bluuebunny/crossref_metadata_2025_split huggingface dataset:
Understanding and Addressing Enrollment Challenges in Pediatric T2D Clinical Trials Compared with T1D
Authors: TERRY AMANDA M. , BOLLEPALLI SUREKA , SMITH LAURA , WALKER ASHBY F. , GAL ROBIN L. , BEAULIEU LINDSEY C. , EDELEN RACHEL C. , LESS JOANE E. 
Published: June 2018

Background: While behavior and diet modifications are the first line of defense in treating T2D, pediatric patients requiring additional intervention have few options compared with adults with T2D. The disparity in available treatments can be attributed, in part, to enrollment challenges in pediatric T2D clinical trials that delay FDA approval of new therapies.
Methods: Established in 2008, the Pediatric Diabetes Consortium has connected 49 diabetes research institutes and Industry partners to address enrollment challenges at a structural level. Yet, we must also address the social, economic and cultural barriers to participation specific to T2D pediatric patients.
Barriers: The overall prevalence in 2009 of T1D vs. T2D in youth was 1.93/1,000 compared to 0.24/1,000, with T1D affecting a wider age span. T2D is rarely diagnosed in children &lt;10 years. While there are racial and ethnic disparities in diabetes prevalence overall, they are more pronounced in T2D. Thus, compared to T1D, potential T2D pediatric study participants are fewer, older and more likely to face barriers to participation that include financial concerns, transportation issues, familial disruptions, distrust of research, health illiteracy, language barriers and parents’ inability to miss work.
Conclusion: Addressing barriers is critical to ensure clinical trial success and improved quality of life for these patients. Industry sponsors should make translated materials, such as e-diaries available for non-English speakers, particularly for Spanish speakers and consider quality of life assessments as a secondary outcome. Researchers should partner with community leaders in areas with high T2D prevalence, to establish trust between the patient community and research institution. Additionally, incentives that address families’ social and economic needs should be offered, including direct compensation to offset costs associated with trial participation such as travel and lost income.

Disclosure
A.M. Terry: None. S. Bollepalli: None. L. Smith: None. A.F. Walker: None. R.L. Gal: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Development Center Americas, Inc., Novo Nordisk Inc. L.C. Beaulieu: Research Support; Self; Novo Nordisk Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Takeda Development Center Americas, Inc.. R.C. Edelen: None. J.E. Less: None.
Exploring the Role of Insulin and IGF-I Receptor Signaling in the Pluripotency, Differentiation, and Maintenance of Stem Cells
Authors: OKAWA ERIN , GUPTA MANOJ K. , HU JIANG , SLIPP BRITTANY A. , KULKARNI ROHIT 
Published: June 2018

Pluripotent stem cells (PSCs) express insulin receptors (IR) and insulin-like growth factor-1 receptors (IGF-1R). In human embryonic stem cells (hESCs), IGF-1R is necessary for cell survival, self-renewal and differentiation into endoderm. Data on the role of IR in hESCs is limited; it’s been linked to self-renewal and pluripotency of murine neural stem cells. What’s still unclear is the significance of IR and IGF-1R in modulating stem cell function, pluripotency and differentiation. We created murine induced PSCs (iPSCs) with double knockout (DKO) of IGF-1R and IR. Analysis of 4 individual iPSC clones from 4 control and DKO mice showed similar cell proliferation and morphology. QPCR of pluripotency markers showed significant decreases in Lin28a (p&lt;0.005) and Tbx3 (p&lt;0.0005) expression in DKOs; Lin28a protein levels were also decreased. IPSCs from both groups developed into embryoid bodies in vitro and formed teratomas in vivo, indicating equal abilities to differentiate. With directed differentiation towards a neural lineage, DKOs showed upregulation of neural markers Brn2, Pax6, Sox1, Ngn2 and NeuN. We next examined downstream signaling of IR and IGF-1R. Although both groups showed mTor, Akt and Erk phosphorylation in the basal state, mTor phosphorylation in DKOs was significantly lower (28% of controls; p&lt;0.05). Total mTor and Akt protein levels in DKOs were also lower (31% and 59% of controls, respectively; p&lt;0.05). Prior to stimulation, basal phosphorylation of Stat3 was evident only in DKOs. It was increased 3-fold (p&lt;0.05) upon treatment with IGF-1 or insulin (100 nM) compared to controls. Stimulation with LIF (100 unit/mL) led to Stat3 phosphorylation in both groups; this was 1.5-fold greater in DKOs compared to controls (p&lt;0.005). These data suggest activation of a receptor independent of IR and IGF-1R and/or alterations in downstream proteins in the canonical IR/IGF-1R pathway that allow DKO iPSCs to maintain pluripotency and undergo differentiation.

Disclosure
E. Okawa: None. M.K. Gupta: None. J. Hu: None. B.A. Slipp: None. R. Kulkarni: None.
Flash on Gut Microbiome in GDM and Non-GDM Pregnancies
Authors: FESTA CAMILLA , CORLETO VITO D. , TOSCANO MARCO , BITTERMAN OLIMPIA , DRAGO LORENZO , NAPOLI ANGELA 
Published: June 2018

Aims: A specific composition of gut microbiota can increase insulin resistance. The aim of this pilot study was to find differences between pregnant women with GDM and controls in terms of gut microbiota composition during the 3rd trimester.
Methods: This study was carried out in 20 women, 10 with GDM (IADPSG criteria) (Age 36.2±4.4 years; BMI 24.6 (21.4-26.8)Kg/m2) and 10 controls (Age 32.0±2,7 years; BMI 22.1 (19-24.1)Kg/m2) at the 34-36th week of gestation, when fecal samples were collected. Exclusion criteria: antibiotics/probiotics/symbiotics/metformin use during gestation, GADAb+, twin pregnancy, IBD. Genera and species were detected by using a Next Generation Sequencing technology (Ion Torrent Personal Genome Machine). Statistics: SPSS.
Results: the two groups were well matched a part from age (p=0.04). No difference in weight gain (GDM 12.2±4.9; Controls 12.4±5.1 Kg). With regard to the primary aim we found an higher Relative Abundance of Bacteroides caccae, massiliensis, thetaiotaomicron (respectively 87%, 89,4%, 91%; p&lt;0.05) together with a reduction of Bacteroides vulgatus, Eubacterium eligens, Lactobacillus rogosae, Prevotella copri (respectively 27,4%, 41,5%, 6%, 25%; p&lt;0,05) in women with GDM. No difference in biodiversity indexes.
Conclusion: the recognition of a “GDM-related” gut microbiome could lead to symbiotics/probiotics formula for GDM prevention and/or treatment.

Disclosure
C. Festa: Consultant; Self; Menarini Group. Other Relationship; Self; Merck Sharp & Dohme Corp.. V.D. Corleto: None. M. Toscano: None. O. Bitterman: None. L. Drago: None. A. Napoli: Other Relationship; Self; Merck Sharp & Dohme Corp..
Diabetes Can Accelerate Sarcopenia in the Diaphragm
Authors: YAMAMOTO MASASHI , TAKEMOTO MINORU , MASUYAMA HIDENORI , KOSHIZAKA MASAYA , MAEZAWA YOSHIRO , YOKOTE KOUTARO 
Published: June 2018

The diaphragm is a skeletal muscle that is involved not only in respiration but also in swallowing and lymphatic functions and maintaining posture. Only a few studies have described diaphragm thickness in patients with diabetes. Diaphragm thickness is usually evaluated using ultrasonography (U.S.). However, because evaluation of diaphragm thickness using U.S. is not routinely performed, it is difficult to assess it in a retrospective manner. Therefore, in this study, we developed a new method to evaluate diaphragm thickness in patients with diabetes using computed tomography (CT) and evaluated the correlation between U.S. and CT findings. Then, we evaluated the relationship among diaphragm thickness, age, and blood glucose metabolism. We prospectively evaluated the diaphragm thickness of 50 patients with diabetes using both U.S. and CT. The diaphragm thickness using CT was evaluated in the zone of apposition on contact with the thoracic cavity between the most frontal and dorsal positions, and the results were expressed as a sum of left and right measurements. The mean diaphragm thickness was 3.35 ± 0.64 mm and 3.73 ± 1.00 mm using U.S. and CT, respectively. The diaphragm thicknesses evaluated using both U.S. and CT were significantly correlated with each other (r = 0.3809, P = 0.0063). Then, we studied the data of 1patients with tuberculosis who had undergone CT and had a high morbidity of diabetes. The diaphragm thickness was positively correlated with body weight (r = 0.2911, P = 0.0088) and negatively with age and HbA1c (r = −0.4493, P &lt; 0.0001; r = −0.5507, P &lt; 0.0001, respectively). Moreover, the diaphragm thickness was significantly less in patients with diabetes than in those without diabetes. A thin diaphragm has been found to be related to poor prognosis among patients with acute pneumonia in intensive care units. Our results indicate that diabetes can accelerate sarcopenia of the diaphragm. Because the diaphragm has multiple functions, sarcopenia of the diaphragm in patients with diabetes might affect prognosis.

Disclosure
M. Yamamoto: None. M. Takemoto: None. H. Masuyama: None. M. Koshizaka: None. Y. Maezawa: None. K. Yokote: Research Support; Self; Astellas Pharm Ltd, MSD K.K..
The Changes of Leukocyte Telomere Length after Different Treatments in Patients with Type 2 Diabetes Mellitus (T2DM)
Authors: LIU JUANHONG , MA DELIN , YANG YAN 
Published: June 2018

Objective: The telomere length is closely related with cell growth, proliferation, senescence and carcinogenesis. Increasing evidences demonstrated that there may be a potential importance of telomere biology in type 2 diabetes. In this study, we intend to investigate the effects of different treatments on leukocyte telomere length in T2DM patients.
Methods: 436 T2DM patients randomly selected from the outpatient of Tongji Hospital were divided into 5 groups according to the their treatments: insulin group, acarbose group, metformin group, sulfonylurea group, and control group without any treatment. Clinical characteristics were collected and leukocyte telomere length was measured.
Results: Multiple linear regression analysis revealed that leukocyte telomere length of all T2DM patients was inversely associated with age(r=-0.3401,P&lt;0.01).The leukocyte telomere length had no significant difference among patients with different duration of T2DM (F=0.8913,P=0.4111).We grouped patients based on their treatments and compared the difference of their telomere length. One-way ANOVA analysis showed patients with different treatments had different leukocyte telomere attrition rates (F=61.7, P&lt;0.001). Insulin group had the slowest leukocyte telomere attrition rate (-13.36 ± 4.611) and sulfonylurea group (-14.91 ± 6.428) was slightly faster than insulin group. Leukocyte telomere attrition rates in metformin group (-17.33 ± 7.954) and control group (-17.7 ± 4.384) were almost the same. Acarbose group had the fastest leukocyte telomere attrition rate(-29.69 ± 6.696).
Conclusions: Leukocyte telomere length was decreased with age in T2DM patients, and different therapys had different effects on leukocyte telomere lengths. Insulin had an effect of slowing down the telomere attrition as well as acarbose seemed accelerating it. These results suggest that insulin might slow down aging during the period of T2DM while acarbose accelerate it.

Disclosure
J. Liu: None. D. Ma: None. Y. Yang: None.
Association between Allopurinol and Cardiovascular Events and All-Cause Mortality in Diabetes—A Population-Based Cohort Study
Authors: WEISMAN ALANNA , TOMLINSON GEORGE A. , LIPSCOMBE LORRAINE , PERKINS BRUCE A. , HAWKER GILLIAN A. 
Published: June 2018

Higher uric acid (UA) is associated with cardiovascular events and mortality. Allopurinol, a UA-lowering therapy, may reduce risk of these outcomes. Despite the high prevalence of elevated UA in diabetes, the association between allopurinol and cardiovascular events and mortality in diabetes is unclear.
A population-based cohort was constructed using administrative data in Ontario, Canada. Subjects with diabetes entered on receipt of a new prescription for allopurinol after age 66 (April 1/2002-March 31/2012) and were followed until a composite of all-cause mortality, stroke, myocardial infarction or revascularization. A Cox proportional hazards model was used for each sex, with time-varying allopurinol exposure modeled as yes/no, dose categories and cumulative dose.
Over a median [IQR] follow-up time of 4.7[1.8-7.8] years, the composite outcome occurred in 16,262/23,103 males and 10,566/15,313 females. Allopurinol exposure was associated with a reduction in the composite outcome in a dose-response manner but there was no cumulative dose effect (Table 1).
Any allopurinol exposure and higher allopurinol doses were associated with reduced cardiovascular events and mortality in a large diabetes cohort. Potential mechanisms include an acute reduction of oxidative stress and endothelial dysfunction.
Table 1: Hazard Ratios by Sex.Males (n=23,103)Females (n=15,313)Allopurinol ExposureUnadjusted HRAdjusted HRUnadjusted HRAdjusted HRExposed time v. unexposed time0.82 (0.79, 0.84)0.77 (0.75, 0.80)0.88 (0.85, 0.92)0.81 (0.78, 0.84)Dose categories0mg----&gt;0 and ≤100mg1.03 (0.99, 1.08)0.84 (0.80, 0.88)1.(1.01, 1.12)0.86 (0.81, 0.90)&gt;100 and ≤200mg0.82 (0.78, 0.85)0.75 (0.72, 0.78)0.83 (0.79, 0.87)0.76 (0.72, 0.80)&gt;200mg0.71 (0.68, 0.74)0.75 (0.72, 0.78)0.78 (0.73, 0.82)0.81 (0.77, 0.86)Cumulative Dose (per 100g increase)0.99 (0.98, 1.00)1.00 (0.99, 1.01)0.99 (0.98, 1.01)0.99 (0.98, 1.00)

Disclosure
A. Weisman: None. G.A. Tomlinson: None. L. Lipscombe: None. B.A. Perkins: Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH, Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc., Abbott. Speaker's Bureau; Self; Abbott, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Insulet Corporation. Speaker's Bureau; Self; Insulet Corporation, Dexcom, Inc.. G.A. Hawker: None.
Effect of Insulin Deprivation on Brain Mitochondrial ATP Production and Mitochondrial Proteome in Diabetic Mice
Authors: RUEGSEGGER GREGORY , SHANKARAPPA MANJUNATHA , SUMMER PRISKA , GOPALA SRINIVAS , ZABIELSKI PIOTR , KLAUS KATHERINE , DASARI SURENDRA , LANZA IAN R. , SREEKUMARAN NAIR K. 
Published: June 2018

Accumulating evidence indicates a strong association between diabetic status and degenerative brain disease, including cognitive impairment. Here we hypothesized that although insulin is not necessary for glucose metabolism in brain, like in skeletal muscle insulin is critical for mitochondrial function in brain. We measured oxygen consumption rate (OCR), maximal ATP production rate (MAPR), and reactive oxygen species (ROS) production in isolated brain mitochondria of streptozotocin (STZ) diabetic mice. STZ mice deprived of insulin treatment for 96 hours (D-I), in comparison to nondiabetic mice (ND) showed a significant reduction in State 3 MAPR [1.77±0.14 vs. 2.35±0.27 (pmol/s/ug)], phosphorylation efficiency [0.42±0.04 vs. 0.54±0.07 (mol ATP produced/mol of oxygen consumed)] and respiratory control ratio [2.95±0.16 vs. 3.12±0.18] indicating reduced mitochondrial coupling efficiency during insulin deprivation. Citrate synthase and cytochrome c oxidase activities were significantly decreased in the hypothalamus of D-I compared ND. Surprisingly, no significant differences in ROS emission were detected between ND and D-I suggesting additional factors, potentially elevated ketone bodies, may protect against increased oxidative stress in the D-I brain. Proteomics analysis of the cerebrum found post-translational modification involving oxidative damage of several mitochondrial proteins that potentially cause tau phosphorylation and neurofibrillary degeneration in D-I vs. ND. In STZ mice with continued insulin treatment (D+I), state 3 OCR, MAPR, and phosphorylation efficiency were comparable to ND, demonstrating the restorative effects of insulin and euglycemia on brain mitochondrial function. We conclude that insulin deprivation and hyperglycemia significantly alter brain mitochondrial function. Insulin treatment and control of glycemia could have salutary effects on these parameters.

Disclosure
G. Ruegsegger: None. M. Shankarappa: None. P. Summer: None. S. Gopala: None. P. Zabielski: None. K. Klaus: None. S. Dasari: None. I.R. Lanza: None. K. Nair: None.
Uncontrolled Glycaemia Is the Strongest Predictive Factor of Liver-Related and Cardiovascular Death in Diabetic Patients with Cirrhosis
Authors: HIGUERA-DE LA TIJERA FATIMA , SERVIN-CAAMANO ALFREDO I. , NAVARRO-ESTRADA ALICIA , RÁBAGO-ESCOTO RUTH , CRUZ-ESTRADA ANTONIO , ALEXANDERSON-ROSAS ELVIRA G. 
Published: June 2018

Diabetes is a common comorbidity in cirrhotic patients; there are insufficient studies in this context.
Aim: to investigate risk factors for liver-related death (LRD) and cardiovascular death (CVD) in a cohort of diabetic patients with cirrhosis. Follow-up 10 years. We included 380 diabetics with cirrhosis, according to Child-Pugh: 141(37.1%) A, 170(44.7%) B, 69(18.2%) C. Thirty three (8.7%) died for LRD, 29(7.6%) died for CVD. Those died for LRD, compared with those alive, had higher glucose 211±80 vs. 143±62 mg/dL p&lt;0.0001; HbA1c 8.0±1.4 vs. 6.8±1.1% p&lt;0.0001. Univariate analysis (UA): hepatic encephalopathy (HE) p=0.02; ascites, spontaneous bacterial peritonitis (SBP), HbA1c &gt;7.0%, and decompensated cirrhosis (Child B/C) were factors associated with LRD p&lt;0.0001. Variceal bleeding (VB) was not significant (NS). Multivariate analysis (MA): only HbA1c &gt;7.0% was associated with liver-related death HR=3.0; 95% CI=1.4-6.6 p&lt;0.006. Those died for CVD had higher glucose 230±92 vs. 143±62 mg/dL p&lt;0.0001; HbA1c 8.8±1.6 vs. 6.8±1.1% p&lt;0.0001. UA: ascites p=0.001; HE, SBP, HbA1c ≥7.0% were associated with CVD p&lt;0.0001. Child B/C and VB were NS. MA: HbA1c ≥7.0% was the strongest factor related to CVD HR=8.4; 95% CI=3.1-22.6 p&lt;0.0001. Uncontrolled glycaemia is the most important risk factor predicting LRD and CVD. A tight glycemic control is need in cirrhotic patients.

Disclosure
F. Higuera-de la Tijera: Speaker's Bureau; Spouse/Partner; Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Takeda Development Center Americas, Inc., Sanofi-Aventis, Silanes. A.I. Servin-Caamano: Speaker's Bureau; Self; Novartis Pharmaceuticals Corporation, Takeda Development Center Americas, Inc., Eli Lilly and Company, Sanofi-Aventis, silanes. A. Navarro-Estrada: None. R. Rábago-Escoto: None. A. Cruz-Estrada: None. E.G. Alexanderson-Rosas: Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Takeda Development Center Americas, Inc., Sanofi, Silanes, Novo Nordisk Inc., Novartis Pharmaceuticals Corporation, Janssen Pharmaceuticals, Inc..
The Safety of Linagliptin vs. Other Antidiabetic Agents with Regard to the Risk of Heart Failure Hospitalization in Routine Care in the U.S.
Authors: PATORNO ELISABETTA , MAHESRI MUFADDAL , GOPALAKRISHNAN CHANDRASEKAR , BRODOVICZ KIMBERLY , MEYERS ANDREA , BARTELS DOROTHEE , SCHNEEWEISS SEBASTIAN 
Published: June 2018

The safety of linagliptin with regard to the risk of hospitalization for heart failure (HHF) in patients with type 2 diabetes mellitus (T2DM) as treated in routine care remains of interest. We compared the risk of HHF associated with the initiation of linagliptin vs. other antidiabetic agents. In two large commercial U.S. health insurance datasets (Optum Clinformatics and Truven MarketScan), we identified T2DM patients who initiated linagliptin, sitagliptin, saxagliptin, or sulfonylureas (SU) between 5/2011 and 9/2015 and had no previous Heart Failure (HF) history or HF treatment. We estimated hazard ratios (HR) of HHF in 3 separate propensity score matched cohorts that balanced over 130 baseline characteristics. We combined HRs via a fixed-effects meta-analysis. Mean follow-up was nearly 8 months. Linagliptin initiators had no significant difference in the risk of HHF compared with sitagliptin (HR= 0.83 [95% CI=0.58, 1.20]), saxagliptin (HR= 1.13 [0.74, 1.71]), or SU (HR= 0.71, [0.46, 1.10]). In contrast to high cardiovascular (CV) risk clinical trial populations, in a population of T2DM patients without HF history, aged 57 years on average, we did not find a difference in HHF risk between DPP-4 inhibitors with sufficient certainty. Consistent with prior studies, there may be a reduced HHF risk vs. SU; further evidence is expected from ongoing linagliptin CV outcomes trials.

Disclosure
E. Patorno: Research Support; Self; National Institute on Aging. Other Relationship; Self; Boehringer Ingelheim GmbH, GlaxoSmithKline plc.. M. Mahesri: None. C. Gopalakrishnan: None. K. Brodovicz: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. A. Meyers: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. D. Bartels: Employee; Self; Boehringer Ingelheim GmbH. S. Schneeweiss: Consultant; Self; WHISCON, LLC. Other Relationship; Self; Aetion, Inc.. Research Support; Self; Genentech, Inc., Bayer AG, Boehringer Ingelheim GmbH, U.S. Food and Drug Administration, Patient-Centered Outcomes Research Institute.
Leptin Concentration Predicts Future Metabolic Syndrome Risk in Japanese Americans Independent of Body Composition
Authors: LIAO CHUN-CHENG , FUJIMOTO WILFRED Y. , KAHN STEVEN E. , LEONETTI DONNA L. , BOYKO EDWARD J. 
Published: June 2018

Aims: Leptin has been shown to predict risk of metabolic syndrome (MetS), but it is not known whether this association is independent of body composition. Thus, we examined whether plasma leptin concentration predicted risk of MetS after adjustment for body composition measured using imaging.
Methods: We used the modified ATP III MetS criteria for an Asian population to classify participants in the longitudinal Japanese-American Community Diabetes Study as to presence of MetS. Participants without MetS at baseline (n=283) were followed for its development over 5 years. CT-measured adipose depots included baseline and 5-year intra-abdominal and abdominal subcutaneous fat areas at the level of the umbilicus, subcutaneous mid-thigh fat area, and subcutaneous thorax fat area at the nipple level. Other measurements included fasting plasma leptin and serum HDL-cholesterol and triglyceride concentrations, fasting and 2 hour glucose from a 75 g OGTT, systolic blood pressure (SBP), and medication use. Logistic regression analysis was used to estimate the odds of incident MetS by leptin concentration, body composition, and baseline MetS features.
Results: 65 participants developed MetS at 5-year follow-up. Multivariable logistic regression models showed a lower odds of incident MetS with 1-SD greater leptin concentration (OR = 0.45; 95% CI = 0.25-0.79; p = 0.006) adjusting for age, sex, CT-fat areas at baseline, and 5-year change in CT-fat areas. Additional adjustment for other MetS features at baseline (fasting and 2 hour glucose, triglycerides, HDL-cholesterol, SBP) yielded similar results (OR = 0.38; 95% CI = 0.20-0.71; p = 0.002).
Conclusions: Leptin concentration predicts MetS risk in Japanese Americans independent of body composition. Further research is needed to confirm this association in other populations and to understand potential underlying biologic mechanisms.

Disclosure
C. Liao: None. W.Y. Fujimoto: None. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim GmbH, Elcelyx Therapeutics, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Research & Development, Merck & Co., Inc., Novo Nordisk A/S. D.L. Leonetti: None. E.J. Boyko: None.