bluuebunny/crossref_metadata_2025 huggingface dataset:
1727-P: A Novel Islet-Peripheral Blood Mononuclear Cell Coculture Model for Studying Type 1 Diabetes
Authors: YESILDAG BURCAK , PERDUE NIKOLE , MIR-COLL JOAN , BIERNATH ADELINN , NEELAKANDHAN APARNA , FORSCHLER FELIX , VON HERRATH MATTHIAS G. , WESLEY JOHNNA D.
Published: June 2019

Type 1 diabetes is a heterogeneous group of disorders majorly characterized by autoimmune destruction of pancreatic β-cells, resulting in absolute insulin deficiency. Current research models lack many functions critical for understanding the onset and progression of this disease in humans. Although isolated primary islets are considered the standard tool for diabetes research, their experimental use is challenging due to inherent heterogeneity in size, cellular composition and purity, as well as rapid decline in their functionality and viability ex vivo. Here we investigate a novel co-culture platform of peripheral blood mononuclear cells (PBMCs) and a uniform 3D islet model. Human islet microtissues, produced by optimized dissociation and controlled reaggregation of primary islet cells, were cultured in a one-islet per well format in 96-well plates. They displayed uniform, long-term (>28 days), and robust viability and function enabling high-throughput and longitudinal study of immune cell-endocrine cell interactions and β-cell function. PBMCs in their naïve form or following T-cell specific activation, were combined in various ratios with healthy or stressed islets - preconditioned with a mild cytokine cocktail. Co-culturing of naïve PBMCs and islet microtissues had only a minor impact on β-cell function. Whereas, combination of activated PBMCs and islet microtissues resulted in a PBMC-number dependent decline in islet health shown by increased basal insulin release and decreased glucose-stimulated insulin secretion, insulin content and PDX-1 positive nuclei within each microtissue. The observed destruction correlated with the amount of CD3+ cells infiltrating the microtissues and was significantly augmented by cytokine preconditioning. The established islet-PBMC co-culture platform represents a novel in vitro model to study the autoimmune component of T1D and to screen for compounds that could prevent immune-cell mediated destruction of pancreatic islets.

Disclosure

B. Yesildag: None. N. Perdue: None. J. Mir-Coll: Employee; Self; InSphero. Employee; Spouse/Partner; Roche Pharma. A. Biernath: None. A. Neelakandhan: None. F. Forschler: Employee; Self; InSphero. M.G. von Herrath: None. J.D. Wesley: Employee; Self; Novo Nordisk A/S.
1789-P: Ser/Thr Phosphatase-PP2C Negatively Regulates AS160 and GSK3β Activity in Neuronal Insulin Signal Transduction Pathway
Authors: YADAV YAMINI , DEY CHINMOY S.
Published: June 2019

Serine/Threonine protein phosphatases regulate the activity of insulin signaling molecules involved in glucose homeostasis. Aberration in their functions have been reported in adipocytes, hepatocytes and skeletal muscle cells lead to abnormalities in signal transduction causing diabetes. Neuronal system is insulin responsive. Malfunctions have been reported to lead to development of metabolic disorders like diabetic neuropathy and Alzheimer disease. Our understanding of phosphatase mediated regulation in general is anyway very limited and role of PP2C in insulin signaling pathway in neuronal system is practically non-existent. Further exploration is required to understand the role of Ser/Thr phosphatases in neuronal system. Therefore, the aim of this work was to identify the role of PP2C in neuronal insulin signaling. To achieve this, PP2C in the differentiated Neuro-2a (N2A) cells was inhibited by treating with a potent and specific inhibitor of PP2C, Sanguinarine Chloride (SC), in presence (100nM) or absence of insulin and the effect was tested on the activity of AS160 and GSK3β. In insulin stimulated state inhibition of PP2C caused a significant 37% and 56% of decrease in the phosphorylation of AS160 at Ser588 and Thr642 residues, respectively. Similarly, a 37% decrease was observed in phosphorylation of GSK3β at Ser9. However, the expression of AS160 and GSK3β were found to be unaffected. Data shows for the first time that PP2C mediated dephosphorylation might be involved in regulating the activity of AS160 and GSK3β in neuronal system and hence suggest a possibility of its playing a major negative role in regulating neuronal insulin signal transduction pathway.

Disclosure

Y. Yadav: None. C.S. Dey: None.

Funding

Department of Science & Technology, Government of India, New Delhi; Department of Science & Technology, Government of India, New Delhi (SR/S2/JCB-24/2008(G))
1807-P: Central Leptin Administration Attenuates the Glucose Responsiveness to Epinephrine
Authors: QI YIJING , WHITE B. DOUGLAS
Published: June 2019

Central leptin administration in streptozotocin-induced diabetic rats leads to normalization of blood glucose concentrations, independent of insulin. In previous studies, we observed that leptin-treated rats couldn’t maintain their blood glucose concentration during a short-term fast as well as control rats. We hypothesize that chronic central leptin administration inhibits the ability of counterregulatory hormones to increase hepatic glucose production and blood glucose concentrations by attenuating gluconeogenesis through the inhibition of the cAMP-CREB pathway in the liver.

To test this hypothesis, we determined the glucose responsiveness of leptin-treated nondiabetic and diabetic rats to epinephrine (EPI) injections during the fed and fasted states and whether alterations in blood glucose levels were associated with biochemical changes in the cAMP-CREB pathway in the liver. Baseline blood glucose levels were determined followed by an intraperitoneal injection of EPI or saline to each rat during both the fasting and fed states. Blood glucose levels were monitored for 3 hours post-injection. The area under the curve (AUC) was calculated for each EPI-treated animal and subtracted from the AUC during a saline injection in the same animal. Leptin normalized the daily blood glucose levels in diabetic rats.

Leptin attenuated the effect of EPI during fasting. In the fed state, leptin inhibited the glucose responsiveness to EPI in nondiabetic rats. (The responsiveness to EPI couldn’t be determined in fed diabetic rats due to the high blood glucose concentrations.) Diabetes increased hepatic phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase, and CREB. Leptin treatment of diabetic rats negated the increases in PEPCK and CREB. These results support the hypothesis that chronic central leptin treatment inhibits the cAMP-CREB pathway in diabetic rats and attenuates the effects of counterregulatory hormones to increase hepatic glucose production.

Disclosure

Y. Qi: None. B. White: None.

Funding

Alabama Agricultural Experiment Station (ALA043-1-13014)
183-OR: Placental Growth Factor and Fetal Growth in Women with Type 1 Diabetes Mellitus
Authors: BACON SIOBHAN , BURGER DYLAN , TAILOR MAYUR , TOMLINSON GEORGE A. , MURPHY HELEN R. , FEIG DENICE
Published: June 2019

Background: Maternal hyperglycaemia alone does'nt explain the incidence of large for gestational age offspring (LGA) amongst women with T1DM. Placental vascular development is regulated by angiogenic factors. Placental growth factor (PIGF) is such a factor with a PlGF >100 signifying a well-developed placenta. Co-measurement of PlGF and SFLT-1 (soluble receptor antagonist to VEGF), combined as a ratio, is predictive of maternal vascular perfusion. A low sFLT-1:PlGF (<85) is a marker of good placental health. We assessed if markers of placental function and glycemic control can explain variations in birthweight in women with T1DM.

Methods: Amongst 157 women who participated in CONCEPTT; PlGF, sFLT-1:PlGF and a HbA1c< or >6.5% at randomisation and 34 weeks' gestation were assessed. Two separate linear regression models were used to test for a differential effect of placental function on mean birth weight in those with different levels of glycemic control, one using sFLT-1:PlGF and the other PlGF.

Results: No significant relationship was found between birthweight and markers of placental function and glycemic control at randomisation. At 34 weeks, the relationship of birth weight to sFLT-1: PlGF differed depending upon HbA1c (p=0.007). Where HbA1c< 6.5%, birth weights were similar for a sFLT-1:PlGF <85 (3592g) and >85 (3699g). Where HbA1c > 6.5%, birthweights were higher with a sFLT-1:PlGF < 85 (3809g) vs. > 85 (3355g). A similar pattern emerged for PlGF alone, with a differential effect of a healthy placenta on birthweight dependent upon glycemic control (p=0.013). Where HbA1c<6.5%, birthweights were similar (3635±556g and 3604±602g) with low and high PlGF. Where HbA1c>6.5%, an elevated PlGF (>100) resulted in higher birth weight than in those with lower PlGF (3822g ±679 vs. 3344g ±556).

Conclusion: In women with T1DM, the combination of a healthy placenta with poor glycemic control resulted in the highest birthweights. Tighter glycemic control to avoid LGA is needed in women with healthy placental function.

Disclosure

S. Bacon: None. D. Burger: None. M. Tailor: None. G.A. Tomlinson: None. H.R. Murphy: Advisory Panel; Self; Medtronic MiniMed, Inc. D. Feig: Advisory Panel; Self; Medtronic. Speaker's Bureau; Self; Medtronic.
184-OR: In Utero Exposure to Gestational Diabetes Alters the Transcriptome and Methylome of Human Fetal Stem Cells Revealing an Enrichment of Interferon Related Pathways
Authors: PINNEY SARA E. , JOSHI APOORVA , YIN VICTORIA , MIN SO WON , CONDON DAVID E. , WANG ZHIPING
Published: June 2019

Background: Gestational diabetes (GDM) has profound effects on the intrauterine metabolic milieu, induces marked abnormalities in fetal glucose and insulin secretion and is linked to obesity and diabetes in the offspring, but the mechanisms remain largely unknown.

Objective: To measure changes in gene expression and genome wide DNA methylation in human amniocytes, a fetal stem cell, exposed to GDM in utero.

Methods: EdgeR identified differentially expressed genes from RNASeq via fold change, p-values, and q-values calculated after Bonferoni correction (n=8; 4 per sex). RNA-Seq results were confirmed via QPCR. Ingenuity Pathway Analysis (IPA) identified enriched biological pathways. Differentially methylated regions (DMRs) were determined from Enhanced Reduced Representation Bisulfite Sequencing (ERRBS) (n=16; 8 per sex) by identifying sequential CpGs with significant changes in DNA methylation >5%, and with p<0.05 over the entire DMR.

Results: We identified 20 differentially expressed genes (q<0.10) analyzing data from male and female amniocytes together, but only 4 genes in male only and 2 in female only analyses. Using a significance threshold of p<0.01, we identified 65 differentially expressed genes analyzing all samples together, 46 genes in the male only and 68 in the female only analyses. QPCR confirmed increases in IFI44, ULBP1 and SAMD9L. Differentially expressed genes were strongly enriched for interferon inducible proteins, a novel fetal programming pathway after in utero GDM exposure. IPA showed enrichment in molecular mechanisms of growth, oxidative stress metabolism and GCPR signaling pathways. Offspring sex-specific analysis greatly enhanced DMR identification. Nine DMRs were identified in all, 41 in male and 20 in female samples.

Conclusion: Exposure to GDM in utero leads changes in amniocyte gene expression and DNA methylation with enrichment in interferon inducible pathways.

Disclosure

S.E. Pinney: None. A. Joshi: None. V. Yin: None. S. Min: None. D.E. Condon: None. Z. Wang: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (K08DK090302); National Institute of Environmental Health Sciences (P30ES013508); National Institutes of Health (UL1TR001878)
1879-P: The Liver Mitochondrial Oxidative Phosphorylation Increases in Diabetic Mice
Authors: ALIMUJIANG MIRIAYI , YU MUYU , YIN JUN
Published: June 2019

Mitochondria play critical role in energy metabolism. However, the alteration of mitochondrial function in diabetes is still controversial. To address this issue, we measured the liver and muscle mitochondrial function in animal models characterizing different stages of type 1 and 2 diabetes. Streptozotocin-induced diabetic mice, db/db mice and high-fat diet-induced obese mice were used in this study. Both in early stage (3 weeks after STZ injection) and late stage (3 months after STZ injection) of type 1 diabetic mice, liver mitochondrial oxidative phosphorylation (OXPHOS) increased significantly, among which the complex IV-dependent oxygen consumption rate (OCR) was the most prominent, indicating that complex IV may play an important role in the pathophysiology of type 1 diabetes. The liver mitochondrial complex I and II-dependent OXPHOS increased greatly in prediabetes and early stage (12-week-old db/db mice) of type 2 diabetes. At the late stage (42-week-old db/db mice) of type 2 diabetes, the OXPHOS declined to almost normal, and alteration of complex I-dependent OCR was the most significant. In contrast, no change of mitochondrial OXPHOS was observed in the muscle of all disease models. Besides, no alteration of ATP, ADP and AMP contents in the tissues was observed. Our in vitro experiments showed that among specific chemical inhibitors to complex I, II, III or IV in mitochondrial respiratory chain, rotenone (complex I inhibitor) and myxothiazol (complex III inhibitor) enhanced glucose consumption and lactate release. But only rotenone decreased glucose output in primary hepatocytes in the absence of cytotoxicity.

In summary, the mitochondrial OXPHOS of liver rather than muscle increases in diabetes. And inhibition of complex I may ameliorate hyperglycemia by reducing hepatic glucose production and inducing glycolysis. Our results provide evidences for using complex I inhibitors (e.g., metformin and berberine) as oral antidiabetic agents.

Disclosure

M. Alimujiang: None. M. Yu: None. J. Yin: None.

Funding

National Natural Science Foundation of China (81670790, 31171128)
1899-P: Glucagon-Like Peptide-1 Receptor Signaling Is Required for an Osteocalcin-Mediated Improvement of Glucose Tolerance
Authors: MIZOKAMI AKIKO , HIRATA MASATO
Published: June 2019

In the past decade, multiple studies have revealed that osteoblast-derived hormone osteocalcin, in its uncarboxylated form (GluOC), could reverse the diabetic conditions by affecting multiple aspects of systemic glucose and energy metabolism, male fertility, and brain function. Metabolic effects of GluOC are primarily achieved by its ability to stimulate insulin secretion and pancreatic β-cell proliferation either directly, or indirectly through stimulating the secretion of glucagon-like peptide-1 (GLP-1) from intestinal endocrine cells through its putative receptor GPRC6A. We have previously reported that oral administration of GluOC, the most common and safe route of drug administration, reduced the fasting blood glucose level, improved glucose tolerance, and increased the fasting serum insulin concentration as well as the β-cell area in the pancreas in wild type mice. However, these effects were abolished by the prior subcutaneous administration of exendin (9-39), a GLP-1 receptor antagonistic peptide, suggestive of the requirement of GLP-1 receptor signaling for orally-administered GluOC effects. In this study, we examined the effect of GluOC using GLP-1 receptor-knockout mice to explore the involvement of GLP-1 receptor signaling in the GluOC-mediated improvement of glucose handling. We found that long-term oral administration of GluOC rather triggered glucose intolerance, enhanced gluconeogenesis, lipid accumulation in the liver, and adipocyte hypertrophy in GLP-1 receptor-knockout mice. Furthermore, we revealed that inactivation of GLP-1 receptor signaling in association with GluOC promotes FoxO1 action, leading to gluconeogenesis. These results indicate that the beneficial effect of GluOC on glucose and lipid metabolism is dependent on functional GLP-1 receptor signaling.

Disclosure

A. Mizokami: None. M. Hirata: None.

Funding

Japan Society for the Promotion of Science (16K20421, 17K19766)
1993-P: Deconstruction of the Role of the Amylin and Calcitonin Receptors in the Regulation of Body Weight and Glucose Tolerance
Authors: LARSEN ANNA T. , SONNE NINA , ANDREASSEN KIM V. , KARSDAL MORTEN ASSER , HENRIKSEN KIM
Published: June 2019

Dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for treatment of T2D and obesity due to their beneficial effects on body weight, blood glucose and insulin sensitivity, effects that are superior to those of amylin. However, it is unknown how dual receptor activation by DACRAs compare to activation of either the amylin or the calcitonin receptor in vivo, and to what extent the calcitonin receptor is involved in the beneficial metabolic effects of DACRAs. In this study, we compared the effects of a highly potent DACRA, KBP, rat amylin (rAMY), rat calcitonin (rCT) and the combination of rAMY and rCT on long term efficacy on body weight, food intake and glucose tolerance. High fat fed Sprague Dawley rats were treated 4 weeks with KBP (5 µg/kg/day), rAMY (300 µg/kg/day), rCT, (300 µg/kg/day) and the combination of rAMY and rCT (300+300 µg/kg/day). To compensate for the different activity profiles, peptides were delivered by continuous subcutaneous infusion. Chronic treatment with KBP, rAMY and the combination of rAMY and rCT resulted in a 17%, 11% and 8% vehicle-corrected weight loss, respectively, while rCT alone had no effect. All treatments significantly reduced food intake in the initial phase of the study, while KBP and rAMY resulted in a prolonged reduced food intake. Interestingly, KBP was superior in terms of body weight loss (p<0.001) even though rAMY and KBP reduced the accumulated food intake equally. Moreover, KBP and rAMY improved oral glucose tolerance with significantly reduced insulin levels. Again, KBP was superior to the other treatments (p<0.001).

In conclusion, dual activation of amylin and calcitonin receptors by KBP has beneficial effects on body weight and glucose tolerance superior to that of activating either receptor alone. This was despite correcting for the different activity of the peptides. Understanding of the dual or single receptor activation mechanisms is high pharmaceutical interest.

Disclosure

A.T. Larsen: None. N. Sonne: None. K.V. Andreassen: Employee; Self; Nordic Bioscience. M.A. Karsdal: Employee; Self; Nordic Bioscience. K. Henriksen: Employee; Self; Nordic Bioscience. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Nordic Bioscience. Other Relationship; Self; Nordic Bioscience.
2009-P: Molecular Mechanisms of Obesity-Associated Vascular Vulnerability via Signals of Appetite Regulation
Authors: MORI KENTARO , TSUCHIYA KYOICHIRO , NAKAMURA SUGURU , SHIBA KUMIKO , MIYACHI YASUTAKA , OGAWA YOSHIHIRO , KITAMURA KENICHIRO
Published: June 2019

Background: Obesity is a risk factor of hypertension and abdominal aortic aneurysm (AAA). Melanocortin 4 receptor (MC4R) is activated by α-melanocyte-stimulating hormone (α-MSH) to mediate most of the anorectic effects of leptin. In humans, deficiency or mutation of MC4R is the most common monogenic form of obesity. However, it remains unknown whether MC4R signaling affects the development of obesity-associated hypertension, vascular vulnerability and aortic aneurysm.

Methods and Results: MC4R-knockout (KO) mice fed a high-fat/high-sucrose diet (HF/HS) for 20 weeks displayed obesity associated with hyperleptinemia compared to HF/HS-fed wild type (WT) mice. MC4R-KO mice exhibited hypertension, increase of medial thickness and elastic lamina destruction, and elevation of inflammatory and fibrosis-related genes including TGF-β and osteopontin (OPN) in aortae. MC4R-KO mice showed higher incidence of angiotensin II (Ang II, 500 ng/kg/min)-induced AAA (73%) than WT mice (8%). MC4R-KO mice with ob/ob background exhibited lower incidence of Ang II-induced AAA (50%) than MC4R-KO mice, but higher than ob/ob mice (12.5%). Treatment of OPN-blocking antibody decreased Ang II-induced AAA incidence in HF/HS-fed MC4R-KO mice. In vascular smooth muscle cells (VSMCs), leptin (100 ng/ml) significantly upregulated OPN gene expression. α-MSH suppressed AngII-induced TGF-β gene expression in VSMCs, and LPS/IFN-γ-induced iNOS gene expression in peritoneal macrophages. However, these effects of α-MSH were abolished in primary macrophages from MC4R-KO mice and RAW264.7 cells pretreated with MC4R antagonist HS024.

Conclusion: Our observation indicates that deficiency of MC4R promotes the vascular vulnerability in mice. It suggests that, not only hyperleptinemia, but also impairment of α-MSH-MC4R signaling in VSMCs and macrophages, may also promote the vascular vulnerability.

Disclosure

K. Mori: None. K. Tsuchiya: None. S. Nakamura: None. K. Shiba: None. Y. Miyachi: None. Y. Ogawa: None. K. Kitamura: None.
2080-P: Endobarrier (EB) in Diabetes/Prediabetes with Obstructive Sleep Apnea (OSA) Study—Maintenance of Improvement after EB Removal
Authors: YADAGIRI MAHENDER , KINNEY FIONA Y. , ASHMAN NATALIE , SHARRATT EMMA S. , GREENWOOD CHERYL , ADAMS JESSICA , WYRES MELANIE C. , LANG MICHAEL H. , BLEASDALE JOHN , FOGDEN EDWARD , ANDERSON MARK , WALTON CHRISTOPHER , GREENSTONE MICHAEL A. , RYDER ROBERT E.
Published: June 2019

EB, a 60cm endoscopically implanted proximal intestinal liner is implanted for up to one year and then removed. We assessed Apnoea Hypopnoea Index (AHI), weight and HbA1c before and during EB treatment and following its removal in the 10 patients with moderate OSA requiring continuous positive airway pressure ventilation (CPAP) {80% female, 6/10 (60%) type 2 diabetes, 4/10 (40%) prediabetes, mean ± SD age 53.5±10.3 years, BMI 38.01±2.9 kg/m2} who have attended at least on follow-up after removal. During EB implant, mean ± SD HbA1c fell by 1.2±1.8% from 7.7 ± 1.7 to 6.6 ± 1.1% (p=0.069), weight by 11.1±4.1 kg from 104.9± 14.6 to 93.8±14.7 kg (p<0.001). Prior to EB, all patients had AHI in the National Institute for Health and Care Excellence (NICE) moderate OSA range (15-29.9 events/hour). During EB treatment, AHI of all patients fell below 15 events/hour, such that they no longer required CPAP, according to NICE guidelines. At follow-up at median (range) 9.65 (3-17.6) months after EB removal latest AHI was below 15 in all patients such that they remained off CPAP. Improvements in other metabolic parameters were also sustained (Table). These results confirm previously demonstrated metabolic improvements from EB in diabesity and demonstrate major benefit in the moderate OSA co-morbidity, allowing patients to discontinue CPAP with maintenance of improvement at follow-up.

Disclosure

M. Yadagiri: None. F.Y. Kinney: None. N. Ashman: None. E.S. Sharratt: None. C. Greenwood: None. J. Adams: None. M.C. Wyres: None. M.H. Lang: None. J. Bleasdale: None. E. Fogden: None. M. Anderson: None. C. Walton: Advisory Panel; Spouse/Partner; Celgene Corporation. Speaker's Bureau; Spouse/Partner; Leo Pharma, Novartis Pharmaceuticals Corporation. M.A. Greenstone: None. R.E. Ryder: Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Bioquest.

Funding

Association of British Clinical Diabetologists
2117-P: Biomarkers Isolated from Extracellular Vesicles Prior to Bariatric Surgery May Be Associated with Postoperative Resolution of Type 2 Diabetes
Authors: HILLYER REBECCA , SULLIVAN TRAVIS , CHRIST KIMBERLY , HODARKAR AMEYA , HODGE MARY BETH
Published: June 2019

Introduction: Bariatric surgery has been shown to lead to resolution of type 2 diabetes mellitus (T2DM) in 78.1% of patients (Buchwald, Am J Med 2009), however, it also confers significant risk for potential complications. It is unclear in the preoperative setting which patients will have resolution of T2DM following bariatric surgery. The objective of this study is to identify if patients who have resolution of T2DM following bariatric surgery express different biomarkers preoperatively from their counterparts who do not have resolution of T2DM.

Methods: Blood samples were obtained from patients who presented to the Center for Surgical Weight Loss with T2DM and either BMI ≥ 40 or BMI ≥ 35 with weight-related comorbidities. All 20 patients studied then underwent gastric bypass or gastric sleeve surgery. At 6 to 12 months postoperatively the patients were evaluated for resolution of T2DM; defined as a hemoglobin A1c less than 6.5 and off all diabetic medications. Extracellular vesicles were isolated from patient serum and analyzed to identify and quantify microRNA and protein biomarkers. The biomarkers in patients who had resolution of T2DM were compared to the biomarkers in patients who had persistent T2DM.

Results: Out of the 395 microRNA detected, there were 10 that were significantly differentially expressed between patients who had resolution of T2DM after bariatric surgery and those who did not. Out of the 71 proteins detected, there were 5 identified that differed significantly between the two groups.

Conclusion: Preoperatively, patients with T2DM who undergo bariatric surgery with subsequent resolution of T2DM may have a different biomarker profile than patients whose T2DM does not resolve following bariatric surgery. If these biomarkers are validated in a larger population of patients, they could be used to help clinicians select patients in the preoperative setting who would benefit most from bariatric surgery.

Disclosure

R. Hillyer: None. T. Sullivan: None. K. Christ: None. A. Hodarkar: None. M. Hodge: None.

Funding

Ellison Foundation; Cancer Prevention and Research Institute of Texas
2134-P: Protection of Beta-Cell Mass from Diabetogenic Condition-Induced Apoptosis by the Inhibition of Mammalian STE20-Like Protein Kinase 1 (MST1)
Authors: SAMEERMAHMOOD ZAHEERBASHA , SIVANANDHAN DHANALAKSHMI , KALITA BISWAJIT , RAMAIAH SOWMYA , SIDDIQUI AMIR , ZOPE BHARAT R. , KADNUR SANJAY V. , KANAVALLI MADHURI , KRISHNAKUMAR V. , SWAMINATHAN SRINIVASAN , RUDRESH G. , MOHIRE SUNIL , BURRI RAGHUNADHA R. , KRISTAM RAJENDRA , JEYARAJ D.A , RAJAGOPAL SRIRAM , DHAKSHINAMOORTHY SARAVANAKUMAR
Published: June 2019

Impaired insulin secretion, a characteristic of type 2 diabetes (T2D) is partly attributed to decreased β-cell mass due to apoptotic cell death under diabetogenic conditions. Current therapies for diabetes do not address apoptotic cell death mediated β-cell deterioration. Mammalian STE20-like protein kinase 1 (MST1) is reported as one of the critical regulators of β-cell apoptosis under diabetogenic conditions, and therefore, inhibition of MST1 in β-cells may offer β-cell protection and preserve β-cell mass under diabetogenic conditions. We carried out an investigation of MST1 modulation, apoptotic signaling in islet samples from healthy controls, T2D patients and in pancreatic cell lines using MST1 specific siRNAs, and a small molecule inhibitor of MST1 (XMU-MP-1, IC50 ∼100 nM) under diabetogenic conditions. Elevated levels of phospho-MST1, cleaved MST1, and pro-apoptotic markers such as cleaved caspase-3 and BIM were observed in islet samples from T2D patients as compared to healthy control, suggesting the activation of MST1 mediated apoptotic pathway under diabetogenic conditions. Similar findings were observed when pancreatic samples from ob/ob mice and control mice were used. siRNA against MST1 and XMU-MP-1 rescued high glucose (25 mM)/high palmitate (500 µM) induced apoptosis in Min6 and INS-1E cells. The rescue of MIN6 and INS-1E cells were associated with the lowering of phospho-MST1, cleaved MST1 and pro-apoptotic markers such as cleaved caspase-3, phospho-H2B, and BIM. Further, once daily (1 mg/kg) dosing of XMU-MP-1 protected the β-cells in an acute streptozotocin-induced diabetic animal model. Increased numbers of insulin-stained pancreatic islets were observed in XMU-MP-1 treated group compared to disease control. Our data suggest that inhibition of MST1 can protect β-cell mass under diabetogenic conditions. Identification and development of specific small molecule inhibitors of MST1 are underway.

Disclosure

Z. Sameermahmood: None. D. Sivanandhan: None. B. Kalita: None. S. Ramaiah: None. A. Siddiqui: None. B.R. Zope: None. S.V. Kadnur: None. M. Kanavalli: None. K. V.: None. S. Swaminathan: None. R. G.: None. S. Mohire: None. R.R. Burri: None. R. Kristam: None. J. D.a: None. S. Rajagopal: None. S. Dhakshinamoorthy: None.

Funding

Jubilant Innovation Inc.
2199-PUB: Insulin Use and Hypoglycemia Prevalence in an Australian Public Hospital Setting
Authors: PIYA MILAN K. , FLETCHER THERESE , MYINT KYAW PHONE , ZARORA REETU , SIMMONS DAVID
Published: June 2019

Aims: Diabetes management in hospital often focuses on tight glycemic control. Insulin use is, therefore, more common in the hospital inpatient setting. We sought to determine the prevalence and patterns of insulin use and hypoglycemia among inpatients with diabetes on medical wards in a tertiary Sydney hospital.

Methods: A daily census was conducted on three medical wards (79 beds) over 44 weeks from June 2017. Inpatients with diabetes were audited using a questionnaire based on the UK National Diabetes Inpatient Audit. Those admitted for >7 days were audited for the last 7 days of admission.

Results: Among 822 patients with diabetes, 96% had T2DM, mean age (SD) was 69.1(12.3) years, 54.8% male. Overall, 29.6% were on insulin on admission but 44.7% were prescribed insulin during their hospital stay. Hypoglycemia (<4.0mmol/L) occurred in 111 patients (13.5%) with 225 episodes, and severe hypoglycemia (<3.0mmol/L) occurred in 39 patients (4.8%) with 52 episodes. Insulin was prescribed during hospital stay in 78.4% of patients who had hypoglycemia, and 92.3% who had severe hypoglycemia. There was a greater prevalence of hypoglycemia out of hours (5pm-8am) compared to 8am-5pm (167 vs. 58 episodes).

Conclusions: Hypoglycemia and severe hypoglycemia were common among hospital inpatients, and insulin use in this group was high. Insulin use was a major risk factor for hypoglycemia, particularly with new insulin initiation and after hours. These data highlight the need to weigh the risk of hypoglycemia against the benefit of tight glycemic control when considering insulin initiation in hospital. Extra vigilance is also needed after hours when there is a higher risk of hypos with fewer staff.

Disclosure

M.K. Piya: None. T. Fletcher: None. K. Myint: None. R. Zarora: None. D. Simmons: Speaker's Bureau; Self; Sanofi-Aventis. Other Relationship; Self; Medtronic.

Funding

South Western Sydney Local Health District
2224-PUB: Comparative Effectiveness of Second-Line Initiation of Basal Insulin Therapy vs. Oral Antidiabetic Drugs Added to Metformin among Patients with Type 2 Diabetes in Taiwan
Authors: CHEN PIN-HAO , KUO SHIHCHEN , OU HUANG-TZ
Published: June 2019

Objective: This study was aimed to assess comparative effectiveness of basal insulin vs. oral antidiabetic drugs (OADs) as 2nd-line added-on treatment to metformin monotherapy on macro- and microvascular complications, hypoglycemic events, and all-cause mortality in patients with type 2 diabetes (T2DM).

Methods: A population-based cohort study was conducted using Taiwan’s National Health Insurance Research Database. Study population was newly-diagnosed with T2DM in 1999-2011, and the new and stable users of basal insulin or OADs (i.e., sulphonylurea [SU], dipeptidyl peptidase-4 inhibitor [DPP-4i]) as 2nd-line add-on treatment to metformin during 2009-2011, and followed until death or the end of 2013. Propensity score matching was applied to achieve comparability in patient baseline characteristics at the time of 2nd-line treatment initiation between basal insulin and OAD users. Cox models were used to evaluate risks of study outcomes associated with use of basal insulin vs. OADs.

Result: Our analyses included 1,064 and 951 basal insulin users 1:1 matched with SU and DPP-4i users, respectively. Compared to SU, use of basal insulin was associated with significantly higher risks of macrovascular events (hazard ratio: 1.36 [95% confidence interval: 1.08-1.71]), microvascular events (1.25 [1.21-1.40]), hypoglycemia (1.88 [1.44-2.46]), and all-cause death (1.50 [1.03-2.20]). Compared to DPP-4i, use of basal insulin yielded a greater risk increase in macrovascular events (1.52 [1.18-1.97]), microvascular events (1.43 [1.27-1.61]), hypoglycemia (3.28 [2.33-4.64]), and all-cause death (2.58 [1.59-4.19]).

Conclusion: T2DM patients who initiated basal insulin vs. SU or DPP-4i as 2nd-line added-on treatment to metformin had higher risks of vascular complications, hypoglycemia, and all-cause death.

Disclosure

P. Chen: None. S. Kuo: None. H. Ou: None.

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (P30DK092926)
2260-PUB: Inpatient Diabetes Patient Brochure: What You Need to Know while You Are in the Hospital
Authors: RUSHAKOFF ROBERT J. , MACMASTER HEIDEMARIE W.
Published: June 2019

Hospitalized patients with diabetes, whether previously on insulin or not, are generally treated with insulin. This change from outpatient medication, the type of insulin, and insulin regimen may be significantly different from what the patient is familiar with and may result in confusion, discomfort or even confrontation about the treatment plan. To ease the transition from outpatient to inpatient, we developed a “Brochure for Patients with Diabetes: What you need to know while you are in the hospital” to help make the patient feel more comfortable about the glycemic care they receive and improve patient satisfaction. The specific items covered in the brochure are: 1) Why the management of your diabetes may be quite different from what you usually do at home; 2) Goals for blood sugars (why different from home: fighting infections, avoiding hypoglycemia); 3) How we manage your blood sugar levels; 4) Blood sugar checks (how often); 5) Diet (restrictions, meals on demand); 6) Discharge planning; 7) Common questions such as use of own meter, reasons for different insulins, pumps, and CGM. The brochure is printed for the patient with the first time any insulin order set is ordered. The brochure is available in Spanish, Chinese and Russian.

Evaluation: We audited brochure distribution to determine percentage of patients who received the brochure and developed a survey to determine the patient’s understanding of the brochure.

Results: Audit results: After upgrades to the order sets so brochure would be printed, 100% of 50 charts had printed brochures. The survey: was hand delivered to 40 consecutive patients on insulin. 32 of the patients had ≧90% correct responses. The remaining 8 averaged 60% correct response.

Conclusion: We successfully produced a brochure that explains inpatient diabetes management to newly admitted patients. Whether the patients who had decreased understanding may have been too ill to completely understand the brochure and possible changes in patient satisfaction remain to be explored.

Disclosure

R.J. Rushakoff: None. H.W. MacMaster: None.
231-LB: Innovative Blood Sampling Technology for Convenient, Nearly Painless, and Accurate Monitoring of Diabetes
Authors: ROMEO ELISA , BRYANT-GREENWOOD PETER K. , CASTORINO KRISTIN N. , LILJENQUIST DAVID R. , JORDAN BRETT L. , HARRINGTON MINDY , HOLSCHER TODD , ALEXANDER CLAIRE , DOKUKIN VICTOR , NERLEKAR MUKUL , WILLIAMSON LUCY , SLOANE JESSICA
Published: June 2019

Monitoring HbA1c levels in individuals affected by diabetes remains the standard of care for ensuring proper management of the condition. Typically, HbA1c is measured by venipuncture or fingerstick blood collection methods at regular intervals, and for nearly all diabetic patients, monitoring HbA1c is a lifelong endeavor. In general, venipuncture and fingerstick are standard blood collection procedures, which are considered inconvenient and painful. Patient surveys have shown that venipuncture induces fear (needle phobia) in more than 20% of adults and in 60% of children. We have designed, developed, and validated an innovative blood sampling device to collect and stabilize capillary blood from the patient’s upper arm. Using small skin incisions and vacuum, the device draws and deposits the blood onto self-contained matrices. The matrices’ cartridge is then shipped at room temperature to a clinical laboratory for HbA1c measurement. We conducted a clinical study at three sites within the U.S. to validate the use of the device on 146 enrolled participants. The primary study objective was to compare HbA1c measurement in samples collected by the device and venipuncture. Pain measurements were conducted to assess the discomfort associated with the use of the device, in comparison to venipuncture and fingerstick. The data demonstrated a strong correlation between the device and venipuncture (y=1.01-0.0131, R2=0.997) over a range of HbA1c values between 4.91 and 13.34%. Device lot-to-lot and operator-to-operator reproducibility studies showed CVs of 0.7% and 0.8%, respectively. Assessment of discomfort showed an average pain score of 1 for the device (on a scale 0 to 10) and the device was preferred over venipuncture and fingerstick by 79% of the subjects. We clinically validated an innovative blood sampling technology that provides a convenient, nearly painless, safe and effective alternative to venipuncture and fingerstick for HbA1c measurement in diabetic individuals.

Disclosure

E. Romeo: Employee; Self; Drawbridge Health, Inc. P.K. Bryant-Greenwood: None. K.N. Castorino: Consultant; Self; Abbott. Research Support; Self; Abbott, Dexcom, Inc., Drawbridge, Novo Nordisk Inc., Sanofi US. D.R. Liljenquist: None. B.L. Jordan: Employee; Self; Drawbridge Health. Employee; Spouse/Partner; Innovation Endeavors, LLC. M. Harrington: Employee; Self; Drawbridge Health. T. Holscher: Employee; Self; Drawbridge Health. C. Alexander: Consultant; Self; CAlexanderConsulting, LLC. V. Dokukin: Employee; Self; Drawbridge Health. M. Nerlekar: Employee; Self; Drawbridge Health. L. Williamson: Other Relationship; Self; Drawbridge Health. J. Sloane: Other Relationship; Self; Drawbridge Health.
2355-PUB: Discontinuation of Dapagliflozin in DEPICT-1 and DEPICT-2 Led to Clinically Meaningful Increases in HbA1c and Body Weight
Authors: GORDON JASON , DANNE THOMAS , BERESFORD-HULME LEE M. , BENNETT HAYLEY , TANK AMARJEET , EDMONDS CHRISTOPHER , THOREN FREDRIK A. , SCHEERER MARKUS F. , MCEWAN PHILIP
Published: June 2019

Concerns about hypoglycaemia and weight gain are barriers to treatment adherence, and consequently glucose control, in type 1 diabetes (T1D). In adults inadequately controlled by insulin alone, DEPICT-1 and DEPICT-2 phase 3 trials showed statistically significant decreases in HbA1c, glycaemic variability and body weight for adjunct dapagliflozin (DAPA), along with moderate reduction in insulin requirements. As adherence to T1D treatment can be a daily challenge, understanding the implications of discontinuation is important. This study evaluated changes in HbA1c, weight and insulin dose following discontinuation of DAPA in the DEPICT trials. Data were analyzed from patients discontinuing DAPA (5 mg or 10 mg, added to insulin) at any point in DEPICT-1 or DEPICT-2 (unplanned or end of study). Annualized rates of change in HbA1c (%) and weight (kg) following discontinuation of DAPA were estimated via linear regression and trajectories derived from mean rates of change. Insulin doses were summarized before and after discontinuation and correlated to analyzes of weight and HbA1c. The main reasons for unplanned discontinuation of DAPA were adverse events and patient withdrawal of consent. Following DAPA discontinuation, annualized changes in HbA1c and weight were +0.99% (95% CI: 0.39, 1.59) and +3.75Kg (1.65, 5.86), respectively (N=91). Mean insulin dose two weeks post-discontinuation was higher than two weeks prior to discontinuation (5mg: +4.0 IU, 10mg: +4.4 IU). These estimates directly contrast to observed reductions in HbA1c, weight and insulin dose associated with DAPA treatment. Discontinuation of DAPA led to significant increases in HbA1c and weight, in addition to higher insulin doses soon after discontinuation. Enabling ongoing DAPA treatment may benefit patients due to the detrimental impact of poor glycaemic control and weight gain on retinopathy, nephropathy and cardiovascular disease shown in long-term T1D studies, such as DCCT and EDIC.

Disclosure

J. Gordon: Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, GlaxoSmithKline plc., Novartis AG, Novo Nordisk A/S, Pfizer Inc., Takeda Canada, Takeda Pharmaceutical Company Limited. T. Danne: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Novo Nordisk A/S, Roche Diabetes Care, Sanofi-Aventis. Speaker's Bureau; Self; Dexcom, Inc. L.M. Beresford-Hulme: None. H. Bennett: Consultant; Self; AstraZeneca. Employee; Self; Health Economics and Outcomes Research Ltd. A. Tank: Employee; Self; AstraZeneca. C. Edmonds: Employee; Self; AstraZeneca. F.A. Thoren: Employee; Self; AstraZeneca. M.F. Scheerer: Employee; Self; AstraZeneca. P. McEwan: Consultant; Self; AstraZeneca. Employee; Self; Health Economics and Outcomes Research Ltd.
2372-PUB: An EHR-Based Tool to Aid Treatment Decisions and Combat Therapeutic Inertia in Patients with Uncontrolled Type 2 Diabetes—A Pilot Study
Authors: PANTALONE KEVIN M. , MISRA-HEBERT ANITA D. , RAJPATHAK SWAPNIL , WEISS TRACEY , HAMATY MARWAN , ZIMMERMAN ROBERT S.
Published: June 2019

An electronic health record (EHR)-based tool was developed for EPIC My Practice at Cleveland Clinic to aid treatment decisions and combat therapeutic inertia in patients with type 2 diabetes (T2D) and suboptimal glycemic control (A1C ≥8%). The tool consists of three separate components activated during an office visit: a best practice alert (BPA) if a patient had an A1C ≥ 8% within the past 6 months, a Smartform (patient summary and order entry form), and a Smartset for T2D medications to achieve patient-centered treatment goals, supplies, laboratory, and consult orders. The provider may acknowledge the BPA and pursue therapy intensification or defer. The tool was piloted for 3 months (primary care providers (PCP) n=12, endocrinology providers n=5). BPA acknowledgement and utilization practices were recorded by specialty. The CollaboRATE survey (3 items, scale 0-9) was used to assess patient perceptions of shared decision-making afforded by the tool. The BPA appeared for 420/1,766 T2D patients at an office-based encounter with a PCP or endocrinology provider. While the BPA was acknowledged at most endocrinology visits (95%) and approximately 50% of primary care visits, use of all three components of the tool only occurred in ∼10% of eligible encounters. The CollaboRATE survey was administered to a subset of 83 patients exposed to the tool. Most chose the highest rating for questions assessing if efforts were made to: 1. help them better understand their health issue (87%), 2. listen to what matters most to them about their health issue (93%) and 3. integrate what matters to them into next steps (92%). Use of an EHR-based tool to aid treatment decisions is variable by specialty, though appears to lead to a high perception of shared decision-making for T2D patients. Additional provider education and improved incorporation of the tool into PCP work-flow may help to address therapeutic inertia in routine clinical practice.

Disclosure

K.M. Pantalone: Consultant; Self; Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; Merck & Co., Inc., Novo Nordisk Inc. Speaker's Bureau; Self; AstraZeneca, Merck & Co., Inc., Novo Nordisk Inc. A.D. Misra-Hebert: Research Support; Self; Agency for Healthcare Research and Quality, Merck & Co., Inc., Novo Nordisk Inc. S. Rajpathak: None. T. Weiss: Employee; Self; Merck & Co., Inc. M. Hamaty: Consultant; Self; Applied Clinical Intelligence, LLC. R.S. Zimmerman: Consultant; Self; Novo Nordisk Inc. Research Support; Self; Merck & Co., Inc., Novo Nordisk Inc. Speaker's Bureau; Self; Johnson & Johnson Diabetes Institute, Merck & Co., Inc.
239-OR: Association between Hemoglobin A1c and Stroke Risk in Patients with Type 2 Diabetes
Authors: SHEN YUN , SHI LIZHENG , NAUMAN ELIZABETH , KATZMARZYK PETER , PRICE-HAYWOOD EBONI G. , BAZZANO ALESSANDRA N. , NIGAM SOMESH , HU GANG
Published: June 2019

Clinical findings regarding the association between hemoglobin A1c (HbA1c) and stroke risk remain inconclusive, especially among patients with diabetes. We aimed to investigate the association between HbA1c and the risk of incident stroke in patients with type 2 diabetes using electronic medical record data from three large healthcare systems in Louisiana. We performed a retrospective cohort study of 27,113 African Americans and 40,431 whites with type 2 diabetes. Cox proportional hazards regression models were used to estimate the association of different levels of HbA1c with stroke risk. During a mean follow-up period of 3.74 years, 8986 patients developed stroke (8438 ischemic and 548 hemorrhagic). Multivariable-adjusted hazard ratios across levels of HbA1c at baseline (<6.0, 6.0-6.9 [reference group], 7.0-7.9, 8.0-8.9, 9.0-9.9, and ≥10%) were 1.05, 1.00, 1.13, 1.21, 1.24, and 1.35 (Ptrend <0.001) for total stroke, 1.04, 1.00, 1.13, 1.21, 1.24, and 1.35 (Ptrend <0.001) for ischemic stroke, and 1.26, 1.00, 1.10, 1.26, 1.22, and 1.40 (Ptrend =0.284) for hemorrhagic stroke. When we used an updated mean value of HbA1c, the U-shaped association of HbA1c with stroke risk did not change. This U-shaped association was consistent among patients of different age, race, sex, body mass index, never and past or current smokers. The U-shaped association was more pronounced among patients taking antidiabetic, lipid-lowering and anti-hypertensive medications compared with those without these medications. In the U-shaped association between HbA1c and the risk of total, ischemic and hemorrhagic stroke among patients with type 2 diabetes, the lowest risk was found among patients with HbA1c at 6-7 mmol/L.

Disclosure

Y. Shen: None. L. Shi: None. E. Nauman: None. P. Katzmarzyk: None. E.G. Price-Haywood: None. A.N. Bazzano: None. S. Nigam: None. G. Hu: None.

Funding

Patient-Centered Outcomes Research Institute (NEN-1508-32257); National Institute of General Medical Sciences (U54GM104940 to G.H., P.K.)