bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Metformin on Lymphoid Cancer Cells
Authors: AHMADI NEEKI , SEN SABYASACHI 
Published: June 2018

Metformin is a commonly prescribed drug for metabolic disorders particularly in type 2 diabetes. In addition to Metformin’s established antidiabetic effect it has a potential for use as an anti-cancer medication, via mitochondrial complex inhibition.
Methods: In order to determine what effect Metformin could have on a common cancer such as lymphoma at a cellular level, we performed a 14 day experiment on the effect of 3 different doses of Metformin (0mM, 0.025mM, 0.25mM) on two different lymphoid cell lines, Jurkat and Jeko. Metformin at 0.025mM, is considered physiological. Cells in culture were collected on Days 3, 7, 10, and 14 and RT-PCR targeted gene expression was carried out focusing on mitochondrial and apoptosis related genes such as cytochrome oxidases (COX2 and 4), nuclear respiratory factor (NRF1), apoptosis gene (P53) and other mitochondrial genes such as PGC1A, SOD2, and TFAM.
Results: Jeko cells showed initial significant mitochondrial gene suppression with Metformin. The suppression in mRNA gene expression however appear to reverse by day 7. By Day 10 there is a uniform up-regulation in mRNA expressions and the effects stabilized by day 14. Our Jurkat cells showed less consistent mRNA level changes, though the pattern was similar.
In summary, Jeko cells, upon initial exposure to Metformin, show a decrease in mitochondrial biogenesis and increased apoptosis. This initial suppression seems to be replaced by over-expression of mitochondrial genes over a period of time and its effects stabilizes by day 10 of exposure. This phenomenon appears to be shown in both cell lines. We plan to corroborate our gene expression findings with Sea-Horse cell respiration studies.
Conclusion: We believe that Metformin initially causes cancer cell damage, however with time the cells are able to escape that phenomenon by up-regulating mitochondrial genes particularly at physiological doses. In order for Metformin to be an effective pro-apoptotic agent in a cancer scenario, brief pulses of supra-physiological doses may be more effective.

Disclosure
N. Ahmadi: None. S. Sen: None.
Success of Interactive, Case-Based Education on Improving Physician Clinical Competence
Authors: LARKIN AMY , HANLEY KELLY L. , HEALY COLLEEN S. , LE ANNE 
Published: June 2018

We sought to determine if interactive, case-based online continuing medical education (CME) could improve the clinical competence of primary care physicians (PCPs) and diabetologists/endocrinologists (D/Es) regarding clinical application of guidelines and individualized diabetes management. A 3-question case-based and 1-question confidence linked pre-/post-assessment study design and McNemar’s chi-squared test were used. P values are shown as a measure of significance. The activity launched May 3, 2017, and data collected through June 6, 2017. PCPs (N=473) demonstrated a lower baseline knowledge level compared to D/Es (N=198) as shown by the following baseline data: 35% of PCPs compared to 61% of D/Es corrently individualized treatment for a patient with T2D and HF.22% of PCPs compared to 37% of D/Es correctly individualized treatment for a patient with newly diagnosed T2D and multiple comorbidities. Significant overall improvements (P &lt; .05) were seen: 26% more D/Es and 36% more PCPs correctly individualized the T2D treatment regimen of a patient with comorbid HF.15% more D/Es and 11% more PCPs addressed the importance of lifestyle modification in a patient with newly diagnosed T2D.47% more D/Es and 49% more PCPs correctly individualized pharmacotherapy intensification in a patient with T2D.20% of D/Es and 32% of PCPs reported an increase in confidence initiating or intensifying treatment in patients with T2D. This study demonstrates the success of interactive, case-based education on improving clinical competence of D/Es and PCPs related to management of T2D. PCPs were found to have lower baseline knowledge and competence compared to D/Es, which is not surprising given the level of specialization in both groups. PCPs may need more foundational education related to guidelines and T2D management than D/Es.

Disclosure
A. Larkin: None. K.L. Hanley: None. C.S. Healy: None. A. Le: None.
Empagliflozin Exhibits Therapeutic Effect in Preclinical Model of Liver Disease (NASH)
Authors: MAYOUX ERIC , KLEIN THOMAS , MARK MICHAEL 
Published: June 2018

Nonalcoholic steatohepatitis (NASH) and diabetes are common conditions that coexist and drive adverse outcomes. Empagliflozin (empa), a sodium-glucose co-transporter-2 inhibitor (SGLT2i), has achieved a 38% reduction in the cardiovascular (CV) and all-cause mortality in type 2 diabetes patients with high CV risks. In preclinical models, SGLT2 inhibitors have been reported to increase insulin sensitivity, decrease body weight and reduce markers of oxidative stress and inflammation in tissues. Therefore, we investigated the effect of empa in a mouse model of NASH and hyperglycemia. Neonatal male mice (2 days after birth) were injected subcutaneously with streptozotocin and then were fed with a HFD from 4 weeks of age. Then from 6 to 8 weeks of age, mice were treated by oral gavage with vehicle, empa (10 mg/kg) in comparison to telmisartan (telmi, 15 mg/kg) as positive control. A group of mice, under normal diet and without STZ injection were used also as normal controls. NAS, (Histological NAFLD Scoring) evaluating fat deposition, inflammation and ballooning as well as mRNA expression for inflammation markers were performed. Blood glucose level was significantly increased in the vehicle group (525 mg/dL,) compared to the normal group (50 mg/dL). Empa significantly decreased the blood glucose (261 mg/dL) while telmi did not (429.4 mg/dL). NAS was significantly increased in the vehicle (4.1) compared to the normal control (0.0) groups and significantly decreased in telmi (1.4) and empa (1.4 ± 1.0) groups compared to the vehicle group. Telmi but also empa reduced collagen deposition and ameliorated the fat deposition. This was accompanied by a significant reduction of hepatic TNFα mRNA (1.7, 2.8 for telmi and empa, respectively compared to vehicle group (5.7). These features may qualify empagliflozin for the therapy of NASH and raise interest to evaluate further the potential of the combination of these two approved drugs, with different modes of action in the treatment of liver diseases.

Disclosure
E. Mayoux: None. T. Klein: Employee; Self; Boehringer Ingelheim GmbH. M. Mark: Employee; Self; Boehringer Ingelheim GmbH.
Effect of a Controlled-Release Mitochondrial Protonophore (CRMP) on Healthspan and Lifespan in Mice
Authors: GOEDEKE LEIGH , CAMPOREZ JOAO PAULO , NASIRI ALI , WANG YONGLIANG , ZHANG XIAN-MAN , SHULMAN GERALD I. 
Published: June 2018

Caloric restriction without malnutrition (CR) is the most robust and reproducible way to extend lifespan and delay the onset of age-related diseases, such as hepatic steatosis, insulin resistance and type 2 diabetes (T2D). Unfortunately, the strict dietary regime necessary to achieve the beneficial effects of CR limits the use of this treatment to retard aging and disease in humans and new therapies are required. In this regard, our lab has recently developed a new class of therapeutic agents that are designed to safely promote liver-targeted mitochondrial uncoupling with a wide-therapeutic index. Our second-generation compound in this class is controlled-release mitochondrial protonophore (CRMP) that is functionally liver-targeted and promotes oxidation of hepatic triglycerides by promoting a subtle sustained increase in hepatic mitochondrial inefficiency. While we have previously demonstrated that this agent safely reverses hypertriglyceridemia, fatty liver, and hepatic inflammation/fibrosis in young-adult diet-induced rodent models of obesity, its effects on healthspan and lifespan remain to be determined. Here, we evaluated the impact of CRMP on hepatic steatosis and insulin action in aged 74-week-old male C57BL/6J mice fed a high-fat diet (HFD; 45% fat) for 12 weeks. Specifically, we demonstrate that CRMP treatment significantly reduced liver triglycerides, diacylglycerols, and transaminase levels independently of changes in body weight, whole-body energy expenditure or food intake. Additionally, long-term CRMP treatment reduced fasting plasma glucose concentrations (P &lt;0.05) and improved whole-body insulin responsiveness, as reflected by a marked increase in the glucose infusion rate required to maintain euglycemia during a hyperinsulinemic-euglycemic clamp. Taken together, these studies provide important proof-of-concept data to support the use of liver-targeted mitochondrial uncouplers to promote healthy aging.

Disclosure
L. Goedeke: None. J. Camporez: None. A. Nasiri: None. Y. Wang: None. X. Zhang: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc.. Research Support; Self; Gilead Sciences, Inc..
Compound C Inhibits NLRP3 Inflammasome through an AMPK-Independent Mechanism
Authors: WANG FANG , YANG WENJUN , WANG LINGHAO , LIU YUXING , MO ZHAOHUI 
Published: June 2018

It has been demonstrated that NLRP3 inflammasome is a key contributor to obesity-related insulin resistance and type 2 diabetes (T2D), which are characterized with chronic, low-grade inflammation. Adenosine monophosphate-activated protein kinase (AMPK) is a principle intracellular energy sensor, which prevents the production of proinflammatory cytokines and has beneficial effects on the protection against T2D. Comound C, an inhibitor of AMPK, has been demonstrated to be not only an inhibitor of AMPK, but also has some actions independent of AMPK inhibition. We unexpectedly found 25uM compound C considerably inhibited IL-1βand IL-18 secretion when THP-1 cells were stimulated with 100ng/ml LPS plus 0.5mM palmitic acid (PA) (P &lt; 0.01). In order to address the underlying mechanism, we examined whether compound C affected NLRP3 inflammasome, a multiprotein complex which controls the processing and production of IL-1β and IL-18. Contrary to our expectations, compound C significantly inhibited NLRP3 inflammasome activation (P &lt; 0.05). Additionally, this effect was reproduced in AMPK siRNA transfected THP-1 cells, indicating that compound C exerts this function through an AMPK-independent mechanism. Mechanistically, we found compound C significantly suppresses mitochondria generated reactive oxygen species (ROS), which is required for NLRP3 inflammasome activation.
In conclusion, we demonstrate for the first time that, compound C significantly inhibited NLRP3 inflammasome in an AMPK-independent manner, suggesting NLRP3 inflammasome is to be the novel target of compound C. And we inferred that compound C inhibit NLRP3 inflammasome may through the suppression of mitochondrial ROS production. These findings offer unique insight into compound C as a novel pharmacological agent with significant therapeutic potential in NLRP3 inflammasome-related disorders including obesity, insulin resistance and T2D. Further studies are needed to identify the effect of compound C on these diseases in vitro.

Disclosure
F. Wang: None. W. Yang: None. L. Wang: None. Y. Liu: None. Z. Mo: None.
The Effect of Metformin and Dapagliflozin on Epicardial Adipose Tissue in Prediabetes and Type 2 Diabetic Patients
Authors: AL-TALABANY SHAWEEN , WEIR-MCCALL JONATHAN , MOHAN MOHAPRADEEP , SINGH JAGDEEP S. , MORDI IFY , GANDY STEPHEN J. , KHAN FAISEL , CHOY ANNAMARIA , HOUSTON JOHN G. , PEARSON EWAN , GEORGE JACOB , STRUTHERS ALLAN D. , LANG CHIM C. 
Published: June 2018

Background: Epicardial adipose tissue (EAT) is an emerging cardio-metabolic risk factor that has been shown to correlate with adverse cardiovascular outcomes through potential local and systemic effects. Consequently, EAT has been proposed as a therapeutic target. The biguanide, metformin, and Sodium-glucose Cotransporter-2 inhibitors have been reported to improve cardiovascular outcomes. We have investigated the effects of both metformin and dapagliflozin, on EAT in patients with prediabetes and type 2 diabetes respectively.
Methods: EAT area measurements were performed blindly on cine 4 chamber views during the end diastolic phase of the cardiac cycle at baseline and at the end of study treatment using CMR scans in patients that participated in two randomized double-blinded placebo controlled trials: (1) MET-REMODEL (ClinicalTrials.gov. NCT02226510) (n=68 patients, mean age 65 ± 8 y; mean BMI 31.9 ± 3.6 kg/m²) with prediabetes and /or insulin resistance who received either metformin (2g /day) or placebo for 12 months and (2) REFORM (ClinicalTrial.gov NCT02397421) (n=56 patients, mean age 67 ± 7 y; mean BMI 32.5± 5.3 kg/m²) with chronic heart failure and type 2 diabetes who received either dapagliflozin (10mg/day) or placebo for 12 months respectively.
Results: Metformin treatment in the METREMODEL trial reduced body weight significantly by 4.2kgs (p=0.001).but did not reduce EAT area (metformin -0.1 ± 3.8 cm² vs. placebo -0.5 ± 2.9 cm² p= 0.7). In the REFORM trial, dapagliflozin reduced body weight significantly by -1.9 kg (p= 0.054) with no significant reduction in EAT area (dapagliflozin -1.00 ± 3.6 cm² vs. placebo -0.7 ± 3.1 p=0.8).
Conclusion: In prediabetes and type 2 diabetes, we found that metformin and dapagliflozin treatment resulted in significant weight loss but had no significant effect on EAT. Our findings suggest that the reported cardiovascular benefits of these two diabetic therapies are not likely to be mediated by effects on EAT.

Disclosure
S. Al-Talabany: None. J. Weir-McCall: None. M. Mohan: None. J.S. Singh: None. I. Mordi: None. S.J. Gandy: None. F. Khan: None. A. Choy: None. J.G. Houston: None. E. Pearson: Speaker's Bureau; Self; Eli Lilly and Company. J. George: None. A.D. Struthers: Research Support; Self; AstraZeneca. Advisory Panel; Self; AstraZeneca. C.C. Lang: None.
Physician Feedback on the Quality of Diabetes Care—An Important Strategy with Moderate Impact
Authors: ZAREI PARMIDA , HAM SANDRA A. , NATHAN AVIVA , SEPULVEDA LUISA , SARGIS ROBERT M. , QUINN MICHAEL T. , HUANG ELBERT , LAITEERAPONG NEDA 
Published: June 2018

Background: Physicians often receive feedback on their quality of diabetes care. However, it is unclear what performance measures (e.g., blood pressure targets) are used in this feedback, whether these measures correspond with diabetes care guideline recommendations, and whether feedback affects their clinical practice.
Methods: In 2016, we mailed a national survey to 1,200 U.S. primary care physicians and endocrinologists. We excluded physicians who did not provide longitudinal care to patients with type 2 diabetes (adjusted response rate, 41% (N=356)). Physicians were asked to report whether they received feedback on their quality of diabetes care, the hemoglobin A1c (A1C), cholesterol, and blood pressure (BP) goals they were encouraged to reach, and the usual A1C, cholesterol, and BP goals they recommend to their patients.
Results: In total, 56% of physicians reported receiving feedback. Among those who received feedback, the most frequent goals were an A1C&lt;7.0% (51%), LDL&lt;100 mg/dL (58%), and BP&lt;130/80 mmHg (37%). In clinical practice, physicians frequently used goals that did not correspond with performance measure goals (A1C, 53%; cholesterol, 51%; systolic BP, 45%; diastolic BP, 47%). Only 22% of physicians reported that receiving feedback on their quality of diabetes care affected their treatment decisions “most of the time”/“almost always,” compared to 40% and 38% reporting “sometimes” and “never”/“rarely,” respectively.
Conclusions: Many U.S. physicians are being measured on their quality of diabetes care using performance measures that are inconsistent with diabetes care guidelines and national quality standards. Further, many physicians may not be strongly influenced by diabetes performance measurement. These discrepancies suggest that the impact of physician feedback on quality of diabetes care may be limited.

Disclosure
P. Zarei: None. S.A. Ham: None. A. Nathan: None. L. Sepulveda: None. R.M. Sargis: Advisory Panel; Self; CVS/Caremark. M.T. Quinn: None. E. Huang: None. N. Laiteerapong: None.
Cost as the Main Driver of T2D Treatment Patterns—Lessons from Real-World Data and Physician Focus Groups
Authors: WU SZE-JUNG , RAVAL AMIT D. , STEPHENSON JUDITH J. , PENG XIAOMEI , WEISMAN HARRY , FARIES DOUGLAS E. 
Published: June 2018

This two-phased study consists of a decision tree model built from real-world claims data to determine factors related to physician choice of 2nd line therapy for type 2 diabetes (T2D) patients after metformin, followed by a physician focus group study to validate results of the data-driven approach. We identified 58patients in the U.S. who initiated sulfonylurea (SU), DPP-4 inhibitor, GLP-1-RA, or insulin after metformin during 2012-2014 from the HealthCore Integrated Research Database. Claims-derived factors, such as demographics, clinical characteristics, and prior healthcare utilization and costs, were selected from a classification and regression tree (CART) model that minimized classification errors. Of factors most predictive of 2nd line drug assignment, patients’ cost sharing for antidiabetic drugs (Relative Importance, RI=1) was 3 times more important than HbA1c level (RI=0.3), and 10 times more important than age, comorbidity, and kidney status (GFR) (RI=0.1). SU was most likely to be assigned to patients with lowest drug spending, moderate HbA1c control, abnormal kidney function, or no comorbid conditions. Similar themes were identified from the four physician focus groups (consisting of 8 endocrinologists and 10 PCPs in NYC and LA) and supported the findings. This study identified a gap in diabetes care where patients often receive SU due to lack of access to other treatment options.

Disclosure
S. Wu: None. A.D. Raval: None. J.J. Stephenson: None. X. Peng: Employee; Self; Eli Lilly and Company. H. Weisman: Employee; Self; Anthem, Inc. D.E. Faries: Employee; Self; Eli Lilly and Company.
Embedding Diabetes Expertise within Primary Care
Authors: CLORE JOHN N. , THURBY-HAY LINDA 
Published: June 2018

Efficient delivery of care within the primary care setting is critical to address the needs of the vast majority of individuals living with diabetes. And yet, as diabetes care has become more complex, primary care providers often find themselves insufficiently prepared and capacity for referral to subspecialty care is lacking. We have designed and implemented a novel program within primary care practices in a large healthcare system. Practices were engaged in a model whereby an interprofessional diabetes team was embedded for 6 months. The team was composed of an endocrinologist, CNS, PharmD and RD. The practices were oriented to the program and questions and concerns addressed. All diabetes metrics were pended as a part of the rooming process. Patient-centered care was delivered in one-on-one visits with the entire team as well as in shared medical appointments. Providers and staff were provided didactic and experiential instruction in practical strategies to diabetes care to ensure that diabetes self-management training (DSMT) was available within the practice once the 6 month program was completed.
Results: 157 patients with type 2 diabetes participated in the initial program. Age (58.4±11.8 years), gender (82F/75M), and HbA1c (9.8±2.0%) characterized the selected population. 40 individuals did not return for a second visit so data were analyzed for those completing at least 2 visits. Over the course of the program, HbA1c fell from 10.3±0.02 to 8.2±0.01%*; adherence to diabetes metrics increased for foot exams (31.2 to 98.1% *), microalbumin (61.1 to 87.2%*) and eye exams (25.5 to 47.1%*, * p&lt;0.01 all comparisons) . All patients were returned to their primary care provider for long term care after completion of the program or once target HbA1c (&lt;7.0%) had been achieved.
Conclusion: Embedding an interprofessional diabetes team within a primary care setting 1) significantly improves HbA1c and overall diabetes care; 2) provides sustainable DSMT services for primary care providers; and 3) focuses greater attention on diabetes.

Disclosure
J.N. Clore: None. L. Thurby-Hay: None.
Characterization of Patients Requiring High-Dose Insulin Infusion for the Management of Hyperglycemia
Authors: FELEKE AFOMIA A. , FULLER RACHAEL C. , ISMAIL REEM , CADIZ MEGAN 
Published: June 2018

There are several validated insulin infusion protocols to help guide intravenous (IV) insulin dose titrations. However, when continued upward titration of insulin infusion is required to achieve glycemic control, little is known to guide how high the infusion rate can be increased without compromising safety and improving efficacy. The purpose of this study was to characterize patients requiring high-dose insulin infusions (rates &gt;20 units/hour) for the management of hyperglycemia and determine the incidence at our institution. A retrospective chart review of all patients aged 18 years or older who received IV insulin infusion between 01/01/2016 and 07/31/2017 at Beaumont Hospital, MI resulted in 82 patients (2.9%) who received high-dose insulin infusion for the management of hyperglycemia. Average age was 62 years old and majority were Caucasian males. Most patients had hyperglycemia associated with risk factors such as: history of type 2 diabetes (71%), obesity (median body mass index (BMI) was 33.9 kg/m2), critical illness (89%), many were surgical patients (&gt;50%), and a large proportion received vasopressors (79%) and corticosteroids (36%). The highest infusion rate observed was 80 units/hour, with a median infusion rate of 6.5 units/hour. Hypoglycemia (BG ≤ 70 mg/dl) was reported in 29% of patients and 11% had recurrent hypoglycemic episodes. Our findings suggest that the overall need for high-dose insulin infusion rates is very low. However, the incidence of hypoglycemia in these patients was substantially high and therefore concerning. Insulin is a high-alert medication requiring implementation of appropriate safety measures to prevent errors and careful investigation is warranted when used in high-doses. We recommend an insulin infusion “time-out” to assess the infusion site, the IV line and insulin bag before exceeding 20 units/hour. Furthermore, institutional policies for soft- and hard-maximum infusion parameters should be established to conserve use.

Disclosure
A.A. Feleke: None. R.C. Fuller: None. R. Ismail: None. M. Cadiz: None.