bluuebunny/crossref_metadata_2025 huggingface dataset:
2077-LB: Regional Differences in Obesity Awareness, Prevalence, and Management in India
Authors: MAKKAR BRIJ , J ARAVINDA , GUPTA AMIT , JETHWANI PRATAP , AGARWAL SANJAY , KAPOOR NITIN , DESHPANDE NEETA
Published: June 2024

Introduction & Objective: India is a large country that can be broadly categorized into regions based on geography with diverse lifestyle and cultural habits. The current observational study explores the disparities in the prevalence of metabolic disturbances and the role of lifestyle habits across regions.

Methods: A nationwide survey conducted via social media and awareness events assessed for sociodemographic nuances and health patterns among participants based on their region.

Results: The survey included 60,325 participants distributed between east, E (N=8736), west, W (N=17387), north, N (N=12694), south, S (N=19018) and central, C (N=2282). The majority (40-42%) were between 30-60 years of age in all groups. Overall male-to-female ratio was 1.9 but was a slightly higher in the central (2.18) and Northern (2.03) regions. Higher proportion of master’s degree holders resided in the North (40.4%), Central (38%), East (38%) than other regions (31-33%). Obesity was highest among the central region (67.3%) and lowest in the west (65.2%). The survey underscored regional variations in chronic diseases: Diabetes (E-45.5%, W-51.9%), N-48.1%, S-54.3%, C-53.1%); High BP (E-43.3%, W-41.4%, N-42.3%, S-40%, C-45.9%); high cholesterol (E-27.3%, W-21.7%, N-26.1%, S-22.9%, C-28.2%). South reported the highest prevalence of diabetes (54.3%), and East, the highest prevalence of high blood pressure (45.9%). South had the highest proportion of screentime spent (18% vs 12-15% other regions) and eating out (22.7% vs 13-16% other regions). Respondents from Central (72%) followed by South (57.2%) were inclined to exercise. Higher proportion of respondents from Central (42%) were willing to receive weight loss related information compared to others (14-21%).

Conclusion: This study contributes to a holistic understanding of the complex interplay between geography, sociodemographic, and health behaviours in India.

Disclosure

B. Makkar: None. A. J: None. A. Gupta: None. P. Jethwani: None. S. Agarwal: None. N. Kapoor: None. N. Deshpande: None.
213-OR: Widespread Age-Associated Changes in the Chromatin Architecture of Skeletal Muscle Cell Types
Authors: MOO KEAGAN G. , D'OLIVEIRA ALBANUS RICARDO , VARSHNEY ARUSHI , ORCHARD PETER , MANICKAM NANDINI , LAAKSO MARKKU , TUOMILEHTO JAAKKO , LAKKA TIMO A. , MOHLKE KAREN L. , BOEHNKE MICHAEL , SCOTT LAURA , KOISTINEN HEIKKI A. , COLLINS FRANCIS S. , PARKER STEPHEN
Published: June 2024

Introduction & Objective: Genome-wide association studies (GWAS) have found >1,000 signals associated with type 2 diabetes (T2D), most of which occur in noncoding genomic regions. T2D risk increases with age, and aging is accompanied by changes in the epigenomic landscape. Together, these findings suggest that age-related epigenomic change may contribute to T2D risk. Here we profile age-associated epigenomic changes in skeletal muscle, a T2D relevant tissue.

Methods: We analyzed single nucleus ATAC-seq data from 284 Finnish skeletal muscle biopsies (donor age 20-79 years; mean = 60) to identify age-associated patterns in chromatin accessibility. We used Type 1, 2a, and 2x muscle fiber, endothelial, and fibro/adipogenic progenitor nuclei for analysis. To find age-associated open chromatin regions (OCRs) without assuming linearity, we used Auto-Regressive Integrated Moving Average (ARIMA) models. We then characterized these OCRs with k-means clustering as well as logistic and linkage disequilibrium score (ldsc) regression enrichment tests.

Results: Across cell types 6.2 - 15.5% of tested OCRs were age-associated (11,925 - 23,143 OCRs). These OCRs clustered into four patterns of age association: linear positive (Up)/negative (Down) and parabolic positive (Valley)/negative (Arch). These patterns showed distinct enrichment in both gene sets, such as the fast to slow fiber transition gene set in arch patterned Type 1 OCRs (FDR = 2x10^-6), and chromatin states, such as active enhancer chromatin in down patterned Type 2a OCRs (nominal p = 2x10^-29). Ldsc analysis found T2D GWAS signal enrichment in Type 2a up patterned OCRs (nominal p = 0.03). Additionally, 12 age-associated OCRs are chromatin accessibility quantitative trait loci that colocalize with T2D GWAS signals.

Conclusion: These results highlight age-associated epigenomic changes and enrichment for T2D GWAS signals in skeletal muscle cell types, providing a basis for research into development and aging in a T2D relevant tissue.

Disclosure

K.G. Moo: None. R. D'Oliveira Albanus: None. A. Varshney: None. P. Orchard: None. N. Manickam: Employee; 10x Genomics. M. Laakso: None. J. Tuomilehto: Stock/Shareholder; Orion Pharma, Aktivolabs, Digostics. T.A. Lakka: None. K.L. Mohlke: None. M. Boehnke: None. L. Scott: None. H.A. Koistinen: Other Relationship; AstraZeneca, Novo Nordisk. F.S. Collins: None. S. Parker: Research Support; Pfizer Inc.
221-OR: Skeletal Muscle Insulin Resistance—The Rate-Limiting Step in Humans Is at the Level of the Vasculature
Authors: VAN RAALTE DANIËL
Published: June 2024

Type 2 diabetes (T2D) is characterized by impaired insulin-stimulated glucose disposal in skeletal muscle tissue (SKM), called insulin resistance. Insulin facilitates glucose uptake through GLUT4 recruitment following insulin receptor-mediated signal transduction pathways. Insulin also regulates glucose uptake through 1) regulation of arterial blood flow, 2) capillary recruitment and 3) rate of its own transendothelial transport. The rate-limiting step of insulin on SKM glucose uptake in humans is currently unknown.

In a cross-sectional study, 20 people with T2D [age 67±6 years, BMI 30±4 kg/m2, HbA1c 7.6±1.1%] and 20 matched controls (HC) [age 68±7, years, BMI 29±2 kg/m2, HbA1c 5.7±0.7%] underwent a frequently-sampled 75-g oral glucose tolerance test (OGTT) with paired forearm arterial and venous glucose and insulin concentrations to calculate glucose (FEgluc) and insulin (FEins) fractional extraction. Forearm blood flow was measured by Doppler ultrasound.

Area under the glucose curve was increased in T2D vs HC (p<0.01). FEgluc increased from 4±3% to 16±3% in both groups from the fasted state to T=30 min, but was higher in T2D vs HC from min T=60 to T=120 of the OGTT (p<0.001). Fasting FEins was 13±9% for T2D and 14±12% for HC and peaked at T=15 (27±13% for HC and 22±12% for T2D; p=0.16). FEins was similar between groups during the OGTT. FEgluc/FEins, as measure for insulin metabolic effects, was not different between groups. Brachial arterial blood flow was not changed during OGTT.

We show that FEgluc is reduced in T2D vs HC under physiological conditions. As reduced SKM glucose uptake was not driven by changes in insulin uptake into SKM interstitium, the glucose uptake defect is likely secondary to impaired vascular actions of insulin. With arterial blood flow unchanged, we propose that reduced insulin-induced capillary recruitment may be the key defect. Microvascular recruitment measured by contrast-enhanced ultrasound (CEUS) are being analyzed and are available at the ADA.

Disclosure

D. van Raalte: Consultant; Eli Lilly and Company. Research Support; Eli Lilly and Company, Boehringer-Ingelheim. Consultant; Boehringer-Ingelheim. Research Support; Merck & Co., Inc. Advisory Panel; Merck & Co., Inc. Consultant; Bayer Inc.

Funding

MSD (ROCKIES study)
252-OR: Psychosocial Predictors of Diabetes Self-Efficacy in Young Adults with Youth-Onset Type 2 Diabetes
Authors: TRIEF PAULA M. , WEN HUI , ANDERSON-THOMAS BARBARA J. , BURKE BRIAN K. , BULGER JANE D. , WEINSTOCK RUTH S.
Published: June 2024

Objective: To identify psychosocial predictors of diabetes self-efficacy (DSE) in the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY2) cohort, now young adults with youth-onset type 2 diabetes (T2D).

Methods: In this longitudinal study (T1=baseline, T2=1 year), 348 TODAY2 participants completed measures of: diabetes self-efficacy, beliefs about medicines, depression and anxiety symptoms, diabetes distress, diabetes attitudes, self-management support, and material need insecurities. Multivariable logistic regression models evaluated independent associations of each psychosocial factor with the likelihood of being in the high/low DSE tertile groups at T2; multivariable linear regression assessed associations with T2 DSE as a continuous variable.

Results: Mean (SD) age was 26.0 (2.5) years, 67.9% were women, mean (SD) HbA1c= 9.4 (2.8), with mean (SD) of 2.5 (1.4) complications. Greater self-management support increased the odds of high (vs. low) DSE (OR, 2.23, 95% CI, 1.30-3.83, p=0.004). Greater beliefs that medicines are overused (OR, 0.58, 95% CI, 0.34-0.99, p=0.046), moderate-to-severe depression/anxiety symptoms (OR, 0.30/0.03, 95% CI, 0.09-0.97/0.003-0.34, p=0.045/0.004), food insecurity/healthcare coverage insecurity/≥1/≥2 insecurities decreased the odds of high DSE by 80%/65%/78%/74%; p=<0.0001/0.025/0.001/0.001). More support, fewer depressive and anxiety symptoms, and fewer unmet needs were also predictors of absolute T2 DSE scores.

Conclusions: Cognitions (beliefs that medicines are overused), emotions (depressive/anxiety symptoms), and social factors (self-management support, unmet material needs), were significant longitudinal predictors of DSE in young adults with youth-onset T2D. These potentially modifiable factors should be considered when screening for, and designing, interventions to enhance DSE, to improve health behaviors and forestall the development of complications in this at-risk group.

Disclosure

P.M. Trief: None. H. Wen: None. B.J. Anderson-Thomas: None. B.K. Burke: None. J.D. Bulger: None. R.S. Weinstock: Research Support; Eli Lilly and Company, Tandem Diabetes Care, Inc., Diasome, Amgen Inc., MannKind Corporation, Insulet Corporation, Novo Nordisk. Other Relationship; Dexcom, Inc.

Funding

National Institutes of Health (RO1DK110456, U01-DK61212, U01-DK61230, U01-DK61239, U01-DK61242, and U01-DK61254)
26-PUB: Early Assessment of Imeglimin in India—Patient Profiling and Prescription Patterns in Type 2 Diabetes Management—Early Reassure Study Pool
Authors: SABOO BHARAT , ANUJ MAHESHWARI , GHOSH SUBHAJYOTI , PATIL SHUBHASHREE M.
Published: June 2024

Background and Objectives: Given the increasing prevalence of diabetes, there is a pressing need for effective management strategies. This study focuses on the first-year data since the Imeglimin's (oxidative phosphorylation blocker) launch, examining its utilization in India to assess its initial impact. The primary goals encompass comprehending the patients that benefit most from Imeglimin and determining its role in the present therapeutic scenario.

Methods:A retrospective analysis of 406 T2D patients prescribed Imeglimin was conducted using data from ten diverse centers across India, ensuring a representative sample. Patient profiles, including age, gender, and relevant demographics, were assessed. Prescription patterns were analyzed to glean insights into how Imeglimin is integrated with other diabetic medications, providing insights into its role as monotherapy or combination therapy.

Results:The investigation revealed that Imeglimin was predominantly administered to individuals aged 51-60 (average age of 54.1 years), glycated hemoglobin > 9 (40.8%), and exhibited a male predominance (56.4%). Notably, Imeglimin served as the first-line therapy in 66.4% patients and was frequently prescribed in conjunction with other oral antidiabetic medications (80.3%). Prescription patterns indicated a common combination of Imeglimin with biguanides, followed by dipeptidyl peptidase 4 (DPP-4) inhibitors, with the primary rationale for Imeglimin prescription being the presence of uncontrolled glucose levels.

Conclusion:Imeglimin shows promise as an effective treatment for T2D in the Indian context, showing efficacy across various age groups and particularly in cases of uncontrolled diabetes. Further long-term studies are recommended to assess its efficacy and safety profile over an extended period.

Disclosure

B. Saboo: None. M. Anuj: None. S. Ghosh: None. S.M. Patil: None.
268-OR: Perioperative Fully Closed-Loop vs. Standard Insulin Delivery in Adults Undergoing Major Abdominal Surgery—A Two-Center Randomized Controlled Trial
Authors: KRUTKYTE GABIJA , MARIE CATHERINE GOERG ARNA , GROB CHRISTIAN A. , BELDI GUIDO , SILVIA WENNING ANNA , HOVORKA ROMAN , WILINSKA MALGORZATA E. , HERZIG DAVID , VOGT ANDREAS , GIRARD THIERRY , BALLY LIA
Published: June 2024

Introduction: Major abdominal surgery predisposes to hyperglycemia due to metabolic stress, inflammation, perioperative nutrition support and medication. The aim of the study was to assess the efficacy of fully closed-loop (FCL) versus usual care (UC) insulin delivery for glycemic management in major abdominal surgery patients.

Methods: In this randomized controlled trial (NCT05392452) we compared perioperative use of the CamAPS HX FCL system (Dexcom G6, YspoPump, SC faster insulin aspart) with UC insulin treatment from admission until hospital discharge (max 20 days) at two tertiary hospitals in Switzerland. The primary endpoint was % time in sensor glucose target range (5.6-10.0mmol/L).

Results: Thirty-seven patients (FCL n=18, UC n=19, 27% female, mean±SD age 66±12 years, BMI 27.8±5.7 kg/m2, HbA1C 6.9±1.0 %) were analyzed. Mean±SD % time in target glucose range (5.6-10.0mmol/L) was 80.1±10.0 % with FCL vs 53.7±19.7 % with UC (p<0.001). Time in hypoglycemia (<3.9mM and <3.0mM) did not differ between groups. Total daily insulin dose was significantly higher in the FCL vs UC group (p<0.001).

Conclusions: Perioperative use of FCL insulin delivery in major abdominal surgery patients with complex medical needs results in significantly better glucose control compared to standard insulin therapy without increasing the risk of hypoglycemia.

Disclosure

G. Krutkyte: None. A. Goerg: None. C.A. Grob: None. G. Beldi: None. A. Wenning: None. R. Hovorka: Other Relationship; CamDiab. Research Support; Abbott, Dexcom, Inc., Ypsomed AG. Speaker's Bureau; Ypsomed AG, Abbott, Novo Nordisk, Novartis Pharmaceuticals Corporation. M.E. Wilinska: Consultant; CamDiab. D. Herzig: Speaker's Bureau; Ypsomed AG. A. Vogt: None. T. Girard: None. L. Bally: None.

Funding

Helmut Horten FoundationScherbarth Foundation and intramural grants of the Department of Anaesthesiology and Pain Medicine, University Hospital BernSwiss Foundation for Anaesthesiology and Intensive CareClinic for Anaesthesiology, University Hospital BaselFreiwillige Akademische Gesellschaft Basel
27-PUB: A Systematic Review on the Theranostic Potential of Iron in Diabetes
Authors: PRADIPKUMAR THAKER SHIVAM , SHREYANSH SHREYANSH , MONAPPA VIDYA
Published: June 2024

Background:Iron is an element now synonymous with inflammatory diseases, but in recent years it has shown potential in the pathophysiology of Diabetes. This review aims to cohesively analyze the association of serum iron in Diabetes and evaluate its clinical theranostic potential.

Method:Literature was obtained from PubMed, Embase, and Clinical Key. The search included Keywords,‘“DIABET” AND IRON’.

Result:21 papers were included in the review. Hemochromatosis is an established cause of type-1 and 2 diabetes. In recent years, several studies have found an increase in serum ferritin levels(Mean: 27.6%; Median: 11.9%) among diabetics, not associated with hemochromatosis. This can serve as a predictive marker for the development of microvascular complications in diabetes. The authors suggest this phenomenon may be the result of 2 mechanisms;(1) Hepcidin upregulation, and (2) Mild hemolysis due to increased osmotic fragility with HbA1c. The increased ferritin is associated with insulin resistance which may be attributed to ROS-induced mitochondrial fission. The authors suggest another cause may be apoferritin which stimulates PI3K, causing PDK1 activation and GLUT-4 translocation. This translocation is reduced with increased serum ferritin. Several animal studies have shown substantial improvement in glucose metabolism amongst diabetic mice on iron chelation therapy. Additionally, improved wound healing and nephropathy were found to be significant. Fernández-Real JM, et. al. in 2002, found that Phlebotomy(450mL ) increased insulin sensitivity amongst high ferritin (human)diabetics by 80.6 ± 43.2% from baseline at 4 months(P=0.0049). Iron chelation therapy is a promising potential adjuvant in high ferritin diabetes with microvascular complications, but adequate human trials have yet to be done.

Conclusion:In consideration of the available data, the authors believe that iron and iron chelation may serve an important low-cost effective role in the monitoring and therapeutics of diabetes.

Disclosure

S. Thaker: None. S. Shreyansh: None. V. Monappa: None.
277-OR: Whole-Genome Sequencing Identifies a Rare Noncoding Variant Proximal to METRN Associated with HbA1c Levels
Authors: HAWKES GARETH , PATEL KASHYAP A. , BARROSO INÊS , FRAYLING TIMOTHY M. , MANNING ALISA , WEEDON MICHAEL N.
Published: June 2024

Introduction & Objective: Hundreds of common genetic variants have been associated with type 2 diabetes and glycated haemoglobin (HbA1c). However, the vast majority of these variants lie in regions of the genome which are not protein coding, making it difficult to identify biological pathways. We aimed to identify rare non-coding variants to aid in pinpointing causal genes and variants.

Methods: We performed a whole-genome sequencing association analysis of non-coding variation in 200,000 UK Biobank participants. We stratified our analysis by three genetically-inferred ancestries: European-like (EUR), African-like (AFR) and South Asian-like (SAS).

Results: We identified 4 rare (MAF<0.1%) variants associated with HbA1c, downstream of the haemoglobin alpha gene-cluster based on an analysis of EUR-like participants. In our analysis of 3,184 AFR-like individuals, only one variant (16:715289:T:C) showed evidence of replication. This likely-causal variant lies in the first element of the kozak sequence of meteorin (METRN), and was associated with substantially increased HbA1c levels (beta = 4.87mmol/mol [3.54, 6.21], P = 8.14e-13). We observed no evidence of association with common blood cell traits, circulating glucose, or haemoglobin. We replicated our result in the recently released additional 300,000 UKB WGS samples (beta = 6.02mmol/mol [4.83, 7.20], P = 2.93e-17). We attempted to replicate our findings in All of Us (N = 250,000), but found that the allele was substantially less frequent than in UKB (MAF = 3.7e-6 vs. 1.9e-4). The alternate allele was not present in individuals in TOPMed with HbA1c measures.

Conclusion: Our results suggest that this variant may be a founder effect in the UK population acting through an alteration of glucose uptake to red blood cells. Identification of a novel variant in only 200k individuals with whole-genome sequences suggests a high yield of novel variants and biological pathways from upcoming releases of millions whole-genomes.

Disclosure

G. Hawkes: None. K.A. Patel: None. I. Barroso: Stock/Shareholder; GlaxoSmithKline plc, NeoGenomics (NASDAQ: NEO). T.M. Frayling: None. A. Manning: None. M.N. Weedon: None.

Funding

Innovative Medicines Initiative 2 Joint Undertaking (875534)
280-OR: Manganese Regulates Hepatic Insulin Sensitivity and Glucose Tolerance
Authors: GAMARRA JENNIFER , XIE YUKE , HIGUCHI SEI , HAEUSLER REBECCA
Published: June 2024

Introduction & Objective: Metals are known to be necessary for cellular processes such as signal transduction and in protein conformation, though the characterization of which proteins bind metals is incomplete. Manganese (Mn) is known to be required for life but is one of the least understood metals. We aim to: (i) determine the mechanisms that regulate Mn and (ii) the molecular targets of Mn.

Methods: We used a mouse model of Mn excess that depletes the Mn efflux transporter, Slc30a10, from the liver and intestine (Slc30a10Tbg,Vil). We conducted metabolic studies on mice kept on a standard chow diet or fed a high-fat diet for eight weeks. We used primary hepatocytes treated with Mn ex vivo to perform glucose production assays and assess the phosphorylation cascade in the insulin signaling pathway.

Results: We found that Slc30a10Tbg,Vil mice have a significant improvement in glucose tolerance on a standard chow diet and are protected from impaired glucose tolerance when put on a high-fat diet. We treated hepatocytes with Mn ex vivo and found a significant reduction in glucose production. These data were associated with increased phosphorylation of Akt targets without increased phosphorylation of Akt itself. Using knockout and inhibitor approaches, we found that Mn acts downstream of both insulin receptor and PI3 kinase, suggesting that Mn acts directly on Akt. Fasting and refeeding studies on wildtype mice found Slc30a10 is low during fasting and increases rapidly after refeeding.

Conclusions: These data suggest Mn acts directly on Akt to sensitize hepatocytes to insulin. Further, our finding that Slc30a10 is regulated nutritionally suggests the possibility that controlled access to Mn may be a physiological mechanism to regulate Akt activity. These results highlight a novel role of Mn in the insulin signaling pathway and shed light on how Mn homeostasis is regulated in the liver.

Disclosure

J. Gamarra: None. Y. Xie: None. S. Higuchi: None. R. Haeusler: None.
296-OR: Glucagon and Insulin Cross Talk Regulates Hepatic Glycogen Metabolism
Authors: CAPOZZI MEGAN , BOUSLOV DAVID , SARGSYAN ASHOT , CAMPBELL JONATHAN
Published: June 2024

The fed state is often defined with a glucose-centric focus, where elevated glycemia stimulates insulin and reduces glucagon secretion. However, protein-containing meals that better reflect normal nutrition increase glucagon secretion, producing elevations in both hormones. Glucagon and insulin have opposing effects on hepatic glycogen; glucagon promotes glycogenolysis while insulin promotes storage. Yet, most work in this area has focused on the individual rather than combined actions of these hormones. The purpose of this study was to determine the effect of combined insulin and glucagon on postprandial hepatic glycogen metabolism. We hypothesized that their combined actions increase glycogen flux to enable storage of meal nutrients.

Glucagon and/or insulin were injected into 5-hr fasted wild-type mice to determine the individual versus combined actions on hepatic glycogen content. Next, glucose alone versus a mixed-nutrient meal was gavaged with matching carbohydrate loads, using a 13C6-glucose tracer to assess incorporation of meal-derived glucose into glycogen. Finally, a mixed-nutrient meal with tracer was given to proglucagon null mice (Gcg-/-) to determine the effect on glycogen metabolism.

Glucagon or insulin alone did not alter hepatic glycogen levels, however the combination of both hormones enhanced glycogenolysis. Meal-derived glucose incorporated into hepatic glycogen was higher after a mixed-nutrient meal compared to oral glucose alone. Gcg-/- mice stored significantly less meal-derived glucose as glycogen versus controls.

Our results suggest that the combined actions of glucagon and insulin enhance hepatic glycogen turnover due to both enhanced glycogenolysis and storage of meal-derived glucose as glycogen. These actions enable the liver to have greater metabolic flexibility for nutrient storage in the postprandial state. This may have implications for disease states such as diabetes or metabolic-associated steatotic liver disease, where hormone action is altered.

Disclosure

M. Capozzi: None. D. Bouslov: None. A. Sargsyan: Employee; AstraZeneca. J. Campbell: Research Support; Eli Lilly and Company, Novo Nordisk, Merck & Co., Inc. Advisory Panel; Structure Therapeutics, Inc.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (5K01DK129417)
33-PUB: Triple-Arm, Prospective, Multicentre, Randomized, Open-Label, Active-Controlled Study to Assess Effect on FDC of Teneligliptin 20 mg + Dapagliflozin 10 mg Compared with FDC of Sitagliptin 100 mg + Dapagliflozin 10 mg and FDC of Linagliptin 5 mg+ Empagliflozin 25 mg on 24-Hour Glucose Profile Assessed by Continuous Glucose Monitoring (CGM) in Indian Patients of Type 2 Diabetes Mellitus In Real-World Setting (AMPLIFY-TIR STUDY)—Interim Report
Authors: BARKATE HANMANT V. , PETARE ANUP U. , BHUSHAN SUMIT , CHOUDHARI SANJAY Y. , BRID MANASI , PATIL SAIPRASAD
Published: June 2024

Introduction & Objective: Fixed dose combination (FDC) of Teneligliptin 20 mg + Dapagliflozin 10 mg has been recently approved in India for treatment of T2DM. Study was designed to compare effect of FDC of Teneligliptin 20 mg + Dapagliflozin 10 mg (Arm A) with FDC of Sitagliptin 100 mg + Dapagliflozin 10 mg (Arm B) & FDC of Linagliptin 5 mg + Empagliflozin 25 mg (Arm C) with parameters derived from CGM in Indian T2DM

Results: Present interim analysis report of 50 T2DM patients shows changes in CGM parameters when compared as intergroup between FDC of Teneligliptin 20 mg + Dapagliflozin 10 mg, FDC of Sitagliptin 100 mg + Dapagliflozin 10 mg & FDC of Linagliptin 5 mg + Empagliflozin 25 mg at end of phase II as non-significant (p>0.05). Significant improvement seen in intragroup from Pre-treatment to End of phase II in all efficacy parameter. No serious adverse event reported.

Conclusion: FDC of Teneligliptin 20 mg + Dapagliflozin 10 mg, Sitagliptin 100 mg + Dapagliflozin 10 mg & FDC of Linagliptin 5 mg + Empagliflozin 25 mg had significant improvement in CGM & Glycemic parameters.

Disclosure

H.V. Barkate: Employee; Glenmark Pharmaceuticals. A.U. Petare: Employee; Glenmark Pharmaceuticals. S. Bhushan: None. S.Y. Choudhari: Employee; Glenmark Pharmaceuticals, Sun Pharmaceutical Industries Ltd. M. Brid: None. S. Patil: Employee; Glenmark Pharmaceuticals.
334-OR: Allogeneic Neo-Islets Reduce Insulin Need by up to 1.2 U/kg bw in Autoimmune Type 1 Diabetes Dogs over Three Years without Requiring Antirejection Drugs, Enough to Meet Human Type 1 Diabetes Mellitus Needs
Authors: GOOCH ANNA , WESTENFELDER CHRISTOF
Published: June 2024

The spontaneously diabetic dog is ideal to test therapies intended for humans with T1DM. Neither insulin treated dogs nor humans spontaneously revert. Both have islet autoantibodies, shortened life expectancy, end-organ damage, while dogs need more insulin (humans: 0.5-1; dogs: 1-4 U/kg/day). We tested Neo Islets (NIs), 3-D organoids made of culture expanded islet cells and Mesenchymal Stem Cells in 9 spontaneously DM pet dogs. NI dose = 2x10e5 per kg bw, given i.p. to sedated dogs under ultrasound guidance. Follow up: Blood Glucose Levels monitored with continuous monitors. Insulin needs were recorded, and late follow-up levels of serum Creatinine, BUN and proteinuria were monitored. Each dog served as its own control. UA, full chemistries, lipids, CBC were assessed at baseline, monthly for 3 months, and biannually for 3 years. Results in Figure.

Allogeneic NI treatment is safe and effective (3 year follow up). T1DM dogs require significantly more insulin per kg bw than T1DM humans. Since NIs can produce up to 1.2 U/kg bwt and are dosed on a per kg bw basis, this implies that NIs would be curative for T1DM in humans while not needing anti-rejection drugs, thereby readily exceeding the therapeutic potency of other current biotherapies.

Disclosure

A. Gooch: Employee; SymbioCellTech, LLC. Board Member; SymbioCellTech, LLC. Stock/Shareholder; SymbioCellTech, LLC. C. Westenfelder: None.
337-OR: ADA Presidents' Select Abstract: The LonP1 Protease Maintains Pancreatic ß-Cell Survival by Governing Mitochondrial Protein Folding
Authors: LI JIN , ZHU JIE , RECK EMMA C. , WALKER EMILY M. , SOLEIMANPOUR SCOTT
Published: June 2024

Accumulating evidence indicates that type 2 diabetes (T2D) is a protein misfolding disease. LonP1 is an essential mitochondrial protease that mediates mitochondrial proteostasis through clearance of unfolded or misfolded proteins, but its role in β-cells is unknown. We generated mice bearing β-cell specific deletion of LonP1 (β-LonP1KO) and found that LonP1 deletion led to progressively impaired glucose tolerance with age and decreased glucose-stimulated insulin release (GSIS). LonP1 deficiency also induced β-cell apoptosis resulting in the loss of β-cell mass. In the mitochondria, β-LonP1KO mice exhibited diminished mitochondrial respiration, abnormal mitochondrial ultrastructure, reduced mitochondrial mass, and elevated ROS levels. An accumulation of misfolded mitochondrial proteins, defect of OXPHOS complex assembly, and/or induction of ROS could be primary triggers driving mitochondrial dysfunction and β-cell apoptosis in β-LonP1KO islets. Interestingly, β-cell specific overexpression of the antioxidant enzyme catalase targeted to mitochondria exerted only a modest, transient protective effect on glucose tolerance and β-cell mass in β-LonP1KO mice yet did not relieve accumulation of misfolded mitochondrial proteins, suggesting ROS alone could not account for the phenotype in LonP1-deficient mice. Concordantly, a similar effect of anti-oxidants on β-cell survival and mitochondrial protein misfolding was observed in human islets in the context of LonP1-deficiency. Thus, the LonP1 protease is vital for β-cell survival and mass by governing mitochondrial protein folding, which could be a potential therapeutic target to prevent β-cell failure during the development of T2D.

Disclosure

J. Li: None. J. Zhu: None. E.C. Reck: None. E.M. Walker: None. S. Soleimanpour: Advisory Panel; Novo Nordisk. Research Support; Ono Pharmaceutical Co., Ltd.
361-OR: A Multiomics Approach to Identify Genes Important for the Regulation of Antidiabetic and Anti-inflammatory Lipids
Authors: SANTORO ANNA , KELLER MARK , CHEN ZHENLONG , ATTIE ALAN D. , SIEGEL DIONICIO , CHURCHILL GARY A. , SAGHATELIAN ALAN , KAHN BARBARA B.
Published: June 2024

Introduction: Palmitic Acid esters of Hydroxy Stearic Acids (PAHSAs) are signaling lipids with beneficial metabolic effects. Serum and adipose tissue (AT) PAHSA levels correlate highly with insulin sensitivity in people. PAHSAs enhance insulin sensitivity in diabetic mice. Thus, low PAHSA levels could contribute to the etiology of insulin resistance and T2D. PAHSAs are regulated by synthesis, degradation and incorporation into other lipids. We aimed to identify candidate enzymes that regulate PAHSAs using genetic mouse models in which large changes in PAHSAs are associated with major changes in glucose tolerance and/or insulin sensitivity.

Methods: AT PAHSA levels are increased in mice with Adipose-specific Glucose Transporter 4 overexpression (AG4OX) which induces expression of the lipogenic transcription factor, Carbohydrate-response element-binding protein (ChREBP). Thus, we performed lipidomics and bulk RNA sequencing in perigonadal AT from wildtype, AG4OX, ChREBP knockout and AG4OX crossed to ChREBP KO which reverses the massive elevation of PAHSAs in AG4OX. We also measured PAHSAs in 8 genetically inbred mouse strains. We merged these datasets to identify genes strongly associated with PAHSAs in both models. A subsequent GWAS query for lipid-related SNPs delivered a discrete number of genes to validate as important PAHSA regulators.

Results: All PAHSA regioisomers increase in AT with upregulation of glucose transport and decrease with ChREBP downregulation. PAHSA levels are higher in insulin-sensitive genetic strains. Many genes that strongly associate with 9-PAHSA belong to lipid metabolism pathways. Our single-gene queries in human GWAS support a role for 27 genes in the regulation of lipid metabolism in humans and, potentially, in PAHSA regulation.

Conclusions: These studies provide novel insights into the metabolic pathways and enzymatic machinery responsible for PAHSA metabolism, which may be targeted to prevent or treat T2D in humans.

Disclosure

A. Santoro: None. M. Keller: None. Z. Chen: None. A.D. Attie: None. D. Siegel: None. G.A. Churchill: None. A. Saghatelian: None. B.B. Kahn: Advisory Panel; Janssen Pharmaceuticals, Inc. Consultant; Vida Ventures Advisors, Arrowhead Pharmaceuticals, Inc.

Funding

K01 DK128075 (Anna Santoro), NIH P30 DK135043 (Barbara B. Kahn), NIH R01 DK106210 (Barbara B. Kahn and Alan Saghatelian), and JPB foundation (Barbara B. Kahn)
362-OR: Divergent Roles of METTL14-Mediated m6A in Regulating Brown and White Adipose Tissue Transcriptomes and Systemic Metabolism
Authors: XIAO LING , DE JESUS DARIO F. , JU CHENG-WEI , HU JIANG , WEI JIANGBO , DISTEFANO-FORTI AVA , SALERNO GONZALES VALERIA R. , TSUJI TADATAKA , WEI SIYING , BLÜHER MATTHIAS , TSENG YU-HUA , HE CHUAN , KULKARNI ROHIT
Published: June 2024

N6-methyladenosine (m6A) is among the most abundant post-transcriptional modifications in mRNA, yet its precise cell-type-specific roles in orchestrating gene expression programs remain elusive. Although brown and white adipocytes are both considered fat cells, their unique properties underscore the importance of context-specific post-transcriptional regulation for whole-body metabolism. Here, we provide the first evidence that m6A methyltransferase-like 14 (METTL14) differentially regulates transcriptomes in brown and white adipose tissue (BAT and WAT), leading to divergent metabolic outcomes. We found that human brown and white adipocytes (hBAT and hWAT) display markedly distinct m6A landscapes; besides, in insulin-resistant humans and mice, METTL14 expression differs significantly between the fat depots in the context of correlation with insulin sensitivity. Mettl14-knockout in BAT via Ucp1-cre promotes secretion of specific prostaglandins and improved peripheral insulin sensitivity in mice. Conversely, Mettl14-deficiency in WAT via Adipoq-cre triggers white adipocyte apoptosis, lipodystrophy, and systemic insulin resistance. Integration of m6A-seq and RNA-seq profiling revealed strikingly distinct transcriptomes and m6A methylomes in Mettl14-deficient BAT versus Mettl14-deficient WAT. More specifically, upregulated prostaglandin biosynthesis pathways were enriched in Mettl14-deficient BAT, and TNF-associated and apoptotic pathways were activated in Mettl14-deficient WAT. Using stable METTL14-knockout hBAT or hWAT cell lines, we report that METTL14-mediated m6A negatively regulates gene expression of PTGES2, CBR1, and PGC1a in hBAT, and TRAIL, TNFR1, RIP, and DFFA in hWAT by promoting mRNA decay. These data shed light on the ability of m6A to impact metabolism in a cell-type-specific manner with implications for influencing the pathophysiology of metabolic diseases.

Disclosure

L. Xiao: None. D.F. De Jesus: None. C. Ju: None. J. Hu: None. J. Wei: None. A. DiStefano-Forti: None. V.R. Salerno Gonzales: None. T. Tsuji: None. S. Wei: None. M. Blüher: Speaker's Bureau; Amgen Inc., AstraZeneca, Bayer Inc., Daiichi Sankyo. Advisory Panel; Lilly Diabetes. Speaker's Bureau; Novartis AG. Advisory Panel; Novo Nordisk. Speaker's Bureau; Pfizer Inc., Sanofi. Y. Tseng: Other Relationship; Biohaven. Consultant; LyGenesis. C. He: None. R. Kulkarni: Advisory Panel; Novo Nordisk, Biomea Fusion, Inc. Consultant; Inversago Pharma. Advisory Panel; REDD Pharmaceutical.

Funding

This work is supported by NIH grants R01 DK67536 (R.N.K.), UC4 DK116278 (R.N.K. and C.H.), and RM1 HG008935 (C.H.).
371-P: Different Definition Wording of Severe Hypoglycemia (SH) Yields Variable Prevalence and Incidence Rates
Authors: KUEI LIN YU , YE WEN , HEPWORTH EMILY , ANG LYNN , DE ZOYSA NICOLE , AMIEL STEPHANIE A. , FISHER SIMON J.
Published: June 2024

Introduction & Objective: To determine if different SH definition wording result in different measured SH prevalence and incidence.

Methods: T1D Exchange registrants were surveyed cross-sectionally to collect 6-month SH history with definitions worded from (1) the International Hypoglycemia Study Group (IHSG) 2013 consensus; (2) a large diabetes community website (diabetes.co.uk); (3) a hypoglycemia awareness assessing instrument (HypoA-Q); and (4) the IHSG 2017 consensus. Analyses included McNemar test, kappa statistic, pair-wise Wilcoxon signed-rank test and Spearman correlation coefficient calculation.

Results: 1,580 participants (52% women, median[IQR] age 43[33—58]y, diabetes duration 24[12—37]y, 87% non-Hispanic Caucasian) completed the survey. SH prevalence with the 2013 IHSG definition wording was higher than the website, HypoA-Q and 2017 IHSG definition wording (Figure), with pairwise kappas ranging from fair to good (website definition .75; HypoA-Q .72; the 2017 IHSG definition .69). Compared to the 2013 IHSG definition wording, the website, HypoA-Q and 2017 IHSG definition wording yielded lower incidence. The 2013 IHSG definition wording correlated strongly with the website (rs=.73), HypoA-Q (rs=.72) and moderately with the 2017 IHSG definition wording (rs=.61) (P<.001 for all).

Conclusion: Reported SH prevalence and incidence vary based on definition wording.

Disclosure

Y. Lin: None. W. Ye: None. E. Hepworth: None. L. Ang: None. N. de Zoysa: None. S.A. Amiel: Advisory Panel; Vertex Pharmaceuticals Incorporated. Other Relationship; Sanofi. S.J. Fisher: None.

Funding

National Institutes of Health (U01DK135111, K23DK129724)
38-PUB: Tunable Glucose Limiting Membranes for CGMs
Authors: MARTINEZ ANDRE
Published: June 2024

Introduction & Objective: Glucose limiting membranes (GLM) are essential components of continuous glucose monitors (CGM), often generated as blends of hydrophobic and hydrophilic polymers. Blending may complicate processing steps for manufacturers with issues including a need for multiple solvents and strict control of casting conditions to avoid inhomogeneities and macrophase separation. DSM Biomedical has developed new amphiphilic thermoplastic polyurethanes (TPUs) called the Sparsa platform to serve as single component GLMs that achieve required properties without blending.

Methods: Sparsa TPUs were synthesized via a two-step, prepolymer and chain extension method. The formulation was varied to evaluate impact of polymer hardness and hydrophilicity. Permeability of glucose and oxygen through the membranes were analyzed utilizing a Franz cell experiment and oxygen transmission rate instrument respectively. Microphase architecture was evaluated using AFM and SAXS. Fouling behavior was investigated using a quartz crystal microbalance technique and bovine serum albumin. Biocompatibility was evaluated using the L929 MEM elution test and histology following implantation in a porcine model.

Results: Sparsa TPUs were tunable to desired glucose permeability levels and cast from a single solvent. Microstructure and performance were minimally sensitive to fluctuation in ambient humidity during casting. Protein fouling was substantially reduced compared to conventional TPUs. Sparsa TPUs did not cause cytotoxicity and tissue response was similar or less pronounced than for a commercial CGM sensor.

Conclusion: Sparsa TPUs demonstrate tunability in glucose permeability and simplify production of CGMs. Technical properties and biocompatibility indicate Sparsa TPUs can replace current GLMs with improved or equivalent performance.

Disclosure

A. Martinez: None.
391-P: Targeted Deletion of Rho-Associated Coiled-Coil–Containing Protein Kinase 2 in Kidney Tubules Suppresses Expression and Function of Mineralocorticoid Receptor in Mice
Authors: SEKIGUCHI KENSUKE , MATOBA KEIICHIRO , OHASHI SHINJI , MITSUYOSHI ETSUKO , NAGAI YOSUKE , NISHIMURA RIMEI
Published: June 2024

The mineralocorticoid receptor (MR) is a steroid receptor responsible for fluid and electrolyte reabsorption in kidney tubules. Traditionally, MR has been considered a ligand-activated nuclear transcription factor primarily transactivated by aldosterone. Recent studies have indicated that MR is stimulated in an aldosterone-independent manner by Rac1, a member of the Rho small GTPase family. Rho and its effector Rho-associated coiled-coil-containing protein kinase 2 (ROCK2) plays important roles in various cellular functions such as cell adhesion and cytoskeletal rearrangement. However, the tissue-specific role of ROCK2 in kidney tubules is not fully understood. To investigate the role of ROCK2 signaling in tubules, we generated tubule-specific ROCK2 knockout mice (TR2KO) by crossing Ksp-Cre mice with mice containing loxP sites flanking in Exon 3 of ROCK2. These mice displayed no significant differences in body appearance or blood pressure compared to wild-type mice (WT). However, when sodium reabsorption was activated by low dietary potassium, the urinary excretion of sodium and chloride in TR2KO was significantly higher than that in WT. MR and its downstream target, epithelial sodium channel (EnaC), were significantly downregulated in TR2KO compared with WT at mRNA and protein levels. To identify factors related to the regulation of MR by ROCK2, we obtained several candidates from the Chip Atlas. Among these, the expression of STAT3 protein was significantly reduced in TR2KO. Using HEK293-MR cells, which stably expressed human MR, we found that siRNA-mediated STAT3 deletion led to the downregulation of MR at the mRNA level. These findings provide novel insights into the ROCK2 signaling in kidney tubules and establish a hitherto unidentified regulatory mechanism of MR in modulating electrolyte homeostasis.

Disclosure

K. Sekiguchi: None. K. Matoba: None. S. Ohashi: None. E. Mitsuyoshi: None. Y. Nagai: None. R. Nishimura: Speaker's Bureau; Abbott. Advisory Panel; Abbott Japan Co., Ltd. Speaker's Bureau; Boehringer-Ingelheim, Mitsubishi Tanabe Pharma Corporation, Kowa Company, Ltd., Medtronic, Sanofi, Taiho Pharmaceutical Co. Ltd., Sumitomo Dainippon Pharma Co., Ltd., Teijin Pharma Limited, Eli Lilly and Company, Novo Nordisk A/S. Consultant; Terumo Corporation.
393-P: SZ-A Ameliorates the Nondiabetic Chronic Kidney Disease by Modulating Fatty Acid Metabolism and Restoring Mitochondrial Homeostasis in Rats
Authors: SONG JIAWE , YE JUN , TANG YAN , XIAO XINHUA , LIU YULING
Published: June 2024

Introduction: Current treatment strategies for chronic kidney disease ( CKD ) focus on controlling risk factors, and diabetes is the main cause of CKD progression to end-stage renal disease. SZ-A, a natural medicine for type 2 diabetes approved by the China National Products Administration in 2020, exerts protective effects against the development of diabetic nephropathy. However, the mechanism and whether SZ-A has an effect on kidney damage independent of its glucose-lowering effect have not been thoroughly elucidated. This study aims to evaluate the efficacy of SZ-A in slowing the progression of nondiabetic CKD.

Methods: A rat model of chronic kidney disease induced by adenine was established, and treated with SZ-A or control medication: acarbose or dapagliflozin, daily oral gavage for four weeks. Kidneys from all groups of rats were functionally evaluated and harvested for transcriptome sequencing analysis at the end of the experiment.

Results: Chronic adenine dosing resulted in severe CKD in vehicle-treated rats, as evidenced by significant increases in serum creatinine and UACR. SZ-A dose-dependently attenuated renal injury independent of glucose-lowering effects. This effect of the highest dose of SZ-A was comparable to that of dapagliflozin, whereas acarbose had no effect. In addition, renal fibrosis and inflammation were improved in the SZ-A treatment group compared to the model group. Transcriptomic analysis showed that the renoprotective effect of SZ-A was associated with the upregulation of PPAR signaling pathway and the inhibition of inflammation; in addition, the PPAR signaling pathway was closely related to FAO and mitochondrial homeostasis, and the ameliorative effect of SZ-A on both was verified at both tissue and cellular levels of rat kidney.

Conclusions: The fact that SZ-A is able to attenuate CKD progression in the adenine-induced model corroborates its potential as a therapeutic renoprotector.

Disclosure

J. Song: None. J. Ye: None. Y. Tang: None. X. Xiao: None. Y. Liu: None.

Funding

CAMS Innovation Fund for Medical Sciences (CIFMS, no. 2021-I2M-1-028)
395-P: QingReYiQiHuoXue Formula Attenuates Dyslipidemia and Ferroptosis in DKD HFD/STZ Mice
Authors: WEI YU , ZHANG LILI
Published: June 2024

Background: Diabetic kidney disease (DKD), a common complication of diabetes, increasingly threatens patients. Approximately 20%-40% of diabetic patients develop DKD, with 30%-50% progressing to end-stage renal disease. QingReYiQiHuoXue Formula (QRF) has demonstrated clinical efficacy in treating DKD, yet its underlying mechanisms remain unclear. Purpose: This study aimed to explore the mechanisms of QRF in treating DKD and to validate its effects on lipid abnormalities and ferroptosis in a DKD mouse model.

Methods: An integrated approach, encompassing network pharmacology, molecular biology, pharmacodynamics, and lipidomics, was employed to elucidate the mechanisms of QRF in treating DKD. Network pharmacology was initially used to predict potential pathways and targets of QRF in treating DKD, along with potential targets for ferroptosis from the ferroptosis database. The efficacy was then validated in a DKD mouse model induced by HFD and STZ injection, including blood and urine tests, histopathological analysis, ferroptosis level measurement, and lipidomic analysis.

Results: Through network pharmacology, we discovered that QRF may regulate both the PI3K/AKT/GSK3β signaling pathway and ferroptosis. In vivo experiments confirmed QRF's renal protective effects in HFD/STZ-induced DKD mice, significantly reducing blood glucose levels, ameliorating blood lipid abnormalities, and reducing renal tissue damage. Lipidomic analysis revealed QRF's regulatory effects on renal lipid metabolism, particularly in reducing levels of polyunsaturated fatty acids (PUFAs) associated with ferroptosis. Further validation showed QRF's potential in modulating ferroptosis and the PI3K/AKT/GSK3β signaling pathway.

Conclusion: QRF alleviates renal damage in a diabetic mouse model by modulating the PI3K/AKT/GSK3β signaling pathway, improving lipid metabolism disorders, and suppressing ferroptosis. This study offers preliminary insights into the mechanisms of QRF in treating DKD.

Disclosure

Y. Wei: None. L. Zhang: None.
429-P: The Correlation Analysis between Trajectory Patterns of Triglyceride–Glucose Index and Diabetic Kidney Disease
Authors: YU SHANSHAN , MEN LILI , DU JIANLING
Published: June 2024

Introduction & Objective: The triglyceride-glucose (TyG) index, an effective marker of insulin resistance (IR), has been confirmed to be associated with the risk of cardiovascular events in T2DM patients. However, studies related to the correlation between TyG index and diabetic kidney disease (DKD) is still limited.

Methods: 678 T2DM patients were selected from Metabolic Management Center of the First Affiliated Hospital of Dalian Medical University from October 2016 to October 2022. The patients were divided into groups according to the different change trajectories of TyG index, eGFR, and urinary albumin according to latent class growth model (Figure A-C), and multiple unordered logistic regression was used to analyze the correlation between TyG trajectory, eGFR trajectory and urinary albumin trajectory.

Results: Compared with the middle stable trajectory group of eGFR, the TyG index of patients in the low decline trajectory group and the high stable trajectory group was higher (P<0.001). Compared with the low trajectory group of urinary albumin, the TyG index of patients in the middle trajectory group and high trajectory group was higher (P<0.05). Trajectories of TyG index in T2DM patients were related to trajectories of eGFR and urinary albumin (Table 1).

Conclusion: TyG index is related to DKD in T2DM patients.

Disclosure

S. Yu: None. L. Men: None. J. Du: None.