bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost-Effectiveness of Structured Lifestyle Intervention in Overweight and Obese Adults with Type 2 Diabetes—Results from the Action for Health in Diabetes (Look AHEAD) Study
Authors: ZHANG PING , CHEN HAIYING , ESPELAND MARK , WING RENA R. , MONTEZ MARIA G. , HUCKFELDT PETER J. , EVANS MARY , GREGG EDWARD W. , KNOWLER WILLIAM C. 
Published: June 2018

Look AHEAD is a multicenter randomized clinical trial designed to examine the effects of an intensive lifestyle intervention (ILI), compared with diabetes support and education (DSE), for reducing cardiovascular events in 5,145 adults with overweight/obesity and type 2 diabetes. Here we reported the cost-effectiveness of the ILI, measured in costs per quality-adjusted life year (QALY), relative to DSE as implemented during the 10-year intervention period of the trial.
Health utility (HU) values were measured using HU Index-2, HU Index-3, SF-6D and Feeling Thermometer. Cost were measured in 2012 U.S. dollars. All data were collected prospectively. QALYs were calculated as the product of predicted survival probability and predicted health utility values. Cumulative total cost was calculated as a sum of intervention cost and health expenditures, each of which was calculated as the product of predicted survival probability and predicted intervention cost and health expenditures.
The estimated total and incremental QALYS and costs, and cost-effectiveness ratios (CER) are presented in the Table. ILI was likely to be not cost effective over the 10 year intervention period. Long term health benefits from the follow-up of the study participants can provide important information regarding the long-term cost-effectiveness of ILI.MeasurementsDSE (95% CI)ILI (95% CI)ILI-DSE (95%CI)CE Ratio (95% CI)HUI-2 (QALYs)6.08 (6.03, 6.13)6.10 (6.05, 6.15)0.03 (-0.04, 0.09)-----HUI-3 (QALYs)5.94 (5.88, 5.99)5.94 (5.87, 5.99)0 (-0.08, 0.07)-----SF-6D (QALYs)5.92 (5.88, 5.96)5.99 (5.95, 6.03)0.07 (0.02, 0.12)101,635 (42567, 320360)Feeling thermometer (QALYs)6.03 (5.98, 6.07)6.18 (6.67, 6.77)0.15 (0.10, 0.21)45,487 (23270, 81851)Total cost ($)78,466 (76324, 80708)85,490 (83341, 87666)7,024 (4121, 9932)-----

Disclosure
P. Zhang: None. H. Chen: None. M. Espeland: Consultant; Self; Boehringer Ingelheim GmbH, Janssen Pharmaceuticals, Inc.. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, National Heart, Lung, and Blood Institute. R.R. Wing: None. M.G. Montez: None. P.J. Huckfeldt: None. M. Evans: None. E.W. Gregg: None. W.C. Knowler: None.
CRISPR Mediated Deletion of a Proxy 19.2kb Distal to the T2D GWAS-Implicated SLC30A8 R325W Variant Impacts RAD21 and UTP23 Gene Expression in HepG2 Cells
Authors: HODGE KENYAITA M. , LU SUMEI , LEONARD MICHELLE , PIPPIN JAMES A. , CHESI ALESSANDRA , WELLS ANDREW D. , JOHNSON MATTHEW , GRANT STRUAN F. 
Published: June 2018

Genome wide association studies (GWAS) have revealed multiple loci for type 2 diabetes (T2D). However, given that GWAS generally only reports genomic signals associated with a given trait, there is need for follow-up characterization. Despite key reports of missense variants within SLC30A8 conferring protection of T2D risk, there is still need to better understand the relationship between the GWAS signal and mechanism at this locus. The application of ’Assay for Transposase Accessible Chromatin combined with sequencing’ (ATAC-seq) to Endo-BH1, SGBS and HepG2 cell lines, representing models for pancreatic beta-cells, adipose and liver respectively, allowed us to filter for putatively informative proxy SNPs (r2&gt;0.8) coinciding with open chromatin at this locus. Following sequencing on the Illumina Hi-Seq platform, the sentinel SNP itself coincided with open chromatin, namely rs13266634 (a missense R325W variant), in both Endo-BH1 and SGBS; however, in HepG2 this region was closed while proxy rs9650069 was open, situated 3’ to SLC30A8 and 19.2kb from rs13266634. We elected to generate CRISPR/Cas9 mediated deletions immediately around rs9650069 in a mixed cell setting. Following confirmation of deletion by sequencing, we assessed changes in expression for all genes in the corresponding topological associating domain (TAD), namely SLC30A8, AARD, EIF3H, RAD21, TRPS1 and UTP23. Two genes revealed a significant change in expression when normalized to beta-actin, namely RAD21 and UTP23, yielding 5.58 fold and 4.57 fold decreases, respectively. Given that according to GTEx the expression of SLC30A8 is largely contained to the pancreas, this gene was not expressed in this cell setting and thus the impact of this deletion on this gene could not be assessed. This effort implicates an enhancer element for these genes in a liver cell model as being a part of the machinery genetically controlling this locus.

Disclosure
K.M. Hodge: None. S. Lu: None. M. Leonard: None. J.A. Pippin: None. A. Chesi: None. A.D. Wells: None. M. Johnson: None. S.F. Grant: None.
Heme Deficiency Causes Impaired Glycogen Synthesis in Skeletal Muscle Leading to Insulin Resistance
Authors: NAKAJIMA OSAMU , SAITOH SHINICHI , KIMURA TOMOHIRO , OSAKI TSUKASA , VINCENT KELLY P. , TAKAHASHI KIWAMU , TANAKA TOHRU , NAKAJIMA MOTOWO 
Published: June 2018

In vertebrates, the initial step in heme biosynthesis is the production of 5-aminolevulinic acid (ALA) by ALA synthase (ALAS). The ALAS1 gene encodes a ubiquitously expressed isozyme. Mice heterozygous null for ALAS1 (A1+/-s) experience mitochondrial dysfunction in skeletal muscle, impaired glucose tolerance (IGT) and insulin resistance (IR) past 20-weeks of age (aged A1+/-s) 1). IGT/IR in aged A1+/-s was remedied by oral administration of ALA for 1-week1). By contrast, mitochondrial dysfunction required 6-weeks of ALA administration before improvements could be observed, indicating the phenotype of IGT/ IR is not due to mitochondrial dysfunction1). We found no remarkable change in expressions and phosphorylation of proteins related to insulin signalling such as Akt and GSK3β in skeletal muscle of aged A1+/-s1). Rather, abnormal ultrastructure of glycogen granules and increased glycogen contents were observed in skeletal muscle of aged A1+/-s unlike of less than 15-weeks-old A1+/-s, and those abnormalities of glycogen were reversed after ALA-treatment for 1-week as well as IGT/IR. The quantification of glycogen contents showed that insulin-induced glycogen synthesis was impaired in skeletal muscle of aged A1+/-s, and the reduced de novo glycogen synthesis was recovered in ALA-administrated aged A1+/-s. Glycogen synthase (GS) activities were constitutively activated even at the low concentration of glucose 6-phosphate (G6P) and not augmented at the high concentration of G6P in extracts from skeletal muscle of aged A1+/-s, suggesting that GS fails to respond to allosteric activation by G6P. While, GS activities were normally regulated in those of ALA-administered aged A1+/-s. Taken together, our data suggest that impaired de novo glycogen synthesis in skeletal muscle is relevant to IGT/IR in aged A1+/-s due to constitutively activated GS without allosteric activation by G6P. Ref. 1) Saitoh et al. PLOS ONE in press.

Disclosure
O. Nakajima: None. S. Saitoh: Research Support; Spouse/Partner; Japan Society for the Promotion of Science, SBI Pharmaceuticals Co.,Ltd.. T. Kimura: None. T. Osaki: None. K.P. Vincent: Research Support; Self; Kora Healthcare. K. Takahashi: None. T. Tanaka: None. M. Nakajima: None.
SNP x SNP Interactions Elucidate TCF7L2’s Physiology Conveying Incretin Action
Authors: JAGHUTRIZ BENJAMIN , HENI MARTIN , LUTZ STEFAN Z. , STAIGER HARALD , PETER ANDREAS , HAERING HANS-ULRICH , FRITSCHE ANDREAS , WAGNER ROBERT 
Published: June 2018

Introduction: Genetic polymorphisms in TCF7L2 are the strongest common risk variants for type 2 diabetes. We and others had showed that genetic variation in TCF7L2 affects incretin-stimulated insulin secretion. A recent genome-wide association study discovered variants associated with incretin levels. We hypothesized that these SNPs interact with the well-known TCF7L2 variant rs7903146 on insulin secretion due to their incretin altering effect.
Methods: Insulin secretion was measured with OGTT-based indices that were calculated from insulin, C-peptide and glucose levels in the cross-sectional TUEF-cohort (n=2929). We also measured insulin secretion in a modified hyperglycemic clamp at 10 mmol/l, using additional GLP-1 infusion at the end of the clamp (n=76). Besides rs7903146 in TCF7L2, we genotyped rs17681684 in GLP2R, rs1800437 in GIPR, rs17683011 in SLC5A1, as well as 3 additional variants associated with GIP levels.
Results: Four of the 6 incretin-associated SNPs exhibited at least nominally significant SNP x SNP interactions with rs7903146 in TCF7L2 on insulin secretion measured by the corrected insulin response (CIR). In the hyperglycemic clamp study, rs7903146 in TCF7L2 interacted with rs1800437 (GIPR) on both AUC insulin and C-peptide, and rs17681684 (GLP2R) on AUC C-peptide during the GLP-1 stimulation phase (p&lt;0.05).
Conclusion: These findings corroborate the role of the TCF7L2 variant in mediating incretin action to increase diabetes risk. They highlight the importance of SNP x SNP interactions in the assessment of the genetic architecture of type 2 diabetes.

Disclosure
B. Jaghutriz: None. M. Heni: Research Support; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Merck Sharp & Dohme Corp., Novo Nordisk Inc.. S.Z. Lutz: None. H. Staiger: None. A. Peter: None. H. Haering: None. A. Fritsche: Advisory Panel; Self; Sanofi-Aventis Deutschland GmbH, Novo Nordisk A/S, Eli Lilly and Company, Boehringer Ingelheim GmbH. R. Wagner: None.
Effects of Aerobic and Resistance Training on Circulating Micro-RNA Expression Profile in Subjects with Type 2 Diabetes
Authors: OLIOSO DEBORA , DAURIZ MARCO , BACCHI ELISABETTA , NEGRI CARLO , BONORA ENZO , MOGHETTI PAOLO 
Published: June 2018

Structured exercise programs are of great benefit in order to obtain a proper glycemic control in subjects with type diabetes (T2D). However, whether the metabolic effects of aerobic (AER) and resistance (RES) exercise exert specific changes in the expression profile of circulating miRNAs (c-miRNAs) is still largely unknown. We studied 24 individuals with T2D from the RAED2 Trial (NCT01182948), randomly assigned to AER or RES training protocols (NAER=12; NRES=12). Firstly, the baseline and post-training levels of 179 c-miRNAs were measured by RT-PCR in 6 individuals (NAER=3; NRES=3). Nineteen c-miRNAs exhibited at least 20% fold-change variation from baseline and were thereafter measured in the whole group. Compared to baseline, the expression levels of miR-423-3p, miR-451a and miR-766-3p resulted significantly upregulated after exercise, irrespective of exercise type (type I error rate threshold: 0.0026; 0.05/19 miRNAs). Bioinformatic analysis by miRSystem and Diana Tools revealed that these c-miRNAs targeted genes involved in pathways relevant to fatty acids biosynthesis and metabolic regulation, including LKB1, PI3K, mTOR and IRS signaling pathways. Interestingly, miR-451a and miR-423-3p changes were positively correlated with fat loss after training (rho=0.45 and 0.43, respectively; p&lt;0.05). Both miRNAs, alone or in combination, resulted as independent predictors of fat loss, when entered in generalized linear models including exercise type as covariate. However, only miR-451a eventually survived as predictor of fat loss after further correction for age, sex, BMI and hemoglobin A1c.
In conclusion, physical exercise in individuals with T2D is associated with specific changes of c-miRNAs profile, predominantly clustered along pathways with regulatory significance for fatty acid metabolism. Further investigations are warranted to confirm our findings and to unravel their mechanistic significance.

Disclosure
D. Olioso: None. M. Dauriz: None. E. Bacchi: None. C. Negri: None. E. Bonora: None. P. Moghetti: None.
A Comparison of the Impact of the 2017 ACC/AHA Hypertension Guidelines on Primary Care Populations With and Without Diabetes
Authors: SPERL-HILLEN JOANN M. , ANDERSON JEFFREY P. , DESAI JAY R. , MARGOLIS KAREN L. , CRAIN A. LAUREN , O'CONNOR PATRICK J. 
Published: June 2018

Background: Our objective was to assess the impact on primary care of the 2017 ACC/AHA lowering of the threshold for diagnosing HTN to a BP ≥ 130/80 mm Hg, and pharmacologic treatment intensification recommendations for patients with high CV risk and/or DM who have BP levels 130-139/80-89 mm Hg.
Discussion: 62% of patients with DM and 57% without DM had a BP ≥ 130/80 mm Hg, and over half of these will require reclassification of HTN due to BP 130-139/80-89 mm Hg.Of patients with Stage 1 HTN, 76.8% of patients with DM and 39.4% without DM are already treated (but above goal). 25% of all DM patients (7755/30,608) and 13% of all non-DM patients (22963/176,555) are currently treated with Stage 1 HTN and will require an increase in BP medication to achieve BP &lt; 130/80 mm Hg.7.7% of all DM patients (2344/30,608) and 2.3% of all non- DM patients with CV risk ≥ 10% (3960/176,555) are currently untreated with Stage 1 HTN and medication initiation will be recommended. If pharmacologic treatment initiation recommendations were limited to those with CV risk ≥ 10% for DM patients, BP medication initiation recommendations would decrease from 7.7% to 2.9% (896/30,608) of the DM population.
Conclusion: The 2017 ACC/AHA guideline will result in a significantly increased need for primary care to address BP medication intensification, with a much greater proportional impact on those with DM compared to those without.

Disclosure
J.M. Sperl-Hillen: None. J.P. Anderson: None. J.R. Desai: None. K.L. Margolis: None. A. Crain: None. P.J. O'Connor: None.
No Evidence of a Causal Association between Diabetes-Related Phenotypes and Atrial Fibrillation
Authors: HARATI HADI , ZANETTI DANIELA , INGELSSON ERIK , KNOWLES JOSH 
Published: June 2018

Background: Several epidemiological studies have shown an association between increased fasting and 2-hour plasma glucose (FPG and 2hPG), hemoglobin A1C (A1C), and fasting insulin (FI) and risk of atrial fibrillation (AF). We aimed to assess whether this relation is causal using genetic data from large populations of individuals of European descent.
Methods: Two-sample Mendelian randomization (MR) was used to obtain estimates of influence of the risk factors (FPG, 2hPG, A1C and FI) on risk of the outcome (AF). Instrumental variables (IVs) were constructed using the previously reported single nucleotide polymorphisms (SNPs) associated with each risk factor at p-value&lt;e-8 from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with up to 133,000 nondiabetic participants. Selected SNPs were checked for pleiotropy using the UK Biobank dataset and those associated with the confounders at p-value&lt;e-8 were excluded. AF consortium (AFGen) summary statistics with 22,346 AF cases and 132,086 controls was used for the outcome data analysis.
Results: Two-step MR with inverse variance weighted methods did not show any causal association between diabetes related phneotypes and AF [FPG (30 SNPs, p=0.7), 2hPG (7 SNPs, p=0.3), A1C (11 SNPs, p=0.3), or FI (13 SNPs, p=0.9)]. None of the IVs showed horizontal pleiotropy indicating that the used genetic variants affected the outcome only via their effect on the diabetes related phenotypes (p-values of 0.56, 0.09, 0.099, and 0.31 respectively for FPG, 2hPG, A1C, and FI). Calculated power based on the original set of SNPs in the MAGIC and estimated odds ratio of 1.2 were 99, 94, 99, and 84% respectively for FBG, 2hPG, A1C, and FI.
Conclusion: This MR analysis does not support a causal role between genetically programmed diabetes related traits (FPG, 2hPG, A1C, or FI) and AF. These data suggest that drug treatment to reduce dysglycemia in nondiabetics may not be an effective strategy for AF prevention.

Disclosure
H. Harati: None. D. Zanetti: None. E. Ingelsson: None. J. Knowles: None.
A Pilot Study of Preproinsulin Peptides Reactivity in Chinese Type 1 Diabetic Patients
Authors: XIAN YINGXIN , XU HAIXIA , LV JING , GAO YIFANG , REN WENQIAN , HUANG QIANWEN , JIANG ZIYU , YAN JINHUA , YAO BIN , WENG JIANPING 
Published: June 2018

Type 1 diabetes (T1D) is an autoimmune disease in which auto-reactive T cells infiltrate the pancreatic islets and destroy insulin-producing β cells. Preproinsulin (PPI) is considered as an important autoantigen for developing T1D in Caucasian population, particularly in those bearing T1D associated susceptible alleles DRB1*04:01, DQA1*03:01 and DQB1*03:02. However, whether PPI could trigger similar responses in Chinese T1D patients remains elusive. Peripheral blood mononuclear cells from 19 newly diagnosed T1D (Mean Age =16.7yr) and 32 long term T1D patients (Mean Age =21.3yr) of Chinese Han nationality were isolated and stimulated by a pool of 13 different PPI peptides, which were synthesized according to epitope mapping of the full length PPI. PPI reactive T cells were measured by IFN-γELISPOT assay. Briefly, the mean values in wells with peptides were compared with those in background wells to derive a stimulation index (SI). A specific IFN-γresponse is defined as SI≥3. All patients showed a significant IFN-γresponse to OKT 3 stimulation, and 96% of patients showed positive responses to Pentaxim vaccine. However, we did not detect specific IFN-γresponse to PPI peptides with a range of concentrations (i.e., 1ug/ml to 100ug/ml). To confirm our results, 2 peptides (C19-A3, B9-23) with dominant epitopes known to be presented by DR4 and DQ8 were also tested. In agreement with the PPI peptide pool study, these 2 peptides did not induce specific IFN-γproducing T cells activity. This includes six patients with DQA1*03:01 and DQB1*03:02 alleles. This is the first report describing IFN-γresponse of T cells to overlapping human PPI peptides in Chinese T1D patient. It is worth knowing that, unlike the Caucasian T1D population, around 30% of Chinese T1D population uniquely consist the DRB1*09:01 allele (20% in our study population). Thus, the lack of specific response in our patient cohort suggests that PPI might not be the principal disease causing antigen in Chinese T1D due to the population heterogeneity.

Disclosure
Y. Xian: None. H. Xu: None. J. Lv: None. Y. Gao: None. W. Ren: None. Q. Huang: None. Z. Jiang: None. J. Yan: None. B. Yao: None. J. Weng: None.
Mucosal Gamma/Delta T Cells Increased by i.n. Administration of Gliadin to Four-Week-Old NOD Mice Prevent Diabetes in the NOD-SCID Model of Adoptive Cotransfer of Diabetes
Authors: FUNDA DAVID , GOLIAS JAROSLAV , HAUPT-JORGENSEN MARTIN , BUSCHARD KARSTEN 
Published: June 2018

Beta-cell autoantigens, e.g., insulin, proinsulin, or GAD65, have been investigated both in animal models and human trials for induction of beta-cell specific tolerance to prevent the development of type 1 diabetes (T1D). On the other hand, environmental factors that significantly contribute to the recent outbreak of T1D were less studied, probably due to their complexity. The dietary wheat protein fraction has been associated with high penetrance of the disease, whereas gluten-free diets prevented T1D in animal models. We have previously reported that i.n. administration of gliadin prevented diabetes in NOD mice. Herewith we investigated mucosal gamma/delta T cells that were induced by i.n. administration of gliadin for their regulatory capacity to prevent diabetes in the NOD-SCID model of diabetes co-transfer. I.n. administration of gliadin to 4-week-old NOD mice increased proportion of gamma/delta T cells in pancreatic and mesenteric lymph nodes. Adoptive co-transfer of 2x106 gamma/delta T cells with 1x107 diabetogenic splenocytes led to statistically significant (p&lt;0.01) diabetes prevention. The gamma/delta T cells were characterized for their memory-naïve and mucosal homing properties, or NK-like features by assessing expression of CD8alpha, CD45RB, CD62L, CCR7, CD103 and NKG2D by flowcytometry.
In conclusion, similar to i.n. administration of insulin, i.n. vaccination with gliadin, an environmental antigen with possible ethiological influence in T1D, led to increased proportion of mucosal gamma/delta T cells. These gamma/delta T cells possess regulatory capacity to prevent diabetes transfer in the NOD-SCID model and may represent a novel and safer strategy for prevention or an early intervention in T1D.

Disclosure
D. Funda: None. J. Golias: None. M. Haupt-Jorgensen: None. K. Buschard: None.
Are Liver Cystic Lesions after Islet Transplantation Caused by Streptozotocine?
Authors: KOSINOVÁ LUCIE , PATIKOVA ALZBETA , STICOVA EVA , VOJTÍŠKOVÁ ALŽBěTA , BARTONOVA LENKA , CAHOVA MONIKA , KRIZ JAN 
Published: June 2018

Introduction: Pancreatic islets (PI) transplanted (Tx) into the portal vein cause a permanent exposure of surrounding liver tissue to insulin in high concentration. There were published several papers pronouncing the hypothesis of a direct triggering effect of Tx PI on a development of focal morphological changes in liver tissue (tumors, cysts). At the same time, streptozotocine (STZ) was supposed to play a minor but not negligible role in this phenomenon.
Methods: Syngeneic pancreatic islets were transplanted into the healthy or diabetic (50mg/kg STZ) Brown Norway rats. Group A (n=5)-healthy, Tx of 450 PI into the portal vein; Group B (n=17)-STZ diabetes, Tx of 450 PI into the portal vein; Group C (n=8)-STZ diabetes, Tx of 100 PI under the left kidney capsule; Group D (n=7)-STZ diabetes, human insulin pellet s.c. (changed each 6th week); All recipients were monitored for 10 months including MRI of liver. At the end of study each liver was examined by histology. The ultrastructure of liver was examined by electron microscopy (TEM) 3 hours after injection of STZ.
Results: Tx of PI in suboptimal number normalized fasting blood glucose levels but did not normalize glucose assimilation during IVGTT in all diabetic animals. While liver of Group A recipients remained intact, in animals of Groups B and C multiple voluminous cystic complexes with cholangiocyte cubic epithelium lining were detected after 10 months irrespective of Tx site. In animals of Group D, blood glucose levels were nearly normalized six months after STZ injection and there was no need to replace pellets later on. There were simple, individual cystic lesions within liver in this group after 10 months. There were not any typical lesions in TEM examined samples.
Conclusions: The injection of STZ and subsequent Tx of PI can cause cholagiogenic cystic lesions development in rats. The therapy by human insulin did not stimulate the development of cystic lesions by the equal efficiency. STZ itself cannot cause the cystic transformation of BN rat liver.

Disclosure
L. Kosinová: None. A. Patikova: None. E. Sticova: None. A. Vojtíšková: None. L. Bartonova: None. M. Cahova: None. J. Kriz: None.