bluuebunny/crossref_metadata_2025 huggingface dataset:
368-OR: Activation of a Yap1-Dependent Mesenchymal Program Promotes ß-Cell Failure
Authors: MCKIMPSON WENDY , HOQUE NEHAN , SON JINSOOK , LEE APRIL Y. , ACCILI DOMENICO
Published: May 2022

A critical contributor to the pathogenesis of type 2 diabetes is the failure of insulin-secreting β-cells due to loss of cell number or identity. However, the signaling pathways that trigger these events remain unclear. While β-cells are of endodermal origin, recent studies show endocrine cells that coexpress the mesenchymal marker vimentin in the pancreas with diabetes, although the functional features of these cells are not known. Here, we identify an epithelial-to-mesenchymal (EMT) -like program that is activated in islets of mice and humans with type 2 diabetes. Characteristics of this EMT-like program include increased protein and mRNA abundance of the EMT transcription factor Snail and the mesenchymal adhesion molecule N-cadherin. Lineage-tracing techniques demonstrate that this mesenchymal program is initiated in β-cells that become multi-hormonal, a hallmark of dysfunctional endocrine cells. Interestingly, EMT-like cells minimally express Aldh1a3, a marker of dedifferentiated β-cells. To determine the mechanism driving EMT-like activation in β-cells, we tested stressors that phenocopy the effects of diabetes in islets. Treatment of islets with mitochondrial decouplers as well as oxidative stress increased expression of EMT markers. The transcription factor Yap1 is a known inducer of EMT. While Yap1 is expressed at minimal levels in β-cells, its abundance increased in db/db islets and in primary cells with impaired mitochondrial function. Importantly, chemical inhibition of Yap1 in db/db islets reversed activation of EMT-like factors. Yap1 inhibition also improved insulin secretion. Taken together, we found activation of an EMT-like program in the endocrine pancreas of mice and humans with type 2 diabetes. This program is dependent on increases in Yap1 due to oxidative stress and impaired mitochondrial function, and results in disrupted β-cell function.

Disclosure

W.Mckimpson: n/a. N.Hoque: None. J.Son: None. A.Y.Lee: None. D.Accili: Advisory Panel; Lilly Diabetes.

Funding

NIDDK (1K01DK121873)
369-OR: Defining the Role of RIPK3 in Beta Cells and the Mechanism of Its Activation by ER Stress
Authors: YANG LIU , YANG BINGYUAN , TONG XIN , DAI CHUNHUA , TANG ZIHAN , CHEN WENBIAO
Published: May 2022

Receptor interacting protein kinase 3 (RIPK3) can activate and be activated by ER stress. Islet inflammation associated with underlying activation of RIPK3 is conserved from zebrafish to humans. However, the role of RIPK3 in mammalian beta cells and the mechanism by which ER stress activates RIPK3 are not well defined. To investigate the role of RIPK3 in beta cell function, we generated beta cell specific Ripk3 knockout mice (Ripk3ßKO) in C57BL/6J background with or without the Akita mutation (Ins2C96Y/+, which causes ER stress induced beta cell apoptosis and early onset diabetes) (Ripk3ßKOAkita) . We found that the glucose tolerance was worsened in Ripk3ßKO mice than wildtype controls after 16 weeks of high fat diet. Similarly, Ripk3ßKOAkita mice had higher random blood glucose, lower circulating insulin, and worse glucose tolerance than Akita C57BL/6J mice as early as 4 weeks of age. Unexpectedly, isolated islets from Ripk3ßKO and Ripk3ßKOAkita mice have comparable glucose stimulated insulin secretion (GSIS) and are more resilient to palmitate-induced lipotoxicity than their control counterparts. Similarly, pharmacological inhibition of RIPK3 protected human islets from palmitate-induced impairment of GSIS ex vivo. We are currently investigating the role of specific islet inflammation stages in the divergent GSIS phenotypes between in vivo and ex vivo. To investigate how ER stress activates RIPK3 in beta cells, we tested the effect of inhibiting classic UPR branches on RIPK3 activation in MIN6 cells, a mouse beta cell line. We found that IRE1a activation appears to play an essential role in RIPK3 activation. Interestingly, Ripk3 knockdown in MIN6 cells also decreased IRE1a levels. We next seek to define the mechanism underlying the crosstalk between RIPK3 and IRE1a signaling pathways.

Disclosure

L.Yang: None. B.Yang: None. X.Tong: None. C.Dai: None. Z.Tang: None. W.Chen: None.

Funding

National Institutes of Health (DK117147)
376-P: The Hypoglycemia Awareness Questionnaire (HypoA-Q) Demonstrates Concurrent and Convergent Validity in Adults with Type 1 Diabetes and Hypoglycemia Unawareness
Authors: MATUS AUSTIN M. , FLATT ANNELIESE , PELECKIS AMY J. , DALTON-BAKES CORNELIA V. , RIEGEL BARBARA , RICKELS MICHAEL R.
Published: May 2022

Introduction: Impaired awareness of hypoglycemia (IAH) is a risk factor for severe hypoglycemia in type 1 diabetes (T1D) . Current tools to identify IAH are limited in their ability to characterize unawareness and evaluate hypoglycemia severity. The Hypoglycemia Awareness Questionnaire, including the 5-item Short Form awareness subscale (HypoA-Q SF) , was developed to identify IAH and characterize problematic hypoglycemia. We aimed to evaluate HypoA-Q SF’s concurrent and convergent validity.

Methods: Adults with T1D (n=23, 48% male; median age: 36 years, disease duration: 21 years) completed the (a) HypoA-Q SF, (b) Clarke score and (c) hypoglycemia severity (HYPO) score. Those with IAH defined by Clarke score ≥4 (n=12) and HYPO score ≥90th% were established on hybrid-closed loop insulin delivery as part of an ongoing 18-month clinical trial with 6-monthly completion of HypoA-Q, Clarke and HYPO scores. Mann-Whitney U Test was used to evaluate the HypoA-Q SF’s ability to differentiate between those with and without IAH. Repeated measures correlation was used to assess concordance between HypoA-Q SF score and Clarke / HYPO scores over the 18-month period.

Results: At baseline, HypoA-Q SF demonstrated concurrent validity as scores were significantly different between those with and without IAH (W= 110.5, p < .001) . Over the trial, HypoAQ-SF demonstrated convergent validity as repeated measures correlation analysis revealed significant positive relationships with both Clarke (r = 0.62 p < .001) and HYPO (r = 0.48, p<.01) scores.

Conclusion: These findings support the HypoA-Q SF as a tool to identify IAH and evaluate hypoglycemia severity. Further assessment of the HypoA-Q SF alongside gold-standard clamp-derived measures of autonomic symptom and counterregulatory response to hypoglycemia would be of value to determine score thresholds.

Disclosure

A.M.Matus: None. A.Flatt: None. A.J.Peleckis: None. C.V.Dalton-bakes: None. B.Riegel: None. M.R.Rickels: Advisory Panel; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Consultant; L-Nutra Inc.

Funding

National Institutes of Health (R01DK091331; UL1 TR001878; P30 DK19525)
378-P: Network Meta-analysis of Hypoglycemic Treatment Regimens with Potential Risk of Hypoglycemia in Terms of Glycemic Control and Severe Hypoglycemia
Authors: KODAMA SATORU , SATO TAKAAKI , YAMADA MAYUKO H. , YAMAMOTO MASAHIKO , MATSUBAYASHI YASUHIRO , ISHIGURO HAJIME , IWANAGA MIDORI , FUJIHARA KAZUYA , YAMADA TAKAHO , KATO KIMINORI , WATANABE KENICHI , SONE HIROHITO
Published: May 2022

Insulin and its secretagogues are essential for some patients with type 2 diabetes (T2D) to maintain glycemic control (GC) . However, these drugs are inevitably accompanied by hypoglycemia. Avoiding severe hypoglycemia (SH) is essential considering its poor prognosis. This network meta-analysis aimed to find optimal hypoglycemic treatment regimens for T2D in terms of GC and SH. MEDLINE and EMBASE were used to identify trials comparing 2 or more treatments including insulins and/or SU/glinide and included both GC and SH in study outcomes. Treatment hierarchy was summarized as the surface under cumulative ranking probabilities (SUCRA) . There were 137 eligible trials from which 36 treatments were identified. Insulin plus (+) non-insulin drugs except for SU/glinide (others) had a higher SUCRA for changes in hemoglobin A1c (A1C) compared with only insulins (68.2±5.6% vs. 39.9±6.6%; P=0.01) although the difference in the SUCRA for SH was not significant (P=0.59) . Compared with only insulins, SU/glinide + others had a lower SUCRA for SH (42.4±5.8% vs. 58.5±3.4%, P=0.05) and comparable SUCRA for A1C change (P=1.00) . Cluster analysis indicated that premixed insulin + glucagon-like peptide-1 receptor agonist (Mix-ins+GLP1) consistently belonged to the high-efficacy group for A1C change and achievement of A1C<7.0% and ≤6.5% among the insulin + others therapies. Glinide + thiazolidinedione (TZD) was in groups with high efficacy in terms of A1C change and achievement of A1C<7.0% and high safety regarding SH among SU/glinide + others therapies. Results suggest that in T2D patients adjunctive use of non-insulin drugs (particularly, Mix-ins+GLP1) are recommended for further improving GC and that appropriate combinations of non-insulin hypoglycemic agents (particularly, glinide+TZD) are recommended to avoid SH and extend the time to treatment failure of non-insulin therapy.

Disclosure

S.Kodama: None. K.Kato: None. K.Watanabe: None. H.Sone: Research Support; Astellas Pharma Inc., Eisai Co., Ltd., Kyowa Kirin Co., Ltd., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited. T.Sato: None. M.H.Yamada: None. M.Yamamoto: None. Y.Matsubayashi: None. H.Ishiguro: None. M.Iwanaga: None. K.Fujihara: None. T.Yamada: None.
379-P: Patient and Physician Experience of Hypoglycemia during Basal Insulin (BI) Titration in Type 2 Diabetes (T2D) in the U.S.
Authors: HARRIS STEWART B. , MOHAMMEDI KAMEL , BERTOLINI MONICA , WALKER VALERY , CARLYLE MAUREEN H. , ZHOU FANG L. , SEUFERT JOCHEN , ANDERSON JOHN E.
Published: May 2022

Introduction: Hypoglycemia after BI initiation can negatively impact patient adherence to titration and glycemic target achievement. We report on 2 surveys to better understand patient and physician perspectives/experiences of hypoglycemia during BI titration.

Methods: Adults with T2D and ≥2 claims (≥30 days apart in last 12 months) in the Optum Research Database who initiated BI (February-April 2021) , and physicians who treated ≥30 patients with T2D, ≥1 initiating BI (October 2020-March 2021) , completed a mailed survey.

Results: Responders were 416 patients (51% male, 71% white, mean age 70 years, 72% >years T2D duration) and 386 physicians (45% general practice) . Most physicians reported discussing hypoglycemia signs/symptoms (93%) and how to titrate BI in response to blood glucose (BG) levels (81%) with patients. Among patients who experienced hypoglycemia (49%; Table) , 57% felt very/extremely confident titrating BI during hypoglycemia. Only 35% met fasting BG (FBG) targets. Diabetes Treatment Satisfaction Questionnaire hypoglycemia score (1.34/6) suggests patients felt hypoglycemia was infrequent.

Conclusion: While physicians educate patients on hypoglycemia awareness and BI titration, nearly half of patients surveyed experienced hypoglycemia during titration, and only a third met FBG targets, suggesting new strategies and tools are needed for effective BI titration.

Disclosure

S.B.Harris: Consultant; Abbott, AstraZeneca, Eli Lilly and Company, Novo Nordisk, Sanofi, Other Relationship; Abbott, AstraZeneca, Bayer Inc., Dexcom, Eli Lilly and Company, HLS Therapeutics, Janssen Pharmaceuticals, Inc., Novo Nordisk, Sanofi, Research Support; Applied Therapeutics Inc., AstraZeneca, Canadian Institutes of Health Research, Juvenile Diabetes Research Foundation (JDRF) , Novo Nordisk, Sanofi, The Lawson Foundation. K.Mohammedi: Board Member; Lilly, Novo Nordisk, Sanofi, Research Support; Cyclerion Therapeutics, Inc., Speaker's Bureau; Abbott, AstraZeneca. M.Bertolini: Employee; Sanofi. V.Walker: Consultant; Sanofi-Aventis U.S. M.H.Carlyle: None. F.L.Zhou: Employee; Sanofi, Stock/Shareholder; Sanofi. J.Seufert: Advisory Panel; Abbott, Sanofi-Aventis Deutschland GmbH, Research Support; Boehringer Ingelheim International GmbH, Speaker's Bureau; Abbott Diabetes, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Lilly, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. J.E.Anderson: Advisory Panel; Abbott Diabetes, Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Gelesis, Novo Nordisk, Sanofi, Speaker's Bureau; Eli Lilly and Company.

Funding

Sanofi
38-LB: Physical Activity and Glycemia among Young Adults with Type 1 Diabetes and Overweight or Obesity—Results from Advancing Care for Type 1 Diabetes and Obesity Network (ACT1ON)
Authors: MUNTIS FRANKLIN R. , IGUDESMAN DARIA , CRISTELLO ANGELICA , THOMAS JOAN , ARRIZON- RUIZ NORA , HOOPER JULIE , ADDALA ANANTA , CRANDELL JAMIE , MAAHS DAVID M. , PRATLEY RICHARD E. , CORBIN KAREN , MAYER-DAVIS ELIZABETH J. , ZAHARIEVA DESSI P.
Published: May 2022

The ACT1ON pilot study evaluated the feasibility of three dietary strategies to optimize weight and glycemic management among young adults with T1D and overweight or obesity. As a secondary measure, self-reported physical activity (PA) was collected at baseline, 3-, 6-, and 9-months from 68 young adults with T1D (age 25.5 ± 3.1 years, 72.1% female, HbA1c 7.9 ± 1.8%, BMI 30.4 (27.9 - 33.9)) . Using the Global Physical Activity Questionnaire (GPAQ, n=195) and Previous Day Physical Activity Recalls (PDPAR, n=123) , we estimated weekly minutes of moderate-to-vigorous physical activity (MVPA) . Following the COVID-19 outbreak, a subset of participants wore Garmin Vivosmart4® PA trackers for two weeks at each visit (44 measurements from 27 participants) . Mixed effects regression models assessed the relationship between weekly minutes of MVPA and HbA1c using each PA measure. Median weekly minutes of MVPA were 33% lower following the COVID-19 outbreak compared to pre-pandemic PA levels (p=0.02) per the GPAQ, but not PDPAR (-7.7%, p=0.34) . After adjusting for design, demographic, clinical, and dietary variables, a 1 standard deviation increase in weekly minutes of MVPA (GPAQ) was associated with an absolute increase of 0.27% HbA1c (p>0.001) . A small, statistically non-significant association was observed for PDPAR (β=0.13, p=0.19) ; however, we observed a borderline statistically significant association using the PA tracker data (β=0.231, p=0.08) , despite a smaller sample size (n=44) . These results suggest that among young adults with T1D and overweight and obesity, higher levels of PA may lead to challenges in achieving optimal glycemia. Future work is needed to determine how to best support young adults with T1D and overweight and obesity in attaining both their PA and glycemic management goals.

Disclosure

F. R. Muntis: None. R. E. Pratley: Other Relationship; Bayer AG, Corcept Therapeutics, Dexcom, Inc., Hanmi Pharm. Co., Ltd., Merck & Co., Inc., Metavention, Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. K. Corbin: None. E. J. Mayer-davis: None. D. P. Zaharieva: Research Support; Insulet Corporation, International Society for Pediatric and Adolescent Diabetes, Leona M. and Harry B. Helmsley Charitable Trust. D. Igudesman: None. A. Cristello: None. J. Thomas: None. N. Arrizon- ruiz: None. J. Hooper: None. A. Addala: None. J. Crandell: n/a. D. M. Maahs: Advisory Panel; Abbott Diabetes, Eli Lilly and Company, Medtronic, Novo Nordisk, Sanofi, Consultant; Aditx Therapeutics, Inc., Biospex.

Funding

National Institutes of Health (1DP3DK113358-01)
382-P: Is Sulphonylurea-Induced Hypoglycaemia Hyped among Clinicians?
Authors: VYAS TARJANI C. , SABOO BANSHI D. , CHENNAMSETTI KAUMUDI , KESAVADEV JOTHYDEV , SABOO BHARAT , HASNANI DHRUVI , CHAVDA VIPUL , PANCHAL DHARMENDRA
Published: May 2022

Aim: To assess the risk of hypoglycaemia (TBR) in persons with diabetes who are on SUs with fairly controlled diabetes (HbA1c between 7 to 8%) .

Background: Sulphonylurea (SU) is conventionally used as a powerful glucose lowering agent and is known to increase the risk of hypoglycaemia. This paper is an attempt to study the effect of SUs on persons with diabetes by introducing continous glucose monitoring (CGM/AGP) which can help clinicians optimise diabetes treatment along with nutrition which can reduce the risk of hypoglycaemia.

Methodology: A retrospective analysis was done at our diabetes care centre. A total of 300 persons with type 2 diabetes on AGP and on SU therapy were studied. Only those persons with HbA1c between 7 to 8%, indicating fairly controlled diabetes were included.

Results: It was observed that no hypoglycaemia was present in 74% of the persons under study as per AGP data. Only 26% had hypoglycaemia grade 1 with less than 5% TBR; 2% had hypoglycaemia in TBR more than 5%, out of which only one person reported symptoms of severe hypoglycaemia. One of the AGP data of person with diabetes is attached in the image.

Conclusion: Judicious use of sulphonylureas does not increase risk of hypoglycaemia (Time Below Range) in type 2 diabetics as traditionally believed.

Disclosure

T.C.Vyas: None. B.D.Saboo: None. K.Chennamsetti: None. J.Kesavadev: None. B.Saboo: None. D.Hasnani: None. V.Chavda: None. D.Panchal: None.
384-P: Experiences with Nasal Glucagon from People with Diabetes and Caregivers, Most Mentioned "Feeling Safe": A Qualitative Study
Authors: MITCHELL BETH , SOWELL FRANCE G. , WILLIAMS PAUL , POON JIAT LING
Published: May 2022

Hypoglycemia risk and its impact on daily life is always present for people with diabetes and their caregivers (CG) . With the goal of positively impacting the lives of those who use insulin, advances in glucagon and its delivery, have made it ready-to-use, expanding the community of people who could act in an emergency. This qualitative study elicited experiences from people who own one option, nasal glucagon (NG) . Semi-structured 1:1 interviews were conducted in the US with AwD and CGs of children or AwD following a pre-defined concept elicitation guide and analyzed thematically. The sample included 22 AwD (20 T1DM; 2 T2DM) and 7 CGs of people with T1DM (1 Adult, 6 Children) ; female (72%) ; mean age 38.7 years; college degree 59%; insulin pump 62%. Actual use of NG was reported by 46% of AwD and 43% of CGs. A total of 45 concepts were identified, the majority (81%) identified by the first 5 interviews; saturation (the point at which no new concepts emerge) reached at 25 interviews. The most frequently stated concepts were: feeling safe having NG on hand (93%) ; ease of use for others (90%) ; comfort in having NG as a rescue treatment option (90%) ; confidence in others’ ability to use NG (86%) ; ease of instruction to others (86%) (Figure) . These firsthand experiences give useful clinical insights regarding NG, deepening our understanding for practice considerations.

Disclosure

B.Mitchell: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. F.G.Sowell: None. P.Williams: None. J.Poon: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company.

Funding

Eli Lilly and Company
386-P: ROCK1 Regulation of AMPK in the Development of Diabetic Nephropathy
Authors: NAGAI YOSUKE , MATOBA KEIICHIRO , SEKIGUCHI KENSUKE , TAKEDA YUSUKE , KANAZAWA YASUSHI , KAWANAMI DAIJI , UTSUNOMIYA KAZUNORI , NISHIMURA RIMEI
Published: May 2022

Rho-associated, coiled-coil-containing protein kinase (ROCK) is activated in the diabetic kidney. Studies over the past decade have illuminated ROCK signaling as an essential pathway in the pathogenesis of diabetic nephropathy. Accumulating evidence shows that renal dysfunction among patient with diabetes is associated with abnormal fatty acid oxidation in the kidney. However, the interaction of ROCK and fatty acid oxidation in diabetic kidneys remains unclear. Extracellular flux analyzer demonstrated that deficiency of ROCK1, one of the ROCK isoforms, improves TGF-β-induced mitochondrial dysfunction in primary cultured mesangial cells. ROCK1 deficiency rescued TGF-β-induced downregulation of fatty acid oxidation mediators such as peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) , and carnitine palmitoyltransferase 1A (CPT1A) . An investigation of mechanisms underlying this observation revealed activated ROCK1 axis through the phosphorylation of AMPK and increased expression of PGC-1α. Fluorescence histochemistry showed that ROCK1 deficiency suppresses ROS production induced by mitochondrial damage due to abnormal fatty acid metabolism. Consistent with this result, compared to wild-type mice, ROCK1 knockout mice exhibited reduced albuminuria and histological abnormalities along with the recovery of impaired fatty acid utilization and mitochondrial fragmentation. Furthermore, RNA-seq showed that ROCK1 deficiency in mesangial cells significantly altered the expression of genes involved in metabolic pathway. These observations indicate that ROCK1 is a key player in the development of diabetic renal injury. ROCK1 may be a potential therapeutic target for the treatment of diabetic nephropathy.

Disclosure

Y.Nagai: None. K.Matoba: None. K.Sekiguchi: None. Y.Takeda: None. Y.Kanazawa: None. D.Kawanami: None. K.Utsunomiya: None. R.Nishimura: Speaker's Bureau; Abbott Diabetes, Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Medtronic, Merck & Co., Inc., Novo Nordisk, Ono Pharmaceutical Co., Ltd., Sanofi, Taisho Pharmaceutical Holdings Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited, Terumo Corporation.
403-P: Reduced Mitochondrial DNA Copy Number in Type 1 Diabetes and Nephropathy and Correlates Thereof
Authors: JANUSZEWSKI ANDRZEJ S. , CARROLL LUKE , LOH YIK W. , O'NEAL DAVID N. , JENKINS ALICIA
Published: May 2022

Background: Mitochondrial DNA (Mt-DNA) copy number (mtDNA-CN) has been proposed as a marker of diabetic kidney disease (DKD) . Most studies are in type 2 diabetes. We determined mtDNA-CN in adults with type 1 diabetes vs. non-diabetic subjects, including associations with complications and risk factors.

Methods: Cross-sectional study: 178 T1D adults (mean (SD) age: 38 (14) yrs, 21 (14) yrs T1D, HbA1c: 8.0 (1.5) %, 36% with complications (CX+)) ; 132 non-diabetic adults (CON) (age: 37 (14) yrs, HbA1c: 5.1 (0.4) %) . mtDNA-CN by RT-PCR (ScienCell, Carlsbad, CA) in DNA from whole blood samples.

Results: T1D vs. CON: Median (LQ, UQ) mtDNA-CN in T1D vs. CON: 270.8 (189.4, 348.1) vs. 320.5 (264.4, 410.5) ; p<0.0001. mtDNA-CN was lower in T1D with vs. without DKD (238.2 (179.6, 309.1) vs. 293.7 (197.6, 364.4) ; p=0.02, but did not differ by retinopathy or macrovascular disease. T1D mtDNA-CN tertiles: The highest tertile had lowest CX rate (25% (tertile 3) vs. 41% (tertiles 1+2) , p=0.03. Detectable C-peptide rates increased with higher mtDNA-CN tertiles (55%, 69%, 79%, p=0.02) . There were no differences by sex, smoking, BMI status, metabolic syndrome, HbA1c, exercise, statins or ACE/ARB. Correlates of mtDNA-CN: In T1D: FBG (r=-0.19, p=0.02) , HDL-C (r=0.17, p=0.03) , WCC (r=-0.16, p=0.04) , sVCAM-1 (r=-0.17, p=0.03) and sICAM-1 (r=-0.20, p=0.02) . In CON: WHR (r=-0.22, p=0.03) ; WCC (r=-0.24, p=0.007) . Independent determinants of mtDNA-CN: In T1D: age (-0.25±0.10; p=0.02) , HDL-C (0.27±0.10; p=0.007) , sICAM-1 (-0.42±0.12; p=0.001) . Area under ROC curve 0.72. In CON: pulse pressure (0.25±013; p=0.047) , WCC (-0.41±0.15; p=0.005) , smoking status (never) (0.22±0.13; p=0.09) ; sex (female) (0.35±0.12; p=0.005) . Area under ROC curve 0.74.

Conclusion: T1D per se is associated with lower mtDNA-CN than CON, particularly with DKD. Higher mtDNA-CN in T1D is associated with detectable C-peptide. Age and inflammation related factors are associated with mtDNA-CN. Longitudinal and intervention studies are merited.

Disclosure

A.S.Januszewski: None. L.Carroll: None. Y.W.Loh: None. D.N.O'neal: None. A.Jenkins: Advisory Panel; Abbott Diabetes, Amgen Inc., Board Member; Insulin for Life , International Diabetes Federation Western Pacific Region, Research Support; JDRF, Medtronic, Mylan N.V., NHMRC Australia.
409-P: Long-Term Testosterone Treatment Improves Estimated Glomerular Filtration Rate (eGFR) in Men with Hypogonadism and Type 2 Diabetes Mellitus: Update of Registry Data
Authors: HAIDER KARIM S. , HAIDER AHMAD , SAAD FARID
Published: May 2022

Background: Reduced eGFR is associated with increased risk of cardiovascular disease and mortality.

Methods: Of 370 men with hypogonadism and T2DM, 190 received testosterone undecanoate 1000 mg/12 weeks (T-group) , 180 opted against treatment (CTRL) . Means and standard deviations of absolute measures over 13 years are reported. eGFR was calculated using the MDRD and the CKD-EPI formula.

Results: Mean baseline age: 62.0±5.2, mean (median) follow-up: 9.3±3.1 (10) years. Creatinine (mg/dL) decreased from 0.95±0.15 to 0.81±0.in the T-group and increased from 1.00±0.14 to 1.27±0.22 in CTRL (p<0.00for both) .

Systolic blood pressure (mmHg) decreased in the T-group from 163.0±13.3 to 129.8±6.5 and increased in CTRL from 145.5±14.5 to 162.9±13.1 (p<0.00for both) .

Diastolic blood pressure decreased in the T-group from 97.3±10.7 to 74.8±3.1 and increased in CTRL from 84.7±10.2 to 96.8±7.5 (p<0.00for both) .

T-group: eGFR (MDRD) (mL/min/1.73 m²) increased from 82.5±12.8 to 94.4±9.1. CTRL: eGFR decreased from 77.2±12.1 to 56.9±10.6) (p<0.00for both) .

T-group: eGFR (CKD-EPI) (mL/min/1.73 m²) increased from 84.0±15.4 to 87.5±4.7. CTRL: eGFR decreased from 77.0±13.9 to 49.8±12.3) (p<0.00for both) .

21 deaths (11.1%) and no cardiovascular events occurred in the T-group. In CTRL, 62 deaths (34.4%) , 62 myocardial infarctions (34.4%) and 51 strokes (28.3%) were recorded (p<0.00for all) . Nephropathy occurred in 1 man (0.01%) in the T-group and in 7 (0.4%) in CTRL (p=0.05) .

Conclusions: Long-term testosterone therapy in men with hypogonadism and T2DM prevents age-related deterioration in GFR.

Disclosure

K.S.Haider: Other Relationship; Bayer AG. A.Haider: Other Relationship; Bayer AG. F.Saad: Consultant; Bayer AG, Stock/Shareholder; AbbVie Inc., Bayer AG, GlaxoSmithKline plc.

Funding

Bayer AG
41-OR: ADA President's Select Abstract: The Beneficial Effect of Fenofibrate on Diabetic Retinopathy Is Influenced by PPARA Genetic Variability and Is Mediated by an Increase in FGF21 Levels
Authors: MORIERI MARIO LUCA , SHAH HETAL , TANG YALING , MENDONCA CHRISTINE , JOBE JENNY MARIE , MYCHALECKYJ JOSYF , DORIA ALESSANDRO
Published: May 2022

A PPARA genetic variant (rs6008845) influences the cardiovascular effectiveness of the PPAR-alpha agonist fenofibrate independent of changes in lipid profile. Here we investigated whether the same variant influences fenofibrate effectiveness on diabetic retinopathy (DR) . This was evaluated with regard to DR progression in 592 subjects with prior DR history from the ACCORD Eye Study, and with regard to other pre-specified diabetic eye outcomes in the ACCORD Lipid Study (n=3,650) . The effect of fenofibrate on 93 inflammatory biomarkers was studied in 320 rs6008845 T/T homozygotes from ACCORD Lipid and a large retina-eQTL dataset (GtExEye) was used to evaluate the association between rs6008845 and PPARA expression and derive a Genetic Score (eQtGS) of PPARA expression in the retina. rs6008845 modulated fenofibrate effectiveness on DR progression in a way similar to that previously reported for MACE, with the largest benefit being in rs6008845 T/T (OR 0.10, 95% C.I. 0.02-0.74) and the smallest (OR 0.54, 95% C.I. 0.21-1.42) in C/C homozygotes (p for interaction = 0.01) . The same synergism was found for severe vision loss (p=0.03) . The T allele was associated with higher PPARA retinal expression (P=4×10-38) in GtExEye, and ACCORD subjects with higher eQtGS for PPARA expression had better response to fenofibrate on DR progression (P=0.008) . Among T/T homozygotes, fenofibrate caused a marked increase in serum FGF21 (+0.87 S.D.; 95% C.I. 0.67-1.07, P=10×10-13) . Each S.D. increase in log2 FGF21 was associated with a 45% lower risk of severe vision loss (HR 0.55; 95%C.I. 0.34-0.91, p=0.01) , explaining 90% of fenofibrate benefit on this outcome in T/T subjects (p=0.03) .

In conclusion, fenofibrate effectiveness on DR depends on genetic variants affecting PPARA expression and is mediated by an increase in serum FGF21 - a metabolic and anti-inflammatory cytokine that may therefore be a therapeutic target to treat diabetic eye disease.

Disclosure

M.Morieri: Advisory Panel; Merck Sharp & Dohme Corp., Consultant; neopharmed gentili, SLAPharma, Other Relationship; Lilly, Novo Nordisk, Servier Laboratories. H.Shah: None. Y.Tang: None. C.Mendonca: None. J.Jobe: None. J.Mychaleckyj: None. A.Doria: Research Support; Novo Nordisk Foundation.

Funding

NHLBI HL110400 e HL153559-Italian Ministry of Health - Ricerca Finalizzata - GR-2019-12369702.
425-P: Lessons Learned from a Patient-Centered, Team-Based Intervention for Patients with Type 2 Diabetes at High Cardiovascular Risk: Year 1 Results from the CINEMA Program
Authors: NEELAND IAN , AL-KINDI SADEER G. , TASHTISH NOUR , EATON ELKE , RAHMANI SARA , BERG DIAMOND , RANA MARIAM N. , SULLIVAN CLAIRE , HATIPOGLU BETUL
Published: May 2022

Background: Persons with type 2 diabetes mellitus (T2DM) often experience fragmented and complex care and across multiple specialties. We implemented a patient-centered, multidisciplinary team-based intervention called CINEMA to improve care delivery and outcomes.

Methods: Patients with T2DM at high-risk for cardiovascular disease events, including those with established atherosclerotic cardiovascular disease, elevated coronary artery calcium score >100, chronic heart failure with reduced ejection fraction, and/or chronic kidney disease stages 2-4 were included in the program in Cleveland, OH. The program included 5 cardiologists with a special focus on T2DM, a pharmacist, a certified diabetes care and education specialist/dietician, a nurse navigator, and collaboration with endocrinologists and nephrologists. Data was collected from baseline within 3 months prior to patients’ first visit to up to 1 month after the follow-up visit. From May 2020 through May 2021, there were 316 referrals to the program. Of those referred, 47% met inclusion criteria. Among eligible patients, 96 (64%) completed a baseline and follow-up visit, with mean (std dev) follow-up time of 1 (34) days. Among patients completing the initial 3-month visit, 50% were ≥age 60 years with 48% female and 34% Black patients. Patients had significant reductions from baseline in Hb A1c (-8.7%) , total (-10.4%) , LDL (-15.7%) , and non-HDL (-14.9%) cholesterol, body weight (-3.7%) , and body mass index (-3.8%) (p<0.0for all) . In addition, among eligible patients, 87.5% were started on evidenced-based therapy with SGLT2i (n=24) , GLP-1 RA (n=40) , or both (n=20) to reduce the risk of CVD.

Conclusions: A team-based, patient-centered approach to high-risk disease management appears to be a promising paradigm for care delivery associated with greater use of evidence-based therapies and improved control of multiple CV risk factors.

Disclosure

I. Neeland: Advisory Panel; Boehringer Ingelheim International GmbH, Merck & Co., Inc. Consultant; Nestlé Health Science. S.G. Al-Kindi: None. N. Tashtish: None. S. Rahmani: None. D. Berg: None. M.N. Rana: None. C. Sullivan: None. B. Hatipoglu: None.
429-P: Pro-B-Type Natriuretic Peptide Strongly Predicts Major Cardiovascular Events and Mortality in Cardiovascular Disease Patients with Type 2 Diabetes as Well as in Those without Diabetes
Authors: MAECHLER MAXIMILIAN , SPRENGER LUKAS , MADER ARTHUR , LARCHER BARBARA , VONBANK ALEXANDER , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H.
Published: May 2022

Elevated pro-B type natriuretic peptide (pro-BNP) has been found to be a strong marker of cardiovascular risk in several high-risk populations. However, the power of pro-B type natriuretic peptide (pro-BNP) to predict major cardiovascular events (MACE) and mortality in patients with the combination of established cardiovascular disease and type 2 diabetes (T2DM) is unclear and is addressed in the present study. We enrolled 873 patients with established cardiovascular disease, 579 with angiographically proven stable CAD and 294 with sonographically proven peripheral artery disease. Prospectively, cardiovascular events were recorded over a mean follow-up period of 7.9±3.6 years. At baseline, pro-BNP was significantly higher in patients with T2DM (n=285) than in those who did not have diabetes (1010±26vs. 727±2327 mg/dl; p=0.003) . During follow-up, 257 patients suffered MACE; the event rate was significantly higher in patients with T2DM than in subjects without T2DM (37.8 vs. 26.0%; p<0.001) . pro-BNP predicted both MACE and mortality in the total study population, with standardized adjusted hazard ratios (HR) of 1.37 [1.26-1.48]; p<0.0 and 1.30 [1.21-1.40]; p<0.001, respectively. Further, pro-BNP predicted MACE and mortality in patients with T2DM (HRs 1.37 [1.21-1.55]; p<0.0 and 1.24 [1.10-1.40]; p<0.001, respectively) as well as in those who did not have diabetes (HRs 1.45 [1.26-1.67]; p<0.0 and 1.41 [1.25-1.60]; p<0.001, respectively) . Interaction terms pro-BNP x T2DM were non-significant for both MACE and mortality (p=0.590 and 0.3respectively) , indicating that the power of pro-BNP to predict MACE and mortality did not differ significantly between cardiovascular disease patients with T2DM and those who did not have diabetes. We conclude that pro-BNP strongly predicts MACE and mortality in cardiovascular disease patients with T2DM as well as in those without diabetes.

Disclosure

M.Maechler: None. L.Sprenger: None. A.Mader: None. B.Larcher: None. A.Vonbank: None. A.Leiherer: None. A.Muendlein: None. H.Drexel: None. C.H.Saely: None.
431-P: Waist-to-Body-Mass-Index Ratio and Type 2 Diabetes Mellitus Are Mutually Independent Predictors of Cardiovascular Events in Patients with Coronary Artery Disease
Authors: MADER ARTHUR , SPRENGER LUKAS , VONBANK ALEXANDER , LARCHER BARBARA , MAECHLER MAXIMILIAN , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H.
Published: May 2022

The waist circumference-to-body-mass-ratio (W/BMI-Ratio) has attracted interest as a predictor of cardiovascular risk. Its power to predict cardiovascular events in patients with established coronary artery disease (CAD) is not known and is addressed in the present study. We prospectively recorded cardiovascular events in 1472 patients with angiographically verified coronary artery disease. The mean follow-up time was 6.3±3.2 years. At baseline, there the W/BMI-Ratio did not differ significantly between patients with T2DM and nondiabetic patients (3.5±0.4 vs. 3.6±0.3; p=0.234) . Prospectively, the W/BMI-Ratio significantly predicted the incidence of cardiovascular events (n=439) both univariately (standardized HR 1.36 [1.20-1.52]; p<0.001) and after adjustment for age, gender, smoking, LDL cholesterol, HDL cholesterol, hypertension and T2DM (standardized adjusted HR=1.12 [1.03-1.21], p=0.006) , whereas T2DM predicted cardiovascular events indepently from the W/BMI-Ratio (HR=1.34 [1.09-1.64], p=0.006) . We conclude that the W/BMI-Ratio and T2DM are mutually independent predictors of cardiovascular events in patients with established CAD.

Disclosure

A.Mader: None. L.Sprenger: None. A.Vonbank: None. B.Larcher: None. M.Maechler: None. A.Leiherer: None. A.Muendlein: None. H.Drexel: None. C.H.Saely: None.
433-P: The A Body Shape Index and Type 2 Diabetes Are Mutually Independent Predictors of Major Cardiovascular Events in Patients with Established Cardiovascular Disease
Authors: SPRENGER LUKAS , MAECHLER MAXIMILIAN , VONBANK ALEXANDER , LARCHER BARBARA , MADER ARTHUR , LEIHERER ANDREAS , MUENDLEIN AXEL , DREXEL HEINZ , SAELY CHRISTOPH H.
Published: May 2022

The A Body Shape index (ABSI) is a validated measure of visceral adiposity that is calculated based on waist circumference, height and BMI. Its power to predict major cardiovascular events in patients with established cardiovascular disease (CVD) is unclear and is addressed in the present study.

We prospectively recorded cardiovascular events in a large cohort of 1544 patients with established CVD (1297 patients with angiographically proven stable coronary artery disease and 247 patients with sonographically verified PAD) over a mean follow-up time of 10.0±4.6 years.

At baseline, the ABSI was higher in patients with type 2 diabetes (T2DM; n=502) than in those who did not have diabetes (8.4±0.6 vs. 8.3±0.6; p<0.001) . Prospectively, the ABSI significantly predicted the incidence of MACE (n=507) after adjustment for age, gender, smoking, hypertension, LDL cholesterol, HDL cholesterol, and T2DM (standardized adjusted HRs 1.14 [1.04-1.24]; p=0.004, respectively) . T2DM in turn in this model also significantly predicted MACE with a HR of 1.61 [1.33-1.94]; p<0.0after adjustment for ABSI.

We conclude that ABSI and T2DM are mutually independent risk factors for MACE in patients with established cardiovascular disease.

Disclosure

L.Sprenger: None. M.Maechler: None. A.Vonbank: None. B.Larcher: None. A.Mader: None. A.Leiherer: None. A.Muendlein: None. H.Drexel: None. C.H.Saely: None.
435-P: Sex Differences in Diabetic Cardiovascular Outcomes amongst Patients Admitted for Pneumonia: A Study from the National Inpatient Sample (NIS)
Authors: LEVENTHAL SARAH , RUBINFELD GREGORY , BERGER JEFFREY S. , NEWMAN JONATHAN D. , SMILOWITZ NATHANIEL R.
Published: May 2022

Background: While women have lower risks of cardiovascular disease (CVD) than men, type 2 diabetes mellitus (T2D) seems to be a stronger risk factor for major adverse cardiac events (MACE) for women. No study has evaluated sex differences in MACE for patients with T2D admitted for non-CVD diagnoses in the NIS. Pneumonia is one of the most common primary diagnoses in the inpatient setting.

Methods: Patients hospitalized in 2013 for a primary diagnosis of pneumonia were identified from the NIS. MACE was defined as acute myocardial infarction (AMI) , ischemic stroke, cardiac arrest, or cardiogenic shock, and was compared by sex in patients with T2D. Multivariable logistic regression models were used to estimate odds of in-hospital MACE adjusted for demographics, cardiovascular risk factors, comorbidities, and pneumonia severity.

Results: In 2013, 192,100 patients were admitted for a primary diagnosis of pneumonia, and 50,776 of these patients had T2D. Of the patients with T2D, 50.9% were female. Female patients with T2D were less likely to smoke and had fewer comorbidities than male patients with T2D (all P<0.001) . After adjustment, T2D was associated with increased risk of AMI for women (aOR 1.2; 95% CI 1.1-1.4, P=0.006) but not for men (aOR 1.1; 95% CI 1.0-1.2, P=0.2) . Amongst patients with T2D, there was a similar risk of MACE for women compared to men (aOR 0.9; 95% CI 0.8-1.1, P=0.257) .

Conclusion: While T2D seems to be a stronger risk factor for AMI in female patients, male and female patients with T2D have an overall similar risk of in-hospital MACE when admitted for pneumonia.

Disclosure

S.Leventhal: None. G.Rubinfeld: None. J.S.Berger: Advisory Panel; Amgen Inc., Janssen Scientific Affairs, LLC. J.D.Newman: None. N.R.Smilowitz: Advisory Panel; Abbott.
437-P: NOX5 in Human Peripheral Blood Mononuclear Cells Is a Potential Biomarker for Unstable Diabetic Vascular Disease
Authors: BLOCK TOMASZ J. , SOURRIS KARLY , KHAN WAHEED , KANTHARIDIS PHILLIP , JHA JAY C. , COOPER MARK E. , SHAW JAMES , JANDELEIT-DAHM KARIN
Published: May 2022

Background: Human NADPH oxidase 5 (NOX5) is expressed and functionally active in peripheral blood mononuclear cells (PBMCs) . In those with diabetes, there is increased NOX5 expression in atherosclerotic plaques with associated coronary artery disease (CAD) and within the glomeruli in kidney biopsies. We hypothesise that NOX5 expression in circulating PBMCs is increased in patients with diabetes, particularly in those with comorbid unstable CAD and chronic kidney disease (CKD) .

Methods: 55 males aged 33-83 years underwent elective or emergency coronary angiography/angioplasty at the Alfred Hospital Catheter Laboratory. PBMCs from whole blood were processed for flow-cytometry to measure NOX5 protein. In parallel, NOX5 expression was measured in PBMCs by qPCR. In vitro, human macrophages (THP-1) were incubated in normal (5 mM) and high glucose (25 mM) . NOX5 expression and inflammatory markers were measured by qPCR.

Results: NOX5 protein expression in PBMCs was primarily driven by expression in monocytes (CD 45+/CD14+ cells) and was increased in diabetic and non-diabetic patients with CKD (28.7±4.2 vs. 17.3±1.7 AU; p=0.0038) and in diabetic patients with CKD versus without CKD (27.5±4.1 vs. 14.6±2.3 AU; p=0.012) . CAD with acute presentation was associated with increased NOX5 expression versus elective presentation (25.9±2.9 vs. 16.8±1.9 AU; p=0.0085) , particularly in diabetic patients presenting acutely versus electively (29.1±4.2 vs. 13.9±2.4 AU; p=0.0025) . A 4-fold upregulation of NOX5 gene was observed in patients with CKD versus without CKD irrespective of diabetes or CAD (p=0.018) . In vitro, there was a 2-fold increase in NOX5, TNF-α and IL-6 expression in THP-1 cells exposed to high glucose.

Conclusion: CKD and unstable CAD appear to be key factors for increased NOX5 expression in circulating PBMCs. Measurement of NOX5 in PBMCs may serve as a valuable prognostic biomarker and attractive therapeutic target in patients with clustering diabetic complications.

Disclosure

T.J.Block: None. K.Sourris: None. W.Khan: None. P.Kantharidis: None. J.C.Jha: None. M.E.Cooper: Advisory Panel; Bayer AG, Merck Sharp & Dohme Corp., Consultant; Boehringer Ingelheim International GmbH, Research Support; Novo Nordisk, Speaker's Bureau; AstraZeneca, Servier Laboratories. J.Shaw: None. K.Jandeleit-dahm: None.
438-P: Cardiorenal Benefits of Newer Glucose-Lowering Drugs by Hispanic Ethnicity: A Meta-analysis of Results from Randomized Outcome Trials in Type 2 Diabetes
Authors: TANG HUILIN , CHEN WEI-HAN , BIAN JIANG , O'NEAL LATOYA J. , LACKLAND DANIEL T. , SCHATZ DESMOND , GUO JINGCHUAN
Published: May 2022

Background: Hispanic individuals are at increased risk of diabetes and related complications compared to non-Hispanic White individuals. Thus, we aimed to compare cardiorenal outcomes of newer glucose-lowering drugs between Hispanic and non-Hispanic populations via a meta-analysis of randomized outcome trials.

Methods: We included randomized placebo-controlled cardiovascular (CV) and renal outcome trials of SGLT2 inhibitors, GLP-1RAs, and DPP-4 inhibitors that reported major adverse cardiovascular events (MACE) , CV death/heart failure hospitalization (HHF) , or composite renal outcome, stratified by the Hispanic ethnicity (Hispanic vs. non-Hispanic) . We calculated pooled hazard ratios (HR) with 95% CI using fixed-effects models and tested the differences between the two groups (Pinteraction ) .

Results: We included outcome trials reporting outcomes by Hispanic ethnicity in 89,393 patients with type 2 diabetes. In three SGLT2 inhibitor trials, the risk of MACE varied by ethnicity (HR = 0.70 [0.54-0.91] in Hispanic population and HR = 0.96 [0.86-1.07] in non-Hispanic population) with a Pinteraction = 0.03, while the risks of CV death/HHF (Pinteraction = 0.46) and composite renal outcome (Pinteraction = 0.31) were similar across ethnicity. In five GLP-1RA trials, we observed a similar MACE risk between Hispanic (HR = 0.82 [0.70-0.96]) and non-Hispanic (HR = 0.92 [0.84-1.00]) populations (Pinteraction = 0.22) . In three DPP-4 inhibitor trials, the risk of MACE was greater in Hispanic (HR=1.15 [0.98-1.35]) than non-Hispanic (HR= 0.96 [0.88-1.04]) populations (Pinteraction = 0.045) , while the risk of composite renal outcome was similar between the two groups (Pinteraction = 0.51) .

Conclusion: Compared with non-Hispanic individuals, Hispanics with type 2 diabetes obtain a greater benefit on lowering MACE risk with the use of SGLT2 inhibitors, while a lower benefit with DPP-4 inhibitors.

Disclosure

H.Tang: None. W.Chen: None. J.Bian: None. L.J.O'neal: None. D.T.Lackland: None. D.Schatz: Advisory Panel; Abbott Diabetes, Medtronic. J.Guo: None.
44-OR: NFAT Inhibition Reduces Retinal Vascular Leakage and Inflammation in Diabetic Retinopathy
Authors: DE LA HUERTA IRINA , NUNEZ JORGE L. , POLOWAY JACOB M. , REDDY VARUN , PENN JOHN
Published: May 2022

Purpose: Macular edema resulting from retinal vascular leakage is the leading cause of vision loss in diabetic retinopathy (DR) . The nuclear factor of activated T-cells (NFAT) family of transcription factors is known to upregulate inflammatory cytokines in response to high glucose. This study explored the effect of NFAT inhibition on retinal vascular leakage and inflammation in DR in vivo and in vitro.

Methods: The streptozocin-induced (STZ) model was used as the mouse model of diabetic retinopathy. Hyperglycemia was induced at 4 weeks in C57BL/6J mice and confirmed when fasting plasma glucose became persistently elevated (>300 mg/dL) . Experiments were performed at weeks of hyperglycemia. STZ mice were injected intravitreally with the NFAT signaling inhibitor INCA-6 (25 uM) or vehicle (0.1% DMSO in PBS) . Uninjected eyes of both STZ and control mice served as additional controls. Evans blue dye (EBD) was used to measure retinal vascular leakage. Primary mouse retinal microvascular endothelial cells (MRMECs) were used for in vitro experiments. MRMEC monolayers were treated with INCA-6 (2.5 uM) or with vehicle and cell permeability was induced with mouse VEGF165. The transendothelial electrical resistance (TEER) was measured with the electrical cell-substrate impedance sensing method. MRMEC IL-6 production was investigated by ELISA.

Results: In the STZ model of diabetic retinopathy, EBD vascular leakage was significantly reduced in INCA-6-treated eyes (INCA-6: 0.85 ± 0.57, n=5; vehicle: 1.78 ± 0.38, n= 7; P=0.007) , and in INCA-6 treated eyes compared to untreated eyes (untreated: 2.83 ± 1.63, n=4, P=0.04) . In the VEGF-induced MRMEC monolayer permeability model, INCA-6 significantly preserved TEER compared to vehicle (n=12, P<0.05) and decreased the VEGF-induced production of IL-6 (n=5, P<0.05) .

Conclusions: NFAT inhibition has therapeutic potential to prevent and treat retinal vascular leakage and inflammation in DR.

Disclosure

I.De la huerta: None. J.L.Nunez: None. J.M.Poloway: None. V.Reddy: None. J.Penn: None.

Funding

National Institutes of Health (EY032620) International Retinal Research Foundation Grant Knights Templar Foundation Career Starter Grant
449-P: Assessing Cardiovascular Risk in Prediabetes
Authors: ZIVKOVIC TEODORA BELJIC
Published: May 2022

Prediabetes carries a risk of diabetes and cardiovascular disease (CVD) . Assessment of CVD risk in prediabetes is not as routine, as is assessment of diabetes risk. However, it is not less important. This can be done through conventional SCORE charts and through coronary artery calcium (CAC) score. CAC is examined through multislice CT. Calcifications indicate late-stage subclinical coronary atherosclerosis. The AIM of our study was to assess traditional CVD risk through score charts and CAC in subjects with prediabetes (preDM) and to evaluate whether any correlation exists between the two. After diagnosing preDM with an oral glucose tolerance test and HbA1c, ECG, lipids, body mass index and blood pressure measurements were performed. Subjects were evaluated for CVD risk through Score charts. Thereafter, all subjects were appointed for multi-slice CT to obtain the CAC. A writen consent was obtained from all subjects. Results: 80 subjects with preDM were screened for CVD. CAC score of 0 was present in 35 subjects. Minimal calcifications with a CAC score of 1-AU were present in subjects with preDM. Moderate calcification of 11-100 AU were present in 18 subjects. 12 subjects had significant calcifications with 101-400 AU. Five subjects had a CAC score >400 AU. Evaluation of the Score charts reviled that Score risk below 2% was present in 20 subjects. Score risk of 3-4% was present in 10, 5-9% risk was present in 16 and a score risk of 10-14% was present in 8 subjects. Twenty six subjects with PreDM has a score risk of 15% and more. No significant correlation was found between Score charts and CAC. However, a trend of finding more calcifications in those with a 10% and above Score risk was noted. Conclusion: An approach to CVD risk assessment that combines the traditional Score charts with a more personalized atherosclerosis-imaging model may be appropriate for high risk subjects with pre diabetes.

Disclosure

T.Beljic zivkovic: None.