bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of Urinary Normetanephrine Levels with Increased Insulin Resistance in a General Population
Authors: MURABAYASHI MASAYA , DAIMON MAKOTO , MURAKAMI HIROSHI , KAMBA AYA , MIZUSHIRI SATORU 
Published: June 2018

Since activation of the sympathetic nervous system is associated with both impaired insulin secretion and insulin resistance, or namely with diabetes, evaluation of such activation in ordinary clinical settings appears to be important. Urinary levels of catecholamine metabolite, normetanephrine (NM) may be such a marker. Therefore, we here examined association of urinary NM levels with insulin secretion and resistance evaluated by HOMA indices in a general population. From 1,149 participants of the 2016 population-based Iwaki study of Japanese, 1,037 individuals with fasting blood glucose levels, 64-140 to assess HOMA indices precisely were enrolled in the study (gender (M/F): 407/630; age: 53.4±15.5). The Iwaki study is a health promotion study of people over 20 years old to prevent lifestyle-related diseases and prolong their lifespans, and, the participants were those who believe themselves as healthy. Their urinary NM levels were 0.20±0.mg/grCr. Univariate linear regression analyses showed a significant association of urinary NM levels with HOMA-R (β= 0.1508, p &lt;0.0001) and HOMA-β (β= -0.1354, p&lt;0.0001). Adjustment with age, gender, and multiple factors correlated with HOMA indices (Body mass index, Triglyceride, Hypertension, %fat, HbA1c) showed a significant association with HOMA-R (β=0.1167, p= 0.0012) but not with HOMA-β (β=0.011, p =0.782). Further, analysis with subjects stratified into 2 groups (risk and non-risk) using the optimal cut-off value of NM to predict insulin resistance (HOMA-R&gt;1.6) determined by ROC analysis (0.215 mg/grCr) showed those at risk had an OR of 2.36 (CI: 1.49-3.74) after adjustment for the factors listed above. Increased urinary NM levels seem to be a marker for insulin resistance, or namely risk for diabetes in general.

Disclosure
M. Murabayashi: None. M. Daimon: None. H. Murakami: None. A. Kamba: None. S. Mizushiri: None.
Advanced Nonalcoholic Steatohepatitis Is Associated with Low Serum Lipoprotein(a) Concentrations
Authors: KONISHI KANAKO , MIYAKE TERUKI , SENBA HIDENORI , YAMAMOTO SHIN , FURUKAWA SHINYA , WATANABE TAKAO , KOIZUMI YOHEI , YOSHIDA OSAMU , HIROOKA MASASHI , KUMAGI TERU , ABE MASANORI , MATSUURA BUNZO , HIASA YOICHI 
Published: June 2018

Background: Nonalcoholic fatty liver disease (NAFLD), a complication frequently coexisting with diabetes, is at high risk of progression to nonalcoholic steatohepatitis (NASH), cirrhosis, liver failure, and hepatocellular carcinoma. Advanced NASH and advanced hepatitis C have poor prognoses, and therapeutic intervention is limited. In contrast, NAFLD may be related to serum lipoprotein(a) (Lp[a]) levels. However, the association between serum Lp(a) levels and progression of NAFLD to NASH remains unknown. We therefore investigated this issue among patients with biopsy-proven NAFLD.
Methods: We enrolled 136 patients with biopsy-proven NAFLD (nonalcoholic fatty liver [NAFL], 20 patients; stage 1, 29 patients; stage 2, 32 patients; stage 3, 26 patients; stage 4, 29 patients), and classified them into the advanced NASH group (stages 3 and 4) and the non-advanced group (NAFL, and stages 1 and 2). Serum Lp(a) levels were measured using the turbidimetric latex agglutination method, and data were divided into tertiles.
Results: In total, 76.5% and 47.2% of the patients were diabetic in the advanced NASH group and the non-advanced group, respectively. Serum Lp(a) levels in the advanced NASH group were significantly lower than those in the non-advanced group (P = 0.009). Multivariate analysis, adjusted for age, sex, body mass index, diabetes mellitus, dyslipidemia, and hypertension, showed that lower serum Lp(a) levels were significantly associated with a higher prevalence of advanced NASH; the adjusted odds ratios (95% confidence intervals) for advanced NASH in relation to serum Lp(a) levels of ≤6.1, 6.2-13, and ≥13.1 mg/dL were 1.00 (reference), 0.333 (0.14-0.791), and 0.341 (0.124-0.937), respectively (P for trend = 0.004).
Conclusions: It was concluded that lower levels of serum Lp(a) could be a significant risk factor for advanced NASH and that serum Lp(a) levels may be a useful tool for distinguishing between NASH and NAFL.

Disclosure
K. Konishi: None. T. Miyake: None. H. Senba: None. S. Yamamoto: None. S. Furukawa: None. T. Watanabe: None. Y. Koizumi: None. O. Yoshida: None. M. Hirooka: None. T. Kumagi: None. M. Abe: None. B. Matsuura: None. Y. Hiasa: None.
Parental Type 2 Diabetes and Obesity Development from Childhood to Early Adulthood
Authors: NIELSEN JANNIE , HULMAN ADAM , CUNNINGHAM SOLVEIG A. 
Published: June 2018

Due to shared genes and environment, the home setting may be an effective context to provide multiple individuals at risk of type 2 diabetes (T2D) with preventive efforts. The aim of this study is to investigate whether having a parent with T2D affects the BMI development from childhood through adolescence and into early adulthood.
This analysis used the Panel Study of Income Dynamics (PSID), a nationally longitudinal study of families in the U.S. We used information on diabetes status in parents, household socio-economic characteristics and sex, age and anthropometrics in children and adolescent from 2001-2015 (n=5981). Body mass index (BMI) trajectories in children were fitted using mixed-effects models. Random intercept and slope were included to account for the within-person correlation arising from the repeated measures in the dataset. We used age as the time axis and modeled change with linear, quadratic and cubic terms to account for the non-linear change in BMI.
At baseline, (mean age 12.2 years) children with a parent with T2D were 1.2 years older, had a 3.0 kg/m2 higher BMI than children with no parental T2D (p&lt;0.01 for all tests). The differences occurred with age: There was no significant difference in BMI between the two groups up to 8 years of age. However, at age 8, children with parental diabetes had a 0.41 kg/m2 (0.20-0.61) faster annual increase in BMI than the non-exposed group’s, whose annual increase was 1.03 kg/m2 (0.94-1.11). The rate of annual BMI increase became smaller with age. A maximal separation of 2.04 kg/m2 (1.53-2.55) was reached at 15 years of age, which remained relatively stable in early adulthood.
Children with a parent with T2D as compared to children without parental T2D exhibit a faster increasing BMI trajectory that leads to significant differences in adolescent BMI. This difference persists in early adulthood, when most children no longer live with their parents. Once a parent is diagnosed with T2D, obesity and diabetes prevention may be a priority for the children as well.

Disclosure
J. NIelsen: None. A. Hulman: None. S.A. Cunningham: None.
Residual Beta-Cell Function in Long Duration Type 1 Diabetes (T1D)
Authors: GUBITOSI-KLUG ROSE , BRAFFETT BARBARA , HITT SUSAN M. , ARENDS VALERIE , STEFFES MICHAEL , SAENGER AMY K. , LACHIN JOHN , PALMER JERRY P. 
Published: June 2018

We investigated residual beta cell function in participants from the DCCT/EDIC study with an average of 35 (range 27, 48) years duration of T1D. Between 2015-2017 after 22-24 years of follow-up in EDIC, a 4-hour mixed meal tolerance test was administered to 944 participants and 7 timed plasma specimens were collected and assayed for C-peptide using a chemiluminescent immunoassay (Roche). We defined a significant post-stimulus response as a peak C-peptide concentration &gt;0.03 nmol/L, based on an earlier DCCT study which demonstrated that the risk of microvascular disease progression was markedly higher among participants who entered the trial with values below this concentration. Overall, 71 (7.5%) participants were classified as “responders” with a median peak C-peptide of 0.10 nmol/L (IQR 0.06, 0.15). Among the 873 participants classified as “non-responders”, 46 had detectable peak C-peptide between 0.003 (limit of detection) and 0.029 nmol/L. Responders were slightly older than non-responders (58.5 ± 6.2 vs. 56.5 ± 6.8 y; p=0.02), yet had similar age of onset of diabetes (22.5 ± 7.0 vs. 21.4 ± 7.8 y) and duration of diabetes (35.9 ± 5.1 vs. 35.0 ± 4.9 y). Compared to non-responders, responders had lower HbA1c values (8.6 ± 1.7 vs. 8.9 ± 1.5%; p=0.01) and higher stimulated C-peptide (0.22 ± 0.14 vs. 0.11 ± 0.11 nmol/L; p&lt;0.0001) at DCCT baseline; and had lower insulin requirements both at DCCT baseline (0.54 ± 0.18 vs. 0.67 ± 0.24 units/kg/day; p&lt;0.0001) and throughout DCCT follow-up (0.61 ± 0.20 vs. 0.69 ± 0.19 units/kg/day; p=0.0008). Significantly fewer responders experienced severe hypoglycemia [requiring assistance] throughout the DCCT/EDIC study (45% of responders vs. 70% of non-responders; p&lt;0.0001). Both the initial episode and recurrent episodes of severe hypoglycemia were less frequent with increasing C-peptide concentrations.
In conclusion, beta cell function persists in some very long duration T1D patients and is associated with clinically meaningful reductions in the frequency of severe hypoglycemia.

Disclosure
R. Gubitosi-Klug: None. B. Braffett: None. S.M. Hitt: None. V. Arends: None. M. Steffes: None. A.K. Saenger: Advisory Panel; Self; Alere Inc. J. Lachin: Board Member; Self; AbbVie Inc., Celgene Corporation. J.P. Palmer: None.
Time-to-Peak C-Peptide and Peak Glucose during an Oral Glucose Tolerance Test (OGTT) Are Independent Risk Factors for Type 1 Diabetes (T1D) in Antibody-Positive (Ab+) Individuals
Authors: ISMAIL HEBA M. , XU PING , EVANS-MOLINA CARMELLA , PALMER JERRY P. , SOSENKO JAY 
Published: June 2018

Peak C-peptide (C-P) and glucose levels are known predictors of T1D, but T1D prediction by times to those peak levels has not been studied. We thus assessed T1D prediction by times to peak C-P or glucose during OGTTs in 709 Ab+ Diabetes Prevention Trial-type 1 participants with 2-hour OGTTs [mean age: 13.9±9.6 years; BMI percentile (%ile): 59.3±29.0; 56% male]. Log rank testing and Cox regression with adjustments for age, sex, BMI %ile, proband relation, HLA, and Ab number were used. Risks were higher for time to peak C-P &gt;60 mins [HR: 1.96 (CI: 1.49-2.63), p&lt;0.001)] and for time to peak glucose &gt;30 mins [HR: 2.22 (1.67-2.94), p&lt;0.001)]. With time to peak C-P and peak C-P as covariates, T1D associations were greater for time to peak C-P (X2=22.8 vs. 9.3, both p&lt;0.001). Time to peak glucose and peak glucose associations also remained significant (both p&lt;0.001). Findings were validated in Ab+ relatives in the TrialNet Pathway to Prevention study (Figure); those with a peak C-P &gt;60 mins or a peak glucose &gt;30 mins had higher risk (both p&lt;0.001).
In conclusion, Ab+ relatives with delayed peak C-P or glucose are at higher T1D risk, independent of peak levels. Moreover, the time to peak C-P appears to be more predictive than the peak level. Times to peak C-P and glucose have potential use as predictors of T1D and as markers for progression.

Disclosure
H.M. Ismail: None. P. Xu: None. C. Evans-Molina: None. J.P. Palmer: None. J. Sosenko: None.
Reduced Rate of Acute Complications with Tubeless Insulin Pump Use—Data from 2,640 Patients in the German/Austrian DPV Registry
Authors: BIESTER TORBEN , DANNE THOMAS , BOLLOW ESTHER , SCHWANDT ANKE , HEIDTMANN BETTINA , RAMI-MERHAR BIRGIT , HAAK THOMAS , HOLL REINHARD W. 
Published: June 2018

Little is known about the rates of acute complications when switching from MDI or traditional insulin pumps to tubeless insulin pump therapy. The German/Austrian Diabetes patients follow-up-registry (DPV) includes 2691 patients with type 1 (n=2640), type 2 (n=17) and LADA/other (n=34) diabetes types treated for 1.3±1.3 years with a tubeless insulin pump (Omnipod® Insulin Management System, Insulet Corp, Billerica, MA) since 2013. Patients with type 1 diabetes had a mean age of 12.3 year [IQR 9.6-15.0], diabetes duration 2.5 year [0.7-5.9], HbA1c 7.7% [6.8-8.3]. The prior treatment modality was 59.3% MDI, 37.5% other pump and 2.4% tubeless pump as initial therapy (0.3% unknown). Discontinuation of tubeless pump treatment in patients with type 1 diabetes was 7.3% and occurred after 0.7±0.9 mo. Despite the typical age-dependent increase in HbA1c in this primarily adolescent population, the rate of severe hypoglycemia (Level 3), hypoglycemic coma and DKA decreased between 29% to 76% with Omnipod System use compared to the year prior to treatment switch in the total cohort and type 1 patients with 3 year follow-up (n=835) (Table).
In conclusion, analysis of the DPV registry shows that use of the Omnipod System has high treatment retention rates in type 1 diabetes and is associated with low rates of severe hypoglycemia and DKA in this age-group prone to acute complications.Three Year Outcomes with Omnipod System UseVariable (mean)Total CohortPatients with 3 yr Follow-upPost-OmnipodPost-OmnipodPre-Omnipod (prior year)1 yr (n=2167)2 yr (n=1351)3 yr (n=848)Pre-Omnipod (prior year)1 yr (n=835)2 yr (n=835)3 yr (n=835)Age, yr13.914.714.414.611.512.413.514.4BMI-SDS0.440.540.560.600.430.500.550.61Insulin dose, U/kg/d0.820.760.790.820.790.770.790.83HbA1c, %7.697.597.857.947.557.497.817.97Severe hypoglycemia (Level 3) patients affected per year, %5.25.54.33.75.77.24.73.6Severe hypoglycemia (coma) patients affected per year, %1.51.41.00.51.71.81.40.4DKA patients affected per year, %5.83.33.02.16.63.63.02.2

Disclosure
T. Biester: Speaker's Bureau; Self; Medtronic, Ypsomed AG. T. Danne: Speaker's Bureau; Self; A. Menarini Diagnostics. Advisory Panel; Self; Abbott, AstraZeneca, Bayer AG, Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Dexcom, Inc.. Research Support; Self; Eli Lilly and Company. Stock/Shareholder; Self; DreaMed Diabetes, Ltd.. Research Support; Self; Insulet Corporation. Speaker's Bureau; Self; Menarini Group. E. Bollow: None. A. Schwandt: None. B. Heidtmann: None. B. Rami-Merhar: Speaker's Bureau; Self; A. Menarini Diagnostics, Eli Lilly and Company, Medtronic MiniMed, Inc., Roche Diabetes Care Health and Digital Solutions. T. Haak: Speaker's Bureau; Self; Abbott. Advisory Panel; Self; Roche Diabetes Care Health and Digital Solutions, Sanofi, Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company, AstraZeneca. R.W. Holl: None.
A Comprehensive Type 1 Diabetes Genetic Risk Score Is Associated with Type 2 Diabetes in the Framingham Heart Study
Authors: SRINIVASAN SHYLAJA , LEONG AARON , UDLER MIRIAM , PORNEALA BIANCA C. , MEIGS JAMES B. , RICH STEPHEN S. , DUPUIS JOSEE 
Published: June 2018

It is often difficult to distinguish between type 1 (T1D) and type 2 diabetes (T2D), particularly in young adulthood. Both T1D and T2D have significant genetic contributions to risk and understanding their genetic overlap may offer clinical insight. We examined whether a T1D genetic risk score (GRS) is associated with clinical features and diagnosis of T2D in the Framingham Heart Study (FHS).
We constructed a T1D GRS based on 79 SNPs from fine mapping results, with SNPs weighted by published effect sizes. The GRS included both HLA (27 SNPs) and non-HLA (52 SNPs) regions, and was applied to 1503 participants with T2D. Multivariable regression models assessed the association of the GRS with age of T2D onset, BMI, HbA1C, HOMA-β and HOMA-IR at the exam of diagnosis. Case-control analysis of 1503 cases and 5649 controls was done using multivariate generalized estimating equations (GEE) logistic models to determine the association between the T1D GRS and T2D risk with age and sex as covariates.
In FHS participants, the mean age was 57.2 y, BMI was 30 kg/m2, and HbA1c 6.05%. The T1D GRS was not associated with T2D age of onset, or BMI, HbA1c, HOMA-β and HOMA-IR after excluding participants on medications for T2D. There was a trend towards lower HOMA-β and HOMA-IR values in the top quintile of the GRS (n=244, mean=2.47, SD= 0.7 for ln(HOMA-β) and mean=2.88, SD=0.8 for ln(HOMA-IR)) when compared to the lowest quintile of the GRS (n=260, mean= 2.53, SD=0.8 for ln(HOMA-β) and mean=2.92, SD=0.8 for ln(HOMA-IR)). The T1D GRS was associated with T2D (β = 0.per SD increase in GRS, SE= 0.03, OR =1.1, P = 0.04). When the non-HLA and HLA components of the GRS were tested separately, the results remained significant only for the non-HLA T1D GRS (β = 0.per SD increase in GRS, SE= 0.03, OR=1.1, P= 0.02).
A T1D GRS of non-HLA SNPs is associated with T2D in the FHS participants. Our further analysis with increased sample size in multi-ethnic populations may refine the impact of the T1D GRS to characterize individuals with T2D.

Disclosure
S. Srinivasan: None. A. Leong: None. M. Udler: None. B.C. Porneala: None. J.B. Meigs: None. S.S. Rich: None. J. Dupuis: None.
TOPMed Whole Genome Sequence Combined with Pancreas-Specific Annotation for Rare Variants Tests of Type 2 Diabetes Risk
Authors: MANNING ALISA , MAJARIAN TIM , DE VRIES PAUL S. , WESSEL JENNIFER , MEIGS JAMES B. ,   TOPMED DIABETES WORKING GROUP
Published: June 2018

Genetic studies have shown that common variants associated with type 2 diabetes are enriched in pancreatic-specific regulatory regions. Most whole genome sequence (WGS) studies have used general annotation of regulatory regions not specific to relevant tissues. In contrast, we used functional annotation from pancreatic islets to define rare variant groupings for aggregate tests in coding and non-coding regions in a pilot analysis on chr 10 with 13,200 individuals across six NHLBI TOPMed studies: 2,601 individuals with type 2 diabetes and 10,599 normoglycemic controls with &lt;30X WGS coverage. We identified genes expressed in pancreas and nearby regions showing islet-specific regulatory activity, including open chromatin and chromatin states associated with promoters and enhancers. Variants with minor allele frequency &lt; 1% were aggregated by gene, including the region 5 kbp upstream and downstream of transcribed regions. We only included variants annotated as: "splice acceptor", "splice donor", "splice region", "missense", or "stop gained" within exons expressed in islets, while outside of those exons we included only those variants within “active transcription start sites” and “active enhancer” predicted chromatin states. We performed SKAT association tests, adjusting the association with type 2 diabetes for age, sex, study, and a genetic relatedness matrix to accounted for genetic similarities within families and between populations. Overall, 219 genes (median of 161 variants per gene-region) expressed in islets were included in the analysis: ATP5C1, AVPI1, and YME1L1 reached nominal significance (P&lt;0.01). Chr 10 pilot analyses provide a framework for tailoring rare variant analyses in WGS data through the use of disease-specific functional annotation. WGS analysis in larger samples and additional functional data generated from collaborators in the NIDDK’s AMP-T2D Consortium will extend the genomic spectrum associated with type 2 diabetes risk.

Disclosure
A. Manning: None. T. Majarian: None. P.S. de Vries: None. J. Wessel: Employee; Spouse/Partner; Eli Lilly and Company. J.B. Meigs: None.
ILC1s Alteration in Type 2 Diabetes Patients
Authors: LIU FANGCEN , BI YAN , WANG HONGDONG 
Published: June 2018

Type 2 diabetes (T2DM) is promoted by systemic and low-grade inflammation in adipose tissue(AT). Group 1 innate lymphoid cells (ILC1s) regulate inflammatory processes and exacerbate metabolic dysfunction, but their significance in T2DM pathogenesis remains unknown. Here, a total of 41 newly-diagnosed T2DM subjects (age 43.4±1.9 year, BMI 29.3±1.1 kg/m2) and 43 matched non-T2DM subjects (age 42.5±1.0 year, BMI 28.3±1.2 kg/m2) were recruited and peripheral blood mononuclear cells (PBMCs) and visceral AT were obtained for measurement of ILC1s by flow cytometry. The results showed that the rates of circulating ILC1s were dramatically increased in T2DM subjects relative to non-T2DM patients (2.44%±0.47% vs. 0.56%±0.14%, p&lt;0.001). Compared with those in the lowest circulating ILC1s tertile, subjects in the highest tertile had significantly higher HbA1c, fasting blood glucose (FBG) and Homeostasis model assessment of insulin resistance (HOMA-IR). Further correlation analysis revealed a positive correlation between the rates of circulating and adipose ILC1s (r=0.536, p=0.007). Remarkably, adipose ILC1s were significantly increased in T2DM subjects (1.70%±0.58% vs. 0.23%±0.17%, p=0.024). adipose ILC1s were positively associated with HbA1c (r=0.583, p=0.003) and FBG (r=0.494, p=0.014) after adjustment of age and BMI. In linear regression analysis, adipose ILC1s were the major determinants (β=0.629, p=0.004) of the variations of HbA1c. This study for the first time provided direct human evidence that ILC1s abnormalities are critically involved in the development of diabetes, suggesting their potential role as a therapeutic target in the treatment of T2DM.

Disclosure
F. Liu: None. Y. Bi: None. H. Wang: None.
Spontaneous Diabetic FATZO Mice with Intact Leptin Signaling Develop Peripheral Immune Cell Responses Similar to T2D and Obese Patients
Authors: SUN GAO , YE WEIWEI , AN XIAOYU , XIAO YONG-FU , WANG YIXIN 
Published: June 2018

Introduction: Type 2 diabetes (T2D) and obesity are strongly associated with peripheral immune cell responses. Subsets of T cells in the circulation are correlated with the severity of the diseases, which may serve as novel targets for antidiabetic or obese treatment. Higher numbers of blood Th1, Th17 and Th22 cells of T helper cells were found in disease patients, while Th2 and Treg cells were in reverse correlation of the severity of the disease. FATZO mouse is a new generation of T2D mouse model with intact leptin signaling. The model is featured with slow onset of diabetes and obesity. Here, we aim to characterize the peripheral immune cell responses in FATZO mice for the use of preclinical drug development targeting diabetes or obesity related inflammation.
Methods: Freshly collected blood from 12 FATZO mice at age 6, 12, 22 and 34 weeks were analyzed for the presence of monocytes, B, T, NK, NK-T, CD4+, CD8+ T cells and subsets of T helper cells (Th1, Th2, Th17, Th22, Treg) using FACS. Serum inflammatory cytokines such as IL1, IL2, IL6, IL17, TNFα and IFNγ were also measured.
Results: FATZO mice developed obesity and hyperglycemia from age of 12 weeks. Concomitantly, higher numbers of leukocytes were noticed with an increase and decrease in frequency of B and NK cells respectively. Within T cells, numbers of CD4+ T cells decreased by 20%, while CD8+ T cells increased by 25%. When subsets of T helper cells were assessed, percentages of Th1 and Th17 cells significantly elevated during the development of diabetes and obesity, while frequencies of Th2 and Treg cells declined. Serum inflammatory cytokine measurements showed a tendency in higher levels of serum IL1a when the animals became diabetic.
Conclusion: FATZO mice develop diabetes and obesity with changes in blood immune cell responses that closely mimic disease patients. The results suggest that FATZO might serve as an ideal model for preclinical research for the diabetes and obesity related inflammation.

Disclosure
G. Sun: None. W. Ye: Employee; Spouse/Partner; Crown Bioscience Inc.. X. An: None. Y. Xiao: None. Y. Wang: None.