bluuebunny/crossref_metadata_2025 huggingface dataset:
177-OR: Time Below Range (TBR) and Its Link to Impaired Awareness of Hypoglycemia (IAH) and Severe Hypoglycemia (SH)—Evidence from the Association of British Clinical Diabetologists (ABCD) Study
Authors: DESHMUKH HARSHAL , WILMOT EMMA G. , CHOUDHARY PRATIK , CULL MELISSA L. , RYDER ROBERT E. , SATHYAPALAN THOZHUKAT , WALTON CHRISTOPHER
Published: June 2024

Objectives: The primary objective of this study was to explore the relationship between the Time Below Range (TBR) and Impaired Awareness of Hypoglycemia (IAH) and Severe Hypoglycemia (SH).

Methods: Our study used data from people with diabetes using isCGM in the ABCD audit. Hypoglycemia awareness was evaluated using the Gold score, with a score of ≥4 denoting Impaired Awareness of Hypoglycemia (IAH). SH was defined as hypoglycemia necessitating third-party assistance. Logistic regression analysis was used to identify the association between TBR% (<70 mg/dl) at the last follow-up (used as a continuous independent variable) and follow-up Gold score and the number of SH between isCGM initiation and follow-up. Youden’s J index was used to identify the optimal TBR% cutoffs for detecting IAH and SH.

Results: The study consisted of 15,777 people with diabetes with at least one follow-up, of which TBR data was available for 5030 people. The median TBR% in the study population was 4% (IQR 2%-6.6%). Following adjustment for age, gender, and BMI, TBR was significantly associated with both SH (Beta=0.02 P=0.001) and IAH (Beta=0.01 P=0.006). The determined optimal TBR cutoffs for identifying follow-up IAH and SH were 3.35% and 3.95%, respectively. These cutoffs yielded sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 65%, 43%, 19%, and 85% for IAH and 73%, 42%, 5%, and 97% for SH.

Conclusion: Our study, based on real-world data, shows a clear association between TBR% and IAH and SH in people with diabetes. Our findings broadly align with the international consensus recommending a TBR of <4% in individuals with type 1 diabetes. However, we observed that this cutoff has limited discriminatory power in predicting SH and IAH, emphasising the need for nuanced approaches in establishing optimal TBR thresholds for distinct diabetes-related outcomes.

Disclosure

H. Deshmukh: None. E.G. Wilmot: Other Relationship; Abbott. Speaker's Bureau; AstraZeneca. Other Relationship; Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, embecta, Medtronic, Novo Nordisk. Advisory Panel; Roche Diabetes Care. Other Relationship; Sanofi. Speaker's Bureau; Ypsomed AG. P. Choudhary: Advisory Panel; Abbott, Biolinq. Speaker's Bureau; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, Sanofi. Advisory Panel; Ypsomed AG, Vertex Pharmaceuticals Incorporated. M.L. Cull: None. R.E. Ryder: Speaker's Bureau; Abbott, Besins Healtcare, BioQuest, GI Dynamics. Consultant; GI Dynamics. Other Relationship; Novo Nordisk. T. Sathyapalan: Research Support; Abbott. Advisory Panel; Rhythm Pharmaceuticals, Inc., Pfizer Inc. C. Walton: None.
1772-P: Monocarbonyl Analogs of Curcumin C66 and B2BrBC Modulate Diabetes-Related Gene Expression in Rat Pancreatic Cells
Authors: STOJCHEVSKI RADOSLAV , BOGDANOV JANE B. , HADZI-PETRUSHEV NIKOLA , MLADENOV MITKO , PORETSKY LEONID , AVTANSKI DIMITER
Published: June 2024

Monocarbonyl analogs of curcumin (MACs) lacking a β-diketone moiety have been shown to exhibit improved stability and better bioavailability than curcumin. This study aimed to evaluate the effects of two MACs (C66 and B2BrBC) on the expression of genes related to the onset, development, and progression of diabetes in rat pancreatic RIN-m cells. The cells were cultured in complete RPMI 1640 medium and treated with C66 or B2BrBC (50 μM) or vehicle for 72 h, followed by treatment with streptozotocin (STZ) (1.5 mM) or vehicle for an additional 24 h. Quantitative PCR array analysis was performed using a rat diabetes panel comprising 84 genes. The data demonstrated that C66 and B2BrBC significantly modulated the expression of 16 genes involved in growth regulation in RIN-m cells and genes associated with inflammation, immune response, and energy metabolism. Notably, C66 and B2BrBC inhibited the STZ-induced expression of pro-inflammatory Tnf and Icam1 while increasing the expression of Ins1. Moreover, C66 pretreatment influenced Ctla4 and Serpine1 expression, and B2BrBC pretreatment affected Mapk8, Serpine1, and Igfbp5 levels compared to STZ treatment alone. Cells treated with MACs and STZ showed a different pattern of gene expression for Igfbp5, Gpd1, Agt, Serpine1, Cebpa, Retn, Ccl5, and Srebf1 compared to vehicle-treated cells. Our findings show that C66 and B2BrBC modulate the expression of essential diabetes-related genes, which may serve as a basis for further research on MACs and contribute to the development of novel therapeutic targets and strategies.

Disclosure

R. Stojchevski: None. J.B. Bogdanov: None. N. Hadzi-Petrushev: None. M. Mladenov: None. L. Poretsky: None. D. Avtanski: None.

Funding

Gerald J. and Dorothy R. Friedman New York Foundation for Medical Research
1775-LB: Role for Glucagon-Like Peptide 1 Receptor Agonists in Symptomatic Post-bariatric Hypoglycemia
Authors: ALQAZLAN TAMIM , ALSAEED ASEEL A. , OTHMAN TAREQ T. , ALSHEHRI ALI , ALMEHTHEL MOHAMMED
Published: June 2024

Introduction & Objectives: Post-bariatric surgery patients suffer from weight gain and hypoglycemia. Role of GLP-1 in such patients is not established. We studied the effects of GLP-1 agonists on hypoglycemia, weight and hypoglycemic attitudes and behavior among patients who had bariatric surgery.

Methods: In a cross-sectional study, conducted at a Medical City in Saudi Arabia, adult patients who underwent bariatric surgery and prescribed GLP-1 agonist were included. Data were collected on socio-demographic, medical history, weight, BMI, hypoglycemic episodes, and Hypoglycemic Attitudes and Behavior Scale (HABS). Wilcoxon Ranked Sum, McNemar and test of homogeneity were used to assess the differences before and after the GLP-1.

Results: Out of 21 patients included in the analysis, 33% were male and 48% had diabetes. Vertical sleeve gastrectomy (62%) was the most common procedure. Liraglutide was most common GLP-1 analog used. There was significant reduction in the weight and BMI. In the HABS, except the domain of confidence, other domains remained unchanged post GLP-1. Hypoglycemia episodes per week also showed significant change after GLP-1. Symptoms of hypoglycemia did not change significantly. (Table 1)

Conclusions: In this study, use of GLP-1 was found to have positive impact on weight and hypoglycemia among bariatric surgery patients. Large scale studies are needed to generate more robust evidence.

Disclosure

T. AlQazlan: None. A.A. AlSaeed: None. T.T. Othman: None. A. Alshehri: None. M. Almehthel: None.
1776-LB: Hyperglycemia Stimulates Local Lactate Production in the Hypothalamus
Authors: UZO CHUKWUEMEKA , CHAN OWEN
Published: June 2024

We previously demonstrated that poorly controlled type 1 diabetes leads to an increase in extracellular lactate concentrations in the ventromedial hypothalamus (VMH) that contributes to suppressing the counterregulatory hormone responses to hypoglycemia. The mechanisms underlying the increase in VMH lactate in diabetes are not clear. The current study evaluates whether this lactate is derived from the periphery or whether it is generated locally in the brain. To answer this question, we gave conscious, freely moving male Sprague-Dawley rats a 50% glucose bolus (1g/kg) intravenously and measured changes in interstitial glucose and lactate in the VMH using microdialysis while infusing either artificial extracellular fluid (aECF; N=13) or sodium oxamate (OXA; N = 11), a lactate dehydrogenase-A inhibitor, through microinjection needles that targeted the VMH. Our results show that the glucose bolus led to a rapid and dramatic rise in plasma glucose levels, followed by an increase in plasma lactate (300% and 150% change from baseline, respectively). In addition, glucose and lactate in the hypothalamus also increased significantly. However, in animals treated with OXA, the rise in hypothalamic lactate was significantly reduced (P-value = 0.018). In summary, our data suggest that elevated blood glucose in diabetes possibly triggers the local production of lactate in the brain, which may contribute to the development of counterregulatory failure to hypoglycemia.

Disclosure

C. Uzo: None. O. Chan: None.

Funding

University of Utah Diabetes, Metabolism Research Center
1781-LB: Diet-Induced Upregulation of LRG1 Contributes to Renal Lipotoxicity and Damage in Chronic Kidney Disease
Authors: WEI CONG , MORALES DESIRAE , RYU JIYOON , HADLEY JASON , BAI JULI , DUGGIRALA RAVINDRANATH , LYNCH JANE L. , XIAO LI L. , DONG LILY Q.
Published: June 2024

Obesity and diabetes significantly elevate the risk of chronic kidney disease (CKD). While renal lipotoxicity and damage serve as markers of CKD, the mechanisms driving its progression remain poorly understood. In this study, we measured the protein levels of leucine-rich alpha-2-glycoprotein 1 (LRG1), an adipokine up-regulated in the serum of obese humans and mice, in mouse urine samples. Elevated levels of urine LRG1 were detected in obese mice fed a high-fat diet (HFD) compared to their lean counterparts. Furthermore, whole-body Lrg1 knockout mice exhibited resistance to HFD-induced lipid accumulation and tubular cell damage in the kidney, accompanied by improved ER stress and reduced Chop activity relative to wild-type littermates. Cellular studies revealed that LRG1 treatment alone induced lipid accumulation and fibrogenesis in HK-2 proximal tubule cells by inhibiting fatty acid β-oxidation (FAO) and triggering apoptosis. Moreover, co-treatment of LRG1 with low-dose palmitate acid (50 μM) had a synergistic effect on lipid accumulation in HK-2 cells. In summary, our findings suggest that LRG1 is a urinary protein, and its augmentation in urine may serve as a biomarker for obesity-induced insulin resistance and CKD. Thus, therapeutic targeting of LRG1 could represent an effective strategy to mitigate ectopic fat deposition in the kidney and prevent the exacerbation of obesity-induced CKD.

Disclosure

C. Wei: None. D. Morales: None. J. Ryu: None. J. Hadley: None. J. Bai: None. R. Duggirala: None. J.L. Lynch: Research Support; Beta Bionics, Inc., Novo Nordisk. L.L. Xiao: None. L.Q. Dong: None.

Funding

the Baptist Health Foundation
1783-LB: Acute Hyperglycemia Induces Human Podocyte Apoptosis by Increasing Monocyte Release of TNF-α through ER Stress/ROS Activation of ADAM17/iRhom2 Expression
Authors: MEI ZHANG RONG , OH JISU , KUTZ GRETA A. , DUSSO ADRIANA S. , BERNAL-MIZRACHI CARLOS
Published: June 2024

Introduction: Targeting glycemic control based on hemoglobin A1c (A1c) reduces but does not abolish the onset and progression of chronic kidney disease (CKD), suggesting factors other than A1c contribute to the residual risk. Acute hyperglycemia is associated with the development of microalbuminuria, but the underlying mechanisms are unknown. This study aimed to identify if acute hyperglycemia is directly toxic to podocytes or by inducing a proinflammatory monocyte phenotype to cause podocyte apoptosis.

Methods: Monocytes, isolated from healthy subjects, were cultured under euglycemic (5mM) or hyperglycemic (16.7 mM) conditions +/- 10 nM GLP-1 for 6h. QPCR measured monocyte expression of iRhom2 and Adam17, genes responsible for TNF-α release. THP-1 cells, differentiated to macrophages with 160 nM PMA for 48h, were exposed to 5 or 16.7 mM D-glucose for 24h +/- 10 nM GLP-1. Human immortalized podocytes were exposed to 5 or 16.7 mM D-glucose conditioned media from monocytes or THP-1 macrophages for 24h. Caspase 3/7 assessed podocyte apoptosis. TNF-α was tested by ELISA.

Results: Acute hyperglycemia had no direct effect on podocyte apoptosis, but induced a proinflammatory monocyte and THP-1 secretome with high TNF-α release causing podocyte apoptosis. In monocytes, acute hyperglycemia for 6h was sufficient to increase oxidative and ER stress and induce ADAM17/iRhom2 expression, facilitating TNF-α release. Monocyte and THP-1 exposure to GLP-1 prevented acute hyperglycemia induction of ADAM17/iRhom2 expression, TNF-α release, and podocyte apoptosis.

Conclusion: These results show a mechanism by which acute hyperglycemia accelerates the early onset of CKD, and highlights the anti-inflammatory role of GLP-1 independent of glycemic control to reduce CKD progression in diabetes.

Disclosure

R. Zhang: None. J. Oh: None. C. Bernal-Mizrachi: None.

Funding

American Heart Association Career Development Award (855967)
1796-LB: Adipocyte-Derived Extracellular Vesicles (AdEVs) Contribute to Insulin Resistance and Atherosclerosis in Obesity
Authors: RIMA XILAL Y. , SHANTARAM DHARTI , LIU JOEY Z. , WRIGHT VALERIE P. , DOON-RALLS JACOB , AMARI ANASTASIIA , JALILVAND ANAHITA D. , NEEDLEMAN BRADLEY J. , NORIA SABRENA , BRETHAUER STACY , PERRY KYLE A. , REATEGUI EDUARDO , HSUEH WILLA
Published: June 2024

Introduction: Cardiovascular disease is the leading cause of death worldwide. Obesity is a well-known major risk factor for atherosclerosis with 60% of all atherosclerotic burden due to metabolic syndrome, while other factors remain unknown. Adipose tissue (AT) inflammation is likely a contributor. Recently, extracellular vesicles (EVs) have emerged as potential mediators of intercellular and interorgan communication, with EV secretion from adipocytes increasing 4-fold in obese mice. Adipocytes are a primary source of circulating microRNAs (miRNAs), an essential component of AdEV cargo, as well as lipids. Therefore, we hypothesize that AdEVs impact atherosclerosis and may mediate obesity-accelerated vascular damage.

Methods: To test this hypothesis, we retro-orbitally administered 1010 AdEVs harvested from obese and lean mice into 52-week-old atherosclerosis-prone (LDLR-/-) mice, which develop accelerated complex lesions when consuming a western high-fat diet (WHFD).

Results: Despite matched body weights and similar plasma cholesterol levels post-AdEV injection, en-face analysis of the aorta confirmed a significant increase in the atherosclerotic lesions of mice that received AdEVs from obese donors (25 - 30%; p < 0.0001) compared to those that received AdEVs from lean donors (14 - 20%; p > 0.05), which resembled the effect of the saline control. Moreover, mice that were administered AdEVs from obese donors developed worse insulin resistance after AdEV injection than AdEVs from lean donors (p < 0.05). In humans, AdEVs from obese individuals activated monocyte-derived macrophages and initiated a pro-inflammatory cascade, while AdEVs from lean individuals had similar effects to saline. Furthermore, the AdEVs from lean and obese individuals demonstrated differential expression of miRNA and lipid cargo.

Conclusion: These observations highlight the critical role of AdEVs and their cargo in mediating obesity-associated atherosclerosis.

Disclosure

X.Y. Rima: None. D. Shantaram: None. J.Z. Liu: None. V.P. Wright: None. J. Doon-Ralls: None. A. Amari: None. B.J. Needleman: Speaker's Bureau; Metronics, Intuitive Surgical. Advisory Panel; Revmedica. S. Noria: None. S. Brethauer: None. K.A. Perry: Research Support; Ethicon, Inc. E. Reategui: None. W. Hsueh: None.
1799-LB: Identification of Proteomics Signature for Vascular Complications in Type 2 Diabetes
Authors: FRANCIS HABIB , JANUSZEWSKI ANDRZEJ S. , O'ROURKE MATTHEW , HUANG MICHAEL L. , HARDIKAR ANANDWARDHAN A. , JOGLEKAR MUGDHA V. , SULLIVAN DAVID , JENKINS ALICIA , MOLLOY MARK P. , KEECH ANTHONY C. , BEHALF OF THE FIELD STUDY INVESTIGATORS ON
Published: June 2024

Introduction: Robust predictive measures for Type 2 diabetes (T2D) vascular complications to facilitate early intervention strategies are needed.

Methods: Fasting plasma from 363 Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial participants (mean±SD) age: 61.3±6.4 yrs, 5.6±5.4 yrs T2D, HbA1c: 6.7±1.2% (49.7±13.4 mmol/mol), were collected at baseline and stored (-80°C) until quantitative proteomics analysis of tryptic peptides. Protein signatures associated with future micro- or macrovascular complications (100 and 54 subjects, respectively) were identified using a random forest approach, adjusted for treatment allocation. Exhaustive search using logistic regression was then carried out to optimise models. Pathway analysis was carried out using the NIH functional annotation tool, DAVID Bioinformatics. Resources.

Results: Fifty targets were selected: 14 were associated with microvascular, 13 with macrovascular complications and 23 were common for both. Pathway analysis revealed six main pathways: cholesterol metabolism, platelet activation, complement and coagulation, focal cell adhesion, actin cytoskeleton and hypertrophic cardiomyopathy. In logistic regression, the optimal model for prediction of microvascular complications with overall p<0.0001, AUC=0.74 contained Cadherin-5, Clusterin, Ceruloplasmin, Glutathione peroxidase 3 and Inter-alpha-trypsin inhibitor heavy chain H3. For macrovascular complications the model contained Zinc-alpha-2-glycoprotein and Coagulation factor V (p<0.0001, AUC=0.72). For any micro- or macro-vascular complications, the model contained Cholinesterase, Ceruloplasmin, Mannose-binding protein C and Coagulation factor V (p<0.0001, AUC=0.70).

Conclusion: Proteomic signatures represent a promising first step towards identifying protein signatures associated with T2D complications. Future research will aim at finding therapeutic targets in the metabolic pathways identified by those proteins.

Disclosure

H. Francis: None. A.S. Januszewski: None. A.A. Hardikar: None. M.V. Joglekar: None. D. Sullivan: None. A. Jenkins: Research Support; Abbott, Viatris Inc. Advisory Panel; Abbott. Research Support; Medtronic. Board Member; Insulin for Life. Research Support; Leona M. and Harry B. Helmsley Charitable Trust, Juvenile Diabetes Research Foundation (JDRF), Jaeb Center for Health Research, National Institutes of Health, National Health and Medical Research Council Australia. M.P. Molloy: None. A.C. Keech: Research Support; Abbott, Amgen Inc., Bayer Inc., Kowa Company, Ltd., Mylan. Speaker's Bureau; Novartis Pharmaceuticals Corporation. Research Support; Novartis Pharmaceuticals Corporation, Sanofi, Viatris Inc.

Funding

National Health and Medical Research Council (GNT1147897)
1806-LB: Improvement in Sensory Function and Achieving Remission of Type 2 Diabetes Mellitus through Digital Twin Technology—A One-Year Intervention Study
Authors: SHAMANNA PARAMESH , DHARMALINGAM MALA , VADAVI ARUN , KESHAVAMURTHY ASHOK , BHONSLEY SUCHITRA , MOHAMED MALUK , SHAH LISA , THAJUDEEN MOHAMED , PANANDIKAR MAHIKA , JOSHI SHASHANK R.
Published: June 2024

Introduction and Objectives: Digital twin (DT) platform uses Artificial Intelligence (AI) and Internet of Things, to integrate multi-dimensional data for precision nutrition and health recommendations via the mobile app and by coaches. Remission was defined as A1C levels less than 6.5% without medication for over 3 months. Status of sensory functions were assessed by monofilament test (MF) and vibration perception (VP) in patients on DT platform.

Methods: We monitored 181 T2DM patients, across 4 centers, for remission of T2DM, with a focus on participants with sensory neuropathy. Statistical analysis, including the Pearson correlation coefficient, explored the link between HbA1c levels and change in sensory functions.

Results: Mean age, duration of diabetes, were 44 years (±8.6) and 3.7 years (±2.7). Mean HbA1c decrease was 3.03 (8.9% to 5.8), indicating significant improvements from baseline to Day 360. 75.69% of the participants (n=137) achieved remission. Sensory function evaluations showed significant improvement: 96.4% (26 of 27) improved touch sensitivity in MF test (p=0.0013), and 63.0% (46 of 73) showed better vibration perception in VP test (p<0.0001). The correlation between remission and sensory test improvements was found to be weak, with MF changes showing a very slight negative correlation (r=-0.0187) and VP changes a slight positive correlation (r=0.0798), indicating that achievement of remission is not a strong predictor of sensory function recovery.

Conclusion: DT has a transformative potential for sensory function recovery among T2DM undergoing remission, evidenced by significant improvements in MF and VP tests. However, the minimal correlation between remission and sensory improvement suggests that the recovery of sensory functions in diabetic neuropathy involves a complex interplay of factors, emphasizing the need for comprehensive management approaches and further research into neuropathic recovery mechanisms.

Disclosure

P. Shamanna: None. M. Dharmalingam: None. A. Vadavi: None. A. Keshavamurthy: None. S. Bhonsley: None. L. Shah: Employee; Twin Health. M. Panandikar: None. S.R. Joshi: Consultant; Twin Health, Marico, Franco Indian, Zydus Cadila, Glenmark Pharmaceuticals. Other Relationship; Novo Nordisk, Sanofi, MSD, Abbott Nutrition, Abbott, Biocon, Alkem, USV Private Limited, Boehringer-Ingelheim.
1807-LB: Comparison between Normal and Diabetes Patients’ Foot Neuro Activity
Authors: KIM WI , PARK MIN S.
Published: June 2024

One simple diagnostic method to determine foot insensitivity is a nanofilament test or sending a weak electric shock to the patient to detect their response. However, accuracy is an issue due to controlling neurostimulation in the patient. We have developed a device that can detect neuro signals using an electric wavelength between 3-100Hz. We utilize TGAM, which is typically used to detect EEG signals. The device is connected to three different parts located near the Achilles tendon. Synapse signals were collected from 5 normal and diabetic subjects (fasting glucose level over 180mg/dl) by lifting the foot every 3 seconds for 1 minute, using electrodes coated with AgCl. Analog data from the subjects were converted into decimal data and plotted. From the 1-minute response, diabetes patients generated an average of 18.21 signaling spots, whereas normal subjects generated an average of 26.49 signaling spots. Additionally, the total signal created by normal subjects is 633.42% greater than that of diabetes patients. Based on the results, we can conclude that impaired foot movement occurs in diabetes patients due to high glucose levels, which may delay muscle movement by transmitting smaller signal numbers. Furthermore, the signal stimulation itself is also less than normal. Therefore, the progression of diabetic foot may decrease patient movement due to function loss, resulting from reduced signal activity and poor signal transmission.

Disclosure

W. Kim: None. M.S. Park: None.
1815-LB: Lower Limb Vascularity Indices for Major Adverse Limb Events and Mortality in Individuals with Diabetic Foot Ulcer
Authors: GUPTA ASHISH , RASTOGI ASHU
Published: June 2024

Objectives: We aimed to assess correlation between baPWV and ABI, specifically role of baPWV in participants with normal ABI for major adverse limb events (MALE) and mortality in people with diabetes and first diabetic foot ulcer (DFU).

Research Design and Methods: A total of 16000 patients with type 2 diabetes were screened and 2186 individuals followed until 31st December 2022 or the time of death, whichever occurred earlier. A detailed demographic and diabetes complications were recorded. Whole cohort was divided into three groups based on the presenting ABI: group A: ABI 0.7-0.9, group B-ABI: 0.9-1.2 and Group C:ABI>1.2. Presenting baPWV was divided into quartiles as <1642cm/sec, 1642-1896cm/sec,1897-2210 cm/sec and >2210cm/sec for all individuals.. A stepwise logistic regression was used to determine the most relevant predictors of MALE and all-cause mortality.

Results: Median age of participants was 61(53-67) years, duration of diabetes 10(6-15)years and follow up duration of 6(2-8) years. In comparison with participants having a baPWV<1642 cm/sec, the odds for mortality was significantly higher in individuals with baPWV >2210 cm/sec [OR 1.745(1.315-2.315); p<0.001]. At baPWV 1678 cm/sec, sensitivity was 68% and specificity of 62% for predicting mortality. On multivariate logistic regression predictors of mortality were- Age>57.5 years [OR 1.285(1.007-1.639), p-0.004], eGFR<71.5 ml/min/1.73 m2 [OR 1.434(1.128-1.824); p -0.003], any amputation [OR 1.290(1.002-1.660), p-0.049] and bAPWV >2210cm/sec [OR 1.603(1.160-2.214); p<0.001].

Conclusion: High baPWV is a significant predictor of mortality in people with diabetes presenting with a DFU despite a normal ABI.

Disclosure

A. Gupta: None. A. Rastogi: None.
1818-LB: The Influence of COVID-19 Pandemic on Diabetic Foot Amputations in a Western Amazon Hospital
Authors: CARMO HERCULES M.
Published: June 2024

Introduction: Diabetes mellitus is a multifactorial chronic condition, including dietary habits, lifestyle and social, genetic and economic factors, which affects approximately 3% of the global population. In Brazil, around 17 million people have diabetes, with extensive growth projections. Diabetic foot is a serious and prevalent complication, contributing to over 50% of lower limb amputations, especially in developing countries. The COVID-19 pandemic has exacerbated this situation, directly impacting the lives of patients, leading to lifestyle changes, and altering the medical care of individuals with diabetes.

Objective: Investigate the impact of COVID-19 pandemic on amputations due to diabetic foot complications in the last five years.

Methods: This is a cross-sectional study that investigated the frequency of lower limb amputations due to diabetic foot complications from 2017 to 2022 at the Emergency Hospital of Rio Branco (Brazil), considering the impact of the COVID-19 pandemic.

Results: There was an increase in the quarterly average of surgeries of almost 30% after the start of the Covid-19 pandemic and a significant increase in amputations above the foot was observed when compared to the previous period (p=0,0011). The most affected age group was 40 to 79 years. In the analysis by age group, younger patients tended to have lower-level amputations, while older patients had higher-level amputations, indicating a significant correlation (p=0,0023).

Conclusion: This study found an increase in the prevalence of amputation surgeries due to diabetic foot in Acre during the COVID-19 pandemic. This can be attributed to the suspension of control and educational activities in Primary Care due to social distancing measures, transportation restrictions, and fear of virus exposure. The research emphasizes the need for early screening and treatment, both for physical and psychological health, including health agents, to improve the care of diabetic foot patients.

Disclosure

H.M. Carmo: None.

Funding

CNPQ
182-OR: The Triglyceride-Glucose Index and the Presence of Coronary Artery Disease are Mutually Independent Predictors for the Development of Type 2 Diabetes Mellitus
Authors: PLATTNER THOMAS , LARCHER BARBARA , MADER ARTHUR , VONBANK ALEXANDER , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H.
Published: June 2024

The Triglyceride-Glucose-Index (TyG-Index) is a predictor of cardiovascular event risk and is associated with the metabolic syndrome as well as with type 2 diabetes (T2DM). Whether this parameter also predicts incident diabetes in subjects who do not yet have diabetes is less clear; this issue is adressed in the present study. We prospectively recorded incident diabetes over 4 years in 1296 consecutive nondiabetic Caucasian patients who underwent coronary angiography for the evaluation of established or suspected stable coronary artery disease (CAD). Diabetes was diagnosed according to ADA criteria. At baseline, 701 (54.1%) of our patients had significant CAD with lumen narrowing ≥50% at angiography; the TyG-Index was significantly higher in patients with than in those without significant CAD (8.7 [8.3-9.1] vs 8.6 [8.2-8.9] p=0.003). During follow-up, diabetes was newly diagnosed in 204 patients, i.e. in 15.7% of the study population. The TyG-Index strongly predicted diabetes both univariately (OR 1.72 [1.47-2.00]; p<0.001) and after multivariate adjustment including age, sex, smoking, BMI and HbA1c (OR 1.57 [1.33-1.86]; p<0.001). When we further adjusted for the presence of significant CAD, the TyG-Index remained predictive of incident diabetes (OR 1.54 [1.30-1.83]; p<0.001), while CAD predicted incident diabetes in this model independently of TyG-Index (OR 1.61 [1.14-2.28]; p=0.007). We conclude that the TyG-Index and the presence of CAD are mutually independent predictors for the development of T2DM.

Disclosure

T. Plattner: None. B. Larcher: None. A. Mader: None. A. Vonbank: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None. C.H. Saely: None.
1825-LB: Reproductive Health (RH) and Gestational Diabetes (GDM) Knowledge Mediates the Intervention Effect on the Intention to Communicate in Dyads of American Indian and Alaska Native (AIAN) Female Adolescents and Young Adults (FAYA) at Risk for GDM and their Adult Female Caregivers
Authors: SEREIKA SUSAN M. , MOORE KELLY R. , STOTZ SARAH A. , PEI XUEYING , WANG YOUJIA , CHARRON-PROCHOWNIK DENISE , STOPPING GDM STUDY GROUP THE
Published: June 2024

AIAN women are unduly impacted by GDM. This secondary analysis of Stopping GDM trial data explored possible mechanisms of action of a psycho-behavioral educational intervention targeting healthy behaviors to reduce GDM risk from pre- to post-test among AIAN FAYA. Dyads of FAYA and their adult female caregivers were recruited from 5 sites. Each dyad member independently completed questionnaires regarding RH and GDM knowledge, health beliefs, and intention to initiate discussion with healthcare providers (HCPs) and their corresponding dyad member. Between assessments intervention participants viewed a 45-minute video, the initial component of the intervention. Dyadic mediation analysis was conducted using the Actor-Partner Interdependence Model extended to Mediation (APIMeM) assuming distinguishable dyad members. The sample (N=149 dyads; intervention; n=79; control: n=70) included FAYA (mean age 16.7±3.0 years) and adult female caregivers (mean age 44.1±9.3 years; 81.0% being mothers of FAYA). APIMeM revealed a positive actor indirect effect of the intervention for improvement in the FAYA’s intention to initiate discussion through increases in FAYA’s RH and GDM knowledge (1.53, 95%CI=[0.27, 2.98]). A positive partner indirect effect was also observed for the intervention on the improvement in the FAYA’s intention to initiate discussion through increases in the adult caregiver’s RH and GDM knowledge (0.61, 95%CI=[0.042, 1.42]). No effects were found for changes in health beliefs of FAYA or adult caregivers as mediators of intervention effects on FAYA’s and adult caregiver’s intention to initiate discussion. These results suggest that enhancing RH and GDM knowledge may improve key downstream outcomes such as communication between FAYA, adult caregivers and HCPs for AIAN FAYA at risk for GDM.

Disclosure

S.M. Sereika: None. K.R. Moore: None. S.A. Stotz: None. X. Pei: None. Y. Wang: None. D. Charron-Prochownik: None.

Funding

National Institutes of Health (R01-NR014831)
1833-LB: Methylation of MicroRNAs in Human Skeletal Muscle following Acute Exercise
Authors: ZAPATA BUSTOS ROCIO , ROUST LORI R. , FUNK JANET K. , COLETTA DAWN K.
Published: June 2024

Introduction & Objective: MicroRNAs (miRNAs) are non-coding RNAs that act as epigenetic modulators by regulating gene expression post-transcriptionally. Given their regulatory role in gene expression, epigenetic modifications such as DNA methylation to the miRNA, may affect their expression. Previous work from our group has focused on DNA methylation of protein-coding genes, but recently, we have been exploring the methylation status of miRNAs. This study aimed to identify methylation changes in genes coding for miRNAs following a single exercise session.

Methods: We studied 14 sedentary participants (7 male/7 female): age = 34.5 ± 3.1 years, body mass index = 29.3 ± 1.9 kg/m2 and HbA1c = 5.3 ± 0.1 %. We performed VO2peak tests to determine exercise capacity (VO2peak = 25.5 ± 1.6 mL per Kg per minute) and euglycemic hyperinsulinemic clamps (Rd value = 5.9 ± 0.8 mg per Kg per minute) with vastus lateralis muscle biopsies before and 30 minutes after exercise. We extracted DNA from the muscle biopsies and performed reduced representation bisulfite sequencing followed by MethylSig analysis.

Results: An acute exercise bout resulted in 171 differentially methylated cytosines (P < 0.05 and methylation change ≥ 5%), corresponding to 110 unique miRNA genes. Among them, 101 were hypomethylated, and 70 were hypermethylated following exercise. Hypomethylated miRNAs included Hsa-mir-1225 (5 DMCs, 10-25% decrease) and Hsa-mir-3187 (8 DMCs, 6-14% decrease). Hypermethylated miRNAs included Hsa-mir-375 (2 DMCs, 15-19% increase) and Hsa-mir-1915 (3 DMCs, 14-15% decrease). Enrichment analysis of the miRNAs revealed pathways related to ECM and membrane receptors, immune responses, DNA damage responses, STAT3 signaling, and others.

Conclusion: Our study reveals that an acute exercise bout induces alterations in the DNA methylation of various genes coding for miRNAs. Additional work is needed to elucidate how these methylation alterations influence gene expression and biological pathways.

Disclosure

L.R. Roust: Other Relationship; Fractyl Health, Inc. J.K. Funk: None. D.K. Coletta: None.

Funding

This study was funded by the National Institutes of Health (R01DK094013).
1836-LB: Real-World Impact of a Remote, Digitally Enabled Lifestyle Program with Diabetes-Specific Formula as Part of Low-Calorie Diet among People with Obesity and Type 2 Diabetes—The RESET Study
Authors: TRENELL MICHAEL , TAYLOR LOUISE C. , KERR KIRK W. , RUEDA RICARDO , SULO SUELA
Published: June 2024

Background: Weight management strategies are central to the control and remission of type 2 diabetes (T2D). Yet, scalable interventions remain elusive. We report the real-world outcomes of a scalable, digitally-enabled lifestyle program utilizing diabetes-specific nutrition formula (DSNF) as part of a low-calorie diet for people with obesity and T2D.

Methods: 185 adult participants with recently diagnosed T2D and 27 ≤BMI≤ 45 kg/m2 were recruited from 28 primary care practices (Newcastle upon Tyne, UK). The 12-week weight loss phase included the use of a DSNF (Glucerna®, Abbott) as part of a low-calorie diet (900-1000 kcal/day). The diet was personalized, allowing use of Glucerna® for meal replacement, real food, or a combination of both. Anti-hyperglycemic medication was withdrawn while clinical care remained with the primary clinicians. Behavioral coaching was offered digitally alongside educational content, interactive quizzes, and diet planners.

Results: Participants (55±9 years, 53% male, 70% White) engaged well with the digital service, with 78% (n=145) completing the weight loss phase. Content engagement was high (average 360 minutes content read; 60 minutes 1:1 coaching across five sessions); Glucerna® adherence was >80%. A significant 10% weight loss reduction (-10 kg [95%CI: -12, -8]) and ~1% HbA1c reduction (10.9 mmol/mol [95%CI: -11,-7]) were reported at 3 months. Significant reduction in blood pressure was also reported (p-values<0.01). No significant differences were observed between intent-to-treat and evaluable cohorts.

Conclusions: A remote, digitally-enabled lifestyle program using a DSNF as part of a low-calorie diet significantly improved body weight and diabetes control in people with obesity and T2D.

Disclosure

M. Trenell: Consultant; Changing Health, Abbott Nutrition. L.C. Taylor: Employee; Changing Health Ltd. K.W. Kerr: Employee; Abbott. Stock/Shareholder; Abbott. R. Rueda: Employee; Abbott Nutrition. S. Sulo: Employee; Abbott Nutrition.

Funding

Financial support for this study was provided by Abbott and UK Research and Innovation.
185-OR: The Role of Optical Coherent Tomography in the Estimation of Cardiovascular Risk in Asymptomatic Patients with Type 1 Diabetes
Authors: DUBSKY MICHAL , ROLAND ROBERT , MARHEFKOVÁ NATÁLIA , WOHLFAHRT PETER , NOVODVORSKY PETER , KARMAZIN VLADIMIR , HALUZIK MARTIN , PAZDERNIK MICHAL
Published: June 2024

Introduction & Objective: Data on cardiovascular (CV) risk in patients with type 1 diabetes (T1D) is lacking. Our study aimed to assess coronary arteries in high-risk T1D patients using optical coherent tomography (OCT) to estimate their CV risk.

Methods: Sixty-two patients with T1D > 10 years, age 30-67 years, with no history of CVD were examined by carotid ultrasound and coronary artery calcium (CAC) score. Twelve patients were recognized as high-risk defined as CAC score >400 and/or presence of ≥2 carotid plaques. Patients were subsequently examined by coronary angiography and OCT.

Results: Mean age was 64.5±1.8 years, T1D duration 36±11.5 years, HbA1c 7.5±0.8 % and baseline LDL 88.9±21.3 mg/dl. Thin-cap fibroatheroma (TCFA [Figure-A]) was identified in 7/12 (58.3%) patients and very high-risk plaque (TCFA with lumen area < 3.5 mm2 [B], lipid arch > 180° and macrophages [C]) was present in 4/12 (33.3%) patients. We saw intraluminal thrombus [D] and cholesterol crystal [E] in 3/12 (25%) patients. A strong correlation between OCT stenosis and CAC score at the left anterior descending artery (Pearson’s r=0.75, p=0.005) was identified.

Conclusion: Our study showed that asymptomatic T1D patients with high CAC score and carotid plaques had very severe OCT findings. We observed a significant proportion of high-risk lesions potentially associated with plaque rupture and risk of CV death.

Disclosure

M. Dubsky: None. R. Roland: None. N. Marhefková: None. P. Wohlfahrt: None. P. Novodvorsky: Speaker's Bureau; Sanofi, Boehringer-Ingelheim. Advisory Panel; Boehringer-Ingelheim. Speaker's Bureau; Novo Nordisk A/S. Research Support; Sanofi. Speaker's Bureau; Abbott, Medtronic, Berlin-Chemie AG, Viatris Inc., Novartis AG. V. Karmazin: None. M. Haluzik: Advisory Panel; Sanofi, Novo Nordisk, Eli Lilly and Company, AstraZeneca, Bayer Inc., Johnson & Johnson Medical Devices Companies. Consultant; Merck & Co., Inc., Sanofi, Novo Nordisk, Eli Lilly and Company, AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Johnson & Johnson Medical Devices Companies, Novatin. Research Support; Sanofi. Speaker's Bureau; Sanofi, Novo Nordisk. M. Pazdernik: None.

Funding

Supported by the project National Institute for Research of Metabolic and Cardiovascular Diseases (Programme EXCELES, Project No. LX22NPO5104) - Funded by the European Union - Next Generation EU.
1852-LB: “I realized that I could control my health with better eating habits and exercise”—Significant Improvements in Psychosocial Health and Lifestyle in People with Prediabetes Using Dexcom rtCGM
Authors: CRAWFORD MARGARET A. , HICKS CHRISTIAN , SINGH HARSIMRAN
Published: June 2024

CGM supports diabetes self-management and related behavior modification. We investigated the impact of CGM on psychosocial health and lifestyle behaviors in a prediabetes population.

Glucose data were collected in an observational 12-week US study involving adults with prediabetes or at high risk for diabetes (Study 1, N=47). Patient-reported outcomes (PROs) assessing psychosocial health were collected at baseline and study-end. A subset of Study 1 participated in a qualitative follow-up (Study 2, N=17) and shared their experiences using the Dexcom G6. Qualitative data were analyzed using thematic and content analyses.

Study 1 participants were 63% female, 59% White, median (IQR) age 54 (44, 66), BMI 32 (26, 38) kg/m2, medication count=6 (3, 10). TIR remained high for the duration of the study (100% (96, 100)). PROs reflected significantly improved emotional well-being and self-efficacy for health management and reduced perceived severity of prediabetes using Dexcom CGM. Primary qualitative themes are presented in Table 1.

Use of Dexcom CGM was associated with improved psychosocial health and self-care behaviors in participants with prediabetes. Findings emphasize the value of Dexcom CGM as a behavior modification tool irrespective of individuals’ diabetes and glycemic status.

Disclosure

M.A. Crawford: Employee; Dexcom, Inc. C. Hicks: Employee; Dexcom, Inc. H. Singh: Employee; Dexcom, Inc.
1886-LB: Safety, PK, and Preliminary Efficacy of the Liver-Targeted Mitochondrial Protonophore TLC-6740—A Phase 1 Study
Authors: GANE EDWARD , HUSS RYAN S. , SUR JANE , MURAKAMI EISUKE , WENG STEVE , KIRBY BRIAN J. , SHAH AMRIK , SHULMAN GERALD I. , SUBRAMANIAN MANI , VIJAYAKUMAR ARCHANA , MYERS ROBERT P.
Published: June 2024

Background: Mitochondrial uncoupling is a validated approach to weight loss, however, toxicity due to systemic uncoupling has restricted clinical use. To enhance safety, TLC-6740 was developed as a liver-targeted protonophore (>40x liver/plasma ratio) for the treatment of obesity.

Methods: In this randomized, double-blind Ph 1 study (NCT05822544), healthy subjects received single (SAD; n=48) or multiple ascending doses (MAD; n=60) of TLC-6740 (3-120 mg) PO once daily for 10 days (n=6-8 active vs n=2 placebo/group) while fasting. Eight subjects received TLC-6740 15 mg fasted and then fed to evaluate food effect.

Results: In the MAD cohorts, the proportion of subjects with adverse events (AEs) was 58% with placebo and 50-88% with TLC-6740. All AEs were mild except 3 moderate AEs unrelated to treatment (anal fissure, 30 mg; heating pad burn, 120 mg; viral illness, placebo). No drug-related discontinuations, lab abnormalities, or temperature increases were observed. TLC-6740 had a median steady-state half-life of 18-33 hrs; AUC and Cmax increased in a dose-dependent manner with no impact of food or body weight. TLC-6740 caused significant, dose-dependent reductions in serum total and LDL-C (Figure).

Conclusion: In this Ph 1 study, the liver-targeted protonophore TLC-6740 was well tolerated and led to dose-dependent improvements in lipids, supporting its potential for treatment of obesity.

Disclosure

E. Gane: None. R.S. Huss: None. J. Sur: Employee; OrsoBio, Inc. E. Murakami: Employee; OrsoBio, Inc. S. Weng: Employee; OrsoBio, Inc. B.J. Kirby: Consultant; OrsoBio, Inc. A. Shah: Consultant; OrsoBio, Inc. G.I. Shulman: None. M. Subramanian: Board Member; OrsoBio, Inc. A. Vijayakumar: Employee; OrsoBio, Inc. R.P. Myers: Employee; OrsoBio, Inc.
1892-LB: Impact of Ongoing Treatment with High Concentration Capsaicin Topical System on Affective Distress and Quality of Life in Patients with Painful Diabetic Neuropathy—A Retrospective Cohort Study
Authors: UEBERALL MICHAEL A. , QUANDEL TAMARA , ENGELEN SYLVIA , FREITAS RITA , GARCÍA LUCÍA , ALLEN SAMUEL , EERDEKENS MARIE-HENRIETTE
Published: June 2024

Introduction: Pain, depression, anxiety, and sleep disturbance reduce Quality-of-Life (QoL) in painful diabetic peripheral neuropathy (pDPN).1 Prevalence of affective distress in pDPN is 51.4%.2 It is unclear if emotional distress is impacted by analgesic treatment.3 This analysis evaluates the effect of high concentration capsaicin topical system (HCCTS) on affective distress, QoL and sleep in clinical practice, to analyze predictors of treatment response.

Method: Data of all pDPN patients treated with ≥ 1 HCCTS and followed up for a year, were taken from the German Pain eRegistry (283 pain centers). Assessments included pain rating (VAS), Depression, Anxiety and Stress Scale (DASS-21), Veterans RAND-12, modified pain disability index (mPDI) sleep item and suicidal ideation.

Results: This analysis included 826 patients. Patients with strong/severe symptoms of depression, anxiety, stress (DAS-21) decreased from 33.6%, 38.3 %; 47.5% at baseline to 4.7%, 6.5%, 4.6% after treatment 4, respectively. All results showed significant improvements in patients who received 4 HCCTS treatments (Table 1). Tolerability was consistent with the HCCTS profile.

Conclusion: Ongoing HCCTS treatment results in progressive improvement across assessments of pain, affective distress, sleep, suicidal ideation and QoL.

Disclosure

M.A. Ueberall: Research Support; AbbVie Inc. Speaker's Bureau; Almirall, S.A., GlaxoSmithKline plc. Research Support; Grünenthal. Speaker's Bureau; Kyowa Kirin Co., Ltd., Nestlé Health Science, Teva. Research Support; Dermapharm, Recordati. Speaker's Bureau; Esanum. T. Quandel: None. S. Engelen: Employee; Grunenthal GmbH. R. Freitas: Employee; Novartis Pharmaceuticals Corporation, Grunenthal S.A. L. García: Employee; Grunenthal Pharma S.A. S. Allen: Employee; Averitas Pharma, Inc., Lundbeck. M. Eerdekens: Employee; Grünenthal GmbH.
1897-LB: Active Surveillance of Patients at Risk for Euglycemic Diabetic Ketoacidosis from Sodium–Glucose Cotransport 2 Inhibitors—A Quality Improvement Project
Authors: MCCLURE ELIZABETH B.
Published: June 2024

Introduction: The prescriptions rates of SGLT2 inhibitors have increased last decade both for the management of diabetes as well as heart failure management. With this increase there has been a rise in incidence of euglycemic diabetic ketoacidosis (eDKA) in hospitalized patients. The purpose of this quality improvement project was to determine if active surveillance of at risk patients would reduce time to diagnosis and improve patient outcomes.

Methods: A best practice alert was generated within the electronic health record that would fire for any patients with SGLT2-I on home medication list or taken while hospitalized, with a specific list of lab criteria. For this QI project, a provider from the endocrine team monitored a generated report and reached out to the primary team with diagnostic and treatment recommendations. Teams were instructed to place an Endocrine specialty consult if further guidance or management was needed.

Results: During the five-week trial, 34 patients were identified by the BPA with a wide variety of services identified. Of the 34 patients identified as at risk for eDKA, 41% had diagnosis confirmed with further lab evaluation and 12% definitively did not have euglycemic DKA. Of the fourteen patients with confirmed EKDA, eleven received treatment with dextrose containing IVF and IV insulin as needed. Three patients recovered without treatment or with aggressive oral nutrition repletion. During the five-week trial one patient required transfer to intensive care unit for management. The average time to diagnosis with active surveillance was less than 24 hours.

Conclusion: Active surveillance of the BPA lead to prompt diagnosis and treatment of patient with e-DKA from SGLT-2 inhibitors. The QI project also increased awareness of the BPA as well as the diagnosis of eDKA based on provider feedback. There were also several system-wide opportunities noted to reduce patient risk of development of eDKA.

Disclosure

E.B. McClure: None.