bluuebunny/crossref_metadata_2025 huggingface dataset:
318-OR: Dapagliflozin Acutely Improves Renal Cortical Oxygenation in Individuals with Type 1 Diabetes and Albuminuria
Authors: LAURSEN JENS CHRISTIAN , HEINRICH NIELS S. , MELO JOANA , HADDOCK BRYAN , RASMUSSEN IDA B. , SAFAVIMANESH FARZANEH , HANSEN CHRISTIAN S. , STØRLING JOACHIM , LARSSON HENRIK B.W. , GROOP PER-HENRIK , FRIMODT-MOELLER MARIE , ANDERSEN ULRIK B. , ROSSING PETER
Published: June 2021

Objective: Inhibitors of the sodium-glucose cotransporter 2 slow the progression of diabetic kidney disease, possibly by reducing the proximal tubule transport workload with subsequent improvement of renal oxygenation. We aimed to test this hypothesis in individuals with type 1 diabetes and albuminuria.

Research Design and Methods: A randomized, double-blinded, crossover study with a single dose of 50 mg dapagliflozin and placebo separated by a two-week washout period. Magnetic resonance imaging (MRI) was used to assess renal tissue oxygenation (R2*), renal perfusion (arterial spin labelling) and renal artery flow (phase contrast imaging) at baseline and three and six hours from intervention. Exploratory outcomes, including baroreflex sensitivity, peripheral blood oxygen saturation and peripheral blood mononuclear mitochondrial oxygen consumption rate, were evaluated at baseline and 12 hours from intervention.

Results: We included 15 individuals (33% females) with a mean (±SD) age 58±14 years, median [Q1;Q3] urinary albumin creatinine ratio of 46 [21;58] mg/g and eGFR of 73±32 ml/min/1.73m2. The mean changes (±SE) in renal cortical R2* from baseline to six hours were for dapagliflozin -1.3±0.7 s-1 and for placebo +1.4±0.7 s-1 respectively, resulting in a difference between interventions of -2.6 s-1 (95% CI, -4.5 to -0.7, p=0.001). No between-intervention differences were found in other MRI outcomes, physiological parameters or exploratory outcomes.

Conclusions: Dapagliflozin improved renal cortical R2* without changing renal perfusion and blood flow. This suggests an improved renal cortical oxygenation due to reduced tubular transport work in the proximal tubules.

Disclosure

J. Laursen: None. P. Groop: Advisory Panel; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Mundipharma International. M. Frimodt-moeller: None. U. B. Andersen: Other Relationship; Self; Bayer AG. P. Rossing: Advisory Panel; Self; Astellas Pharma Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Merck KGaA, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Vifor Pharma Management Ltd. N. S. Heinrich: Stock/Shareholder; Self; Akebia Therapeutics, Inc., Novo Nordisk A/S. J. Melo: None. B. Haddock: None. I. B. Rasmussen: None. F. Safavimanesh: None. C. S. Hansen: None. J. Størling: None. H. B. W. Larsson: None.
329-OR: Neural Networks in Examining the Association of Built Environment with Diabetes Prevalence
Authors: ZHENG KEVIN , LAWTON RALPH , ZHENG DANIEL Z. , HUANG ERICH
Published: June 2021

Background: Diabetes is associated with factors such as physical activity, diet, and the environment. Previous studies have shown the use of deep learning and satellite imagery to predict community-level health outcomes. However, no studies have assessed whether these deep learning tools can extract information distinct from demography and socioeconomic status, or can be integrated together for a more robust approach.

Objective: To utilize satellite-imagery based deep learning and traditional survey-based statistical methods to examine the relationship between built environment and diabetes prevalence.

Methods: A convolutional neural network (CNN), a deep learning approach, was used to extract features of built environment from 100,000+ satellite images of Seattle (SEA), Los Angeles (LA), San Antonio (SA), and Memphis (MEM). Diabetes prevalence and population data were retrieved from the CDC PLACES Project and American Community Surveys (ACS). Elastic net and ordinary least squares (OLS) regressions were used to quantify the associations of 1) environmental features and diabetes rates, 2) ACS covariates and diabetes rates, and 3) environmental features and the residuals of the ACS data model.

Results: The all-cities environment CNN model explained 68.2% of variation, while single-city models explained 90.3% (MEM), 81% (SA), 70.5% (SEA), and 46.2% (LA) of variation. ACS OLS models explained 81.2% (all-cities), 84.4% (MEM), 74.1% (SA), 78.1% (SEA), and 76.5% (LA) of variation. The integrated model explained 91.3% (all-cities), 91.5% (MEM), 90.1% (SA), 85.9% (SEA), and 85.9% (LA).

Conclusion: Superior performance of the multimodal analysis, conjoining environmental and population data, demonstrates the capability of CNNs in capturing features of built environment absent from ACS data. Such combined models may enable better understanding of the effects of built environment on diabetes, and guide policymakers in implementing community changes to reduce diabetes prevalence.

Disclosure

K. Zheng: None. R. Lawton: None. D. Z. Zheng: None. E. Huang: Other Relationship; Self; Stratus Medicine, kelaHealth, MedBlue Data.

Funding

National Center for Advancing Translational Sciences (UL1TR002553)
334-OR: Sex Differences in Protein Phosphorylation in Insulin Resistance in Humans at the Cellular Level
Authors: HAIDER NIDA , LEBASTCHI JASMIN , BATISTA THIAGO M. , PAN HUI , DREYFUSS JONATHAN , CARCAMO-ORIVE IVAN , KNOWLES JOSH , KAHN C. RONALD
Published: June 2021

Insulin resistance in muscle precedes and predicts type 2 diabetes in offspring of diabetic parents and is also observed in ~25% of the general population. However, whether these changes represent cell autonomous defects or are secondary to changes in circulating factors is unclear. To define possible cell autonomous determinants of insulin resistance, we have utilized induced pluripotent stem cell (iPSC) differentiated into myoblasts from 20 nondiabetic individuals - 10 insulin sensitive (I-Sen) and 10 insulin resistant (I-Res) as assessed using the steady-state plasma glucose approach. While there was no difference in the ability of the iPSCs to differentiate into myoblasts (iMyos), cells from I-Res individuals show impaired insulin signaling, decreased insulin-stimulated glucose uptake, and glycogen synthase activity compared to iMyos from insulin sensitive individuals, indicating that these cells mirror in vitro the alterations seen in vivo. The global phosphoproteomic analysis using LC-MS/MS uncovered a large network of proteins whose phosphorylation was altered in association with insulin resistance, mostly outside the canonical insulin-signaling cascade. We also observed striking differences in the phosphoproteomic signature of iMyos derived from male versus female subjects. Analysis of the proteins involved reveals that male cells show enhanced phosphorylation of proteins associated with transcription, Rho GTPases, SUMOylation, mRNA splicing, and membrane trafficking, whereas females show a dominance of phosphorylation of proteins involved in the cell cycle, chromatin organization, gene expression, and protein ubiquitination. Taken together, these data demonstrate major alterations in cellular signaling underlying insulin resistance, even in the absence of diabetes, and provide evidence of a super-network of cell signaling differences in males and females that must be considered in understanding cellular regulation in health and disease.

Disclosure

N. Haider: None. J. Lebastchi: None. T. M. Batista: None. H. Pan: None. J. Dreyfuss: None. I. Carcamo-orive: None. J. Knowles: None. C. Kahn: Advisory Panel; Self; ERX Pharmaceuticals, Kaleido Biosciences, Inc., Consultant; Self; Flagship Pioneering, Sana/Cobalt.
338-OR: Reversal of Insulin Resistance by Resveratrol and Hesperetin Combination in Overweight and Obese Subjects Correlates with Decrease in Expression of Thioredoxin Interacting Protein
Authors: XUE MINGZHAN , WEICKERT MARTIN , RABBANI NAILA , THORNALLEY PAUL
Published: June 2021

Trans-Resveratrol and hesperetin combination (tRES-HESP) in randomized, double-blind, placebo-controlled crossover study in overweight and obese subjects corrected insulin resistance; healthy aging through functional food study (HATFF, Clinicaltrials.gov identifier NCT02095873). tRES-HESP is an optimized supplement for induction of expression of glyoxalase 1 (Glo1) via activation of transcription factor Nrf2. Increased Glo1 expression decreases reactive metabolite, methylglyoxal (MG), contributing to insulin resistance through glycation-linked unfolded protein formation and activation of the unfolded protein response (UPR). Herein, we report further analysis of study variables and follow-up reverse translational studies. With tRES-HESP treatment, plasma MG correlated negatively with peripheral blood mononuclear cell (PBMC) quinone reductase activity - a marker of Nrf2 activation (r = - 0.68, P<0.01). For change from baseline of PBMC gene expression with tRES-HESP treatment (assessed by the Nanostring method), change in area-under-the-curve plasma glucose (ΔAUGg) during oral glucose tolerance tests correlated negatively with change in Glo1 expression (r = - 0.56, P<0.05) and correlated positively with change in expression of thioredoxin interacting protein (TXNIP) (r = 0.59, P<0.05). In reverse translational studies, we found tRES-HESP decreased TXNIP expression by 39 ± 1% (P<0.001) in human hepatocyte-like HepG2 cells and 14 ± 3% in BJ fibroblasts in vitro (P<0.01). tRES-HESP may decrease TXNIP expression by decreasing the MG-driven UPR and by direct Nrf2-driven down regulation. TXNIP is a mediator of insulin resistance in liver and skeletal muscle and impaired pancreatic beta-cell insulin secretion. tRES-HESP is suitable for further evaluation for prevention and treatment of type 2 diabetes where decreased TXNIP may contribute to the therapeutic response.

Disclosure

M. Xue: None. M. Weickert: None. N. Rabbani: None. P. Thornalley: None.

Funding

Qatar Foundation; Qatar University
34-OR: Role of Arid5b in Thermogenesis and Adipose Tissue Browning
Authors: SHUKARE MENGISTU LEMECHA , HUANG RUI , EHSANI ALI , ZHANG GUOXIANG , CHALISE JAYA PRAKASH , WHITSON ROBERT H. , ITAKURA KEIICHI
Published: June 2021

Background: Adipose tissue considerably influence metabolic homeostasis and play a central role in regulating whole-body energy and glucose metabolism. Previously, we have reported that mice with the global deletion of Arid5b are lean and have less fat in white and brown adipose tissues. However, this role is unknown in adipocyte specific Arid5b knockout (5bFKO) mice.

Aim: We investigated the effects of adipose-specific deficiency of Arid5b on systemic glucose homeostasis and adipose tissue metabolism.

Result: Deletion of Arid5b in adipose tissue using adiponectin promoter-driven Cre recombinase significantly improved glucose tolerance with significant reduction of insulin level. Body weight of 5bFKO mice was significantly reduced at the later age. Core body temperature of 5bFKO mice was significantly higher compared to the control mice. Robust increase in the protein expression of uncoupling protein 1 (Ucp1) was observed in inguinal white adipose tissue (iWAT) of 5bFKO mice housed at ambient temperature. This phenotype was further confirmed by prolonged cold exposure where Ucp1 and mitochondrial proteins such as pyruvate dehydrogenase (PDH), mitochondrially encoded cytochrome c oxidase (MTCO1) and ATP5A were substantially increased in iWAT of adipocyte specific Arid5b deficient mice. Gene expression of beige adipogenesis markers such as cell death inducing DFFA like effector A (Cidea) and iodothyronine deiodinase 2 (Dio2) were also significantly increased indicating browning of iWAT. Furthermore, loss of Arid5B in fat led to significant reduction in macrophages and total immune cells in iWAT. All together these results show that the deletion of Arid5b could promote browning of iWAT.

Conclusion: These findings demonstrate that Arid5b regulates thermogenic genes expression to promote beige adipocytes formation and controls adipose inflammation. Inhibition of Arid5b may provide a novel therapeutic approach for obesity and diabetes.

Disclosure

M. Shukare: None. R. Huang: None. A. Ehsani: None. G. Zhang: None. J. Chalise: None. R. H. Whitson: None. K. Itakura: None.
340-P: Nocturnal Hypoglycemia Prediction in Hospitalized Patients with Type 1 Diabetes Using Combined Supervised and Unsupervised Ensemble Learning
Authors: BERIKOV VLADIMIR , SEMENOVA JULIA F. , KLIMONTOV VADIM
Published: June 2021

The Aim: To assess the efficacy of combined supervised and unsupervised ensemble machine learning based on continuous glucose monitoring (CGM) data for short-term prediction of nocturnal hypoglycemia (NH) in hospitalized patients with type 1 diabetes (T1D).

Materials and Methods: We analyzed CGM records with a minimal duration of 72 hours obtained from 406 adult patients admitted to tertiary referral hospital. An episode of NH was defined as ≥3 consequent glucose values of <3.9 mmol/L recorded between 0 and 6 am. Depending on predictor sequence length (30 min - 1 h) and horizon (H) of forecasting (5-30 min), we obtained 209-256 and near 4∙104 records with and without NH respectively. Twenty nine metrics, including mean, minimal and maximum glucose, range, gradient, linear, quadratic and cubic trend coefficients, dynamic time wrapping similarity-based indices, and a number of glucose variability indices, were evaluated. The ensemble clustering was used for extraction of representative samples. Random Forest ensemble model was applied for NH prediction. The obtained quality metrics were averaged over 100 random partitions of the dataset on training and testing subsets.

Results: The quality metrics did not depend significantly on predictor sequence length; we used 30 min as a baseline. Depending on H, values of sensitivity and specificity varied from 98% and 97% (H=5 min) to 85% and 87% (H=30 min). The false alarm ratio values were very high (>90%) due to the unbalanced nature of data. Minimal glucose, low blood glucose index, and increment in the penultimate value of sequence were the most important predictors assessed with Random Forest algorithm.

Conclusions: The results demonstrate the usefulness of ensemble machine learning models based on CGM time series data for prediction of NH events in hospitalized patients with T1D. Additional studies are needed for improving false alarm ratio metrics of forecasting quality.

Disclosure

V. Berikov: None. J. F. Semenova: None. V. Klimontov: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Sanofi, Research Support; Self; Boehringer Ingelheim International GmbH, Speaker’s Bureau; Self; AstraZeneca, Medtronic.

Funding

Russian Science Foundation (20-15-00057)
359-P: Congestive Heart Failure and the Metabolic Syndrome Are Mutually Independent Predictors of Nonalcoholic Fatty Liver Disease
Authors: MAECHLER MAXIMILIAN , VONBANK ALEXANDER , LARCHER BARBARA , MADER ARTHUR , SPRENGER LUKAS , MUTSCHLECHNER BEATRIX , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H.
Published: June 2021

Nonalcoholic fatty liver disease (NAFLD) is associated with both the metabolic syndrome (MetS) and congestive heart failure (CHF). The MetS is highly prevalent in CHF patients; however, the single and joint associations of the MetS and CHF with NAFLD have not been investigated yet. This issue therefore is addressed in the present study.

We investigated 202 patients with CHF and 670 controls who did not have signs or symptoms of CHF and in whom significant coronary artery disease was ruled out angiographically. The presence of NAFLD was determined using the validated fatty liver index (FLI).

The prevalence of the MetS was 61.9% in CHF patients and 45.7% in controls (p<0.001). FLI values and prevalence rates of NAFLD (FLI≥60) in non-CHF subjects without MetS were 40±25 and 25.0%, respectively. They were significantly higher in non-CHF, but MetS patients (71±22, p<0.001 and 69.3%, p<0.001, respectively), in CHF patients without MetS (54±24, p<0.001 and 42.9%, p=0.002, respectively) and in CHF patients with MetS (76±20, p<0.001 and 82.4%, p<0.001, respectively). In multivariate analysis of covariance, the MetS and CHF proved to be mutually independent predictors of FLI after adjustment for age, sex, BMI, LDL-C, history of smoking and hypertension (F=296.94; p<0.001 and F=21.68; p<0.001, respectively); concordantly, the MetS and CHF independently predicted the presence of NAFLD in logistic regression analyses, with adjusted odds ratios of 6.67 [4.83-9.21]; p<0.001 and 2.52 [1.67-3.79]; p<0.001, respectively.

We conclude that CHF and the MetS are mutually independent predictors of NAFLD.

Disclosure

M. Maechler: None. C. H. Saely: None. A. Vonbank: None. B. Larcher: None. A. Mader: None. L. Sprenger: None. B. Mutschlechner: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
365-P: Remnant Cholesterol in Patients with Established Cardiovascular Disease Predicts Cardiovascular Events Both among Patients with Type 2 Diabetes and among Nondiabetic Subjects
Authors: MADER ARTHUR , SPRENGER LUKAS , VONBANK ALEXANDER , LARCHER BARBARA , MAECHLER MAXIMILIAN , MUTSCHLECHNER BEATRIX , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H.
Published: June 2021

Remnant cholesterol, which is calculated as total cholesterol minus LDL cholesterol minus HDL cholesterol has attracted interest as a marker of cardiovascular event risk. The power of remnant cholesterol to predict cardiovascular events in patients with established cardiovascular disease is unclear and is addressed in the present study. We enrolled 1822 consecutive patients with angiographically proven stable CAD (n=1472) and sonographically proven peripheral artery disease (n=350). Prospectively, cardiovascular events were recorded over a mean follow-up period of 6.2±3.2 years. At baseline, remnant cholesterol was significantly higher in patients with T2DM (n=608) than in nondiabetic subjects (27±25 vs. 21±21 mg/dl; p<0.001). During follow-up, 584 of our patients suffered cardiovascular events; the event rate was significantly higher in patients with T2DM than in nondiabetic subjects (45.4 vs. 32.2%; p<0.001). Remnant cholesterol in Cox regression models adjusting for age, sex, hypertension, smoking, body mass index and LDL cholesterol independently predicted cardiovascular events in the total study population (standardized adjusted HR 1.15 [1.07-1.23]; p<0.001), and in patients with T2DM as well as in nondiabetic subjects (standardized adjusted HRs 1.17 [1.03-1.34]; p=0.013 and 1.12 [1.01-1.23]; p=0.028, respectively). From our data we conclude that remnant cholesterol in patients with established Cardiovascular Disease predicts cardiovascular events both among patients with T2DM and among nondiabetic subjects.

Disclosure

A. Mader: None. C. H. Saely: None. L. Sprenger: None. A. Vonbank: None. B. Larcher: None. M. Maechler: None. B. Mutschlechner: None. A. Leiherer: None. A. Muendlein: None. H. Drexel: None.
368-P: Type 2 Diabetes Mellitus Increases Epicardial Adipose Tissue Senescence in Subjects with Coronary Artery Disease during Elective Cardiac Surgery
Authors: MRAZ MILOS , TRNOVSKA JAROSLAVA , KASPEROVA BARBORA JUDITA , DVORAKOVA IVETA , LACINOVA ZDENKA , HLAVACEK DANIEL , MAHRIK JAKUB , IVAK PETER , NETUKA IVAN , HALUZIK MARTIN
Published: June 2021

Cellular senescence is a novel mechanism suggested to contribute to the development of type 2 diabetes mellitus (T2DM) and cardiovascular diseases. Here, we analyzed the expression of senescent markers in myocardium and adjacent adipose tissue of subjects with and without coronary artery disease (CAD) and T2DM undergoing elective cardiac surgery. Eleven subjects with CAD and T2DM (DM group), 13 subjects with CAD without T2DM (CAD group) and 8 subjects without both CAD and T2DM (C - control) group undergoing elective cardiac surgery (CABG and/or valvular surgery) were included into the study. Samples of subcutaneous (SAT) and epicardial (EAT) adipose tissue and myocardium form right atrial wall were taken along with standard biochemical and anthropometric parameters at the beginning and end of surgery. mRNA expression of senescent markers p21 and p16 was assessed using qRT PCR. All 3 groups did not differ with respect to age (65.2 ± 6.9 vs. 61.7 ± 9.8 vs. 57.9 ± 12.3 years for DM vs. CAD vs. C, n.s.) or BMI (30.8 ± 3.9 vs. 28.5 ± 3.9 vs. 30.2 ± 3.4 kg/m2, n.s.), while DM group showed higher levels of fasting glucose (8.4 ± 1.6 vs. 5.9 ± 1.1 vs. 5.9 ± 0.9 mmol/, p=0.005) and HbA1C (52.5 ± 8.9 vs. 38.9 ± 4.2 vs. 31.5 ± 8.9 mmol/mol, p<0.001) relative to others. At the beginning of surgery no difference in mRNA expression of either factor could be seen in any of the examined tissues except of increased expression of p16 in the myocardium of CAD group (p=0.044 vs. C group). In DM subjects, cardiac surgery significantly increased mRNA expression of p21 in myocardium (p=0.15 vs. C and CAD group) and EAT (p=0.002 vs. C group), while not such change could be seen in the nondiabetic CAD and C group. To conclude, in CAD subjects T2DM is associated with increased cellular senescence in EAT and myocardium during elective cardiac surgery. This mechanism might at least partially explain the more detrimental outcomes of CAD patients with as compared to without T2DM.

Disclosure

M. Mraz: None. M. Haluzik: Advisory Panel; Self; AstraZeneca, Lilly Diabetes, Novo Nordisk, Consultant; Self; Sanofi. J. Trnovska: None. B. Kasperova: None. I. Dvorakova: None. Z. Lacinova: None. D. Hlavacek: None. J. Mahrik: None. P. Ivak: None. I. Netuka: None.

Funding

Ministry of Health of the Czech Republic (RVO-VFN64165, NV19-0200118); IKEM (IN00023001)
369-P: Wound Repair by P53 Silenced Human Endothelial Cell-Derived Conditioned Media, In Vitro
Authors: RIVERA DAYNA K. , NANDULA SESHAGIRI RAO , SEN SABYASACHI
Published: June 2021

Introduction: Diabetes is associated with impaired wound healing. Studies have demonstrated that endothelial progenitor cells (EPCs) and mature human endothelial cells (EC) are susceptible to apoptosis in hyperglycemic environment and p53 gene silencing prevents cellular senescence and helps vascular regeneration. Our goal was to test whether cell conditioned media obtained from p53 silenced human cells can also improve cellular regeneration.

Methods: Ad-human-P53 (TP53)-shRNA was used to silence P53 and Ad-scrambled-null-shRNA was used as control. To collect condition media, different human cells such as HEK, human CD14+ve cells and HUVEC (human umbilical vein endothelial cells) were cultured in exosome free FBS media for 5 days, following transduction with Ad-p53sh or Ad-null, as the case may be. After transduction, cells were grown in media containing 2% BSA (with no FBS and growth factors) for only 24 h and the collected supernatant was concentrated 10-fold to obtain the conditioned media (CM). Endothelial regeneration or wound healing was tested using endothelial wound healing assay kit (from Cell Biolabs # CBA-120-T).

Results: We compared CM obtained from null and p53sh in HEK, CD14+ve and HUVEC cells on human endothelial cells. Proliferation capacity of the endothelial cells was greater with p53sh CM compared to null and non-transduced CM. The CM obtained from the untreated and null samples did not show increased proliferation in any of the 3 kinds of cells tested. The CM from p53sh HUVEC was more effective than CM from other cells. We are analyzing the CM (exosome and non-exosome fraction) for identification of specific secretory proteins.

Conclusion: P53 silencing appears to improve HUVEC paracrine factors and this particular modality of cell free therapy may have therapeutic role in treating diabetes complications and even aging.

Disclosure

D. K. Rivera: None. S. Nandula: None. S. Sen: None.

Funding

American Heart Association
372-P: Type 2 Diabetes and Risk of Major Cardiovascular Events in Peripheral Artery Disease vs. Coronary Artery Disease Patients
Authors: SAELY CHRISTOPH H. , VONBANK ALEXANDER , LARCHER BARBARA , MADER ARTHUR , MAECHLER MAXIMILIAN , SPRENGER LUKAS , MUTSCHLECHNER BEATRIX , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ
Published: June 2021

The prevalence of type 2 diabetes (T2DM) is higher in peripheral artery disease (PAD) than in coronary artery disease (CAD) patients, and PAD overall confers higher cardiovascular risk than CAD. How the incidence of major cardiovascular events compares between PAD and CAD patients when analyses are stratified by the presence of type 2 diabetes (T2DM) is unclear and is addressed in the present study. We prospectively recorded major cardiovascular events and death over 10.0±4.7 years in 923 patients with stable CAD, of whom 26.7% had T2DM and in 292 patients with PAD, of whom 42.1% had T2DM. Four groups were analyzed: CAD patients without diabetes (CAD/T2DM-; n=677), CAD patients with T2DM (CAD/T2DM+; n=246), PAD patients without diabetes (PAD/T2DM-; n=169) and PAD patients with T2DM (PAD/T2DM+; n=123). When compared to the incidence of MACE in CAD+/T2DM- patients (25.1%), it was significantly higher in CAD+/T2DM+ patients (35.4%; p<0.001), in PAD+/T2DM- patients (30.2%; p=0.022) and in PAD+/T2DM+ patients (47.2%; p<0.001). Patients with both PAD and T2DM in turn were at a higher risk than CAD+/T2DM+ or PAD+/T2DM- patients (p=0.001 and p<0.001, respectively). The incidence of MACE did not differ significantly between PAD+/T2DM- and CAD+/T2DM+ patients (p=0.413). Compared to patients with CAD, Cox regression analyses after multivariate adjustment showed an adjusted hazard ratio of 1.46 [1.14-1.87], p=0.002 for the presence of PAD. Conversely, T2DM increased the risk of MACE after multivariate adjustment in CAD and PAD patients (adjusted HR 1.58 [1.27-1.98], p<0.001).

In conclusion, our data show that T2DM and the presence of PAD are mutually independent predictors of MACE. Patients with both PAD and T2DM are at an exceedingly high risk of MACE.

Disclosure

C. H. Saely: None. H. Drexel: None. A. Vonbank: None. B. Larcher: None. A. Mader: None. M. Maechler: None. L. Sprenger: None. B. Mutschlechner: None. A. Leiherer: None. A. Muendlein: None.
374-P: Oleate Prevents Palmitate-Induced Abnormalities in Insulin Signaling in Human Cardiac Progenitor Cells
Authors: DORIA ROSSELLA , CACCIOPPOLI CRISTINA , SCHIPANI ROSSELLA , GENCHI VALENTINA ANNAMARIA , LEONARDINI ANNA , NATALICCHIO ANNALISA , PERRINI SEBASTIO , CIGNARELLI ANGELO , LAVIOLA LUIGI , GIORGINO FRANCESCO
Published: June 2021

Myocardial ectopic lipid deposition has been associated with insulin resistance and cardiovascular risk. Palmitate, one of the most abundant saturated fatty acids, has been shown to impair insulin signaling in multiple cell types. Human cardiac progenitor cells (CPC) represent a compartment of multipotent stem cells essential for constant tissue repair and renewal in the adult heart. In this study, the ability of palmitate to impair insulin signaling, and the modulatory effects of oleate, a mono-unsaturated fatty acid, on palmitate-induced abnormalities were investigated in human CPC isolated from control subjects undergoing cardiac surgery. Human CPC express insulin receptor (IR), as assessed by quantitative RT-PCR and immunoblotting. Specifically, in human CPC both IR isoforms, A (IR-A) and B (IR-B), were identified, and IR-A was more expressed than IR-B. Exposure of human CPC to 100 nM insulin for 15 minutes resulted in increased Akt and p44/p42 MAPK phosphorylation (p<0.05), evidenced by immunoblotting. Treatment of human CPC with 0.25 mM palmitate for 24 h impaired the ability of insulin, added for the last 15 minutes, to phosphorylate both Akt and p44/p42 MAPK (p<0.05), without no effect on total Akt and p44/p42 MAPK protein levels. Interestingly, palmitate was able to increase both IR-A and IR-B mRNA levels (p<0.05), and to reduce IR protein expression (p<0.05). Co-incubation of palmitate with 0.1 mM oleate prevented the ability of palmitate to reduce insulin-induced Akt phosphorylation (p<0.05), but did not rescue the impaired p44/p42 MAPK phosphorylation. In addition, co-treatment with oleate also prevented both palmitate-induced upregulation of IR-A and IR-B mRNA (p<0.05), and downregulation of IR protein levels (p<0.05).

In conclusion, oleate prevents some of the palmitate-induced impairments in insulin signaling in human CPC, thus contributing to cardiac protection from lipotoxicity-induced metabolic alterations.

Disclosure

R. Doria: None. F. Giorgino: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk, Roche Diabetes Care, Sanofi, Research Support; Self; Lilly Diabetes, Roche Diabetes Care. C. Caccioppoli: None. R. Schipani: None. V. Genchi: None. A. Leonardini: None. A. Natalicchio: Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Sanofi. S. Perrini: None. A. Cignarelli: None. L. Laviola: Advisory Panel; Self; A. Menarini Diagnostics, Abbott, AstraZeneca, Lilly Diabetes, Novo Nordisk Inc., Roche Diabetes Care, Sanofi-Aventis, Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Medtronic.
377-P: Effect of Severe Hypoglycemia on Myocardial Cardiac Function in Type 1 Diabetes
Authors: FAHRMANN ELKE R. , ADKINS LAURA J. , LAMICHHANE RAJAN , DRISCOLL HENRY
Published: June 2021

Objective: Associations between severe hypoglycemia (SH) and cardiovascular disease (CVD) have been reported in epidemiological studies. Mechanisms for the relationship between SH and CVD are not well understood. While associations of HbA1c and traditional CVD risk factors with myocardial function in subjects with type 1 diabetes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study have been reported, it is unknown whether an association of SH with myocardial function exists.

Methods: We evaluated cardiac magnetic resonance (CMR) data of 1017 subjects. Associations of SH with CMR parameters using generalized linear models were examined. At time of CMR, subjects had been followed over ~ 22 years. SH was defined as SH requiring assistance of another party. A subset was defined as SH accompanied by coma and/or seizure (SHCS).

Results: At time of CMR, 660 subjects had a SH history (407 subjects with coma and/or seizures). Median age [interquartile range] was 50 [44, 54] years, 48% were females, and median diabetes duration was 26.6 [23.5, 31.4] years. SH was positively associated with end diastolic volume (EDV) by +4 ml, p<0.01 and end systolic volume (ESV) by +2.7 ml, p<0.01, left ventricular mass (LVM) by +2.8 mg, p<0.05, and negatively correlated with ejection fraction by -0.8%, p<0.05. Its SHCS subset was positively associated with EDV by +3.4 ml, p<0.01, LVM by 2.6 mg, p<0.05, stroke volume by +1.9 ml, p<0.05, and cardiac output by +0.15 L/min, p<0.05. Sensitivity analyses were consistent with results.

Conclusion: The effect of SH on cardiac function might be one of the mechanisms to explain the association between SH and CVD. It needs to be examined whether SH is associated with myocardial scars. Further studies are required to investigate whether the magnitude of SH effect on myocardial function increases with older age and leads to a clinically relevant CV event, especially in diabetic subjects with established coronary heart disease.

Disclosure

E. R. Fahrmann: None. L. J. Adkins: None. R. Lamichhane: None. H. Driscoll: None.
383-P: Comparative Study of Serum Testosterone Levels in Male T2DM and Nondiabetic Subjects as a Risk Marker for Atherosclerotic Coronary Artery Disease
Authors: DAS AMIT K. , BHAGAT ABHINAV , SINHA NEERAJ
Published: June 2021

Background: Historically, higher levels of serum testosterone were presumed deleterious to the cardiovascular system. cardiovascular disease (CVD) risk factors prevalence were increased due to low testosterone levels.

Material and Methods: This was a prospective observational study, conducted among men with type 2 diabetes with documented CAD (n = 60) and controls healthy men (n = 50). Pearson correlation between sex hormones and CAD risk factors was done. The association between sex hormones and CAD risk factors among patients was analyzed by multiple logistic regression. The statistical significance was set at the 0.05 level.

Result: Mean age of diabetics was 44.5 ±7.9 years and non diabetics was 42.54 ± 5.63 years. 56% of Diabetics and 20 % non diabetics had lower levels of total testosterone. 68% of Diabetics and 26 % non diabetics had lower levels of free testosterone. Mean SHBG levels in Diabetics and non - diabetics was 8.6 ± 1.8 and 16 ± 3.2. Prevalence of Hypogonadism was 22% in Diabetics and 10% in Non diabetics. Among the cases, a significant positive correlation was found between total testosterone/FTI and waist circumference, W/H ratio, triglyceride levels, hs-CRP, and CIMT (P < 0.01). In addition, a significant negative correlation was found between total testosterone and FTI with high-density lipoprotein-cholesterol levels (P < 0.01). The multiple logistic regression analysis showed that total testosterone levels (P < 0.01) and SHBG (P < 0.01) are independently associated with the occurrence of atherosclerotic CAD in T2DM men.

Conclusion: We conclude that increased serum testosterone levels and low SHBG in T2DM men are associated with the development of atherosclerotic cardiovascular risk factors.

Disclosure

A. K. Das: None. A. Bhagat: None. N. Sinha: None.
396-P: Delayed Chronic Kidney Disease (CKD) Diagnosis in Type 2 Diabetes (T2D)
Authors: HARINDHANAVUDHI TASMA , FREESE REBECCA L. , CARAMORI LUIZA
Published: June 2021

Background: CKD diagnosis is under recognized in T2D. We determined the interval between biochemical and clinically documented CKD diagnosis in a retrospective cohort of adults seen in the clinics of a large academic center between 1/1/11-7/31/20.

Methods: Biochemical CKD diagnosis was defined as 2 estimated glomerular filtration rate (eGFRcr) <60 ml/min/1.73 m2 (CKD-EPI) and/or 2 out of 3 albumin-to-creatinine ratios (ACR, spot urine) >30 mg/g, ≥3 months apart. KDIGO GFR and ACR categories were used. Clinical CKD diagnosis was defined by presence of any CKD code in the electronic health record.

Results: 139,369 unique patients with T2D (60±15 yrs; 47% female; 83% white) were seen during the study period. 62,201 (44.6%) and 53,352 (38.3%) had at least one GFR or ACR, respectively, and 53,141 (38.1%) had both lab measurements. 15,770 (25.3%) had CKD by eGFR criteria. The median interval between biochemical and clinical diagnosis was 1.9 yrs (range 0.003-17.9), longer among patients on CKD stage G3a (2.1 yrs, [0-18.0]) than on G3b (1.5 [0-16.2] yrs; P<0.001) or G4 (1.2 [0-16.0] yrs; P<0.001). 13,647 (15.6%) had CKD by ACR criteria. Out of the 24,368 patients who had albuminuria on a given sample, 7,866 (32.3%) reverted to normoalbuminuria and 2,152 (8.8%) died before repeating ACR. Median interval between biochemical (ACR criteria) and clinical CKD diagnosis was 1.3 [0-15.5] yrs for stage A2 and 1.1 [0-9.3] yrs for A3; P<0.00001. Among patients who had both eGFR and ACR measurements, the median interval between biochemical (either by GFR or ACR) and clinical diagnosis was 1.7 [0.002-18.0] yrs.

Conclusions: Our study indicates low screening rates and delayed CKD diagnosis documentation in T2D. This was particularly marked at earlier disease stages, although significant documentation delay was also common among patients with more severe CKD. These findings suggest lack of physician awareness, which may lead to suboptimal care. Screening and documentation of CKD is of paramount importance to improve CKD care in T2D.

Disclosure

T. Harindhanavudhi: Stock/Shareholder; Self; Dexcom, Inc. R. L. Freese: None. L. Caramori: Consultant; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Research Support; Self; Bayer Healthcare Pharmaceuticals Inc., Novartis Pharmaceuticals Corporation, Speaker’s Bureau; Self; Bayer AG.
4-OR: Racial/Ethnic Disparities in Diabetes Self-Care in Young Adults (YA) with Type 1 Diabetes (T1D)
Authors: SADIQ RABAIL , FAZZARI MELISSA , NAHVI SHADI , CUNNINGHAM CHINAZO , AGARWAL SHIVANI
Published: June 2021

Background: Racial/ethnic disparities in diabetes self-care among YA with T1D may contribute to worse outcomes. We conducted a secondary data analysis of the Young Adult Racial Disparities in Type 1 Diabetes (YARDD) study to determine racial-ethnic differences in self-care and contributory factors.

Methods: The YARDD study recruited a diverse cohort of YA with T1D aged 18-28 years from six diabetes centers across the U.S. and collected cross-sectional information on sociodemographics, social determinants of health, clinical factors, psychosocial variables, and diabetes self-care. We performed multivariable linear regression to examine the association of race/ethnicity with a measure of diabetes self-care (Self-Care Inventory Revised (SCI-R)), and related factors.

Results: We included 299 YA with T1D: median age 20 years (IQR 19-22); 55% female (n=162); 33% each non-Hispanic White, non-Hispanic Black, and Hispanic. Compared with White YA, Black YA reported slightly lower SCI scores (B= -6.81/100, P=0.006), while Hispanic YA reported similar scores (B=-1.33/100, P=0.58). In multivariate analyses, race/ethnicity accounted for little variability in SCI score (adjusted R-squared=0.02), while age, sex and diabetes distress explained significant variability (adjusted R-squared=0.24). Diabetes distress scores on the Diabetes Distress Scale were slightly higher in Black YA than Hispanic or White YA (B= 0.38/6.0, P=0.01).

Discussion: In this large national study of YA with T1D, race/ethnicity was not independently associated with differences in diabetes self-care after accounting for demographic, social determinant, psychosocial, and clinical factors. However, diabetes distress was slightly higher among Black YA with T1D and had a strong association with diabetes self-care, providing a potential race-specific target for intervention.

Disclosure

R. Sadiq: None. M. Fazzari: None. S. Nahvi: Research Support; Self; Pfizer Inc. C. Cunningham: Employee; Spouse/Partner; GE Healthcare, Stock/Shareholder; Spouse/Partner; GE Healthcare. S. Agarwal: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (K23DK115869); National Center for Advancing Translational Science (UL1TR002556)
404-P: Advanced Liver Fibrosis Is Associated with an Increased Risk of Chronic Kidney Disease in Patients with Type 2 Diabetes and NAFLD
Authors: SEO DA HEA , CHO YONGIN , AHN SEONG HEE , SEO SEONG HA , HONG SEONGBIN , LEE YONG-HO , KIM SO HUN
Published: June 2021

Objectives: Nonalcoholic fatty liver disease (NAFLD) is associated with chronic kidney disease (CKD). However, the causal relationship between NAFLD and the development of CKD is uncertain, particularly in patients with type 2 diabetes. We aimed to investigate the association between the presence and severity of NAFLD and incident CKD in patients with type 2 diabetes.

Research Design and Methods: In this longitudinal cohort study of patients with type 2 diabetes, 3,188 patients with preserved renal function were followed for the occurrence of incident CKD. NAFLD was defined as the presence of hepatic steatosis on ultrasonography without any other causes of chronic liver diseases. Advanced liver fibrosis of NAFLD was defined as NAFLD fibrosis score >0.675. CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2.

Results: At baseline, 1,729 (54.2%) patients had NAFLD, of whom 94 (5.4%) had advanced liver fibrosis. During the follow-up of 8.3 ± 3.6 years, 472 (14.8%) patients developed incident CKD, 220 (15.1%) in the non-NAFLD group, 226 (12.8%) in the hepatic steatosis alone group and 26 (27.7%) in the advanced liver fibrosis group. There was no increased risk of incident CKD in the NAFLD group compared with the non-NAFLD group (p = 0.79). However, among patients with NAFLD, advanced liver fibrosis was associated with an increased risk of CKD (adjusted hazard ratio [HR] 1.78 (95% confidence interval [CI] 1.14-2.76), p=0.011).

Conclusions: Advanced liver fibrosis in NAFLD is independently associated with an increased risk of incident CKD in patients with type 2 diabetes.

Disclosure

D. Seo: None. Y. Cho: None. S. Ahn: None. S. Seo: None. S. Hong: None. Y. Lee: None. S. Kim: None.

Funding

National Research Foiundation (2017R1D-1A1B03034581)
414-P: Apparent Diffusion Coefficient on Diffusion-Weighted Magnetic Resonance Imaging Predicts the Progression of Renal Damage in Diabetic Nephropathy
Authors: KITSUNAI HIROYA , TAKIYAMA YUMI , NAKAGAWA NAOKI , HASEBE NAOYUKI , OKIZAKI ATSUTAKA , HANEDA MASAKAZU
Published: June 2021

Renal damage in diabetic nephropathy (DN) is evaluated by biochemical tests such as urine albumin-to-creatinine ratio (UACR) and serum estimated glomerular filtration rate (eGFR). On the other hand, renal biopsy, which is rich in definitive information, is rarely performed because of its complexity and high invasion. To evaluate whether diffusion-weighted magnetic resonance imaging (DW-MRI) could be a noninvasive approach for distinguishing DN, we performed MRI scanning of the subjects with 6 b-values (b = 0, 50, 100, 350, 400, 700) and analyzed the parameters using the kidney imaging software (Hitachi, Ltd., Tokyo). A total of 40 subjects were enrolled, 25 of whom had type 2 diabetes with or without hypertension (T2D), 9 had nondiabetes but hypertension (HT), and 6 were healthy volunteers (Control). T2D showed lower values of apparent diffusion coefficient (ADC) 0-700 compared with HT (129.0 ± 2.12 x10-5mm2/s in T2D vs. 132.5 ± 1.43 ×10-5mm2/s in HT, p<0.001). In addition, T2D with HT (n=15) had lower ADC0-700 compared with T2D without HT (n=10) (p < 0.01). Interestingly, T2D with non-DN nor HT presented lower ADC0-700 compared with HT (p<0.05). ADC0-700 in T2D were correlated with serum eGFR (r = 0.40, p <0.05) and inversely correlated with serum creatinine (r = - 0.40, p <0.05), cystatin C (r = - 0.54, p <0.01) and UACR (r = - 0.57, p <0.01). On the other hand, ADC0-700 in HT were not correlated with any of parameters of the renal function. Multivariate regression analysis with a stepwise forward method identified UACR as the only factor associated with the ADC0-700 values (β = - 0.68, p <0.001). Accumulating evidences show that lower levels of ADC on DW-MRI indicate greater fibrosis in various organs. Therefore, cortical ADC0-700 could predict the progression of the renal damage such as tubulointerstitial fibrosis. DW-MRI might provide a convenient diagnostic tool in the evaluation of DN.

Disclosure

H. Kitsunai: None. Y. Takiyama: Other Relationship; Self; Gilead Sciences, Inc., Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Mochida Pharmaceutical Co., Ltd., Roche Diabetes Care, Taisho Pharmaceutical Co., Ltd. N. Nakagawa: None. N. Hasebe: None. A. Okizaki: Research Support; Self; Fuji-Film Toyama Chemical Co., Ltd., Nihon Medhi-physics. M. Haneda: Advisory Panel; Self; Eli Lilly Japan K. K., Nippon Boehringer Ingelheim Co. Ltd., Novo Nordisk Inc.

Funding

Japan Society for the Promotion of Science (20K17420)
417-P: AGE Precursor Methylglyoxal Leads to Behavioral Pattern Changes Characteristics of Alzheimer’s Disease in Mice
Authors: LI WAI YIN , WU SZE LOK , LEE FIONA CHEUK YAN , YUE KEVIN
Published: June 2021

Purpose of the Study: Diabetes mellitus (DM) is characterized by chronic hyperglycemia and diabetic complications. Exacerbated cortical neuronal degeneration were observed in Alzheimer’s disease (AD) patients with DM. DM is considered a risk factor of AD, as DM-induced activation of stress responses in central nervous system (CNS) such as oxidative stress and neuroinflammation may lead to various neurodegenerative disorders. Abnormal accumulation of methylglyoxal (MG), one of the most reactive advanced glycation end-product (AGE) precursors, is found in the serum of diabetic patients. As MG is reported to induce brain cells impairment, like neuronal cell death, in CNS, and increased levels of AGEs have also been observed in brains of AD patients, hence the effect of MG leading to subsequent symptoms of AD was investigated.

Methods: C57BL/6 mice were treated with MG solution (60mg/kg) or saline (100μl of 0.9% saline as sham control) by intraperitoneal injection for 9 weeks. The Morris water maze (MWM) was used to examine the spatial learning ability and cognition of mice. Footprint, escape latency and time spent in the target quadrant were measured and recorded.

Summary of the Results: Significantly longer escape latency was observed in the MG-treated mice than that of the control group starting from Day 3. The mean escape latency of the MG-treated group was 13.41sec. while that of the control group was 5.450sec. in Day 5. It was also demonstrated in the probe trial that there was a significant reduction of the percentage time spent in the target quadrant of the MG-treated mice (44.07 ± 2.720) than that of the control group (58.29 ± 4.324).

Conclusions: MG could induce AD symptoms causing spatial learning ability impairment and cognition decline in mice. MG may therefore play a role in the dysfunction of brain cells and dysregulation of CNS resulting in Alzheimer’s disease.

Disclosure

W. Li: None. S. Wu: None. F. Lee: None. K. Yue: None.
419-P: Correlation between 24-Hour Urinary Electrolyte and Urinary Albumin in Patients with Type 2 Diabetes
Authors: WANG YANRU , ZHANG MENGYU , LI HONG , QU SHEN
Published: June 2021

Objective: To explore the characteristics of 24-hour urinary electrolyte excretion in patients with type 2 diabetes mellitus (T2DM), and its correlation with urinary albumin and early renal injury.

Methods: A total of 1475 T2DM and 265 nondiabetic patients (ND group) from 2018 to 2020 were enrolled. According to the urinary albumin excretion rate (UAER), T2DM patients were divided into normal albuminuria group (NA group): UAER < 30mg/24h; Microalbuminuria group (MA group): UAER 30~300 mg/24 h; massive albuminuria group (PR group): UAER > 300mg/24h. The characteristics of 24h urinary electrolyte excretion in different groups were observed and the correlation between 24h urinary electrolyte excretion and urinary albumin was analyzed.

Results: We found that 24h urinary potassium, sodium, chlorine, phosphorus and magnesium in all subgroups of T2DM were higher than those in ND group (P < 0.001), 24h urinary calcium in ND group was higher than that in PR group (4.3±2.1 vs. 3.2±2.5, P < 0.001), but lower than that in NA group (4.3±2.1 vs. 4.7±2.8, P < 0.001). As urinary albumin increased, 24h urinary calcium of T2DM patients showed a decreasing trend while the other urinary electrolytes showed an increasing trend (P < 0.001). Urinary albumin was positively correlated with 24h urinary potassium, sodium, chlorine, phosphorus, magnesium (r=0.133~0.169, P < 0.001) and negatively correlated with 24h urinary calcium (r= -0.130, P < 0.001). Multiple linear regression showed that 24h urinary potassium was an independent influencing factor of urinary albumin (β = 0.178, P < 0.001).

Conclusion: There is a difference in 24h urinary electrolyte excretion between T2DM and nondiabetic patients. The urinary electrolyte excretion of T2DM patients varies with urinary albumin. 24h urinary electrolyte excretion changes before the appearance of albuminuria, which may be an indicator of early renal injury. High urinary potassium may serve as a parameter to predict early diabetic nephropathy.

Disclosure

Y. Wang: None. M. Zhang: None. H. Li: None. S. Qu: None.