNAT1 flox/flox mice to the UCP1-Cre mice. NMNAT1 deletion reduced NAD+ levels by approximately 50%, accompanied by the accumulated precursors, including NMN and NaMN in BAT. Despite the significant reduction of BAT NAD+, NMNAT1-bKO mice showed comparable body weight, normal glucose tolerance and insulin sensitivity, and unchanged systemic energy metabolism, including O2 consumption, CO2 production, and RER in the metabolic cage studies. Further cold challenges and high-fat diet feeding did not induce any differences in the metabolic phenotype. RNA-seq analysis of BAT from NMNAT1-bKO and control mice under cold challenge revealed enrichment of genes involved in mitochondrial function and lipid metabolic process. These results show that BAT NMNAT1 is necessary for maintaining NAD+ levels but dispensable for systemic energy metabolism, possibly due to compensatory upregulation of mitochondrial genes.

Disclosure

X. Shen: None. W. Song: None. Y. Cao: None. X. Jiao: None. Y. Zhu: None. C. Jang: None. Q. Yang: None.

Funding

National Institutes of Health (R01DK121146)
1513-P: Physiological Level of Fructose Together with Glucose Promotes Brown Adipogenesis and Facilitates Fatty Acid Transport and Metabolism in Differentiated Mouse Brown Adipocytes
Authors: WU XIANGDONG , ELSAID SALAHELDEEN A.A. , SENG TEE SUI
Published: June 2024

Because of its thermogenic property in response to cold and overnutrition, brown adipose tissue in adult humans has become an attractive therapeutic target for treatment of obesity, atherosclerosis and other metabolic syndromes. It is unknow if fructose impacts adipogenesis, metabolism and functions of brown adipocytes. To address the question, we isolate brown preadipocyte from newborn mouse pups, immortalized the cells, and differentiated cells in culture medium with different sugars (1g/L glucose, 1g/L glucose plus 1g/L fructose, 1g/L fructose). Fructose plus glucose increased expression of adipogenesis markers including PPAR-γ, UCP-1 and C/EBP1. Fructose alone decreased adipogenesis proteins. Moreover, fructose alone increased CD36 but decreased FABP4 expression, suggesting cells need to uptake more fatty acid in compromise of carbon shortage from glucose, but fatty acid could not be effectively transported to organelles such as mitochondria, ER or Golgi because of lack of FABP4. In contrast, Fructose plus glucose increased FABP4 although it did not change of CD36, suggesting fatty acid could effectively be trafficked to organelles. Fructose plus glucose did not change phosphorylation of p38-MAPK but enhanced the phosphorylation of Erk at Thr202 and Tyr204. As to Akt, the site of Ser473 phosphorylation decreased, not at Thr308. Our data indicates physiological level of fructose together with glucose promotes brown adipogenesis, enhances thermogenic protein UCP-1, facilitates fatty acid transport and metabolisms in differentiated mouse brown adipocytes.

Disclosure

X. Wu: None. S.A.A. Elsaid: None. S. Tee: None.
1526-P: Alpha Cells Facilitate Neuronally-Stimulated Insulin Secretion at Fasting Glucose
Authors: TRIMIGLIOZZI KELLY , WIEDEMANN SOPHIA J. , MEIER DANIEL T. , BOENI-SCHNETZLER MARIANNE , DONATH MARC Y.
Published: June 2024

Introduction: Pancreatic islets are richly innervated by parasympathetic neurons and in turn neuronal stimulation can induce insulin secretion even in the fasted state. A prime example of this neuronally-driven insulin secretion is the cephalic phase insulin response, which is the release of insulin in the anticipation of a meal and occurs prior to changes in blood glucose. We recently found IL-1b to be in an important mediator of cephalic phase insulin secretion, however the mechanisms enabling neuronally-mediated insulin release from pancreatic islets in the fasted, low glucose state are still unknown.

Methods: We treated overnight-fasted mice with exogenous glucagon pre-treated with atropine and assessed insulin secretion. Using transgenic mice in which exclusively alpha cells are ablated, we studied the contribution of glucagon in cephalic phase insulin secretion. With isolated islets of wild-type and alpha cell-ablated mice we assessed insulin and glucagon secretion at 3.5mM glucose after co-stimulation with IL-1b and a muscarinic agonist (carbachol). Further, we blocked both glucagon and GLP-1 receptors to investigate which receptor glucagon acts on in our isolated islets setting.

Results: We found that exogenous glucagon can stimulate insulin secretion and this stimulation was absent in atropine-pretreated mice. Further, alpha-cell ablated mice do not exhibit a cephalic phase insulin response. In vitro, co-stimulating islets with the carbachol and IL-1b stimulated insulin secretion at basal glucose, and this was not the case in alpha cell-ablated islets. Lastly, we found that glucagon acts both on the glucagon and GLP-1 receptor to enable carbachol and IL-1b stimulated insulin release.

Conclusion: Alpha cells are essential for cephalic phase insulin secretion and this neuronally-mediated beta-cell response relies on glucagon or GLP-1, thereby positioning alpha cells as an important facilitator of neuronally-stimulated insulin secretion at fasting glucose.

Disclosure

K. Trimigliozzi: None. S.J. Wiedemann: None. D.T. Meier: None. M. Boeni-Schnetzler: None. M.Y. Donath: Advisory Panel; Novo Nordisk, Lilly Diabetes, Boehringer-Ingelheim. Research Support; Boehringer-Ingelheim, Olatec.
1528-P: Investigate Functional Dynamics of Neuropeptides in Acute Brain Slices to Predict Anorexigenic Efficacy
Authors: PEKCEC ANTON , ALTAS BEKIR , BRUSCHETTA GIUSEPPE , BUZZANCA ANNA , DOERR JONAS , LAM DANIEL , LINCOLN KATHLEEN A. , MACK VOLKER
Published: June 2024

Obesity represents the largest and rapidly escalating global health crisis in the world, predominantly attributed to a disequilibrium between caloric intake and energy expenditure. Contemporary therapeutic strategies predominantly employ anorexigenic peptides such as GLP-1 and GIP receptor agonists. The physiological response is mediated by specific neuronal clusters of the hypothalamus, particularly the arcuate nucleus, which harbors a complex neuronal network that plays a pivotal role in modulating satiety and hunger signaling within the brain. Therefore, elucidating the neuronal responses within the arcuate nucleus is critical for profiling novel compounds and combinations thereof, to discover innovative and more efficacious therapeutic strategies. We have established an integrated opto-neurophysiology setup that combines functional calcium imaging and electrophysiological recordings in acute brain slices of the hypothalamus. We make use of different cell labeling strategies including chemical and genetically encoded calcium indicators (GECIs) to mark neuronal populations within the arcuate nucleus, and have successfully captured distinct neuronal responses to various neuropeptides within a suitable assay window. Our platform enables sequential monitoring of individual or combined neuropeptides in vitro, allowing for differentiation on a neuronal network level. Finally, we provide evidence that the selection of differential combinations through such screening results in more efficacy in food intake and body weight loss. Therefore, this approach not only enables the in vitro profiling of compounds in acute applications but also supports suitable screening for novel combinations within the native hypothalamic or any obesity associated neuronal circuitry, thereby to achieve enhanced synergistic efficacy for anti-obesity treatment in vivo.

Disclosure

A. Pekcec: Employee; Boehringer-Ingelheim. B. Altas: Employee; Boehringer-Ingelheim. G. Bruschetta: Employee; Boehringer-Ingelheim. A. Buzzanca: Employee; Boehringer-Ingelheim. J. Doerr: Employee; Boehringer-Ingelheim. D. Lam: Employee; Boehringer-Ingelheim. K.A. Lincoln: Employee; Boehringer-Ingelheim. V. Mack: Employee; Boehringer-Ingelheim.
1530-P: Mind over Metabolism—Dorsal Vagal Neurons Can Improve Glucose Tolerance, Reduce Heart Rate, and Suppress Anxiety-Like Behavior
Authors: CONLEY NICHOLAS J. , CAMPBELL JOHN , VANDERVOORT LANE
Published: June 2024

Parasympathetic neurons of the dorsal motor nucleus of the vagus (DMV) play a crucial role in regulating glucose metabolism via the vagus nerve, making them potential targets for diabetes treatment. We sought to identify and investigate these neurons by chemogenetically activating them in awake, behaving mice during glucose tolerance tests. We virally targeted hM3Dq receptors to DMV neurons by the co-expression of Chat- and Phox2b- driven recombinases in our transgenic mouse model (Chat-Cre;Phox2b-Flp;dsHTB mice). The experimental protocol involved recording baseline glucose levels (after fast), followed by the injection of the hM3Dq ligand, Clozapine-n-oxide (CNO), or vehicle. After a 30min wait, we administered glucose (i.p) and conducted tail blood glucometry at 5min intervals from -30min to 120min. Average blood glucose readings were compared between CNO and vehicle. Our findings indicate that activating DMV neurons significantly improves glucose tolerance 5min after glucose injection: Vehicle-5min: 276.8 ± 12.8, CNO-5min: 218.8 ± 12.0, p=0.0459, n=8 (RM two-way ANOVA with Šídák’s). To identify specific DMV neurons involved in glucose regulation, we selectively activated a molecular subtype characterized by co-expression of Calb2 and Chat. Activating Calb2+ DMV neurons with CNO also substantially improved glucose tolerance compared to vehicle at both 5- and 15-minute time points: Vehicle-5min: 281.4 ± 12.7, CNO-5min: 242.3± 8.6, p=0.0459; Vehicle-15min: 411.0 ± 14.0, CNO-15min: 335.5 ± 9.2, p=0.0016, n=16 (RM two-way ANOVA with Šídák’s). Together our data indicates that activating DMV neurons generally or Calb2+ DMV neurons specifically improves glucose tolerance. These findings identify a specific vagal motor neuron population which can control glucose tolerance and so may lead to novel therapeutics for diabetes and other metabolic disorders.

Disclosure

N.J. Conley: None. J. Campbell: None. L. VanderVoort: None.

Funding

American Diabetes Association (1-18-INI-14)
1533-P: Leptin-Sensitive Sensory Nerves Mediate Cross Talk between Interscapular Brown Adipose Tissue and Proopiomelanocortin Neurons
Authors: YANG XIAOHUA , MUNOZ MARCOS D. , LUO PEI , TORRES IRIZARRY VALERIA C. , YE HUI , CARRILLO-SÁENZ LESLIE , ANTONY NIMISHA , WEE LIEW CHONG , XU PINGWEN
Published: June 2024

Adipose tissues communicate with the central nervous system (CNS) through secreted adiponectins, including leptin. Recent studies have shown that, in addition to its role as an endocrine hormone, leptin also communicates with the brain through leptin-sensitive spinal sensory nerves (SS) located in the L1-L3 dorsal root ganglia (DRG) that innervate white adipose tissues. Interestingly, we observed a high expression of the leptin receptor (LEPR) in the T1-T3 DRGs, which are primarily associated with interscapular brown adipose tissue (iBAT). These findings suggest that iBAT leptin may exert metabolic functions as a paracrine sensory signal. Supporting this idea, injecting a low dose of leptin into iBAT activated LEPR signaling in the T1-T3 DRG without affecting circulating levels of leptin. Additionally, it selectively stimulated LEPR-positive T1-T3 DRG neurons. These findings indicate that LEPR not only exists in iBAT-associated DRG, but also responds to leptin and mediates neuronal activation. Interestingly, infusion of leptin into the iBAT also stimulates proopiomelanocortin neurons in the arcuate nucleus of the hypothalamus (POMC/ARH). This suggests a potential crosstalk mediated by LEPR-positive SS between iBAT and POMC/ARH. The presence of this crosstalk is further supported by the anatomical connection between POMC/ARH neurons and iBAT-associated sensory nerves, as demonstrated by transsynaptic dual tracing. Importantly, the stimulatory effects of iBAT leptin infusion on ARH neurons are abolished when iBAT-associated sensory nerves are chemically ablated or when POMC/ARH neurons are genetically ablated. Taken together, our results indicate that iBAT has a structural and functional basis for paracrine leptin signaling via SS, which interacts with POMCARH neurons to regulate energy homeostasis. Keywords: Leptin; POMC; DRG; Spinal sensory nerve; Interscapular brown adipose tissue

Disclosure

X. Yang: None. M.D. Munoz: None. P. Luo: None. V.C. Torres Irizarry: None. H. Ye: None. L. Carrillo-Sáenz: None. N. Antony: None. C. LIew: None. P. Xu: None.
1541-P: The Role of Microglia Estrogen Receptor Alpha Signaling in Obesity Pathogenesis
Authors: VELASCO AGUAYO INMACULADA , JAFARI TRISTAN Z. , FREY JEREMY , SANTIAGO OLIVIA D. , THALER JOSHUA , DORFMAN MAURICIO D.
Published: June 2024

The sex steroid estrogen reduces susceptibility to obesity and its metabolic complications by suppressing food intake, enhancing energy expenditure, improving insulin sensitivity, and reducing immune cell activation. However, the mechanisms involved remain incompletely understood. In rodents, high-fat diet (HFD) feeding is associated with increased inflammatory activation of microglia (brain myeloid cells) in the mediobasal hypothalamus (MBH), which promotes diet-induced obesity (DIO). Importantly, surgical or chemical castration exacerbates HFD-induced microglial activation, an effect reversed by estrogen replacement therapy. Therefore, we hypothesize that estrogen reduces DIO susceptibility through a cell-autonomous anti-inflammatory action on microglia via the nuclear receptor estrogen receptor alpha (ERα). To test this hypothesis, we generated a mouse model with microglia-specific deletion of ERα (MG-ERαKO). We found that MG-ERαKO male mice exposed to HFD for 15 weeks have increased weight gain and fat mass relative to control mice, attributable to a significant reduction in energy expenditure. In contrast, HFD feeding of MG-ERαKO female mice did not elicit a body weight difference with controls. Nevertheless, a small but significant reduction in insulin sensitivity was observed in both sexes of MG-ERαKO mice. Immunohistochemical analyses of MBH brain sections from MG-ERαKO mice demonstrated higher immunoreactivity for the microglial marker IBA1 along with an increase in microglial number and cell size, all indicators of a more activated cellular profile. These findings strongly support a sex-specific action of estrogen to limit the metabolic complications of HFD feeding through microglial ERα signaling.

Disclosure

I. Velasco Aguayo: None. T.Z. Jafari: None. J. Frey: None. O.D. Santiago: None. J. Thaler: Consultant; Eli Lilly and Company. M.D. Dorfman: None.
1556-P: Glucocorticoid-Induced Insulin Secretion via the Hypothalamic–Pituitary–Adrenal–Islet Axis Is Needed for Proper Body Weight Regulation and Pancreas Development
Authors: MEIER DANIEL T. , RACHID LEILA , DONATH MARC Y.
Published: June 2024

Prohormone convertase 1/3 (PC1/3) is a protease involved in processing of various prohormones. Inactivation mutations in PC1/3 are associated with severe obesity in mice and humans. Mechanistically, it is not well understood which misprocessed hormones induce this obesity phenotype. PC1/3 processes proopiomelanocortin (POMC) into peptides that regulate body weight via modulating the melanocortin system. To shed light on this mechanism, we deleted PC1/3 from POMC-expressing tissues, thereby blocking the processing of POMC to melanocortin-stimulating hormones (MSH) and adrenocorticotropic hormone (ACTH). Surprisingly, body weight was only mildly and transiently increased in young POMC-specific PC1/3 knockout mice, however later in life a prominent underweight developed. These mice had an impaired hypothalamic-pituitary-adrenal (HPA) axis which resulted in inadequately low basal and ACTH-stimulated circulating glucocorticoid levels. Further, basal circulating insulin levels were strongly reduced and glucose tolerance impaired. In aged underweight PC1/3 knockout mice, corticosterone replacement therapy increased body weight to the level of control mice and normalized insulin levels as well as glucose tolerance. In addition, glucose-stimulated insulin secretion from isolated islets and total islet insulin content from POMC-specific PC1/3 knockout mice were reduced. In line with this, pancreas weight and beta-cell mass were reduced, suggesting that there are islet intrinsic developmental and secretory pathologies present in these mice. Our data show that insufficient levels of endogenous glucocorticoids negatively impact pancreas development and insulin secretion, and that this is associated with an impaired body weight development. All these phenotypes are reversible by steroid replacement therapy, suggesting that the HPA axis regulates body weight development via insulin secretion.

Disclosure

D.T. Meier: None. L. Rachid: None. M.Y. Donath: Advisory Panel; Novo Nordisk, Lilly Diabetes, Boehringer-Ingelheim. Research Support; Boehringer-Ingelheim, Olatec.
1561-P: Insulin Secretion Is Markedly Impaired in Young, Lean Rwandan Adults with New-Onset Type 2 Diabetes
Authors: MUGENI REGINE , SMITH GORDON I. , SUMNER ANNE E. , CADE WILLIAM T. , REEDS DOMINIC
Published: June 2024

Introduction: 80% of cases of type 2 diabetes mellitus (T2D) occur in low- and middle-income countries and primarily afflicts lean people; the reasons for this are unclear but may relate to fat-distribution and/or pancreatic function. We aimed to: 1) compare insulin-secretion rates (ISR) between lean, (BMI <25kg/m2) Rwandan adults with and without new-onset (<1yr) T2D; and 2) to examine the impact of elevated WC (<85cm for women and <90cm for men, >75th %ile of group) on ISR and insulin resistance in people with T2D.

Methods: BMI, WC, and a 3-hour frequently-sampled oral-glucose tolerance-test were performed in 23 Rwandans; 15 with T2D (7 Male) and 8 healthy people (5 Male). ISR was determined by mathematical-modeling. Groups were compared with students t-test or ANOVA were appropriate.

Results: Healthy and T2D groups were well matched for age (43±3y vs 46±2 y) and BMI (22±1 vs 22±1 kg/m2), respectively. Glucose area under the curve (AUC) was lower (1179±55 vs 2150±196 mg.ml-1.min, P<0.05) and insulinogenic-index was greater (91±18 vs 23±8, P<0.01) in healthy people than people with T2D, respectively. Rwandans with T2D and normal WC had an ISR-AUC ~2 fold lower (54±9 vs 117±20, P=0.07) than T2D and elevated WC. HOMA-IR was greater in Rwandans with T2D and elevated WC than healthy people (2.2±0.4 vs 0.9±0.1, P<0.05).

Conclusions: In lean Rwandan people with new-onset T2D but normal WC, alterations in insulin secretion rather than insulin-resistance predominate. In contrast, in Rwandans with T2D and elevated WC, insulin resistance rather than insulin secretion may be a major factor. This suggests that the pathogenesis of T2D differs based on WC in Rwandans with implications for prevention and therapy.

Disclosure

R. Mugeni: None. G.I. Smith: None. A.E. Sumner: None. W.T. Cade: None. D. Reeds: None.

Funding

McDonnell FoundationP30DK056341P30DK092950
1570-P: A Human Unique Role of RNA-Binding Protein HuR in Nonalcoholic Steatohepatitis
Authors: TAKAOKA SHOHEI , JASO VERA MARCOS E. , RUAN XIANGBO
Published: June 2024

Introduction & Objective: Overnutrition-induced obesity heightens the risk of cardiometabolic diseases, necessitating an understanding of how it disrupts gene expression for preventive strategies against obesity-related diseases. The RNA-binding protein human antigen R (HuR) has demonstrated a crucial role in post-transcriptional gene regulation, exhibiting protective effects against nonalcoholic steatohepatitis (NASH) in mouse models. However, the HuR's protective role in human NASH remains uncertain due to potential differences in HuR binding between human and mouse untranslated regions. This study aims to elucidate the role of HuR in human NASH using chimeric mice with humanized livers and cultured human cells.

Methods: Knocking down human HuR was performed in humanized mouse livers, and the impact was assessed by RNA-seq. In human cells, HuR overexpression and co-overexpression with peroxisome proliferator-activated receptor alpha (PPARA) were conducted. Additionally, Western blotting was employed to analyze HuR protein expression in liver samples obtained from healthy donors and NASH patients.

Results: Knocking down human HuR in the humanized liver led to the upregulation of RXRA and fatty acid oxidation-related (FAO) genes. Concurrently, overexpression of HuR in human cells suppressed RXRA protein expression. Furthermore, HuR inhibited PPARA-induced expression of FAO genes by suppressing the PPARA cofactor RXRA. Western blotting analysis revealed elevated HuR and reduced RXRA protein levels in the livers of NASH patients.

Conclusion: This study indicate that HuR is induced in human NASH and suppresses RXRA and FAO genes, suggesting HuR may aggravate NAFLD progression in humans, which is opposite to HuR studies using traditional mouse genetic models.

Disclosure

S. Takaoka: None. M.E. Jaso Vera: None. X. Ruan: None.
1581-P: Evaluation of a Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD) Clinical Pharmacy Service
Authors: SALLAM SANDY , AHMED AIJAZ , GU XIN
Published: June 2024

Introduction & Objective: The purpose of this study is to evaluate the impact of pharmacist integration into the management of patients with MASLD. There are no known studies to date that have investigated the impact of a pharmacist integration within a hepatology clinic for MASLD management. The primary objectives are pharmacist intervention types and 6 month and 12 month clinical outcomes.

Methods: This is a retrospective cohort study of 220 patients referred to the clinical pharmacy service and/or a group patient education program coordinated by the pharmacist, between July 2018 to December 2021. Inclusion criteria included adult patients with established care at a Hepatology clinic with a formal diagnosis of MASLD by liver biopsy or non-invasive testing who have at least one cardiometabolic risk factor. Information on patient demographics, pharmacist interventions, and baseline, 6 month, and 12 month post-intervention clinical parameters were collected from the Electronic Medical Record. Data was analyzed using descriptive statistics, Paired t test, and Wilcoxon Signed Rank Test.

Results: Majority of patients were living with obesity (74.1%) and had Alanine Transaminase (ALT) elevations at baseline (60%). The most frequent pharmacist intervention was cardiometabolic medication recommendations. Weight loss from baseline was demonstrated at 6 months (5.09 lbs, p<0.05) and maintained at 12 months (6.9 lbs, p<0.05). Reduction in ALT was also observed at 6 months (14.38 U/L, p<0.05) and 12 months (20.15 U/L, p<0.05). Reductions were seen in Hemoglobin A1c (0.26%, p<0.05), Low-Density Lipoprotein (9.23mg/dL, p<0.05), and Triglycerides (16.63mg/dL, p=0.0629) at 12 months.

Conclusion: Patients referred to this novel clinical pharmacy service demonstrated significant and sustained weight and ALT reduction at 12 months, which may translate into MASLD improvement. They also experienced significant improvements in most cardiovascular clinical parameters.

Disclosure

S. Sallam: None. A. Ahmed: Advisory Panel; Novo Nordisk. X. Gu: None.
1586-P: Association between PCSK7 Levels and NAFLD Severity in KADEM Study
Authors: QADDOUMI MOHAMMAD , ABUBAKER JEHAD , AL-KHAIRI IRINA , CHERIAN PREETHI T. , SRIRAMAN DEVARAJAN , THANGAVEL ALPHONSE T. , CHANNANATH ARSHAD M. , ABDUL-GHANI MUHAMMAD , ALMULLA FAHD , ABU-FARHA MOHAMED
Published: June 2024

Introduction: The increased obesity rates worldwide are associated with increased rates of Non-alcoholic fatty liver disease (NAFLD). Proprotein Convertase Subtilisin/Kexin type 7 (PCSK7) is an enzyme involved in lipid metabolism but its role in the development and progression of NAFLD remains unclear. This study aims to investigate the association between PCSK7 levels and NAFLD severity.

Methods: A total of 255 participants were recruited in KADEM study and screened for NAFLD using liver FibroScan machine. Participants were divided into two groups based on controlled attenuation parameter (CAP) scores: 208 dB/m with CAP scores above 294 dB/m, and 47 with CAP scores >294 dB/m. PCSK7 levels were measured using ELISA.

Results: PCSK7 levels were higher in people with a CAP score >294 dB/m, with levels of 0.9 ± 0.1 ng/mL compared to 0.5 ± 0.1 ng/mL in individuals with CAP scores lower than 294 dB/m (p=0.022). When the population was divided into tertiles based on CAP scores, PCSK7 levels were 0.30 ± 0.1 ng/mL for CAP scores ≤229, 0.7 ± 0.1 ng/mL for CAP scores between 230-271, and 0.8 ± 0.1 ng/mL for CAP scores ≥272 (p<0.001). PCSK9 levels were positively associated with CAP score (r=0.387, p<0.001), HbA1C (r=0.497, p<0.001), FBG (r=0.497, p<0.001), insulin (r=0.497, p<0.001), HOMA-IR (r=0.480, p<0.001), TG (r=0.366, p<0.001), LDL (r=0.133, p=0.049), and VLDL (r=0.366, p<0.001), while negatively associated with HDL (r=-0.271, p<0.001).

Conclusion: Our findings indicate a significant association between elevated PCSK7 levels and increased NAFLD severity implicating a potential role for PCSK7 in NAFLD pathogenesis.

Disclosure

M. Qaddoumi: None. J. Abubaker: None. I. Al-khairi: None. P.T. Cherian: None. D. Sriraman: None. A.T. Thangavel: None. A.M. Channanath: None. M. Abdul-Ghani: None. F. Almulla: None. M. Abu-farha: None.

Funding

Dasman Diabetes Institute (RA HM-2019-030)
1587-P: Guideline-Directed Interventions and Diabetes Education in Improving Liver Health in Type 2 Diabetes Mellitus—An Observational Study of FIB-4 and Liver Stiffness Metrics
Authors: PADHYE DAKSHATA
Published: June 2024

We evaluated the efficacy of guideline-directed intervention and diabetes education for lifestyle modification in liver health in T2DM on active treatment (n=229). We performed a comparative analysis of baseline and follow-up FIB-4 and liver stiffness measures. The FIB-4 scores slightly decreased on average from baseline (mean 2.478) to the last assessment (mean 2.362), with a wider variation in the data at the last measure (increased standard deviation). Median values remained consistent at 2. Liver stiffness measures (kPa) decreased on average from 14.59 to 13.7 with a consistent range of variability. The median decreased from 10.9 to 8.9, suggesting an overall improvement in liver stiffness. BMI values remained relatively stable from baseline (mean 30.03) to follow-up (mean 30.08), with a slight increase in variation and a higher maximum value at the last measurement. The study showed a marginal but positive trend in liver health, with a slight decrease in FIB-4 scores and a more notable improvement in liver stiffness, indicating potential therapeutic benefit. Despite these improvements, BMI values remained stable, indicating that the positive liver outcomes may not be directly associated with changes in body weight. Further investigation may be required to understand the underlying factors contributing to liver health improvements.

Disclosure

D. Padhye: None.