bluuebunny/crossref_metadata_2025 huggingface dataset:
544-P: Efficacy and Safety of Insulin Degludec in Adults with T2D Macroalbuminuria and Chronic Kidney Disease Stage 2 and 3B
Authors: DE LUCAS MARIA DOLORES GARCIA , BUENO BEATRIZ AVILES , OLALLA JULIAN , LOPEZ-FERNANDEZ JUDITH
Published: June 2019

This retrospective, observational study compared clinical outcomes of adults with T2D and chronic kidney disease (CKD) with macroalbuminuria switching from Gla-100/IDet/Gla-300 to IDeg. Endpoints were HbA1c change, hypoglycemia and units of insulin used (mean follow-up period, 36 months) in 90 patients. We established 2 groups: 46 patients with CKD stage 2 (CKD2) and 44 patients with CKD stage 3B (CKD3B). Hypoglycaemia was defined according to ADA criteria. The median age was significantly higher in the CKD3B (71.50±6.36 vs. 63.52±8.82 years). Average evolution of T2D was of 17 years in both. The CKD3B group had significantly more cardiovascular comorbidity (AMI, arteriopathy, hypertension, CHF) than CKD2. Initial basal insulin in both groups were detemir in 22.2%, glargine 100 in 60% and glargine 300 in 17.8% patients. A statistically significant improvement were observed in HbA1c (-1.71±0.25% in CKD2 and -1.28±1.17% in CKD3B p<0,0001) and in basal glycaemia (p<0.0001). Daily insulin basal dose decreased significantly in both groups at 36 months post-switch vs. pre-switch (p <0.001 and p <0.035 respectively). Hypoglycemia was significantly lower (81,3% to 34,2%, all p <0.001) post-switch vs. pre-switch. Renal function remained stable with a decrease in albuminuria in both groups.

Conclusion: Degludec is effective, efficient and safe in renal patients with T2D and macroalbuminuria.

Disclosure

M. Garcia de Lucas: Speaker's Bureau; Spouse/Partner; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. B. Aviles Bueno: Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. J. Olalla: None. J. Lopez-Fernandez: Consultant; Self; Lilly Diabetes, Sanofi. Other Relationship; Self; Almirall, S.A., Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., GEBRO, Janssen Pharmaceuticals, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., mundifarma, Novo Nordisk Inc., Sanofi.
548-P: Baicalin Attenuates Fibrosis Process in Human Renal Proximal Tubular Cells in Hyperglycemic Condition
Authors: NAM JUNGEUN , KIM JUNG HYE , PARK KAHUI , LEE SANG BAE , NAM JI SUN , PARK JONG SUK , PARK SU JEONG , KIM YU SIK , AHN CHUL WOO
Published: June 2019

Background: Baicalin, isolated from Scutellaria baicalensis, has been reported to have anti-inflammatory effect by inhibiting expression of cell adhesion molecules and migration of leukocytes in vascular cells. However, there is a limited evidence on its anti-inflammatory effect in hyperglycemia-associated milieu in other cells. Hyperglycemia and its associated factors are known to induce diabetic nephropathy by exacerbating inflammation, especially, in proximal convoluted tubule. Herein, we investigated whether baicalin exerts anti-inflammatory and anti-fibrosis effects on human renal proximal tubular cells in hyperglycemia induced conditions.

Method: HK-2 cell was maintained in normal glycemic (5.78mM glucose) or in hyperglycemic (30mM glucose) condition with or without advanced glycation end-products (AGE) and tumor necrosis factor alpha (TNFα). In each condition, baicalin was treated at 10uM. Cell viability was determined by MTT assay. Gene and protein expression of multiple inflammatory and fibrosis markers including toll-like receptor 2 (TLR2), TLR4, fibronectin, collagen IV α1 (ColIVα1), collagen IV α2 (ColIVα2), transforming growth factor β (TGFβ), intercellular adhesion molecule 1 (ICAM1), and vascular adhesion molecule 1 (VCAM1) were evaluated by PCR and WB, respectively.

Results: Baicalin had no effect on cell viability. Baicalin significantly decreased gene expression of ColIVα2 in response to TNFα stimulation in normal glycemic condition (p=0.038). In hyperglycemic condition, baicalin decreased gene expressions of ICAM1 (p=0.049) and VCAM1 (p=0.049) significantly in AGE treated cells; and it significantly decreased gene expressions of TGFβ (p=0.038) and ICAM1 (p=0.017) in TNFα treated cells. Baicalin also decreased protein expression of ICAM1 in response to AGE (p=0.048) and TNFα (p=0.040) stimulation in hyperglycemic condition.

Conclusion: Baicalin attenuated fibrosis process by hyperglycemia associated factors in HK-2 cell.

Disclosure

J. Nam: None. J. Kim: None. K. Park: None. S. Lee: None. J. Nam: None. J. Park: None. S. Park: None. Y. Kim: None. C. Ahn: None.
550-P: Age at Diabetes Onset and Risk for Diabetic Kidney Disease
Authors: CARPENTIER CHARLYNE , DUBOIS SEVERINE , ABOULEKA YAWA , DULY-BOUHANICK BEATRICE , HADJADJ SAMY , COUTANT REGIS , ROUSSEL RONAN , VELHO GILBERTO , MARRE MICHEL
Published: June 2019

Diabetic kidney disease drives premature mortality among patients with type 1 diabetes. The role of age at diabetes onset is controversial. We analyzed risk for diabetic kidney disease according to age at onset of type 1 diabetes using follow-up of type 1 diabetic patients attending our tertiary referral center. 340 type 1 diabetic patients attending the Angers University Hospital in France between 1989 and 2000, were followed-up to 2018 or death. They were divided in tertiles of ages at type 1 diabetes onset: T1:1-13, T2:14-23, and T3: 24-40 years. The primary endpoint was first occurrence of macroalbuminuria (>300mg albumin/g creatinine), doubling of serum creatinine, estimated glomerular filtration rate (eGFR, CK-EPI formula) <60ml/min/1.73m2, end stage renal disease (ESRD), or all-cause death. Multivariate analyses were done. Of 114 T1 participants, 11 (9.6%) developed macroalbuminuria, 5 (4.4%) doubling of serum creatinine, 14 (12.3%) eGFR<60ml/min/1.73m2, 8 (7%) ESRD, and 14(12.3%) died. Of 119 T2 participants, 8 (.6.7%) developed macroalbuminuria, 1 (0.8%) doubling of serum creatinine, 7 (5.9%) eGFR<60ml/min/1.73m2, 4(3.3%) ESRD, and 15(12.6%) died. Of 114 T3 participants, 3 (2.8%) developed macroalbuminuria, 1 (0.93%) doubling of serum creatinine, 4 (3.7%) eGFR<60ml/min/1.73m2, none ESRD, and 31(29%) died. Using multivariate analysis, age<14years at type 1 diabetes onset increased risk for kidney disease: T1 vs. T2 HR=2.35(95% CI1.20-4.58), T1 vs. T3 HR=3.61(1.30-9.27), p<0.01.

Conclusions: Age <14 at type 1 diabetes onset was an independent risk factor for kidney disease in this >20-year monocentric follow-up study.

Disclosure

C. Carpentier: None. S. Dubois: None. Y. Abouleka: None. B. Duly-Bouhanick: Research Support; Self; Novo Nordisk A/S, Sanofi, Servier. S. Hadjadj: Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Servier. Research Support; Self; Bayer AG, Janssen Research & Development. Speaker's Bureau; Self; Abbott, Valbiotis. R. Coutant: None. R. Roussel: Advisory Panel; Self; Merck Sharp & Dohme Corp., Sanofi. Consultant; Self; Abbott, AstraZeneca, Eli Lilly and Company, Medtronic, Novo Nordisk A/S, Physiogenex. Research Support; Self; Janssen Pharmaceuticals, Inc. G. Velho: None. M. Marre: Advisory Panel; Self; Servier. Board Member; Self; Merck Sharp & Dohme Corp., Novo Nordisk A/S.
568-P: Pain Threshold of Intraepidermal Nerve Terminal Reflects Small Nerve Fiber Function and Rises in Early Phase of Diabetes
Authors: SASAKI HIDEYUKI , KISHIMOTO SHOHEI , OGAWA KENICHI , KURISU SEIGO , NANJO KISHIO
Published: June 2019

We measured pain threshold of intra-epidermal nerve terminal (PINT) which is a simple and noninvasive method that can measure pain threshold of A delta fiber by intra-epidermal electrical stimulation. We aimed to investigate normal value, prevalence of abnormality and clinically associated factors to PINT and quantitative vibratory perception threshold (QVT). PINT and QVT were measured by a portable peripheral nerve testing device PNS-7000, and a vibration sensation meter AU 02-B in 656 Japanese regional health checkup examinees (40-75 years old; years old). Glucose tolerance; normal (N), pre-DM, newly diagnosed DM (NDM) and known DM (KDM), and neuropathic findings (pain, paresthesia, numbness in legs and reduced ATRs) were also determined. Relationship between age, glucose tolerance, neuropathic findings and PINT or QVT were investigated by simple and multivariate analyses. In 445 non-DM subjects without neuropathic findings, normal limit value of PINT (mA) was set by quantile regression method, and relationship between prevalence of PINT or QVT abnormalities and clinical factors were examined. As results, PINT was not changed under 70 years old, then somewhat elevated. QVT elevated from 50 years old. PINT was not associated with QVT. PINT was significantly elevated in NDM and KDM. QVT was elevated in diabetes and hypertension. Among the neuropathic findings, PINT was significantly associated with only pain. By multiple regression analyses, significant aggravating factors of PINT were aging and glucose intolerance. Normal values of PINT were > 0.4 (<69 years old) and >0.5 (70< years old) Prevalence of PINT abnormality were 3%, 4%, 13% and 9% in N, pre-DM, NDM and KDM, respectively. They were significantly increased with the deterioration of glucose tolerance. QVT abnormality was not significantly increased with glucose intolerance.

In conclusion, PINT reflects small nerve fiber function, and associates with DM. So, PINT may be a useful for diagnosis and evaluation of small fiber neuropathy.

Disclosure

H. Sasaki: None. S. Kishimoto: None. K. Ogawa: None. S. Kurisu: None. K. Nanjo: None.

Funding

Japan Society for the Promotion of Science
581-P: Impacts of Glucose Fluctuation Management on Nerve Function in Type 2 Diabetes Patients with the First Episode of Cerebral Infarction
Authors: LI JIANING
Published: June 2019

Objective: The purpose of this study was to assess the effects of glucose fluctuation management on nerve function (The National Institute of Health Stroke Scale, NIHSS), life ability (Modified Ranking Scale, MRS), and quality of life (Stroke Impact Scale, SIS) in type 2 diabetes patients with the first episode of cerebral infarction.

Methods: This was a randomized control trial. 75 type 2 diabetes patients with the first episode of cerebral infarction were randomized into 2 groups: control group (n=37) with usual care, focused on A1c control, targeting A1C <7%, and intervention group (n=38), targeting both A1c <7% and daily glucose fluctuation (LAGE <80mg/dl).

Results: After 6 months, the data of 63 patients were finally analyzed (30 in the control group, 33 in the intervention group). There was no difference (P>0.05) in the reduction of A1c between 2 groups, but the reductions of LAGE (P=0.030), 1,5-AG (P=0.023), 2hPG (p=0.041), and LDL(p=0.046) were significantly different between two groups. The NIHSS score in intervention group was better than in the control (2.35±0.81 vs. 3.50 ±2.24, p=0.047 group. In terms of quality of life, there was no significant difference in total score of SIS between the two groups, but in the intervention group, the scores in the strength, hand function, and participation dimensions were higher than those in the control group (P=0.041, P=0.049, P=0.048, respectively). No significant difference was identified between two groups in scores of MRS and SDSCA.

Conclusions: Blood glucose fluctuation management can add values to A1c management in improving nerve function for type 2 diabetes patients with first episode of cerebral infarction.

Disclosure

J. Li: None.
588-P: Diabetes Leads to Sodium-Glucose Cotransporter 2 (SGLT2) Increase in the Retina
Authors: LELEY SAMEER P. , LUO QIANYI , ALEX ALPHA L. , BHATWADEKAR ASHAY D.
Published: June 2019

Introduction: Diabetes is the leading cause of microvascular disorders such as diabetic retinopathy (DR). There are no treatments for DR and finding new drug targets is of considerable interest. SGLT2 inhibitors, a newer class of antidiabetics are promising in the management of diabetes, however, the potential role of SGLT2 in diabetic retinal microvasculature remains unknown. We hypothesized that diabetes will lead to an increase in SGLT2 in the retina and that its inhibition will be beneficial in protecting retinal vasculature from the insult of diabetes milieu.

Methods: The retinal sections of diabetic (db/db; an animal model of type 2 diabetes) and control (db/m) mice were analyzed for SGLT2 expression using confocal microscopy. In parallel, the mRNA levels of SGLT2 were determined using qRT-PCR. Human retinal endothelial cells (HRECs) were treated with the SGLT2 inhibitor dapagliflozin (0.1, 1, 10 nM) to perform a glucose uptake assay and to determine its effects on mRNA levels of SGLT2.

Results: The mRNA levels of SGLT2 were significantly higher (p<0.05) in the retina of db/db mice, 1.1 ± 0.46, n=5, when compared to db/m retinas, 0.06 ± 0.02, n=4. The confocal microscopy revealed SGLT2 expression throughout the retina and around the retinal blood vessels, brighter fluorescence was observed in the db/db retina. Treatment of HRECs with 10 nM dapagliflozin led to a significant decrease in SGLT2 mRNA (p<0.05); dapagliflozin: 7.95 ± 4.7, n=4; vehicle: 26 ± 3.6, n=8. The dapagliflozin inhibition demonstrated a profound decrease in glucose uptake in HRECs at all concentrations. Untreated: 2012 ± 388, n=3; 0.1 nM: 545.7 ± 296, 1 nM: 358.2 ± 241.5, 10 nM: 70.67 ± 138.9; p<0.01 as compared to untreated; n=6.

Conclusion: Our studies suggest that SGLT2 is significantly upregulated in the retina during diabetes and that SGLT2 potentially plays a critical role in retinal glucose transport. In future, SGLT2 inhibition could be a useful treatment option to slow down or prevent the onset of diabetic retinopathy.

Disclosure

S.P. Leley: None. Q. Luo: None. A.L. Alex: None. A.D. Bhatwadekar: None.

Funding

National Eye Institute; Indiana University Center for Diabetes and Metabolic Diseases
591-P: Feasibility of Implementing Point-of-Care Diabetic Retinopathy Screening into the Workflow at a Pediatric Diabetes Clinic
Authors: WOLF RISA M. , THOMAS CHRYSTAL G. , ALVIN LIU T. Y. , CHANNA ROOMASA
Published: June 2019

Background: The prevalence of diabetic retinopathy (DR) in youth with type 1 diabetes (T1D) and type 2 diabetes (T2D) is 5.6% and 9.1%, respectively. The ADA recommends yearly screening for DR. Only two-thirds of youth with diabetes receive their annual dilated eye exam. In order to save time off from school/work for our patients and their families, we implemented point of care (POC) diabetic retinopathy screening in our pediatric diabetes clinic. We studied the impact on workflow, imaging time, and operator experience.

Methods: As part of a larger prospective longitudinal study, we measured the implementation of DR screening and its impact on workflow, imaging time, and analyzed the camera operator learning curve.

Results: We screened 39 youth with diabetes, average age 11.46y (range 6-17y). 35 (89%) had T1D, 4 (11%) had T2D. Patients were imaged without pharmacological dilation after their multidisciplinary diabetes team visit, or during a break between providers. Imaging was performed by a technician with no prior background in ocular imaging. Average imaging time was 7min14sec (SD 2.55, range 3.5-16.66). Analysis of technician operator learning curve showed average imaging time of 7min45sec for first 20 cases, compared to 6min44sec for second 19 cases. Images of readible quality were obtained with 1 attempt in 75%, and with 2 or more attempts in 25% of patients. All patients were able to be imaged.

Conclusions: The use of a non-mydriatic fundus camera for diabetic eye screening in pediatrics is feasible, even in young children. It takes very little time, and requires minimal operator training. The overall rates of DR are low in children, and POC DR screening improves adherence to ophthalmic screening guidelines, and saves time off from school/work for diabetes youth and their families.

Disclosure

R.M. Wolf: None. C.G. Thomas: None. T. Liu: None. R. Channa: None.

Funding

Johns Hopkins Children's Center
594-P: Homocysteine as a Predictor for Diabetic Retinopathy Risk and Management
Authors: TAWFIK AMANY M. , MOHAMED RIYAZ , ALHUSBAN SUHIB , CHU SUNG MIN , KHALIL ABRAHAM Q. , BARTOLLI MANUELA , AL-SHABRAWEY MOHAMED
Published: June 2019

Diabetic retinopathy (DR) is one of the most significant microvascular complications of diabetes mellitus (DM) and is the most common cause of blindness in people under the age of 65. The ability to accurately predict patient susceptibility and prognostic implications of the disease is essential to its optimal management. Unfortunately, the current screening process for DR restricts the population that can be evaluated and the disease goes undetected until irreversible damage occurs. Therefore, a reliable and inexpensive screening process for DR would greatly increase the number of patients that can be evaluated and identify individuals in the early stages of DR in need of further assessment and treatment. Our previous work has shown that elevated blood homocysteine (Hcy) levels disrupted blood retinal barrier integrity, induced retinal ischemia and neovascularization, activated endoplasmic reticulum and oxidative stress pathways and induced epigenetic modifications in the retina. The current study aimed to evaluate Hcy as a biomarker in DR screening. Hcy levels were measured by ELISA and immunolocalization methods in serum, vitreous and retina of diabetic patients as well as in serum and retina of different animal models of DM representing type 1 diabetes (T1DM) (STZ mice, Akita mice and STZ rats) and db/db mice which exhibit features of human type 2 diabetes (T2DM). Our results revealed increased Hcy levels and immunostaining in serum, vitreous and retina of diabetic patients and experimental animals’ models of diabetes. Moreover, optical coherence tomography (OCT) and fluorescein angiography (FA) were used to evaluate the retinal changes in mice eyes after Hcy-intravitreal injection into the eyes of normal wild type (WT) and diabetic (STZ) mice. Hcy-induced changes in mice retina which were aggravated under diabetic conditions.

In conclusion, our data reported Hcy as a strong candidate for use as a biomarker in DR screening. Furthermore, targeting Hcy clearance could be a future therapeutic target for DR.

Disclosure

A.M. Tawfik: None. R. Mohamed: None. S. Alhusban: None. S.M. Chu: None. A.Q. Khalil: None. M. Bartolli: None. M. Al-Shabrawey: None.

Funding

American Heart Association (16SDG30700016)
595-P: Progression of Retinopathy in Adolescents with Type 1 Diabetes
Authors: VELAYUTHAM VALLIMAYIL , LIEW GERALD , JANUSZEWSKI ANDRZEJ S. , CHO YOON HI , BENITEZ-AGUIRRE PAUL Z. , CRAIG MARIA E. , JENKINS ALICIA , DONAGHUE KIM C.
Published: June 2019

Aim: Current guidelines recommend screening for retinopathy from 11 years in youth with type 1 diabetes (T1D) and 2-5 years T1D duration. We examined the longitudinal progression and regression of retinopathy in adolescents seen at our Diabetes Complications assessment service (DCAS) clinic.

Methods: We analyzed digitized retinal photographs taken from 2000-2018 (n=814) in youth with >3 assessments. Retinopathy was graded using the modified Airlie house classification. Generalized estimating equations were used to explore the association between progression/regression and covariates (HbA1c, gender, and diabetes duration).

Results: Mean age at baseline was 13.3+2.6 years, mean T1D duration 6.1+>3.4 years and mean follow- up 7.4 years. Retinopathy was present in 18.7% (n=152) at baseline assessment; with progression in 32.6% (n=266), regression in 7% (n=57) and persistence in 60.3% (n=491). Of those with progression, 185/266 (22.7%) had one step and 81 (9.9%) had > 2 step progression. Factors associated with retinopathy progression were HbA1c and T1D duration and for regression T1D duration (Table 1). Neither height nor SBP was significant for other outcomes.

Conclusion: In adolescents with T1D, retinopathy persistence or progression was greater than of regression. Follow-up of into adulthood will inform the development of appropriate retinopathy screening schedules.

Disclosure

V. Velayutham: None. G. Liew: None. A.S. Januszewski: None. Y. Cho: None. P.Z. Benitez-Aguirre: None. M.E. Craig: None. A. Jenkins: Advisory Panel; Self; Abbott, Australian Diabetes Society, Medtronic. Research Support; Self; Abbott, GlySens Incorporated, Medtronic, Mylan. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk Inc. K.C. Donaghue: None.
599-P: Diabetic Retinopathy (DR) Screening Performance of General Ophthalmologists, Retina Specialists, and Artificial Intelligence (AI): Analysis from a Pivotal Multicenter Prospective Clinical Trial
Authors: IPP ELI , SHAH VIRAL N. , BODE BRUCE W. , SADDA SRINIVAS R.
Published: June 2019

A prospective study (NCT03112005) evaluated DR screening using the EyeArt AI eye screening system and dilated ophthalmoscopy by board-certified ophthalmologists against the ETDRS clinical reference standard (CRS) of adjudicated expert grading of 4-wide field stereoscopic fundus photographs. A total of 497 subjects with diabetes from 10 U.S. clinical centers underwent undilated 2-field fundus photography for analysis by the EyeArt system, dilated ophthalmoscopy, and dilated 4-wide field stereo fundus photography for the CRS. Performance (Table) of dilated ophthalmoscopy against CRS for identifying referable DR [moderate non-proliferative or higher on the International Clinical Diabetic Retinopathy severity scale or clinically significant macular edema] indicates significant variability across retina specialists and general ophthalmologists. In a previous study, this AI system has been shown to achieve sensitivity 89.0% [95% CI: 87.7-90.2%] and specificity 91.6% [95% CI: 91.0-92.2%] against 7-field ETDRS reference standard. We await the results of the EyeArt system in this multicenter study to verify its ability to provide a more consistent performance for detection of referable DR to facilitate DR screening in primary care and endocrinology clinics.

Disclosure

E. Ipp: Research Support; Self; Eyenuk Inc., Novartis Pharmaceuticals Corporation. V.N. Shah: Advisory Panel; Self; Sanofi US. Consultant; Self; Dexcom, Inc. B.W. Bode: Consultant; Self; ADOCIA, Lexicon Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; Becton, Dickinson and Company, Dexcom, Inc., Diasome Pharmaceuticals, Inc., Eli Lilly and Company, Eyenuk Inc., Insulet Corporation, National Institutes of Health, Novo Nordisk Inc., Sanofi Research & Development, Senseonics, Xeris Pharmaceuticals, Inc. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi US, Senseonics. Stock/Shareholder; Self; AgaMatrix, Glytec, LLC. S.R. Sadda: Consultant; Self; Carl Zeiss Meditec, Centervue, Heidelberg Engineering, Optos. Other Relationship; Self; Nidek. Other Relationship; Spouse/Partner; Topcon.

Funding

Eyenuk Inc.
603-P: Circulating Inflammatory Cells and Inflammasome Activation in Diabetics with Diabetic Retinopathy (DR)
Authors: DUPONT MARIANA D. , LONGHINI ANA LEDA , SREEJIT GOPALKRISHNA , PRASAD RAM , NAGAREDDY PRABHAKARA , GRANT MARIA B.
Published: June 2019

Increasing evidence points to inflammation as a key component in diabetes-associated retinal perturbations, however, the underlying molecular mechanisms are not yet fully understood. The aims of this study were to characterize peripheral blood mononuclear cells (PBMC) in diabetics with and without DR and to elucidate the biologic role of NLRP3 inflammasome in these cells. PBMC from 33 diabetics (T1D n=9 and T2D n=24) and 18 controls were assessed by flow cytometry. To examine the inflammasome activation, monocytes and neutrophils were treated with the TLR-2 agonist, peptidoglycan (PGN) (10µg/ml) for 3 hours followed by stimulation with a potassium ionophore, nigericin. NLRP3, IL-1β, Caspase-1, IL-18 levels were assessed. Neutrophil counts were significantly higher (1.6 folds, p<0.0002) in diabetics with proliferative diabetic retinopathy (PDR)(45.88%) compared with nondiabetics (28.21%). Increased classical monocytes (88.66%, p<0.0580) were observed in subjects with DR compared to controls (77.66%). Diabetics demonstrated decreased lymphocytes (43.36%, p<0.0007) compared with nondiabetics (58.77%). Lymphocytes were most reduced in T2D with PDR (38.88%) compared to non-DR subjects (43.21%). Expression analysis of inflammasome genes in response to PGN treatment showed a significant increase in monocytes and neutrophil IL-β mRNA expression in diabetic and controls, but no difference whether DR was present or not. Neutrophil IL-β was increased in diabetics at baseline compared to controls. This study demonstrates that increased neutrophils and classical monocytes and reduced lymphocytes are associated with DR. In vitro inflammasome activation studies could not distinguish differences in the level of activation between neutrophils and monocytes obtained from complication-free diabetics and diabetic with DR suggesting the need for repeated measurements of their activation status if these parameters are being used as biomarkers of DR progression.

Disclosure

M.D. DuPont: None. A. Longhini: None. G. Sreejit: None. R. Prasad: None. P. Nagareddy: None. M.B. Grant: None.

Funding

National Institutes of Health (EY028037)
606-P: Point-of-Care Retinal Photography Is Effective in Identifying Diabetic Retinopathy in Patients Not Routinely Followed by Ophthalmology in the Intermountain West
Authors: WAHL MATTHEW , HAYNES ANN , LITCHMAN MICHELLE L. , FAGERLIN ANGELA , DELANEY REBECCA K. , NEUBERGER JULIE , ADJEI-POKU GLADYS S. , SERRATO MARISOL , HARTNETT MARY ELIZABETH , FISHER SIMON
Published: June 2019

Early detection and treatment of diabetic retinopathy (DR) can reduce blindness risk by >90%. Due to limitations in access to specialized eye care, the majority of people with diabetes (PWD) are not screened routinely. This project aims to determine if implementation of a point-of-care retinal screening program for PWD not routinely followed by ophthalmology would be effective in detecting DR in the Intermountain West region of the U.S. PWD who had not had a dilated eye exam within the last year underwent fundus photography during a regularly scheduled diabetes visit at the University of Utah Diabetes and Endocrinology Center. Non-mydriatic retinal images were classified by a vitreoretinal specialist as to DR severity based on the International Clinical Diabetic Retinopathy and Macular Edema Severity Scale. Abnormal findings were present in 49% of 116 patients imaged: Mild-moderate non-proliferative diabetic retinopathy (NPDR) in 16%, moderate-severe NPDR in 13%, proliferative retinopathy in 4% and hypertensive retinopathy in 13%. Point-of-care retinal imaging effectively identified DR and other retinal conditions in the Intermountain West. The finding of serious eye conditions in PWD not routinely followed by ophthalmologists supports the importance of improving ease of access for eye screening in diabetes care.

Disclosure

M. Wahl: None. A. Haynes: None. M.L. Litchman: None. A. Fagerlin: None. R.K. Delaney: None. J. Neuberger: None. G.S. Adjei-Poku: None. M. Serrato: None. M. Hartnett: None. S. Fisher: None.
614-P: Optimal Control of Glucose and Lipid Profiles Is Critical to the Effective “Neo-Islet” Therapy of Insulin Dependent Pet Dogs
Authors: GOOCH ANNA , CHOWDHURY SABIHA S. , WESTENFELDER CHRISTOF
Published: June 2019

We demonstrated that ip administration of “Neo-Islets” (NIs; co-aggregation of allogeneic, culture-expanded Islet cells (ICs) with Adipose derived Stem Cells (ASCs)), resulted in their omental engraftment in immune-competent, diabetic NOD mice. This achieved durable euglyciemia without immunosuppression, and with physiologic delivery of insulin and other islet hormones (SCTM 2017;6:1631). We are conducting an FDA guided pilot study (INAD 012-1248) of this technology in spontaneously T1DM pet dogs (see abstract this session). ICs and ASCs are known to be subject to gluco- and lipotoxicity. We undertook this study to determine whether the Hypertriglyceridemic (HTG) and/or DM milieu has an adverse effect (lipotoxic and/or glucotoxic) on dog ASCs and ICs and NIs.

Accordingly, serum was collected from HTG, DM dogs enrolled in INAD 012-776 before and after control of HTG and glucose levels, and from non-DM HTG dogs. These sera were added separately (10%) to DMEM at either 5mM or 17mM glucose for dog ASC and IC cultures. Growth rates and gene expression profiles were assessed.

Serum from DM (glucose 123-742 mg/dL) dogs with untreated HTG (range 656-1248 mg/dL; normal 20-248 mg/dL) killed ICs at either 5 or 17 mM glucose, and failed to support the expansion of ASCs in 17mM glucose. For ASCs grown in 17mM glucose expression of IL-6 and IGF-1 were downregulated. In contrast, sera from DM dogs with controlled HTG (range 146-656 mg/dL), and serum from HTG (range 742-1114 mg/dL), non-DM dogs supported the growth of both cell types in either medium with no changes in gene expression. In agreement with these in vitro results, an uncontrolled NI-treated study dog failed to respond to therapy, while HTG and glucose-controlled dogs have shown up to 50% reduced need for insulin 12 months post therapy.

Conclusion: These data demonstrate the need for optimal glucose and lipid control to prevent destruction of the NI cells when treating DM.

Disclosure

A. Gooch: Board Member; Self; SymbioCellTech. S.S. Chowdhury: Employee; Self; SymbioCellTech. C. Westenfelder: Consultant; Self; SymbioCellTech.
615-P: A Novel Lipid-Lowering Drug Pemafibrate Enhances Effects of Statins in Serum Lipids in Japanese Patients with Type 2 Diabetes
Authors: KUSUNOKI MASATAKA , NATSUME YUKIE , OSHIDA YOSHIHARU , MIYATA TETSURO
Published: June 2019

Many patients with type 2 diabetes mellitus have dyslipidemia, often both hypercholesterolemia and hypertriglyceridemia. Conventionally, statins in combination with fibrates have been relatively contraindicated in patients with abnormal renal function and are carefully administered in those with normal renal function. In this study, pemafibrate (PFB), a new fibrate, was additionally administered to type 2 diabetic patients with both hypercholesterolemia and hypertriglyceridemia who were already receiving statins, to evaluate the efficacy and safety of the coadministration.

Fourteen patients receiving pitavastatin (1, 2, or 4 mg/day) or rosuvastatin (2.5 or 5 mg/day) for 6 months were additionally administered PFB (0.1 mg, twice daily) for 1 month. Eleven patients receiving lipid-lowering drugs other than statins also additionally received PFB for 1 month. Blood samples were collected before and after the administration of PFB to measure the serum levels of biochemical parameters.

In patients who received PFB in addition to statins, significant improvement was seen in the following lipid parameters: total cholesterol (195 ± 44 deceasing to 177 ± 37 mg/dL, P < 0.05), HDL cholesterol (54 ± 16 to 58 ± 16 mg/dL, P < 0.05), the LDL cholesterol/HDL cholesterol ratio (2.08 ± 0.45 to 1.76 ± 0.57, P<0.05), and triglyceride (246 ± 150 to 137 ± 47 mg/dL, P < 0.05). The drug did not affect hepatic function. In patients who received PFB in addition to lipid-lowering drugs other than statins, only significant decrease of the serum triglyceride was noted. Additional administration of PFB had no effect on body weight, BMI or serum creatinine kinase (CK).

PFB administered with statins yielded a marked improvement of blood lipid profile than PFB administered with lipid-lowering drugs other than statins. No effects were noted on the hepatic function parameters or serum CK. The results suggest the efficacy and safety of PFB in combination with statins.

Disclosure

M. Kusunoki: Other Relationship; Self; Kaken Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd. Y. Natsume: Other Relationship; Self; Kaken Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd. Y. Oshida: None. T. Miyata: Research Support; Self; Bayer AG, Daiichi Sankyo Company, Limited.
62-LB: Quantifying Insulin-Mediated and Noninsulin Mediated Glucose Disposal during Exercise in Patients with Type 1 Diabetes
Authors: NGUYEN THANH-TIN P. , JACOBS PETER G. , CASTLE JESSICA R. , WILSON LEAH M. , BRANIGAN DEBORAH , GABO VIRGINIA , SENF BRIAN , GUILLOT FLORIAN H. , YOUSSEF JOSEPH EL
Published: June 2019

Introduction: Glycemic control during exercise is challenging for people with type 1 diabetes. Better quantification of insulin dynamics at different exercise intensities and across insulin loading conditions is necessary for accurate insulin dosing during exercise.

Methods: Twenty seven participants with type 1 diabetes were evaluated during 3 separate 10-hour fasting aerobic exercise studies with low, medium, and high levels of insulin infusion (100%, 150%, and 300% of basal rate) across two exercise arms: moderate (40-45% of VO2 max), and intense (60-65% of VO2 max) exercise. Glucose levels were clamped during a 3-hour run-in period, followed by 45 minutes of exercise on a treadmill. 6,6-2H2-dideuterated glucose was infused to match endogenous glucose production during the entire trial. Glucose tracer data were fitted to a two-compartment ODE model, solved via Bayesian inference. We intend to quantify insulin and non-insulin mediated disposal of glucose by observing the rate of disposal (Rd) across different rates of insulin infusion in each exercise arm.

Results: Area under the curve (AUC) of Rd during 45 minutes of moderate exercise increased by 0.084 mmol/L for every percent increase in baseline insulin infusion rate (95% CI=0.064-0.104, p<0.001). AUC during intense exercise increased by 0.109 mmol/L (95% CI= 0.079-0.139, p<0.001). Mixed-effects model analysis showed no difference between exercise arms.

Conclusion: Results indicate Rd is substantial during exercise but that the difference in glucose uptake during aerobic exercise at 40-45% VO2 max may be comparable with 60-65% VO2 max.

Disclosure

T.P. Nguyen: None. P.G. Jacobs: Stock/Shareholder; Self; Pacific Diabetes Technologies. J.R. Castle: Advisory Panel; Self; Novo Nordisk Inc., Zealand Pharma A/S. Consultant; Self; Dexcom, Inc. Research Support; Self; Dexcom, Inc., Xeris Pharmaceuticals, Inc. L.M. Wilson: None. D. Branigan: None. V. Gabo: None. B. Senf: None. F.H. Guillot: None. J. El Youssef: None.

Funding

National Institutes of Health
623-P: Impaired Nrf2 Function Corresponds with Delayed Wound Healing in Diabetes
Authors: KUHN JOSEPH , DAVID JOSHUA A. , VILLARREAL PONCE ALVARO P. , ABDOU SALMA , SULTAN DARREN , KWONG JENNIFER , RABBANI PIUL S. , CERADINI DANIEL
Published: June 2019

Imbalance in the production of reactive oxygen species predisposes diabetic patients to delayed wound healing, but treatments that directly address this imbalance are lacking. Nrf2 and its natural inhibitor, Keap1, maintain redox homeostasis. However, the exact contribution Nrf2 makes to healing is unclear. Here we demonstrate that Nrf2 loss of function in discreet layers of the epidermis corresponds with substantial oxidative stress burdens and a concomitant delay in healing human tissue. Compared to nondiabetic human epidermal keratinocytes (NHEKs), diabetic human epidermal keratinocytes (DHEKs) exhibit a pro-inflammatory cytokine profile and decreased transcription of downstream antioxidant genes. Silencing Keap1 in DHEKs led to restoration of a cytokine profile conducive to healing (5-fold increase in TGF-b, p=0.0251, and 2-fold reduction in TNFa, p=0.019), a recovery in the expression of antioxidant genes, normalization of oxidative stress loads, and improvement in keratinocyte proliferation compared to siNS-DHEKs. Keap-1 silenced DHEKs recover the ability to migrate in scratch assays with significant improvement over siNS-DHEKs as early as 2 hours post-injury (1255 vs. 1560 mm2, p=0.014). In surgical specimens of wounded nondiabetic skin, Keap1 levels decrease, intranuclear Nrf2 increases, resulting in increased antioxidant gene expression to maintain redox homeostasis. However, in the wounds of diabetic patients, Keap1 remains elevated with a corresponding decrease in active Nrf2. In particular, the basal epidermis of wounded diabetic skin demonstrates a 77% decrease (p=<0.0001) in the expression of Nrf2. We present evidence that human diabetic epidermal Nrf2 dysfunction likely coincides with that of wounded tissue and results in reduced antioxidant gene expression, a rise in reactive oxygen species, and impaired re-epithelization. Exploiting the Nrf2 pathway may show great potential as a therapeutic strategy to minimize pathologic wound burden in the diabetic population.

Disclosure

J. Kuhn: None. J.A. David: None. A.P. Villarreal Ponce: None. S. Abdou: None. D. Sultan: None. J. Kwong: None. P.S. Rabbani: None. D. Ceradini: None.

Funding

American Diabetes Association/Pathway to Stop Diabetes (1-16-ACE-08 to D.C.)
627-P: Efficacy and Safety of Allogeneic Platelet Rich Plasma in Treatment of Diabetic Patients with Lower Limb Ulcers: A Pilot Study
Authors: DENG WUQUAN , HE MIN , CHEN BING , MA YU , ARMSTRONG DAVID , BOEY JOHNSON
Published: June 2019

Background and Objective: To observe the feasibility, efficacy and safety of al-PRP in the treatment of diabetic lower extremity ulcers. Furthermore, to explore the difference between au-PRP treatment, al-PRP treatment and only conventional treatment groups.

Methods: A total of 75 inpatients with diabetic lower limbs ulcer (DLLU) were divided into au-PRP group (n=20), al-PRP group (n=25), conventional treatment group (n=30). All three groups were administered basic diabetic treatments. In addition, the above three different treatment methods were given. The feasibility, curative effect and safety of au-PRP in the treatment of DLLU were evaluated by observing wound healing time, the average daily healing area and adverse reactions.

Results: No significant differences were observed in duration of diabetes, age, glycosylated hemoglobin, ankle brachial index, transcutaneous oxygen partial pressure, high-sensitivity C-reactive protein, IL-6, etc. among three groups (P>0.05). There was no significant difference in ulcer area and ulcer number between the three groups (8.43±6.93 cm2 vs. 5.64±3.91 cm2 vs. 9.73±9.72 cm2, P=0.19); The times and average of PRP treatment between two PRP groups have no significant difference (P>0.05). In the healing time, the al-PRP group and the au-PRP group were significantly shorter than the control group (56.9±29.22 days vs. 55.6±33.8 days vs. 88.0±43.4 days, P<0.01), while there was no significant difference between the al-PRP group and the au-PRP group (P>0.05). There was no significant difference in the average daily healing area (mm2) between the three groups (P>0.05). No significant adverse reactions (infection, itchy skin, redness, rash, etc.) were observed in two PRP groups.

Conclusions: Al-PRP can effectively and safely promote the healing of diabetic lower extremity wounds. Al-PRP could be used as a beneficial cell therapy supplement when au-PRP is limited.

Disclosure

W. Deng: None. M. He: None. B. Chen: None. Y. Ma: None. D. Armstrong: None. J. Boey: None.

Funding

Natural Science Foundation of Chongqing (81500596)
63-OR: The Physiological Effects of Extrapancreatic Glucagon in Totally Pancreatectomized Patients Evaluated Using Glucagon Receptor Antagonism
Authors: JUEL CAROLINE T.B. , LUND ASGER B. , REHFELD JENS F. , WEWER ALBRECHTSEN NICOLAI JACOB , HOLST JENS J. , VILSBØLL TINA , KNOP FILIP K.
Published: June 2019

We have recently shown a hyperglucagonemic response to meal test and oral glucose tolerance test (OGTT) in totally pancreatectomized (PX) patients. Here, we employed a glucagon receptor antagonist (GRA) to determine the physiological implications of extrapancreatic glucagon secretion in PX patients. In a double-blinded, randomized, cross-over study, 9 PX patients (age: 61.3±4.3 [mean±SEM] years; BMI: 22.6±1.6 kg/m2) and 9 matched healthy controls (age 65.9±2.9 years; BMI: 23.9±0.9 kg/m2) were examined during two 3-hour 75-OGTTs. Before the tests, subjects ingested 300 mg of the GRA, LY2409021 (Eli Lilly and Company), and placebo, respectively. Patients received their regular dose of insulin the night before each experimental day, but no insulin was given during the experiments. In the healthy controls, the GRA resulted in lower fasting levels of glucose (4.3±0.1 vs. 5.2±0.1 mmol/l, P=0.001), but higher post-OGTT plasma glucose excursions (as assessed by baseline-subtracted area under the curve (bsAUC): 926±92 vs. 467±72 mmol/l×min, P=0.002) compared to placebo. In the PX patients, the GRA and placebo resulted in similar fasting plasma glucose concentrations (11.3±0.9 vs. 12.5±0.8 mmol/l, P=0.266) and post-OGTT glucose excursions (bsAUC: 1,671±96 vs. 1,693±152 mmol/l×min, P=0.398), respectively. In the healthy controls, the GRA resulted in significantly higher fasting concentrations of glucagon (33.1±5.5 vs. 13.0±3.7 pmol/l, P=0.023), which, nevertheless, were suppressed by OGTT to similarly low levels as observed with placebo. In the PX patients, equal fasting glucagon concentrations (3.2±0.7 vs. 4.7±1.9 pmol/l, P=0.373) and similarly exaggerated plasma glucagon responses to OGTT were observed with the GRA and placebo (bsAUC: 1,636±573 vs. 1,034±542 pmol/l×min, P=0.113). In this study, antagonizing the glucagon receptor in totally pancreatectomized patients did not influence fasting or post-OGTT glucose levels.

Disclosure

C.T.B. Juel: None. A.B. Lund: None. J.F. Rehfeld: None. N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. T. Vilsbøll: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S.
630-P: Systemic Inflammatory Response Syndrome (SIRS) Criteria as a Predictor of Clinical Outcomes in Diabetic Foot Infections
Authors: AHN JUNHO , RYAN EASTON C. , WUKICH DANE , FONTAINE JAVIER LA , CRISOLOGO PETER A. , LAVERY LAWRENCE A.
Published: June 2019

Aim: Previous investigations have identified presence of systemic inflammatory response syndrome (SIRS) as an indicator of severe foot infection in patients with diabetes mellitus (DM). The aim of this study was to assess whether SIRS is correlated with outcomes in patients with diabetic foot infections (DFI).

Methods: We retrospective reviewed 173 diabetic patients admitted to hospital with moderate and severe DFI according to Infectious Diseases Society of America (IDSA) guidelines confined to skin and soft tissue infection. We used SIRS criteria to define severe infection based on the presence of at least two of the following: heart rate >90 beats per minute, temperature >38°C or <36°C, respiratory rate >20 breaths per minute and white blood cell count >12,000/mm3 or <4,000/mm3.

Results: Of the 173 subjects, 50 (36.5%) met SIRS criteria. Patients with severe infections based on SIRS criteria were significantly younger (49.0±10.4 vs. 54.2±10.8 years, p=0.014), more often had type 1 DM (10.0% vs. 1.1%, p=0.032), less often had a history of a previous foot ulcer (48.0% vs. 66.7%, p=0.040) and had longer hospital stay (8.0±6.1 vs. 11.7±11.3 days, p=0.024). There was not a significant difference in the number of surgical procedures (1.1±1.4 vs. 1.2±1.4, p=0.40), amputation procedures (24% vs. 27.6%, (odds ratio [OR] 0.76, 95% confidence interval [CI] 0.33, 1.720), duration of antibiotic treatment (30.1±42.5 vs. 31.6±48.5 days, p=0.47), proportion of healed wounds (74.0% vs. 66.7%, p=0.304), time to healing (142.6±102.8 vs. 131.9±103.1 days, p=0.67). reinfection (34.0% vs. 42.5%, p=0.29), hospital readmission (30.0% vs. 47.1%, p=0.072) or mortality (4.0% vs. 5.7%, p=1.0).

Conclusion: SIRS criteria for severe infections in diabetic patients with skin and soft tissue infections were not associated with worse outcomes other than longer hospital stay. Further investigation is needed to identify factors that portend worse outcome in those with foot STI in the setting of DM.

Disclosure

J. Ahn: None. E.C. Ryan: None. D. Wukich: Consultant; Self; Orthofix. Other Relationship; Self; Arthrex. J. La Fontaine: None. P.A. Crisologo: None. L.A. Lavery: Consultant; Self; Bayer US, Boehringer Ingelheim Pharmaceuticals, Inc., Medline Industries, Inc. Research Support; Self; Cardinal Health, EO2 Concepts, Integra LifeSciences, MedImmune, Osiris Therapeutics, Inc.
634-P: Poor Adherence to Medication and HbA1c Level Predict Risk of Amputation in Patients with Diabetes Mellitus—Historical Cohort Study Using a Nationwide Claims Database
Authors: KANEKO MASANORI , FUJIHARA KAZUYA , OSAWA TAEKO , HARADA MAYUKO , KITAZAWA MASARU , MATSUBAYASHI YASUHIRO , YAMADA TAKAHO , YAMANAKA NAUTA , SEIDA HIROYASU , SONE HIROHITO
Published: June 2019

Poor adherence to medication is a clinically relevant issue closely associated with incidence and deterioration of complications in those with diabetes mellitus (DM). Although an elevated HbA1c level is an established risk factor for lower limb amputation, few studies have evaluated the impact of medication adherence combined with HbA1c levels on lower limb amputation. Thus, we analyzed data from 6,957 patients with DM whose records for oral hypoglycemic agents were available for at least 1 y. Medication adherence was evaluated by the proportion of days covered (PDC), with PDC <70% defined as poor medication adherence. Lower limb amputation was defined by ICD-10 codes and medical procedures. Cox regression model identified variables related to the incidence of amputation. In a mean follow-up of 5.5 y, 9 amputations occurred (0.24/1000 person-years). Mean PDC was 55.7%, with 55.6% of patients non-adherent. Results of multivariate Cox regression analysis showed that HbA1c level and PDC were independently associated with the incidence of amputation (HR (95% CI) 1.19 (0.81-1.76), 0.06 (0.01-0.45)). Compared with PDC ≥70% and HbA1c <9.0%, those with PDC <70% and HbA1c ≥9.0% had an approximately 26 times higher risk for amputation (Figure). This implies the necessity of increasing adherence to medication to prevent lower limb amputation in DM.

Disclosure

M. Kaneko: None. K. Fujihara: None. T. Osawa: None. M. Harada: None. M. Kitazawa: None. Y. Matsubayashi: None. T. Yamada: None. N. Yamanaka: None. H. Seida: None. H. Sone: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kowa Pharmaceutical Europe Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited.