bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of Intensive Lifestyle Intervention and Metformin with Frailty in the Diabetes Prevention Program (DPP) Outcomes Study (DPPOS)
Authors: HAZUDA HELEN P. , PAN QING , CRANDALL JILL P. , FLOREZ HERMES , LUCHSINGER JOSE A. , VENDITTI ELIZABETH M. , KRISKA ANDREA , GOLDEN SHERITA , BRAY GEORGE ,   DPP RESEARCH GROUP
Published: June 2018

Objective: To examine whether odds of frailty differ by DPP intervention arms (intensive lifestyle intervention [ILS], metformin [MET], placebo [PLB] after long-term follow-up in the DPPOS.
Methods: DPP, a randomized trial of individuals at high risk of diabetes, lasted 2.8 years, after which there was a 13-month bridge period in which 16 sessions of group ILS was offered to all participants. During DPPOS, ILS was offered lifestyle reinforcement semi-annually and MET received unmasked metformin. Frailty was measured initially in DPPOS Year 8 in 2385 participants and repeated in 2264 of these in Year 10 (12 and 14 years after randomization). Using Fried criteria, presence of 3 of 5 characteristics (slow walking speed, weak grip strength, unintentional weight loss, low physical activity, and exhaustion) was classified as frail, 1 or 2 pre-frail, and 0 non-frail.: GEE models adjusting for visit year were employed with repeated measures pooled from Years 8 and 10 to estimate pairwise odds ratios between ILS, MET and PLB for the outcomes of frail and pre-frail vs. non-frail.
Results: Odds of frailty vs. non-frailty were 37% lower in ILS compared to PLB (Table) and MET (OR=0.629, CI= 0.420-0.942, p=0.024). There were no significant treatment group differences in odds of pre-frailty.
Conclusion: ILS intervention in persons at high risk of diabetes may reduce frailty in later life.12 years Post-randomization14 years post-randomizationOdds of Frailty vs. Non-Frailty Pooled over both examsTreatment GroupPrevalencePrevalence OR (95% CI) compared with placeboP-valuePre-FrailtyFrailtyPre-FrailtyFrailtyPlacebo42.8%5.7%43.7%5.4%1 (referent)n/aMetformin45.8%5.4%42.5%5.3%0.994 (0.694-1.424)0.976Lifestyle46.8%3.0%46.3%3.6%0.625 (0.419-0.934)0.022

Disclosure
H.P. Hazuda: None. Q. Pan: None. J.P. Crandall: None. H. Florez: Advisory Panel; Self; Sanofi. J.A. Luchsinger: None. E.M. Venditti: None. A. Kriska: None. S. Golden: None. G. Bray: Advisory Panel; Self; Herbalife International of America, Inc., Novo Nordisk A/S. D. Research Group: None.
Transforming Pediatric T2D Clinical Research—A Network Model
Authors: GAL ROBIN L. , BEAULIEU LINDSEY C. , KEELIN KIMBERLY D. , LESS JOANE E. , NELSON BRYCE A. , WINTERGERST KUPPER A. , KLINGENSMITH GEORGEANNA J. , TAMBORLANE WILLIAM V. 
Published: June 2018

Background: Treatment options for youth with type 2 diabetes (T2D) are limited compared to those for adults with T2D. As pediatric clinical trials in T2D are difficult to complete, due to lower prevalence and population related recruitment challenges, clinical sites are often reluctant to participate. Protocol design, often not appropriate for pediatrics, administrative and financial burden related to study participation further reduce site interest.
Methods: The Pediatric Diabetes Consortium (PDC) is a network of 49 U.S. diabetes centers working together to improve care for children with diabetes. Recognizing challenges associated with pediatric T2D clinical trial participation, the PDC developed a network model to improve efficiency for both sites and sponsors.
Innovations: A consulting group was formed to assist with protocol design appropriate for T2D pediatric studies. A PDC master agreement with sites eliminates need for negotiation of standard contract language between sponsor and each site, allowing for a single contract between the PDC and sponsor. A single budget, based upon a clinical trial budget template, reflecting actual site costs, is negotiated by the PDC for all sites. Central archiving of site metrics eliminates need for a feasibility survey before site selection occurs. Monthly site calls led by an investigator oversight committee provide opportunities to discuss enrollment strategies, study challenges and best practices, and provide real-time feedback to sponsor.
Conclusion: Efficiencies established by the PDC network model reduce workload for sites and start-up timeline for sponsors. Population-appropriate trial design improves recruitment opportunities. Ongoing site engagement helps to identify and mitigate protocol issues in real-time. The network model improves likelihood of successful trial operations. To date, 26 PDC sites have participated in at least 1 of 3 studies, enrolling 137 across studies so far, contributing to successful recruitment ahead of projected schedule.

Disclosure
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.. K.D. Keelin: None. J.E. Less: None. B.A. Nelson: Speaker's Bureau; Self; Dexcom, Inc.. K.A. Wintergerst: None. G.J. Klingensmith: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Foundation. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceuticals U.S.A., Inc..
The Acute Effect of Empagliflozin on Fractional Excretion of Sodium and eGFR in Youth with Type 2 Diabetes
Authors: BJORNSTAD PETTER , LAFFEL LORI M. , TAMBORLANE WILLIAM V. , SIMONS GUDRUN , HANTEL STEFAN , EYNATTEN MAXIMILIAN VON , GEORGE JYOTHIS T. , MARQUARD JAN , CHERNEY DAVID 
Published: June 2018

Sodium-glucose cotransporter-2 (SGLT2) inhibition reduces hyperfiltration in adults with T1D, likely by inducing natriuresis, which stimulates tubuloglomerular feedback. This exploratory analysis aimed to examine whether these renal effects occur acutely within 24 hours of SGLT2 inhibition following a single exposure to empagliflozin (EMPA) in youth with T2D. In this single-administration, open-label, randomized, parallel-group study (NCT02121483), 27 patients with T2D (mean age 14.1 years, 67% girls, mean BMI 35.5 kg/m2) received EMPA 5, 10 or 25 mg. The effects of EMPA on fractional sodium excretion (FENa+) and estimated GFR (eGFR as assessed by Zappitelli-combined creatinine and cystatin C equation) were investigated by pooling the three doses of EMPA for analyses. At baseline, mean (SD) baseline FENa+ was 0.55% (0.46), and eGFR was 123.4 ml/min/1.73m2 (15.6). After a single dose of EMPA, the adjusted mean change from baseline in FENa+ was +0.81% (95% CI 0.27, 1.36; p=0.006). The adjusted mean change from baseline in eGFR was -5.5 ml/min/1.73m2 (95% CI -8.3, -2.7; p=0.0006). In eGFR subgroups of interest, eGFR decreased by -6.7 (9.7) ml/min/1.73m2 in patients with hyperfiltration (n=8, eGFR &gt;119.1 ml/min/1.73m2, [95th percentile of eGFR for obese youth in NHANES]) and by -5.0 (6.0) ml/min/1.73m2 in patients with normofiltration (n=19). SGLT2 inhibition following a single dose of EMPA was associated with acute natriuresis and attenuation of elevated GFR in youth with T2D, suggesting a reduction in intraglomerular pressure. Further mechanistic studies are required to define changes in renal function, and longer-term trials examining renal protective effects in youth with diabetes are needed.

Disclosure
P. Bjornstad: Consultant; Self; Boehringer Ingelheim GmbH. L.M. Laffel: Consultant; Self; Eli Lilly and Company, Novo Nordisk Inc., Sanofi US, MannKind Corporation, Roche Diagnostics Corporation, Dexcom, Inc., Insulet Corporation, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Johnson & Johnson Diabetes Institute, LLC. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceuticals U.S.A., Inc. G. Simons: Employee; Self; Boehringer Ingelheim GmbH. S. Hantel: Employee; Self; Boehringer Ingelheim GmbH. M. von Eynatten: Employee; Self; Boehringer Ingelheim GmbH. J.T. George: Employee; Self; Boehringer Ingelheim GmbH. J. Marquard: Employee; Self; Boehringer Ingelheim GmbH. D. Cherney: Consultant; Self; AbbVie Inc.. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company. Consultant; Self; Sanofi. Other Relationship; Self; Merck & Co., Inc.. Consultant; Self; Mitsubishi Tanabe Pharma Corporation. Other Relationship; Self; Janssen Pharmaceuticals, Inc..
Identification of Gastric Mucosa Key Pathways and Genes in Obesity and Obesity-Related Diabetes via Gene Microarray Analysis
Authors: WEN XIN , ZHANG YI , WU RUI J. , ZHU CUILING , CUI RAN , HUI YOU , MEI FANG Y. , GAO JINGYANG , QU SHEN , BU LE 
Published: June 2018

Background: Gut uses variety of pathways to establish closely contact with obesity and obesity related diabetes, including gut-brain cross-talk, gut microbiota, immune pathway and gastrointestinal hormones. In this study, we aimed to identify the key pathways and genes of gastric mucosa in obesity patients with or without type 2 diabetes.
Methods: Our study was divided into three groups, healthy control group with normal BMI, patients with simple obesity(OB) and obesity with type 2 diabetes mellitus(OD), three cases in each groups. Gastric mucosal tissues were isolated then analyzed by gene microarray. The differentially expressed genes were screened by functional enrichment analysis and pathway analysis.
Results: 262 up-regulated genes and 265 down-regulated genes were differentially expressed between OB and normal-BMI patients. Besides, 1756 up-regulated genes and 1053 down-regulated genes were differentially expressed between OD and control subjects (fold change&gt;2 p &lt; 0.05). For DEGs comparisons in each group, 13 genes were co-up regulated, 10 genes were co-down regulated, and an additional 12 genes showed different trends. After analyzing the biological process and molecule function of differential expression genes, these genes were found to play crucial roles mainly in cellular metabolic, protein binding and other biological process. The analysis of KEGG showed that the relevant genes participate in Citrate cycle, NF-kappa B and PI3K-Akt signaling pathway.
Conclusions: During the process of obesity and obesity related diabetes, in gut there is not only one specific gene or pathway, but multiple genes and pathways that change. The effects of genes expressed in gastric mucosa mainly influence cellular metabolic processes, NF-kappa B and other proinflammatory signaling pathway.

Disclosure
X. Wen: None. Y. Zhang: None. R.J. Wu: None. C. Zhu: None. R. Cui: None. Y. Hui: None. F.Y. Mei: None. J. Gao: None. S. Qu: None. L. Bu: None.
Adolescents at High-Risk for Developing Type 2 Diabetes and/or Polycystic Ovary Syndrome Can Be Identified Using a Simple Questionnaire while in High School
Authors: KARAKAS SIDIKA 
Published: June 2018

Introduction: Family history of type 2 diabetes (T2DM), obesity, acanthosis nigricans, skin tags, hirsutism and/or menstrual irregularities are associated with increased risk for developing T2DM, metabolic syndrome and polycystic ovary syndrome (PCOS). Early identification of adolescents at risk can provide opportunities for timely preventive interventions.
Methods: We created a simple questionnaire (UCD-QUES) which includes 5 sections: 1) Anthropometrics; 2) Signs of insulin resistance (pictures of acanthosis nigricans and skin tags); 3) Family history of DM; 4) Menstrual history; 5) Hirsutism (Figure of an adolescent female marking the areas susceptible to hirsutism). The UCD-QUES for male students included only the first 3 sections. We administered the UCD-QUES to 232 students (163 F, 69 M), attending grades 9-12 in 5 Sacramento, California high schools.
Results: Self-reported ethnic distribution of the students was: 35% Hispanic, 20% Asian, 17% white and 15% black. Weight distribution was: 39% were overweight (26%, BMI: 25-29.9) or obese (13%, BMI&gt;30). Family history indicated: 22% had one or more 1st degree relative, and 51% had at least one 2nd degree relative with DM. Acanthosis nigricans or skin tags were reported by 14%, hirsutism by 15%, and irregular periods by 38%. One out of 8 female adolescents (13%) fulfilled the clinical criteria for PCOS, but only 2 students had ever heard of PCOS.
Conclusion: Adolescents who are at risk for developing DM, metabolic syndrome or PCOS can be identified by high-school-based screening using a simple questionnaire. Further research is required to determine 1) whether focusing preventive efforts to these high-metabolic risk adolescents can increase the success of the interventions while cutting cost, and 2) whether identification of high-risk adolescents can provide multi-generational benefits by creating access to their high-risk families and protecting their offspring.

Disclosure
S. Karakas: None.
Late Reactive Hypoglycemia (RHG) as a Common Early Sign of Glycemic Dysfunction in Obese Adolescent Girls
Authors: CARREAU ANNE-MARIE , RAHAT HASEEB , REYES YESENIA GARCIA , PYLE LAURA , NADEAU KRISTEN J. , CREE-GREEN MELANIE 
Published: June 2018

Many obese adolescent girls describe symptoms of hypoglycemia, but this has not been systematically assessed. Due to pubertal insulin resistance (IR), hormonal responses to an oral glucose tolerance test (OGTT) may occur beyond the typical 2h sampling interval. We sought to determine how often reactive hypoglycemia (RHG) occurs in these girls. 56 girls aged 12-20 years, BMI percentile ≥ 90th, were enrolled in a study including fasting metabolic labs and a 6h OGTT with frequently sampled glucose, C-peptide, insulin, GLP-1 and glucagon. RHG was defined as a blood glucose (BG) &lt; 70 mg/dL with a ≥ 20 mg/dL drop from the previous sample. Comparisons between those with and without RHG were performed with a Student’s t-test. 50% of girls had BG &lt;70mg/dL (mean nadir was 62 mg/dL); 18% were &lt;65 mg/dL and 12% &lt; 60 mg/dL. The median time for lowest BG was 240 min (range 210-360 min) after the glucose load. Girls with RHG were slightly younger (15.1±1.8 vs. 16.2±1.5 years; p=0.02). The groups had similar BMI percentile (97.8 vs. 96.8) and percent fat mass, but tended to have more visceral fat (10.1% vs. 8.1%; p=0.08). Fasting glucose and insulin were not different between groups, but HOMA-IR tended to be higher in RHG (7.0±5.4 vs. 4.9±2.2, p=0.07). The area under the curve of insulin and glucose for the first 180 min of the OGTT was higher in RHG (p=0.01 and p=0.04, respectively), with impaired glucose tolerance tending to be more frequent in RHG (63% vs. 40%; p=0.08). The mean insulin peak for the RHG was at 150 min, vs. 30 min post-drink in the normal group. At 240 min, glucagon tended to be higher in RHG (81 vs. 67 pg/ml; p=0.06). RHG defined as a BG &lt;70 mg/dL following a rapid drop, is common in girls with obesity in response to liquid sugar, and occurs later than detectable with a standard 2h OGTT. RHG appears to be secondary to an overly robust, late insulin response. This pattern is likely related to IR, may precede further dysglycemia and may be severe enough to cause a counter regulatory response, arguing to avoid consuming liquid sugar in isolation.

Disclosure
A. Carreau: None. H. Rahat: None. Y. Garcia Reyes: None. L. Pyle: None. K.J. Nadeau: None. M. Cree-Green: None.
Alterations in Novel Signals in the Gut–Adipose Axis–A Pilot Study in Insulin-Resistant Children with Obesity and Biopsy-Proven Nonalcoholic Steatohepatitis
Authors: DI GUGLIELMO MATTHEW D. , MANSOOR SANA , UPPAL VIKAS , FURUYA KATRYN N. , KUMAR SEEMA , BALAGOPAL P. BABU 
Published: June 2018

Background: Body weight homeostasis and the progression of obesity to comorbidities such as nonalcoholic steatohepatitis (NASH), type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) involve the gut-brain axis, a complex and highly coordinated system of peripheral appetite hormones and centrally mediated neuronal regulation. Data on the role of a gut-adipose axis in children with obesity-related comorbidities are sparse. We determined novel signals in the gut-adipose axis such as pro-uroguanylin (PUG) produced in the gut and spexin, predominantly produced in white adipose tissue along with traditional appetite/satiety hormones in insulin-resistant children with (NASH) and simple obesity.
Method: A total of 29 children (age: 8-17 years) in three groups, normal weight (NW; n=11; BMI&lt;85th%), obese (n=9; BMI&gt;95th%) and biopsy-proven NASH (n=9; NAS-score&gt;2) were studied. Spexin, PUG, leptin, total (T)- and high molecular weight (HMW)-adiponectin and insulin were measured.
Results: Spexin, PUG and both T and HMW adiponectins were lower in children with NASH compared to both children with simple obesity and their NW counterparts, while leptin and insulin were higher (p&lt;0.05). Spexin/leptin ratio and concentration of PUG were significantly lower (p&lt;0.05) in children with NASH vs. simple obesity, whereas leptin and insulin were higher (p&lt;0.05).
Conclusions: Lower concentrations of novel signals such as PUG and spexin in the current study suggest that perturbations in the gut-brain axis occur at an early age in the clinical course of obesity and NASH. The potential role of these novel gut-adipose axis signals, by themselves or in unison with other factors, in diagnosing and/or monitoring the development and/or progression of obesity-related comorbidities such as NASH, T2DM and CVD as well as the potential development of more directed therapies appears to be promising and warrants further studies.

Disclosure
M.D. Di Guglielmo: None. S. Mansoor: None. V. Uppal: None. K.N. Furuya: None. S. Kumar: None. P. Balagopal: None.
Vitamin D Levels Are Associated with Risk Factors for Type 2 Diabetes and Metabolic Syndrome in Chinese Youths
Authors: GAO SHAN , HAN LANWEN , FU JUNLING , LI GE , LI MING , WILLI STEVEN M. 
Published: June 2018

Evidence regarding association between vitamin D deficiency and metabolic syndrome (MS) remains controversial and relatively sparse among youth. We aimed to explore the relationship between serum 25-hydroxyvitamin D [25(OH)D] levels and risk factors for type 2 diabetes and MS in Chinese adolescents and young adults. A total of 559 subjects aged 14-28 years with high risk of MS were recruited from the Beijing Child and Adolescent Metabolic Syndrome Study cohort in 2012. All subjects underwent a 2h-oral glucose tolerance test. The concentrations of 25(OH)D, glucose, insulin and lipids were determined. MS was defined by the 2009 harmonized definition. The prevalence of vitamin D deficiency (&lt; 20 ng/ml) was 78.3%. After adjusting for age, gender and visiting season, 25(OH)D levels were negatively correlated with percent body fat, LDL-C, fasting and 2h-glucose levels (all p &lt; 0.05). 25(OH)D levels were significantly lower in subjects with obesity, high TG, type 2 diabetes, or MS, compared to their counterparts, respectively (all p &lt; 0.05). After adjustment for potential confounders including body mass index, subjects in the lowest vs. highest tertile of 25(OH)D levels was 2.5 times more likely to have MS (Odds 95% CI: 1.13-5.45, p &lt; 0.05). Vitamin D deficiency was very common in this young Chinese population with risk for MS. Given the negative association between vitamin D level and cardiometabolic risk factors, effective sun exposure and vitamin D supplementation should be encouraged in youths, particular in those with high MS risk.

Disclosure
S. Gao: None. L. Han: None. J. Fu: None. G. Li: None. M. Li: None. S.M. Willi: Advisory Panel; Self; Boehringer Ingelheim GmbH. Other Relationship; Self; Caladrius Biosciences, Inc.. Consultant; Self; GlaxoSmithKline plc., JAEB Center For Health Research.
Diabetes Retinopathy (DR) Relates to Complication Risk in Young Persons with T1D
Authors: KATZ MICHELLE , KING GEORGE L. , SUN JENNIFER , LAFFEL LORI M. 
Published: June 2018

Young persons who develop DR may represent a high-risk group for early development of other complications. In young persons with youth-onset T1D, we evaluated associations between DR status and markers of other T1D complication risk. Youth (N=127), mean age 21.7 y (range 10.7-31.9), mean T1D onset 6.3 y (range 0.5-17.6) underwent DR assessment (ETDRS-protocol 7 field fundus photos); renal, neuropathic, and CVD risk screenings; and risk screening by blood/urine studies. DR was classified as none (No DR, 37%), mild nonproliferative (Mild DR, 46%), and more than mild NPDR (Advanced DR, 17%). More severe DR was associated with greater age, T1D duration, A1c, and weight status (Table). DR severity was associated with neuropathy, vascular stiffness by pulse wave (aortic AIx), and inflammatory, oxidative stress, and endothelial activation markers (CRP, isoprostane, e-selectin). Paradoxically, greater DR was associated with less PAI-1. After adjustment for age, T1D duration, weight, and A1c by ANCOVA, DR status was associated with differences in cooling threshold (7.6, 8.6, 12.3, p=.0003) and e-selectin (39.8, 34.0, 46.0, p=.02). Young persons with DR have high risk for neuropathic, renal, and CVD complications. While PAI-1 is lower, markers of inflammation and oxidative stress are higher in this group. Optimal glycemic control must be prioritized to prevent or delay DR progression and other complications in young persons with DR.
Unadjusted Associations Between Clinical Factors and DR Status, *indicates ln transformed p valueClinical FactorNo DR (n=47) Mean or Median or %Mild DR (n=59) Mean or Median or %Advanced DR (n=21) Mean or Median or %P value ANOVA or Chi-squareAge (yrs)/T1D Duration (yrs)/A1c (%)18.9/13.2/8.022.6/15.8/8.625.8/19.6/9.1&lt;.0001/&lt;.0001/.03Sex (% male)/Overweight/obese (%)60/3236/6148/57.05/.009Urinary Albumin Excretion* /eGFR per 1.73m27.3/128.26.4/141.29.3/140.6.04/.02Neuropathy (MNSI)/Warm Threshold/Cold Threshold1.3/14.6/7.11.9/15.3/8.63.0/18.2/13.4.004/.005/&lt;.001Mean SBP/Mean DBP/Aortic AIx110/68/2.0112/71/9.0115/74/11.1.2/.008/.003PAI1* (ng/ml)/CRP* (mg/l)/IGF1 (ng/ml)36.8/0.8/207.526.2/2.5/160.614.4/2.7/138.8&lt;.001/.002/.002E-selectin(ng/ml)/Urine isoprostane* (ng/ml)40.8/0.2034.5/0.3441.8/0.40.1/.002

Disclosure
M. Katz: None. G.L. King: Research Support; Self; Sanofi-Aventis. J. Sun: Other Relationship; Self; Novartis Pharmaceuticals Corporation. Research Support; Self; Genentech, Inc., Optovue, Incorporated, Boston Micromachines Corporation, Adaptive Sensory Technology, Kalvista Pharmaceuticals, Inc.. Other Relationship; Self; Novo Nordisk Inc. L.M. Laffel: Consultant; Self; Eli Lilly and Company, Novo Nordisk Inc., Sanofi US, MannKind Corporation, Roche Diagnostics Corporation, Dexcom, Inc., Insulet Corporation, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Johnson & Johnson Diabetes Institute, LLC..