bluuebunny/crossref_metadata_2025 huggingface dataset:
253-LB: Ethnic Differences in Pancreatic Hormone Secretion in Health and T2D
Authors: DOLIBA NICOLAI M. , ROMAN JEFFREY , ROZO ANDREA V. , QIN WEI , LIU CHENGYANG , NAJI ALI , RICKELS MICHAEL R. , ATKINSON MARK A. , POWERS ALVIN C. , BRISSOVA MARCELA , KAESTNER KLAUS H. , STOFFERS DORIS A.
Published: May 2022

Purpose: We tested the hypothesis that a critical biologic determinant of T2D disparities is based on ethnicity-related differences in pancreatic islet function.

Methods: Utilizing donor tissues from the NIDDK-funded Human Pancreas Analysis Program (HPAP) , we examined both insulin and glucagon secretion from nondiabetic and diabetic Caucasian and African American donor islets. Initially, a physiological amino acid mixture was used to stimulate glucagon secretion, followed by low and high glucose to stimulate insulin secretion and suppress glucagon secretion. During the high glucose step, IBMX (0.1 mM) is added to potentiate secretion of both hormones. Insulin and glucagon concentration in perifusates and islet extracts was measured by radioimmunoassay or ELISA. Statistical comparisons were drawn by repeated measures ANOVA.

Results: Comparing nondiabetic islets, we observed overlapping insulin secretion profiles between both ethnicities; however, glucagon secretion was distinctly greater in both nondiabetic African American (+111%) islets compared to nondiabetic Caucasian islets, under all interventions. In T2D, the reduction in insulin secretion was significantly greater in African American T2D donors (high glucose -76%; IBMX -76%) compared to Caucasian T2D donors (high glucose -47%; IBMX -50%) . More strikingly, glucagon secretion in T2D donors was markedly different based on ethnicity. Whereas Caucasian T2D islets exhibited a similar baseline of glucagon secretion compared to Caucasian controls, there was a marked reduction of glucagon secretion overall in African American T2D donors (-70%) compared to their corresponding controls. The largest detected difference was in IBMX-potentiation of glucagon secretion, which is higher in Caucasian T2D donors (+103%) but significantly decreased in African American T2D donors (-76%) . Preliminary analysis of hormone content in a subset of the donor islet preparations revealed no differences according to ethnicity.

Conclusions: We propose that ethnicity-related differences in nondiabetic islet function may contribute to the enhanced risk of T2D.

Disclosure

N. M. Doliba: None. M. Brissova: None. K. H. Kaestner: None. D. A. Stoffers: Other Relationship; Biomarin, Correlagen. J. Roman: None. A. V. Rozo: None. W. Qin: None. C. Liu: None. A. Naji: None. M. R. Rickels: Advisory Panel; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Consultant; L-Nutra Inc. M. A. Atkinson: None. A. C. Powers: None.

Funding

This work is supported by 3UC4-112217-01S1 and U01-DK123594-02, UC4-DK-112217, UC4-DK-112232, and U01-DK-123716.
305-OR: Quiescence Abrogates Stress-Induced Senescence-Associated Secretion Phenotype in Adipose-Derived Stem Cells and May Enhance Their Therapeutic Effects on Diabetic Complications
Authors: FUNAKI MAKOTO , HATA AKIKO , YOSHIDA MITSUTERU , MIYAMOTO NAOKI , IKUTA TAKAHISA , UEMURA YUTA , AKIZUKI MINATO , TANGOKU AKIRA , YUMOTO HIROMICHI , OGAWA HIROHISA , OYA TAKESHI
Published: May 2022

The anti-inflammatory functions of adipose-derived stem cells (ADSC) are receiving much attention as potential treatment for diabetic complications, although it is not yet established. Cellular stresses render ADSC prematurely senescent, in which senescent ADSC propagate instead of suppressing inflammation in neighboring cells and tissues through their secretory profile, which is called senescence-associated secretion phenotype (SASP) . In diabetes, ADSC exhibit SASP, which decreases the feasibility of ADSC-based therapies. We previously reported that ADSC become quiescent when cultured on a substrate whose stiffness mimics that of adipose tissue. Here, we investigated the effect of quiescence on high glucose-induced SASP in ADSC. When cultured in three-dimensional (3D) gels, ADSC became quiescent and showed upregulated indolemine 2,3-dioxygene in response to tumor necrosis factor α and interferon γ stimulation to mimic inflammation ex vivo. High glucose treatment upregulated MCP-1 in ADSC cultured on plastic tissue culture plates, and their conditioned medium decreased the viability of HUVEC, an endothelial cell line. However, even under high glucose conditions, transferring ADSC from plastic to 3D gels attenuated MCP-1 expression, and their conditioned medium restored the viability of HUVEC. Transplantation of gels containing ADSC into mice resulted in vascular formation in those gels, and enhanced wound healing was suggested. These results open up the possibility that quiescence will eliminate SASP in ADSC even under hyperglycemia and promote the ability of ADSC to have therapeutic effects on diabetic complications.

Disclosure

M.Funaki: Board Member; Mechanogenic, Inc. H.Ogawa: None. T.Oya: None. A.Hata: None. M.Yoshida: None. N.Miyamoto: None. T.Ikuta: None. Y.Uemura: None. M.Akizuki: None. A.Tangoku: None. H.Yumoto: None.
306-OR: Modified Approach for Improved Islet Allotransplantation into Prevascularized Sernova Cell Pouch Device: Preliminary Results of the Phase I/II Clinical Trial at University of Chicago
Authors: BACHUL PIOTR J. , PEREZ-GUTIERREZ ANGELICA , JUENGEL BRADEN , GOLAB KAROLINA , BASTO LINDSAY , PEREA LAURENCIA , WANG LINGJIA , TIBUDAN MARTIN , THOMAS CELESTE , PHILIPSON LOUIS H. , BARTH ROLF , FUNG JOHN , WITKOWSKI PIOTR
Published: May 2022

Introduction: After the pilot study demonstrated safety of the Sernova Cell Pouch (SCP) , we modified islet transplantation (ITx) conditions for improved engraftment in the SCP.

Methods: SCPs were implanted in the abdominal anterior rectus sheath of 7 patients with T1DM and problematic hypoglycemia. Immunosuppression was initiated 1 month after SCP implantation and a marginal dose ITx of highly purified islets 1 month later. A second ITx was scheduled 6 to 12 months later. Sentinel SCPs are explanted for histopathology 3 months after ITx. Graft function is monitored by blood glucose (BG) , C-peptide and insulin usage.

Results: Seven patients underwent 27 study-related surgeries with wound infection in 2 (7.4%) patients after SCP implantation. One patient discontinued following device excision and the second patient’s infection resolved. SCPs are well tolerated with implant durations exceeding 35 months. Three patients received two ITx into SCPs, resulting in new, measurable islet function documented by detectable levels of stimulated C-peptide. A supplemental, single intraportal ITx was sufficient for the first two patients to achieve ongoing insulin independence and freedom from severe hypoglycemic events for over 22 and 4 months with HbA1c 5.4 and 5.5%, respectively. The third patient discontinued insulin support 2 months after a single supplemental intraportal ITx and presented normal blood glucose control during MMTT on post-transplant day 75 with fasting and peak values of 97 and 142mg/ml, respectively, serum C-peptide of 1. and 3.39 ng/ml and HbA1c of 5.8%. The other three patients on study are progressing as planned. All have received SCP implants and at least one ITx.

Conclusion: ITx with SCP demonstrates long-term safety and efficacy in an early subset of trial patients. Ongoing results for transplanted SCPs have led to procedural adjustments to further optimize clinical outcomes.

Disclosure

P.J.Bachul: None. L.H.Philipson: Advisory Panel; Nevro Corp., Research Support; Dompé, Novo Nordisk, provention BIo. R.Barth: None. J.Fung: n/a. P.Witkowski: Advisory Panel; Sernova, Corp., Vertex Pharmaceuticals Incorporated. A.Perez-gutierrez: None. B.Juengel: None. K.Golab: None. L.Basto: None. L.Perea: None. L.Wang: None. M.Tibudan: None. C.Thomas: None.
328-OR: Evaluation of Mobile Health Technology–Based Diabetes Education System for Self-Management of Patients with Type 2 Diabetes Mellitus
Authors: SI CHEN , LU JINGYI , BAO YUQIAN , ZHOU JIAN , JIA WEIPING
Published: May 2022

Ongoing research has established that mobile health applications (apps) are feasible tools for improving self-management of diabetes and to maintain glycemic control. This single-arm, multi-center, observational study evaluated the effectiveness of an app-based diabetes education program in improving HbA1c among patients with type 2 diabetes mellitus (T2DM) treated with premixed insulin for 12 weeks. A total of 9426 patients were included. Primary endpoint was the change in HbA1c from baseline to week 12. Secondary endpoints included the association of HbA1c reduction with number of diabetes education courses completed and learning mode, and the association of SMBG frequency with diabetes education courses. According to the number of diabetes education courses completed, the patients were divided into 3 groups: 0-4 courses, 5-29 courses, and ≥30 courses. After 12 weeks of engagement in app, there was a decrease in HbA1c levels (9.84 ± 1.47 % vs. 7.36 ± 1.15 %) with 36% of patients achieving HbA1c target at week 12. The HbA1c control rate was the highest among patients completing ≥30 courses (49%; mean change: -2.9%) , followed by those who completed 5-29 courses (38%; -2.7%) and 0-4 courses (35%; -2.4%) (P<0.0001) . Besides, the frequency of SMBG testing increased with the ascending number of courses completed (≥30 courses: 7.4 times/week; 5-29 courses: 3.5 times/week; 0-4 courses: 1.2 times/week; P<0.0001) . HbA1c reduction (-2.7% vs. -2.4%; P<0.0001) and the proportion of patients with HbA1c <7% (42% vs. 35%; P<0.0001) were significantly lower in patients who preferred audio-visual learning over visual learning for diabetes course engagement. To summarize, participants who completed more diabetes education courses had better HbA1c reduction over 12 weeks and better self-management of blood glucose with the app.

Disclosure

C.Si: None. J.Lu: None. Y.Bao: None. J.Zhou: n/a. W.Jia: None.
334-OR: Pemvidutide (ALT-801) , a Balanced (1:1) GLP-1/Glucagon Dual Receptor Agonist, Induces Rapid and Marked Weight Loss without the Need for Dose Titration in People with Overweight/Obesity
Authors: KLEIN SAMUEL , NESTOR JOHN J. , HARRIS M. SCOTT , SUYUNDIKOV ANVAR , CASPER ROB , STEELE STACI M. , PAYNE JACQUES D. , KRISHNAN VYJAYANTHI , ROBERTS M. SCOT , BROWNE SARAH K.
Published: May 2022

Background: Weight loss is the cornerstone of therapy for people with overweight/obesity. Pemvidutide is a dual GLP-1/glucagon receptor agonist that provides GLP-1/glucagon agonism in a balanced (1:1) ratio, which is hypothesized to enhance weight loss and minimize gastrointestinal intolerance.

Methods: 34 subjects with overweight/obesity (BMI 25.0-40.0 kg/m2) without diabetes were randomized in double-blind manner to pemvidutide (1.2, 1.8 or 2.4 mg) or placebo subcutaneously weekly for 12 weeks without dose titration or lifestyle therapy. Study endpoints included safety/tolerability, weight loss and cardiometabolic outcomes.

Results: At 12 weeks, significant weight loss was achieved with 1.8 mg (10.3%) and 2.4 mg (9.0%) of pemvidutide, and significant improvements or trends in cardiometabolic risk factors were observed at all pemvidutide doses (Table 1) . No increases in heart rate, fasting glucose or HbA1c were observed in any group. Mild, transient nausea was the most frequent adverse event (AE) ; no severe/serious AEs or AE-related study discontinuations were reported.

Conclusion: Pemvidutide induces robust weight loss and improves cardiometabolic risk factors without dose titration. These data support the development of pemvidutide as a promising treatment for obesity and its comorbidities.

Disclosure

S.Klein: Advisory Panel; Altimmune, Consultant; Janssen Research & Development, LLC, ProSciento, Research Support; Janssen Research & Development, LLC. S.K.Browne: Employee; Altimmune. J.J.Nestor: Consultant; Altimmune, Employee; EuMederis Pharmaceutials, Inc., Mederis Diabetes, LLC, Spitfire Pharma, Inc. M.Harris: Employee; Altimmune. A.Suyundikov: Employee; Altimmune. R.Casper: Employee; Altimmune. S.M.Steele: Employee; Altimmune. J.D.Payne: None. V.Krishnan: Employee; Altimmune. M.Roberts: Employee; Altimmune.

Funding

Altimmune, Inc.
337-OR: Tirzepatide Improved Markers of Islet-Cell Function (Fasting Glucagon and HOMA2-B) and Insulin Sensitivity (Fasting Insulin and HOMA2-IR) Compared with Semaglutide in People with Type 2 Diabetes
Authors: BROWN KATELYN , LANDO LAURA FERNANDEZ , BERGMAN BRANDON , THOMAS MELISSA K. , LIU BING , LEE CLARE
Published: May 2022

Tirzepatide (TZP) achieved significantly greater HbA1c and weight reductions with all doses (5, and 15 mg) vs. semaglutide 1 mg (SEMA) in a Phase 3 trial of 1879 people with type 2 diabetes (T2D) on background metformin (mean age 56.6 years; T2D duration 8.6 years; baseline HbA1c 8.3% [67 mmol/mol]; BMI 34.2 kg/m2) (SURPASS-2) . Changes in fasting markers of islet cell function and insulin sensitivity were assessed by mixed model repeated measures in the modified intent-to-treat population. At 40 weeks, all TZP doses improved HOMA2-B, calculated with C-peptide, as indicated by a significant increase by 97-120% on average with TZP, compared to 84% with SEMA. Fasting glucagon levels, adjusted for fasting serum glucose, significantly decreased by 53-55% on average with TZP and 15 mg doses compared with SEMA (48%) . All TZP doses improved insulin sensitivity as reflected by a significant decrease by 16-24% on average of HOMA2-IR, calculated with insulin, compared to a decrease by 5% with SEMA. Fasting insulin levels were also significantly reduced by 9-21% on average with all TZP doses compared to an increase of 0.6% with SEMA. Dual GIP/GLP-1 receptor agonist TZP significantly improved markers of islet cell function and insulin sensitivity compared to selective GLP-1 RA SEMA in people with T2D.

Disclosure

K. Brown: Employee; Eli Lilly and Company. L. Fernandez Lando: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. B. Bergman: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. M.K. Thomas: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. B. Liu: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. C. Lee: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company.

Funding

Eli Lilly and Company
355-OR: WATCH-DM Identifies Diabetic Cardiomyopathy: A Multicohort Analysis
Authors: SEGAR MATTHEW W. , PATEL KERSHAW , VADUGANATHAN MUTHIAH , CHANDRA ALVIN , WILLETT DUWAYNE L. , PANDEY AMBARISH
Published: May 2022

Introduction: Diabetic cardiomyopathy (DbCM) , a transitional phenotype that may precede overt heart failure (HF) onset, is characterized by abnormalities in cardiac structure or function in DM in the absence of cardiovascular disease (CVD) or major risk factors. Whether WATCH-DM, a validated risk score to identify incident heart failure (HF) among individuals with DM, can identify DbCM is unknown.

Methods: Adults without known prevalent CAD or overt HF were pooled from 2 community-based cohort studies (ARIC and CHS) . Presence of DbCM in patients with DM was defined using different definitions (Figure) . Adjusted logistic regression and restricted spline models were used to evaluate the association of WATCH-DM and the individual components of DbCM.

Results: Among 2,241 individuals with DM, the prevalence of DbCM was 9.8% and 62.8% applying the most and least restrictive definitions, respectively. For every 1-unit increase, the WATCH-DM score was associated with higher risk of LV hypertrophy and diastolic dysfunction (odds ratio [95% CI] = 1.20 [1.15-1.27] and 1.[1.05-1.13], respectively) , but not LA enlargement (Figure A) . Across definitions, higher WATCH-DM scores were associated with a higher risk of DbCM (Figure B) .

Conclusions: The WATCH-DM risk score is associated with higher prevalence of DbCM and may be a useful tool in screening for DbCM.

Disclosure

M.W.Segar: None. K.Patel: None. M.Vaduganathan: Advisory Panel; American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Pharmacosmos, Relypsa, Roche Diagnostics, and Sanofi, Other Relationship; Novartis and Galmed , Research Support; Amgen, AstraZeneca, Boehringer Ingelheim, Novartis, Roche Diagnostics, and Sanofi, Speaker's Bureau; Novartis and Roche Diagnostics. A.Chandra: None. D.L.Willett: None. A.Pandey: Advisory Panel; Lilly, Consultant; Tricog, Research Support; Applied Therapeutics, Gilead Sciences, Inc.
36-OR: Bromocriptine Quick Release (BCQR) Improves Vascular Health in Youth with Type 1 Diabetes Even if Normal Weight
Authors: SCHÄFER MICHAL , BROWNE LORNA , TRUONG UYEN , BJORNSTAD PETTER , SNELL-BERGEON JANET K. , BAUMGARTNER AMY , HUNTER KENDALL S. , REUSCH JANE , BARKER ALEX J. , SCHAUER IRENE E. , NADEAU KRISTEN J.
Published: May 2022

Background: Global vascular dysfunction is well-recognized in youth with type 1 diabetes (T1D) , accentuating lifetime cardiovascular event risk and making therapeutic strategies to mitigate vascular dysfunction a high priority. In the BCQR-T1D study, we tested the hypothesis that BCQR, a medication used in obese adults with type 2 diabetes, would improve vascular health in T1D youth.

Methods: BCQR-T1D was a placebo-controlled, random-order, double-blinded, cross-over study investigating cardiovascular and metabolic impacts of BCQR in T1D. Youth were randomized 1:1 to phase-1: 4-weeks of BCQR or placebo after which blood pressure (BP) , peripheral vascular stiffness by brachial artery distensibility (BrachD) , and central aortic stiffness by pulse wave velocity (PWV) , relative area change (RAC) and distensibility from phase-contrast MRI, were performed. Following a 4-week washout period, phase 2 was performed in identical fashion with the alternate treatment.

Results: Forty-two adolescents (mean age 15.9 years, HbA1c 8.6%, BMI %ile 71.4, T1D duration 5.8 years) with T1D were enrolled. Compared to placebo, BCQR therapy decreased systolic (∆ = -5 mmHg, p<0.001) and diastolic BP (∆ = -2 mmHg, p=0.039) . BCQR reduced ascending aortic (AA) PWV (∆ = -0.4 m/s, p=0.005) , and increased RAC (∆ = -2.6%, p=0.022) and distensibility (∆ = 0.%/mmHg, p=0.010) . In the thoraco-abdominal aorta, BCQR decreased PWV (∆ = -0.2 m/s, p=0.013) and increased distensibility (∆ = 0.%/mmHg, p=0.032) . Of interest, in the normal-weight participants, BCQR improved systolic BP (∆ = -5 [95.0%CI: -7, -1] mmHg, p= 0.009) , AA PWV (∆ = -0.4 [95.0%CI: -0.7, 0] m/s, p= 0.030) and BrachD (∆ = 0.56 %/mmHg, p=0.023) , and tended to improve AA distensibility (∆ = 0.[95.0%CI: -0.01, 0.19] %/mmHg, p= 0.084) .

Conclusions: BCQR improved BP, central and peripheral aortic stiffness and pressure hemodynamics in T1D adolescents over 4 weeks vs. placebo, even if normal weight, supporting future longer-term studies.

Disclosure

M.Schäfer: None. I.E.Schauer: None. K.J.Nadeau: None. L.Browne: None. U.Truong: None. P.Bjornstad: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Horizon Therapeutics plc, LG Chem, Lilly, Novo Nordisk, Consultant; AstraZeneca, Bristol-Myers Squibb Company. J.K.Snell-bergeon: Stock/Shareholder; GlaxoSmithKline plc. A.Baumgartner: None. K.S.Hunter: None. J.Reusch: Advisory Panel; Medtronic. A.J.Barker: None.

Funding

JDRF BROM QR THERP3-SRA-2015-125-M-R
374-P: Identifying the Role and Mechanism by Which GDF15 Enhances the Counterregulatory Response to Hypoglycemia
Authors: LI ZONGYU , ZHANG XINYI , ZHU WANLING , XU QIAN , YU CHUYUE , LIMA BRUNA G. COSTA , LI XIRUO , ISRANI-WINGER KAVITA , NASIRI ALI , ZHANG CUILING , CHANG RUI , HWANG JANICE J. , WANG ANDREW , PERRY RACHEL J.
Published: May 2022

Severe hypoglycemia is the leading acute mortality risk in patients with diabetes. The counterregulatory gluconeogenic and glycogenolytic response to hypoglycemia is the primary adaptive mechanism to enable survival. To better understand the hormonal response that orchestrates hypoglycemia counterregulation, we employed the insulin tolerance test (ITT) and hyperinsulinemic-hypoglycemic clamp to mimic the two common settings in which hypoglycemia can occur in patients: postprandial insulin overdose and elevated basal insulin infusion, respectively. We found that Growth Differentiation Factor 15 (GDF15) can be induced (33.5±2.1 vs. 172.4±29.2 pg/ml, P<0.in ITT and 46.2±11.6 vs. 2865±547.3 pg/ml, P<0.0in the clamp) . GDF15 mRNA and protein are upregulated in kidney, and the GDF15 tdTomato reporter mouse demonstrates the expression of GDF15 in the S3 segment of the proximal tubule. GDF15 increases hepatic gluconeogenesis (26.1±2.2 vs. 33.5±1.6 mg/kg/min, P<0.05) by increasing intrahepatic lipolysis in a beta-adrenergic receptor-2 (Adrb2) -dependent manner. To investigate the role of GDF15 counterregulation in diabetes, we utilized a streptozotocin (STZ) -induced type 1 diabetes (T1D) model. Mice with T1D exhibit impaired GDF15 production in an ITT. Additionally, we found that recurrent hypoglycemia impairs endogenous glucose production during hypoglycemia in mice (27.5±4 vs. 10.5±1.3 mg/kg/min, P<0.01) , which may result from lower GDF15 production (1372±248.2 vs. 648.5±71.3 pg/ml, P<0.05) . In humans, hypoglycemic clamps in healthy volunteers can induce GDF15 production (p=0.01) , although this induction was absent in patients with T1D. Conclusion: These data show the kidney can produce GDF15 in response to hypoglycemia, thereby increasing hepatic gluconeogenesis to enable survival. However, T1D patients are unable to initiate a functional GDF15 signaling pathway resulting in an impaired glucose counterregulatory response to hypoglycemia.

Disclosure

Z.Li: None. C.Zhang: None. R.Chang: None. J.J.Hwang: None. A.Wang: Research Support; NGM Biopharmaceuticals. R.J.Perry: None. X.Zhang: None. W.Zhu: None. Q.Xu: None. C.Yu: None. B.G.Costa lima: None. X.Li: None. K.Israni-winger: None. A.Nasiri: None.

Funding

National Institutes of Health (P30 DK045735) National Institutes of Health (R37 CA258271-01A1)
375-P: Indirect Treatment Comparison (ITC) of Three Ready-to-Use Glucagon Treatments for Severe Hypoglycemia: Baqsimi, Gvoke, and Zegalogue
Authors: GIMENEZ MARGA , KHUNTI KAMLESH , SYRING KRISTEN , BAKER LEVENIA A. , CHENJI SURESH , THRELKELD REBECCA J. , YAN YU , MATSUHISA MUNEHIDE
Published: May 2022

Objective: To evaluate and compare the efficacy and safety of 3 ready-to-use glucagon treatments for severe hypoglycemia in adults and children with diabetes: Baqsimi (nasal glucagon) , Gvoke (glucagon injection) , and Zegalogue (dasiglucagon injection) .

Methods: A systematic literature review was conducted to identify randomized clinical trials assessing the efficacy and safety of ready-to-use glucagon vs. reconstituted injectable glucagon. Bayesian fixed-effect network meta-analysis was used to perform the ITC of Gvoke and Zegalogue vs. Baqsimi. Endpoints included the proportion of participants achieving treatment success, maximum blood glucose, and treatment-emergent adverse events. Mean time to treatment success and to maximum blood glucose were also analyzed for Gvoke vs. Baqsimi, but not for Zegalogue due to reporting differences (mean vs. median) .

Results and Conclusion: Ten trials were included in the ITC, including 4 for Baqsimi, 3 for Gvoke, and 3 for Zegalogue. Baqsimi had comparable efficacy with Gvoke and with Zegalogue (Table) , and all 3 treatments achieved high treatment success (>98%) in adults and children with diabetes. In adults, results from the combined T1D and T2D analysis were consistent with the T1D analysis, except a statistically significant faster time achieving treatment success observed for Baqsimi vs. Gvoke in the combined analysis.

Disclosure

M. Gimenez: Advisory Panel; Eli Lilly and Company, Medtronic, Novo Nordisk, Sanofi. Speaker's Bureau; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Sanofi. K. Khunti: Consultant; Abbott, Amgen Inc., AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Lilly, Merck Sharp & Dohme Corp., Napp Pharmaceuticals Limited, Novartis AG, Novo Nordisk, Roche Diabetes Care, Sanofi-Aventis Deutschland GmbH, Servier Laboratories. Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. K. Syring: Employee; Eli Lilly and Company. L.A. Baker: None. R.J. Threlkeld: Employee; Lilly Diabetes. Y. Yan: Employee; Eli Lilly and Company. M. Matsuhisa: Research Support; Nissui, Sysmex Corp. Speaker's Bureau; Astellas Pharma Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited.

Funding

Funded by Eli Lilly and Company.
407-P: Skin Autofluorescence Is Associated with Tubular Injury Represented by Urinary Excretion of Liver-Type Fatty Acid–Binding Protein in People with Diabetes
Authors: YAMAGAMI HIROKI , YASUI SAYA , HOSOKI MINAE , HORI TAIKI , HARA TOMOYO , MITSUI YUKARI , KURAHASHI KIYOE , NAKAMURA SHINGEN , OTODA TOSHIKI , YUASA TOMOYUKI , YOSHIDA SUMIKO , KURODA AKIO , MATSUHISA MUNEHIDE , ENDO ITSURO , AIHARA KEN-ICHI , ABE MASAHIRO
Published: May 2022

Background: Advanced glycation end product (AGE) accumulation is thought to be an independent predictor for cardiovascular disease in people with diabetes and renal failure. Since it has remained unclear whether AGE has a clinical impact on diabetic kidney disease (DKD) , the aim of this study was to determine the association between AGE accumulation, measured as skin autofluorescence (AF) , and the progression of DKD.

Methods: Skin AF was measured by AGE reader® and spot urine biomarkers, including albumin and liver-type fatty acid-binding protein (L-FABP) , were determined as the urine albumin-to-creatinine ratio (uACR) and the urine L-FABP-to-creatinine ratio (uL-FABPCR) in 300 Japanese people with diabetes (173 males and 127 females, mean age, 67.8 ± 10.7 years) . The relationships between skin AF and those urine biomarkers of DKD were statistically evaluated.

Results: Simple regression analysis showed that skin AF was associated with uACR (p<0.05) , log-transformed uACR (p<0.01) and uL-FABPCR (p<0.001) . On the other hand, multivariate regression analysis including clinical confounding factors showed that skin AF independently contributed to the increment of uL-FABPCR (P <0.05) but not to that of uACR (P=0.399) or log-transformed uACR (P=0.315) .

Conclusion: Skin AF was associated with urinary L-FABP but not with albuminuria in people with diabetes. The results suggest that skin AF can serve as a novel predictive factor for the development of diabetic tubular injury.

Disclosure

H.Yamagami: None. T.Yuasa: None. S.Yoshida: None. A.Kuroda: None. M.Matsuhisa: Research Support; Nissui , Sysmex Corp., Speaker's Bureau; Astellas Pharma Inc., Eli Lilly and Company, Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk, Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. I.Endo: None. K.Aihara: None. M.Abe: None. S.Yasui: None. M.Hosoki: None. T.Hori: None. T.Hara: None. Y.Mitsui: None. K.Kurahashi: None. S.Nakamura: None. T.Otoda: None.
412-P: Acute Hyperglycemia-Induced Endoplasmic Reticulum and Oxidative Stress Increases Monocyte Cholesterol Content and Cytokine Secretion
Authors: ZHANG RONG MEI , OH JISU , KUTZ GRETA A. , BAMBOUSKOVA MONIKA , DUSSO ADRIANA S. , BERNAL-MIZRACHI CARLOS
Published: May 2022

Background: Cardiovascular disease (CVD) is an inflammatory disorder enhanced by diabetes. The mechanisms by which recurrent acute hyperglycemia promotes inflammation and CVD are unclear. We showed that acute hyperglycemia mediates increased monocyte cholesterol uptake and cytokine release, but the underlying signaling pathways are unknown. We hypothesized that acute hyperglycemia-induced oxidative and ER stress in circulating monocytes increases cholesterol uptake and a pro-inflammatory phenotype.

Methods: Circulating monocytes from 35 healthy subjects were isolated and exposed to euglycemic (5mM) or hyperglycemic (16.7 mM) conditions with or without inhibitors of ER stress (4 phenyl butyric acid) or oxidative stress (N-Acetyl cysteine) for 2 or 6 hrs to assess changes in LDL or oxLDL uptake and cytokine (TNF-α, IL1-β) release.

Results: We found that acute hyperglycemia-induced ER and oxidative stress increased total and free cholesterol content via enhanced LDL (18% and 26%, p<0.05) and oxLDL (56% and 30%, p<0.05) uptake as a result of enhanced CD36 and LDL receptor expression. Conversely, inhibiting monocyte oxidative stress or ER stress attenuated monocyte LDL and oxLDL uptake. Finally, blocking monocyte ER stress decreased acute hyperglycemia-induced monocyte TNF-α (87% and 40%, p<0.05) and IL1-β (41% and 44%, p<0.05) secretion after 2 and 6 hrs.

Conclusion: Recurrent acute hyperglycemia promotes inflammation by increasing monocyte ER and oxidative stress, which accelerates cholesterol uptake, cholesterol deposition, and cytokine secretion. Future studies are needed to test if acute hyperglycemia-induced monocyte cholesterol deposition is a mechanism to contribute to increased CVD in diabetes.

Disclosure

R.Zhang: Research Support; American Heart Association. J.Oh: None. G.A.Kutz: None. M.Bambouskova: None. A.S.Dusso: None. C.Bernal-mizrachi: None.
415-P: Leptin Treatment Has Vasculoprotective Effects in Lipodystrophic Mice
Authors: STÜRZEBECHER PAULINA E. , KRALISCH SUSAN , SCHUBERT MARIE R. , FILIPOVA VANINA , HOFFMANN ANNETT , BLÜHER MATTHIAS , MIEHLE KONSTANZE , EBERT THOMAS , LAUFS ULRICH , TÖNJES ANKE , BOECKEL JES-NIELS
Published: May 2022

Introduction: Adipose tissue (AT) is involved in interorgan crosstalk by releasing adipokines such as leptin. Loss of AT, as seen in the human disease of lipodystrophy syndromes (LD) , results in low leptin levels, severe metabolic pathologies and increased risk for premature atherosclerosis. Therapeutical substitution of leptin improves the metabolic conditions and reduces the risk of death in LD patients. The effect of this treatment on atherosclerotic lesion development and endothelial integrity is unknown. We hypothesize that leptin exerts vasculo-protective effects and limits atherosclerosis.

Methods and Results: Endothelial cell (EC) inflammation (ICAM-1, -5.2-fold control, p<0.05) and endothelial to mesenchymal transition (EndMT) (SM22, -2.3-fold control, p<0.05) was reduced by leptin treatment in vitro at mRNA and protein level as determined by qPCR, immunoblot and immunofluorescence. The beneficial effect of leptin on EndMT was further confirmed by single cell sequencing. In a second step, we used a combined lipodystrophic and atherosclerosis-prone mouse model (LDLR-/-;aP2-nSREBP) and analyzed the effect of leptin treatment on the development of atherosclerosis in vivo. Histological sections of the aortic roots showed reduced plaque protrusion into the vessel lumen (-31%, p<0.05, n=4-6) by leptin. Macrophage infiltration into the atherosclerotic lesion was reduced after 16 weeks of leptin substitution, which is in accordance with the reduced permeability of the endothelial layer after leptin treatment seen in vitro (-10.8-fold, p<0.05, n=3) .

Conclusion: In vitro, leptin acts anti-inflammatory and reduces EC permeability and EndMT. In a lipodystrophic mouse model, leptin substitution reduced hallmarks of instable plaques like EndMT, plaque protrusion and macrophage invasion. In addition to an improvement of the metabolic complications of LD, leptin may also support endothelial identity and function and therefore be beneficial for the vasculature in LD patients.

Disclosure

P.E.Stürzebecher: None. A.Tönjes: None. J.Boeckel: None. S.Kralisch: None. M.R.Schubert: None. V.Filipova: None. A.Hoffmann: None. M.Blüher: Consultant; AstraZeneca, Lilly, Novo Nordisk A/S, Pfizer Inc., Sanofi, Speaker's Bureau; Bayer AG, Boehringer Ingelheim International GmbH, Novartis AG. K.Miehle: None. T.Ebert: Consultant; Sanofi, Santis, Research Support; AstraZeneca, Novo Nordisk. U.Laufs: None.

Funding

Collaborative Research Center SFB1052 “Obesity Mechanisms” (SFB-1052/C06)
43-LB: Diabetes Distress, Depression, Perceived Stress, and Medication Adherence in Type 2 Diabetes (T2D)
Authors: MUSTAFIZ FAYEL , HOOGENDOORN CLAIRE J. , GONZALEZ JEFFREY S.
Published: May 2022

Objective: Diabetes distress and depression are associated with treatment nonadherence among adults with T2D. Evidence for the independence of these effects has been mixed. Whether perceived stress, or the degree to which situations in life in general are appraised as stressful, can account for these effects has not been examined. We tested whether perceived stress was associated with objective T2D medication adherence and whether effects of diabetes distress and depression showed independence from perceived stress.

Methods: Participants (N = 104, Age = 56.57 ± 9.32; A1C = 7.75 ± 1.55; 39% insulin use; 24% Latino, 24% White, 62.5% Black, 5.7% Other) completed validated self-reports of perceived stress, diabetes distress and depression and had oral medication adherence electronically monitored (EM) over 3 months. Multiple regression evaluated the association between perceived stress and EM medication adherence when modeled with covariates as well as with diabetes distress and depression.

Results: Perceived stress was correlated with lower EM adherence (r = -.24, p = .013) ; however, when accounting for age, insulin use, and days of EM monitoring, the association was attenuated (β = -.14, p = .109) . Diabetes distress (β = -.29, p = .001) and depression (β = -.34, p < .001) were associated with lower adherence after covariate adjustment, when each were adjusted for perceived stress (diabetes distress: β = -.32, p = .005; depression: β = -.48, p < .001) , and when both were modeled together with perceived stress (diabetes distress: β = -.22, p = .044; depression: β = -.41, p = .002) . In this final model, perceived stress showed an unexpected positive association with adherence (β = .27, p = .035) .

Conclusion: The associations of diabetes distress and depression with treatment nonadherence were not accounted for by perceived stress in this diverse sample of adults with T2D. Their independent associations with treatment nonadherence support both constructs as important targets for intervention.

Disclosure

F. Mustafiz: None. C. J. Hoogendoorn: None. J. S. Gonzalez: Consultant; Virta Health Corp.
441-P: Oleate Prevents Palmitate-Induced Abnormalities in Insulin Signaling in Human Cardiac Progenitor Cells by Inhibiting p38 MAPK and c-Jun Phosphorylation
Authors: DORIA ROSSELLA , CALDERONI ISABELLA , CACCIOPPOLI CRISTINA , GENCHI VALENTINA ANNAMARIA , SANTARPINO GIUSEPPE , LEONARDINI ANNA , NATALICCHIO ANNALISA , PERRINI SEBASTIO , CIGNARELLI ANGELO , GIORGINO FRANCESCO , LAVIOLA LUIGI
Published: May 2022

Elevated saturated fatty acid deposition in the heart results in insulin resistance, stress kinase activation, and increased cardiovascular risk in humans. The viability of human cardiac progenitor cells (hCPC) is essential for myocardium homeostasis. This study investigates the ability of palmitate, a saturated fatty acid, to impair insulin signaling in hCPC isolated from right auricle biopsies, and the potential protective effects of oleate, a mono-unsaturated fatty acid. hCPC were found to express both insulin receptor (IR) isoforms, IR-A and IR-B, with higher IR-A:IR-B ratio. Exposure of hCPC to 100 nM insulin for 15 min induced Akt (S473) phosphorylation (p<0.05) . However, treatment with 0.25 mM palmitate, but not with 0.1 mM oleate, for 24 h resulted in impaired insulin-induced Akt phosphorylation (p<0.05) with no effect on total Akt protein levels. Palmitate, but not oleate, also induced p38 MAPK (T180/Y182) and c-Jun (S63) phosphorylation (p<0.05) . Pretreatment for 1 h with 15 µM SB202190, a p38 MAPK inhibitor, or with 20 µM SP600125, a JNK inhibitor, significantly inhibited the ability of palmitate to impair insulin-induced Akt phosphorylation (p<0.05) . Interestingly, co-incubation of palmitate with oleate abolished the palmitate-induced p38 MAPK and c-Jun phosphorylation (p<0.05) and inhibition of insulin-induced Akt phosphorylation (p<0.05) . In addition, palmitate, but not oleate, was associated with downregulation of IR protein levels (p<0.05) , although with increased expression of total IR mRNA, IR-A, IR-B, and increased IR-A/IR-B ratio (p<0.05) . Co-incubation with oleate also prevented the palmitate-induced changes in IR (p<0.05) .

In conclusion, oleate prevents the palmitate-induced abnormalities in insulin signaling in hCPC, largely by counteracting p38 MAPK and JNK activation. Hence, oleate supplementation might limit lipotoxicity, thus contributing to cardiac protection.

Disclosure

R.Doria: None. F.Giorgino: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk, Consultant; Lilly Diabetes, Sanofi, Research Support; Lilly Diabetes, Roche Diabetes Care, Takeda Pharmaceutical Company Limited. L.Laviola: Advisory Panel; Lilly Diabetes, Novo Nordisk, Roche Diabetes Care, Sanofi, Speaker's Bureau; A. Menarini Diagnostics, Abbott Diabetes, Medtronic, Terumo Corporation. I.Calderoni: None. C.Caccioppoli: None. V.Genchi: None. G.Santarpino: None. A.Leonardini: None. A.Natalicchio: Consultant; Novo Nordisk, Other Relationship; AstraZeneca, Lilly Diabetes, Sanofi. S.Perrini: None. A.Cignarelli: None.
46-OR: Differential Effects of RBP3 and Anti-VEGF on Retinal Dysfunctions in Diabetic Retinopathy
Authors: LI QIN , ONIZUKA SATORU , PARK KYOUNGMIN , PARK HYUNSEOK , LI QIAN , FICKWEILER WARD , FU JIALIN , WU I-HSIEN , KING GEORGE L.
Published: May 2022

Background: Anti-vascular endothelial growth factor (anti-VEGF) therapy has revolutionized the treatment of severe diabetic retinopathy (DR) , but significant subset of patients showed inadequate response to anti-VEGF. We have previously reported that retinol binding protein 3 (RBP3) prevented hyperglycemia induced retinal pathologies and progression to severe DR. Hypothesis: RBP3 and Anti-VEGF have differential protective profiles in preventing retinal dysfunctions induced by diabetes.

Methods and Results: Recombinant human RBP3 (rhRBP3, 5ug/ml) and anti-VEGF (Avastin, 250mg/ml) inhibited VEGF-induced retinal vascular permeability (RVP) by 70% when intravitreal injections were given together in Lewis rats (P < 0.01) . After 2 months of diabetes induced by streptozotocin (STZ) , intravitreal injection of rhRBP3 and anti-VEGF for 3 days suppressed RVP by 64% and 53% (P < 0.01) in Lewis rats. This was accompanied by reductions of VEGF levels by both proteins. Electroretinogram (ERG) amplitudes of A wave, B wave, C wave were decreased in rats after 2 months of diabetes (P < 0.01) . rhRBP3 increased amplitudes of C wave (P < 0.01) , while anti-VEGF did not improve any waveforms. Furthermore, rhRBP3 decreased retinal mRNA expression of Cd11b and Tnfa (P =0.1) in diabetic rats. In cultured primary bovine Müller cells, rhRBP3 decreased mRNA expressions of Tnfa and Il-6 induced by high glucose (25mM) (P < 0.01) , whereas, anti-VEGF showed no effect. Metabolic function studies using Seahorse assays showed that isolated retina from intravitreal rhRBP3 treated rats exhibited reduced glycolysis rate in ECAR while anti-VEGF treatments had no effects.

Conclusions: Both intravitreal anti-VEGF and RBP3 treatments normalized retinal vascular dysfunctions caused by diabetes. However, only RBP3 reversed abnormal neural-retinal dysfunctions and elevated inflammatory cytokines induced by hyperglycemia, possible by decreasing glucose uptake and glycolysis levels in retinal cells.

Disclosure

Q.Li: None. S.Onizuka: None. K.Park: None. H.Park: None. Q.Li: None. W.Fickweiler: None. J.Fu: None. I.Wu: None. G.L.King: Advisory Panel; Medtronic, Research Support; Janssen Pharmaceuticals, Inc.
548-P: Food Insecurity during COVID-Is Associated with Worse Outcomes among People with Type 2 Diabetes
Authors: STEVENSON JULIA , GOWEN REBECCA , YE EMILY , WOOD RICHARD
Published: May 2022

Background: Low food security is associated with increased barriers to diabetes management, and COVID-has exacerbated food insecurity in the United States. This study assessed correlation between food insecurity and health outcomes among people with type 2 diabetes (T2D) during the first year of the COVID-pandemic from March 2020 to March 2021.

Methods: In March 2021, 3,235 adults with T2D completed an online questionnaire which included the validated 2-item Hunger Vital Sign screening tool to assess risk of household food insecurity in the last 12 months. Health and demographic information were collected.

Results: Twenty percent of the sample were at risk of food insecurity within the last 12 months. Those at risk of food insecurity were more likely to report adverse physical health outcomes and poor mental well-being. Disparities in outcomes between those at risk and those not at risk were present across household income brackets. Among those at risk of food insecurity, 35% reported spending less on food to be able to pay for diabetes medications or supplies in the last 12 months, whereas only 4% of those not at risk reported the same.

Conclusions: Food insecurity risk during the first year of COVID-is associated with a variety of adverse health outcomes for people with T2D. As the pandemic continues, further attention must be devoted to improving accessibility of nutritious food for people with diabetes.

Disclosure

J.Stevenson: Other Relationship; Abbott Diabetes, Ascensia Diabetes Care, Beta Bionics, Inc., Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, LifeScan, Medtronic, Roche Diabetes Care, Tandem Diabetes Care, Inc. R.Gowen: Other Relationship; Abbott Diabetes, Ascensia Diabetes Care, Beta Bionics, Inc., Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, LifeScan, Medtronic, Roche Diabetes Care, Tandem Diabetes Care, Inc., Virta Health Corp. E.Ye: Employee; dQ&A. R.Wood: Other Relationship; Multiple companies and patient organizations (>10) .
55-LB: Effect of Dapagliflozin on Renal and Hepatic Glucose Kinetics in T2DM and NGT Subjects
Authors: CHEN XI , SOLIS-HERRERA CAROLINA , TRIPATHY DEVJIT , HANSIS-DIARTE ANDREA A. , CHILTON ROBERT , CERSOSIMO EUGENIO , DEFRONZO RALPH A.
Published: May 2022

We previously have shown that both acute and chronic SGLT-2 inhibition increases endogenous glucose production (EGP) . However, the organ - liver versus kidney - responsible for the increase in EGP has not been identified. We assessed the effect of a single dose of Dapagliflozin or Placebo on renal glucose production in 13 T2DM (age=57.5±1.8 yrs, BMI = 30±1.4 kg/m2) and 9 NGT (age 42±2 3 yrs, BMI = 30±1.1 kg/m2) subjects. Renal glucose production was measured using arteriovenous balance technique across the kidney combined with [3-3H] glucose infusion and PAH infusion (for determination of renal blood flow) before and 4 hours after administration of Dapagliflozin (10 mg) and Placebo; thus, each subject served as their own control. EGP increased following DAPA in both T2DM (2.00±0.11 to 2.43±0.15, P<0.05) and NGT (1.72±0.11 to 2.1±0.16, p<0.05) , while it decreased after placebo in T2DM (2.02±0.12 vs. 1.15±0.06) and NGT (2.10±0.2 vs. 2.05±0.1) (both p<0.01, DAPA vs. placebo) . The fractional renal extraction of glucose (0.02± 0.004 vs. 2.99 ± 1.0, p=0.001 in T2DM, and 0.02± 0.004 vs. 1.62± 1.4 in NGT, p=NS) and renal glucose uptake (0.067 ± 0.02 vs. 0.347 ± 0.06 in T2DM and 0.08 ± 0.02 vs. 0.27 ± 0.08 mg/kg.min in NGT) were higher following DAPA vs. placebo (p<0.05) and were entirely explained by the increase in glucosuria. There was a small, non-significant increase (0.065 & 0.032 mg/kg.min, respectively) in renal glucose production (RGP) following dapagliflozin in T2DM and NGT compared to the 0.45 mg/kg.min increase in total body EGP.

Conclusion: A single dose of Dapagliflozin significantly increases EGP which primarily is explained by an increase in hepatic glucose production.

Disclosure

X. Chen: None. C. Solis-herrera: Speaker’s Bureau; Novo Nordisk. D. Tripathy: None. A. A. Hansis-diarte: None. R. Chilton: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Nova Biomedical. E. Cersosimo: Research Support; AstraZeneca. R. A. Defronzo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Intarcia Therapeutics, Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Speaker’s Bureau; AstraZeneca.

Funding

Astra Zeneca
55-OR: Veterans with Type 2 Diabetes: An Explanatory Sequential Mixed-Methods Approach to Understanding Diabetes Distress
Authors: LEWINSKI ALLISON , CROWLEY MATTHEW J. , JEFFREYS AMY S. , COFFMAN CYNTHIA , WHITFIELD CHELSEA , HOWARD TERESA , SHAPIRO ABIGAIL , MCCONNELL ELEANOR S. , TANABE PAULA , BARCINAS SUSAN J. , BOSWORTH HAYDEN B.
Published: May 2022

Diabetes Distress (DD, i.e., regimen, emotional, interpersonal, clinician) in adults with type 2 diabetes (T2DM) is associated with poor glycemic control, poorer diet and exercise, and more T2DM complications. We describe a multi-phased study to develop and test a tailored intervention to reduce DD to improve health outcomes. Phases 1-3 identified factors related to DD in Veterans with T2DM to inform intervention development. We used an explanatory sequential mixed methods design to identify how Veterans with T2DM experienced DD. Veterans (n=210) completed measures (DD, depression, empowerment, stigma) . A subset of Veterans (n=36) also completed in-depth qualitative interviews. We fit a multivariable linear regression to examine associations with DD score. We completed thematic analysis on interview transcripts. We integrated measurement and interview data using matrices and analyzed results by medication type, hemoglobin A1c (HbA1c) , and severity of DD (low, moderate, high) . Mean age was 63 years (SD 10.2) ; 15% female; 69% non-white; 56% on insulin; mean A1c 8.9% (SD 2.0) ; mean DD score was 2.0 (SD 0.9) , indicating moderate distress. In the regression model, female gender (β= -0.31; 95% CI: -0.57, -0.04) , diagnosis of multiple mental health comorbidities vs. one condition (β=-0.29; 95% CI: -0.55, -0.03) , higher depression symptom (β=0.15; severity (95% CI: 0.08, 0.23) and stigma (β=0.02; 95% CI: 0.01, 0.04) were associated with higher DD. Higher T2DM self-efficacy (β=-0.34; 95% CI: -0.51, -0.18) was associated with lower DD. Interviews elaborated on themes including the impact of pain and comorbidities on DD. Integrating the measurement and interview data indicated that experiences of DD varies by many characteristics based on medication type, HbA1c, and severity of DD. Elucidating contributors to DD in Veterans using mixed methods will improve our ability to develop a tailored intervention addressing DD in a manner relevant to Veteran populations.

Disclosure

A.Lewinski: Other Relationship; Otsuka America Pharmaceutical, Inc., PhRMA Foundation. S.J.Barcinas: None. H.B.Bosworth: Advisory Panel; Sanofi, Board Member; preventics diagnostics, Consultant; VIDYA, webmed, Research Support; Boehringer Ingelheim International GmbH, improved Patient Outcomes, Merck & Co., Inc., Novo Nordisk, Otsuka America Pharmaceutical, Inc. M.J.Crowley: None. A.S.Jeffreys: None. C.Coffman: None. C.Whitfield: None. T.Howard: None. A.Shapiro: None. E.S.Mcconnell: None. P.Tanabe: None.

Funding

Durham Center of Innovation to Accelerate Discovery and Practice Transformation (CIN 13-4) and VA HSR&D grants #18-234 (to AAL) and #08-027 (to HBB) .