bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteomic Profile of Adipose Tissue-Derived Exosomes and Their Potential Role on Placental Glucose Metabolism in Gestational Diabetes Mellitus
Authors: JAYABALAN NANTHINI , ORMAZABAL VALESKA , LAI ANDREW , LAPPAS MARTHA , SALOMON CARLOS 
Published: June 2018

Emerging studies suggest that adipose tissue derived exosomes involves in regulating insulin action and glucose homeostasis. In this study, we hypothesised the protein content of adipose tissue derived exosomes (exo-AT) differs in normal glucose tolerant (NGT) and gestational diabetes mellitus (GDM) pregnancies which lead to changes in placental glucose metabolism. Human omental adipose tissue was obtained from GDM (n=60) and BMI-matched NGT (n=48) pregnancies at the time of term Caesarean section. Exosomes were isolated from tissue-conditioned media by differential centrifugation and characterised using nanoparticle tracking analysis and SWATH mass spectrometry. The effect of exosomes on human placental cells was evaluated using a Human Glucose Metabolism RT² Profiler PCR Array. The total number of exosomes (number of vesicles/mg adipose tissue/24 hour) were significantly higher in GDM compared to NGT. The number of exosomes positively correlated with maternal BMI and fetal weight. We identified 122 proteins upregulated in the exo-AT from GDM compared to NGT. Ingenuity pathway analysis revealed the upregulated proteins are associated with mitochondrial dysfunction and oxidative phosphorylation (OXPHOS). When compared to NGT exo-AT, GDM exo-AT increased ALDOB, PGK2 and GCK in placental cells. The data obtained in this study suggest that exosomes secreted from adipose tissue regulates placental glucose metabolism in GDM. Improving the communication of exo-AT to placental tissues may serve as an effective intervention strategy to prevent the consequences of GDM such as fetal overgrowth.

Disclosure
N. Jayabalan: None. V. Ormazabal: None. A. Lai: None. M. Lappas: None.
SGLT2 Inhibitors and Stroke Risk in Patients with Type 2 Diabetes—A Systematic Review and Meta-analysis
Authors: GUO MAN , XU YONG 
Published: June 2018

Aims: SGLT2 inhibitors are a novel drug used to treat diabetes. They also have positive cardiovascular benefits. However, there is some debate regarding possible effects of SGLT2 inhibitors on stroke risk. Here, we conduct a meta-analysis of relevant RCTs to evaluate the effects of SGLT2 inhibitors on stroke risk with T2DM.
Materials and Methods: We searched Pubmed, Embase, CENTRAL and ClinicalTrials.gov from database inception up to September 19, 2017. We included RCTs that enrolled patients with T2DM, compared SGLT2 inhibitors vs. placebo or other comparators for at least 24 weeks, and reported the observed effects of SGLT2 inhibitors on stroke events. Subgroup analyses were performed for gender, age, duration of diabetes, race, BMI, and HbA1C levels. A random-effects meta-analysis was performed to calculate the RR with 95% CI.
Results: We identified 32 eligible trials enrolling 75,540 participants that compared three SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) to placebo and other active antidiabetic treatments. The incidence of stroke in groups with SGLT2 inhibitor monotherapy or combination therapy was not significantly different from that in control groups, with RR=1.01 (95% CI 0.93-1.10, p=0.972) and RR=1.0 (95% CI 0.92-1.09, p=0.846), respectively. There were no significant differences in RRs between three SGLT2 inhibitors; canagliflozin, RR=0.91; dapagliflozin, RR=0.99; and empagliflozin, RR=1.03. Subgroup analyses showed that the RR values were not affected by gender, age, duration of diabetes, BMI, and HbA1C levels; however, there was a small racial disparity, with black participants having a lower incidence of stroke than white or Asian participants.
Conclusions: SGLT2 inhibitor therapy does not increase stroke incidence, and no significant differences in the RR for stroke were observed among three SGLT2 inhibitors (class effect). However, black patients did have a lower stroke incidence than white or Asian patients.

Disclosure
M. Guo: None. Y. Xu: None.
Presentation and Clinical Characteristics of Patients with Maturity Onset Diabetes of the Young (MODY) at Women and Children’s Hospital of Buffalo
Authors: SAADEH LINA , MASTRANDREA LUCY D. 
Published: June 2018

Background: Maturity onset diabetes of the young (MODY) is a monogenic form of diabetes. It is rare, representing the final diagnosis in 1-2% of individuals with diabetes. In the pediatric cohort, it can be confused with type 1 diabetes. Clinical diagnosis is suspected in the case of hyperglycemia, lack of autoantibodies, and autosomal dominant transmission. This retrospective chart review evaluated the clinical presentation and characteristics of patients diagnosed with MODY by our practice with a goal of identifying patients that can be candidates for genetic testing.
Methods: Using ICD10 codes for MODY, we performed a retrospective chart review of patients carrying MODY diagnosis confirmed by genetic testing, who received their care at the Diabetes Center at Women and Children’s Hospital of Buffalo.
Results: We identified 10 subjects with confirmed genetic testing for MODY. Median age of presentation with hyperglycemia was 13.1 years (range of 3.6-17.3 years). Median HbA1c at presentation was 6.3% (range 6%-14%). While the initial referring diagnosis was elevated fasting BS (FBS) in 50% of subjects, FBS (mean 120±21 mg/dL) was abnormal for all but 1 subject at their first contact visit. All subjects had negative pancreatic autoantibodies. In our cohort, confirmatory testing was as follows: MODY2 (n = 6), MODY3 (n = 2), MODY 4 (n=1), and MODY5 (n=1). Three subjects were assigned a MODY diagnosis prior to genetic testing. Two were siblings with family history of maternal MODY2. The third subject had a history of polycystic kidney disease, septate uterus, and HbA1C in the prediabetes range. This subject was assigned a presumptive diagnosis of MODY 5 prior to genetic test.
Conclusion: In our practice, all subjects with confirmed MODY diagnosis had negative pancreatic autoantibodies with most meeting criteria for prediabetes diagnosis. Clinicians should have a high index of suspicion for MODY in subjects who do not fit criteria for T1DM or T2DM.

Disclosure
L. Saadeh: None. L.D. Mastrandrea: Research Support; Self; Novo Nordisk Inc., AstraZeneca, Sanofi-Aventis. Advisory Panel; Self; Pediatric Diabetes Consortium. Other Relationship; Self; American Academy of Pediatrics. Advisory Panel; Self; JAEB Center For Health Research.
Trends in Type 2 Diabetes Mellitus Complications, Drug Utilization, and Laboratory Outcomes, 2012–2017
Authors: NAIR RADHIKA , ZHAO ZHENXIANG , GANDHI PRANAV , LI YONG , BRODOVICZ KIMBERLY , MEAH YUNUS A. , KALIRAI SAMANEH , MORETZ CHAD , MACKENZIE MICHELE , CURTIS BRADLEY , PREWITT TODD G. 
Published: June 2018

Understanding the natural progression of type 2 diabetes mellitus (T2DM) is crucial in determining the appropriate approaches to care and effective management among these patients. Patients with a diagnosis for T2DM between January 2012 to December 2013 and treated with a non-insulin glucose-lowering medication were identified from a large national health plan using medical and pharmacy claims. The first occurring diagnosis for T2DM was considered the index date. Patients were required to be enrolled ≥ 6 months prior to index and be 18-89 years at index. Based on presence or absence of diagnosis for T2DM during the pre-index period, patients were categorized as prevalent or incident. Patients were followed for a maximum of five years allowing longitudinal assessment of T2DM progression and trends in comorbidities, treatment regimens, and laboratory outcomes. The quarterly cohorts declined from 147,900 and 20,066 in 2Q2012 to 52,091 and 11,454 in 2Q2017 in the prevalent and incident cohorts, respectively. Despite the increasing utilization of glucose-lowering medications, glycemic control remained suboptimal, with increasing prevalence of complications such as kidney disease in both prevalent and incident cohorts as patients progressed through their diabetes.

Disclosure
R. Nair: Other Relationship; Self; Eli Lilly and Company. Z. Zhao: None. P. Gandhi: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Y. Li: None. K. Brodovicz: Employee; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Y.A. Meah: Employee; Self; Humana Inc. S. Kalirai: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. C. Moretz: None. M. MacKenzie: Other Relationship; Self; Boehringer Ingelheim GmbH. B. Curtis: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. T.G. Prewitt: None.
SGLT2 Inhibitors Suppress Alpha-Adrenergic Tone and Morning Elevation of Plasma Glucose Levels
Authors: YAMAUCHI KEISHI 
Published: June 2018

Previously, we reported that morning plasma glucose (PG) elevation before wake-up (W1) and after wake-up (W2), occur through different mechanisms in patients with type 2 diabetes. W1 was related to insulin deficiency as already-known reports. W2 could be explained by heightened ambient alpha-adrenergic tone, within the normal range since urinary normetanephrine was strongly related to W2. Urinary normetanephrine are reflected production levels of norepinephrine. Although epinephrine activates both of α and β adrenergic receptors, norepinephrine only stimulates α adrenergic receptor. In the study, we estimate the effect of SGLT2 inhibitors on urinary metanephrines, other antagonistic hormones and W2. Ipragliflozin (50mg) or dapagliflozin (5mg) administered 8 diabetic patients with W2 for 3 month. Those with insulin therapy or overtly elevated fasting PG (&gt;11 mmol/L) were excluded. SGLT2 inhibitors suppressed δPG(8 am PG minus 6 am PG) (2.7±1.1 mmol/L to 1.9±0.9 mmol/L, p&lt;0.05)(Figure) and urinary normetanephrine(0.27±0.19 mg/gCre to 0.20±0.11 mg/gCre, p&lt;0.05). But those did not change urinary metanephrine(0.19±0.10 mg/gCre to 0.17±0.mg/gCre, p&gt;0.05) and other antagonistic hormones. Adrenergic tone-induced alterations of glucose metabolism may be mediated via regulation of SGLT2 inhibitor.

Disclosure
K. Yamauchi: None.
Diabetes Prevalence in North America and Caribbean Region in 2017 and 2045
Authors: HUANG YADI , KARURANGA SUVI , BOYKO EDWARD J. , MALANDA BELMA 
Published: June 2018

Aims and Objectives: Diabetes is a serious and increasing global epidemic, and accurate estimates are essential for more efficient allocation of resources. The International Diabetes Federation (IDF) North America and Caribbean Region (NAC) consist of the U.S.A, Mexico and Canada, as well as 25 Caribbean countries and territories. The new edition of the International Diabetes Federation (IDF) Atlas (IDF, 2017) provides estimates of the numbers of people (18-99 years) living with diabetes in the IDF North America and Caribbean (NAC) Region.
Methodology: Estimates for diabetes in adults were taken from 24 data sources in the IDF NAC region, representing 14 out of 28 countries. Selected characteristics of these data sources are as follows: Barbados, Mexico, Suriname, Trinidad and Tobago and the U.S. had studies conducted within the last five years; Belize, Haiti, Mexico and the U.S. Virgin Islands had studies that performed oral glucose tolerance tests. Prevalence rates for other countries may be underestimated due to limited data sources on oral glucose tolerance test. The details of the methodology were described in IDF Diabetes Atlas 8th Ed.
Results and Conclusion: Approximately 50.1 (41.8-56.1) million people or 13.1% (10.9-14.6%) of adults aged 18-99, are living with diabetes in the IDF NAC region in 2017. The age-adjusted prevalence is 10.8%, which is highest among all seven IDF regions. If the trend continues, the number of people with diabetes is projected to reach 73.4 (58.8-83.4) million in 2045. About 37.6% of those people living with diabetes in this region are estimated to be undiagnosed in 2017. The number of deaths attributed to diabetes from age 20 to 99 years is 378,720 in 2017. The total healthcare expenditure related to diabetes in NAC region is USD 439,858 million in 2017 and will reach USD 508,315 million by 2045. Diabetes exerts a heavy burden in this region. Therefore effective diabetes prevention and management programs should be implemented in order to control diabetes prevalence.

Disclosure
Y. Huang: None. S. Karuranga: None. E.J. Boyko: None. B. Malanda: None.
Trends in Glycemic Control Based on A1C Factorisation across Different Clinical Settings
Authors: CHAWLA PURVI M. , ASHTEKAR CHANDRASHEKHAR , DHOPE RAHUL M. , SHAIKH AMBARI FIRDOUS. , KOTHARI MIKHIL C. , CHAWLA MANOJ S. 
Published: June 2018

Approximately, 20-40% patients with diabetes achieve the glycemic target (A1C&lt; 7%), globally. A retrospective analysis of glycemic trends based on A1C across three diabetes speciality centers [metro city (A), second tier city (B), district headquarter (C)] including 11,162 patients [A (n=3601), B (n=815), C (n=6746)] either newly diagnosed or following up at over past two years, was undertaken. Being treated as per standard guidelines with at least one HbA1c level reported within this period and classified as well-controlled (A1C &lt;7%) or uncontrolled (A1C &lt;7%) based on glycemic factorization. Table 1 shows the ANOVA results[1264 patients (11.32%) achieving an A1C &lt;6%, and 2709 patients (24.27%) between 6-6.9% across centers]; representing well-controlled patients and the uncontrolled patient population (A1C&gt;7%). The latter group with 22.52% (n=2514) and 23.49% (n=2622) patients with A1C between 7-7.9% and 8-9.9% respectively, represented a group that should be aggressively treated to mitigate the “missed opportunities” in achieving glycemic control and increase the overall percentage of patients achieving target goals. Furthermore, sub-group analyses across individual centers (A, B, C) revealed that differences in factorized HbA1c levels were statistically highly significant (p=0.002) necessitating a high-quality, uniform standard of care, irrespective of the setting to help burden of this disease.
Table 1 - Glycemic Factorisation Across Three Different Diabetes Care Centers Over 24 Months.HbA1c FactorisationMetro City (A)Second Tier City (B)District Headquarter (C)TotalPercentage (%)&lt; 626152951126411.326-6.99991871523270924.277-7.910371911286251422.528-9.99112241487262223.4910-10.9183724827376.611-11.9116303615074.54&gt;1294596568097.25Total3601815674611162

Disclosure
P.M. Chawla: Speaker's Bureau; Self; Sanofi. Speaker's Bureau; Spouse/Partner; Eli Lilly and Company, IPCA LABORATORIES, Novo Nordisk A/S, MSD PHARMACEUTICALS PVT. LTD., Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. C. Ashtekar: Speaker's Bureau; Self; Novo Nordisk A/S, USV Private Limited, MSD Pharmaceuticals Pvt. Ltd., Abbott, LUPIN, Eris Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation. R.M. Dhope: Speaker's Bureau; Self; USV Private Limited, SUNPHARMA, LUPIN, Novartis Pharmaceuticals Corporation, AstraZeneca, SERDIA PHARMACEUTICALS, GLENMARK. A.F. Shaikh: None. M.C. Kothari: None. M.S. Chawla: Speaker's Bureau; Self; IPCA Laboratories, Eli Lilly and Company, Novo Nordisk A/S, MSD Pharmaceutical Pvt. Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca. Speaker's Bureau; Spouse/Partner; Sanofi.
Hidden Epidemic—Half of T1DM Is Diagnosed in Adulthood
Authors: SALAM MAAMOUN , BAO YICHENG , HERRICK CYNTHIA J. , MCGILL JANET B. , HUGHES JING 
Published: June 2018

Objective: To determine the distribution of age of onset of T1DM in an adult cohort of patients with T1DM.
Methods: T1DM patients from an adult academic diabetes center provided informed consent, completed a questionnaire and gave permission for medical record review. Demographics included age, gender and race. T1DM diagnosis was confirmed by history, occurrence of DKA, C-peptide and/or positive T1DM autoantibodies. Patients with diabetes due to pancreatic disease, chemotherapy, genetic syndromes or unclear etiology were not included.
Results: Of the 1167 confirmed cases of T1DM, 563 (48.2%) were male and 604 (51.8%) were female; 107 (9.2%) were African-American and 1060 (90.8%) were Caucasian or other (&lt;1% Asian). Mean age of participants was 46.9 +/- 16.2 years. T1DM was diagnosed at ages &lt;1 to 78 years with mean age at onset of 21.3 +/- 14.4 years. Age at onset of &lt;18 years occurred in 576 participants (49.4%), 18-30 years in 313 (26.8%), and &gt;30 years in 278 (23.8%). Males and females age at onset of T1DM ≥18 years were 53.1% and 48.3% respectively, NS (p=0.11). African-Americans and non-African-Americans diagnosed with T1DM at ≥18 years: 52.3% and 50.5% respectively, NS (p=0.71). In a subset of patients with current age ≥30 (n=971), the mean age of onset of T1DM was 23.2+/-14.8 years.
Conclusion: In this cohort of adults with T1DM, over half of all patients were diagnosed at age ≥18 years, and 23.8% at age &gt;30 years. This trend was consistent across race and gender and more pronounced in the subset with age ≥30 years. These findings challenge historical data that the mean age of onset of T1DM is in childhood. The strength of this dataset is accuracy of age of onset and diagnosis. The major limitation is that it is not population based. Because the reported age at onset of T1DM is highly dependent on the age of the cohort studied, epidemiologic studies of T1DM should include the entire age spectrum. Better awareness of T1DM in adults is needed to provide appropriate medical management and to ensure patient safety.

Disclosure
M. Salam: None. Y. Bao: None. C.J. Herrick: Stock/Shareholder; Spouse/Partner; Cardinal Health. J.B. McGill: Research Support; Self; AstraZeneca. Consultant; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Aegerion Pharmaceuticals. Consultant; Self; Bayer AG, Dexcom, Inc., Intarcia Therapeutics, Inc.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc., MannKind Corporation. Research Support; Self; Novartis Pharmaceuticals Corporation. Consultant; Self; Novo Nordisk A/S. J. Hughes: None.
Genetic Effects on Enhancer Activity in Human Pancreatic Islets
Authors: VARSHNEY ARUSHI , PARKER STEPHEN ,   FUSION TISSUE STUDY
Published: June 2018

Genome-wide association studies (GWAS) have identified &gt;100 single nucleotide polymorphisms (SNPs) that modulate risk for type 2 diabetes (T2D) and related traits. Using functional genomic profiling, we and others have shown that T2D GWAS SNPs are significantly enriched to overlap pancreatic islet stretch enhancer chromatin states, implicating these regulatory elements as biological mediators of disease risk. Recent studies that integrate genetic variation and islet gene expression have identified expression quantitative trait loci (eQTL) that nominate target effector transcripts for T2D GWAS SNPs. However, the subset of causal regulatory SNPs that mediate genetic control of gene expression are unknown. To help close this gap in knowledge, we have performed capped analysis of gene expression (CAGE) on RNA enriched for active enhancers (eRNA-CAGE) across 40 human islet samples. Comparison of these profiles to previously published islet chromatin maps revealed significant enrichment for active chromatin states (P&lt;0.001). Interestingly, we observe unbalanced bidirectional transcription at chromatin-defined intronic enhancer regions, where the predominant direction of enhancer transcription is concordant with the transcribed direction of the endogenous gene, suggesting interactions between gene and enhancer activity. One such example is an ABCC8 intronic enhancer that we previously functionally validated using a mouse transgenic reporter assay. We further performed genotyping and imputation, which allowed us to run an eRNA-QTL scan. We identified 4associations (P&lt;0.for beta distribution adjusted P-value; QTLtools package), which are significantly enriched (P=7.3x10-7) to occur in islet active enhancer chromatin states. Notably, we found islet eRNA-QTL that overlap T2D GWAS SNPs and islet eQTL. Together, these results form a genetic map of human islet enhancer activity that is a foundation for interpreting regulatory mechanisms at T2D GWAS loci.

Disclosure
A. Varshney: None. S. Parker: None.
Inhibition of PPAR Gamma, Adipogenesis, and Insulin Sensitivity by MAGED1
Authors: WANG QINGHUA , TANG JING , GAO XIANG , RUAN HAI-BIN 
Published: June 2018

Adipocytes serve as critical integrators of energy balance and glucose homeostasis by storing excess energy to prevent ectopic fat accumulation in non-adipose tissues and by secreting various adipokines to modulate whole-body metabolism. Peroxisome proliferator-activated receptor-γ (PPARγ) is a master regulator of adipogenesis and a target of the thiazolidinedione (TZD) class of antidiabetic drugs; therefore, identifying novel regulators of PPARγ action in adipocytes is essential for the future development of therapeutics for diabetes. MAGE Family Member D1 (MAGED1), by acting as an adaptor for ubiquitin-dependent degradation pathways and a co-factor for transcription, plays an important role in neural development, cell differentiation, and circadian rhythm. Here, we showed that MAGED1 expression was downregulated during adipogenesis and MAGED1 inhibited preadipocyte proliferation and adipogenesis in vitro. Mechanistically, MAGED1 bound to PPARγ and suppressed the stability and transcriptional activity of PPARγ. Compared to wild type littermates, MAGED1-deficient mice showed increased levels of PPARγ protein and its target genes, more CD29+CD34+Sca-1+ adipocyte precursors, and hyperplasia of white adipose tissues (WATs) at young ages. Moreover, MAGED1-deficient mice developed late-onset obesity as a result of decreased energy expenditure and physical activity. However, these mice were metabolically healthy as shown by improved glucose clearance and insulin sensitivity. Lipid profiling showed that obesity in MAGED1 knockout (KO) mice did not cause increased levels of serum lipids. On the other hand, expression and secretion of adipokines such as leptin and adiponectin were upregulated in KO mice. Taken together, our data identify MAGED1 as a novel negative regulator of PPARγ activity, adipogenesis, and insulin sensitivity in mice. MAGED1 might therefore serve as a novel pharmaceutical target to treat obesity-associated insulin resistance.

Disclosure
Q. Wang: None. J. Tang: None. X. Gao: None. H. Ruan: None.