bluuebunny/crossref_metadata_2025 huggingface dataset:
Medicare Diabetes Prevention Program Final Rules May Limit Beneficiary Access and Widen Health Disparities
Authors: RITCHIE NATALIE , GRITZ MARK
Published: June 2018

Introduction: The Centers for Medicare and Medicaid Services recently issued final rules for the Medicare Diabetes Prevention Program (MDPP), offering an unprecedented opportunity to provide lifestyle intervention to the estimated 48.3% of seniors with prediabetes. The MDPP is based on the widely disseminated National Diabetes Prevention Program (NDPP), which has lesser but still beneficial risk-reduction outcomes among racial/ethnic minority participants. We assess the extent to which the MDPP’s pay-for-performance reimbursement model may cover costs of service delivery to diverse Medicare beneficiaries.

Methods: Denver Health Medical Center is a safety net healthcare system that provided the yearlong NDPP to 232 diverse Medicare beneficiaries between 2013-2017, primarily through grant funding. Based on their NDPP attendance and weight loss outcomes, we compared projected performance-based-payments (e.g., $160 for ?5% weight loss) to service costs.

Results: Participating Medicare beneficiaries were 40.6% Hispanic, 31.6% non-Hispanic black, and 26.9% non-Hispanic white. Only 4.7% of beneficiaries achieved all attendance and weight loss outcomes associated with the maximum $470 payment for services in months 1-12. Overall beneficiary performance would result in an average reimbursement of $138.52 (SD=142.58). Program delivery costs were $800.64 per-participant, leaving an average gap of $662.12 per beneficiary served.

Discussion: Numerous MDPP suppliers are needed to reach Medicare beneficiaries with prediabetes, yet insufficient reimbursement is a likely deterrent. Health disparities may also widen as suppliers serving diverse populations will likely receive especially low payments, threatening their MDPP delivery. Higher payments appear needed and are supported by strong return-on-investment findings. A risk-adjusted model that accounts for demographic differences in outcomes is also needed to promote health equity.

Disclosure

N. Ritchie: None. M. Gritz: None.
Individuals with Single Islet Autoantibody Positivity (SA+) at Type 1 Diabetes (T1D) Diagnosis Have Distinct Characteristics
Authors: REDONDO MARIA J. , SOSENKO JAY , LIBMAN INGRID , MCVEAN JENNIFER J. , ATKINSON MARK A. , BECKER DOROTHY J. , GEYER SUSAN ,   THE TYPE 1 DIABETES TRIALNET STUDY GROUP
Published: June 2018

Multiple autoantibody positivity (MA+) usually precedes clinical T1D. However, a subset of patients who develop T1D have SA+. We hypothesized that individuals who at T1D diagnosis express SA+ compared with MA+ have different demographic, metabolic, immunologic and genetic characteristics. We studied 620 TrialNet participants who developed clinical T1D (median age=12.3 years [range=1.4-58.6], 47.5% male, 88% white). Using multivariable modeling and adjusting for potential confounders, we investigated differences between participants with SA+ vs. MA+ (of autoantibodies to GAD65 [GADA], insulin [mIAA], IA2, ZnT8 and ICA) at T1D diagnosis. We found 95 participants who had SA+ (70% GADA+) and 525 participants with MA+. In univariate analyses, individuals with SA+ vs. MA+ were older at T1D diagnosis (median 16.4 vs. 11.7 years, p<0.0001) and had higher fasting C-peptide (1.87 vs. 1.47 nmol/L, p=0.007), higher 30-0 minute C-peptide difference (1.42 vs. 1.18, p=0.009) and lower Index60 (composite measure of fasting C-peptide, 60-min glucose and 60-min C-peptide) (2.31 vs. 2.68, p=0.0005). Gender, race, ethnicity, BMI-Z-score, presence of HLA DR3-DQ2 and/or DR4-DQ8, fasting glucose, AUC glucose and AUC C-peptide were not significantly different. By multivariable analyses, SA+ at onset corresponded with older age (OR=1.05, p<0.0001), lower Index60 (OR=0.77, p=0.008), and lower likelihood of mIAA+ (OR=0.27, p<0.0001) and GADA+ (OR=0.25, p<0.0001); gender, HLA, BMI-Z-score and other autoantibody types were not significantly different. Independent factors of being SA+ differed between DR3/DR4-DQ8 heterozygous participants (older age and not having mIAA+ or GADA+) (p<0.01) and those not DR3/DR4-DQ8 (lower Index60 and not having GADA+) (p<0.01).

In conclusion, the number of islet autoantibodies at T1D diagnosis is associated with distinct characteristics, which may suggest heterogeneous pathogenesis with relevance for T1D prevention and treatment.

Disclosure

M.J. Redondo: None. J. Sosenko: None. I. Libman: Consultant; Self; Novo Nordisk A/S. J.J. McVean: Speaker's Bureau; Self; Medtronic MiniMed, Inc. M.A. Atkinson: Other Relationship; Self; Patent Issued. D.J. Becker: None. S. Geyer: None.
A Comparison of HbA1c and Index 60 Thresholds for Identifying Autoantibody Positive Individuals at High Risk for Type 1 Diabetes (T1D)
Authors: JACOBSEN LAURA M. , ISMAIL HEBA M. , CLEMENTS MARK A. , SCHATZ DESMOND , SOSENKO JAY
Published: June 2018

Current ADA standards include HbA1c values 5.7%-6.4% as an indicator of prediabetes. However, there is little information with regard to HbA1c as a specific predictor of T1D. We thus compared HbA1c with Index 60, a T1D marker, for identifying individuals at high risk for T1D. Index 60 was derived from a proportional hazards regression model for T1D that included log fasting C-peptide, 60-minute glucose, and 60-minute C-peptide. Diabetes Prevention Trial-type 1 participants with Index 60<2.00 at baseline were followed for the first (incident) OGTT exceeding an Index 60≥2.00 threshold (n=85). Similarly, those with HbA1c values <6.0% at baseline were followed for the first (incident) HbA1c ≥6.0% (n=77). Those with both incident Index 60≥2.00 and incident HbA1c ≥6.0 were excluded. At the incident OGTTs, those with HbA1c ≥6.0 were older (19.2±12.2 years vs. 12.7±7.2 years; p<0.001). The cumulative incidence for T1D was higher (log rank p<0.001) after Index 60≥2.00 than after HbA1c ≥6.0 (3- and 4-year risks for HbA1c ≥6.0: 0.41 and 0.45; 28/77 diagnosed vs. 3- and 4-year risks for Index 60≥2.00: 0.78 and 0.92; 60/85 diagnosed). The hazard ratio for Index 60≥2.00 vs. HbA1c ≥6.0 (with age adjustment) was significant [HR: 1.96 (1.20, 3.16); p=0.006]. Intervals from incident Index 60≥2.00 and HbA1c ≥6.0 to diagnosis were 1.2±0.9 (0.1-3.8) years and 1.0±1.0 (0-4.7) years, respectively (p=0.50). The 59 individuals who had OGTTs on the date of incident HbA1c ≥6.0 had higher 30-0 minute C-peptide (with age adjustment) than those with incident Index 60≥2.00 (2.8±1.9 ng/ml vs. 1.6±1.0 ng/ml; p<0.001).

In conclusion, Index 60≥2.00 was superior to HbA1c ≥6.0 at identifying individuals at high risk for T1D. Moreover, those with incident HbA1c ≥6.0 were much older with higher C-peptide levels, suggesting heterogeneity. These findings add support for including C-peptide together with glucose in developing predictors and pre-diagnostic endpoints that are specific for T1D.

Disclosure

L.M. Jacobsen: None. H.M. Ismail: None. M.A. Clements: Speaker's Bureau; Self; Medtronic. Advisory Panel; Self; Glooko, Inc.. D. Schatz: None. J. Sosenko: None.
Burden of Cardiovascular Risk Factors and Disease in Type 1 Diabetes—Results of the Australian National Diabetes Audit (ANDA)
Authors: PEASE ANTHONY J. , EARNEST ARUL , NANAYAKKARA NATALIE , RANASINHA SANJEEVA , FLACK JEFF R. , DAVIS WENDY A. , KILMARTIN GLORIA M. , WISCHER NATALIE , ZOUNGAS SOPHIA
Published: June 2018

Aims: To evaluate burden of cardiovascular risk factors and associations with cardiovascular disease (CVD) among adults with type 1 diabetes attending Australian diabetes centers.

Methods: De-identified, prospectively collected data from patients with type 1 diabetes aged ≥18 years included in ANDA-2015 were analysed. Cardiovascular risk factors (age, sex, diabetes duration, HbA1c, BP, high density lipoprotein-cholesterol (HDL-C), BMI, smoking status and albuminuria) and associations with CVD inclusive of stroke, myocardial infarction, coronary artery bypass graft/angioplasty and peripheral vascular disease were assessed. Likelihood ratio test and restricted cubic splines assessed for interactions and non-linear associations. Discriminatory ability of multivariate models was assessed with area under the receiver operating characteristic curves (AUC).

Results: Data from 1,169 patients were analysed. Median (IQR) age and diabetes duration were 37.0 (24.9-52.0) and 16.0 (8.0-27.0) years respectively. Cardiovascular risk factors were prevalent including hypertension (22%), dyslipidemia (89%), overweight or obesity (56%), ever smoking (39%), albuminuria (31%), and an HbA1c >7.0% (53mmol/mol) (81%). Older age, longer diabetes duration, smoking and antihypertensive use were positively associated, while higher HDL-C was negatively associated with CVD (all p<0.05). Association with CVD and diabetes duration remained constant until 20 years when a linear increase was noted. The multivariate model demonstrated good discriminatory ability for CVD (AUC 0.88; 95% CI 0.85-0.92).

Conclusions: Cardiovascular risk factors were prevalent and strongly associated with CVD among adults with type 1 diabetes. Given the approximate J-shaped association between diabetes duration and CVD, the impact of cardiovascular risk stratification and management before and after 20 years duration will need to be further assessed.

Disclosure

A.J. Pease: None. A. Earnest: None. N. Nanayakkara: None. S. Ranasinha: None. J.R. Flack: None. W.A. Davis: Speaker's Bureau; Self; Eli Lilly and Company. Speaker's Bureau; Spouse/Partner; Novo Nordisk A/S. Advisory Panel; Spouse/Partner; Novo Nordisk A/S. Research Support; Spouse/Partner; Novo Nordisk A/S. Other Relationship; Spouse/Partner; Novo Nordisk A/S. Speaker's Bureau; Spouse/Partner; Merck Sharp & Dohme Corp.. Advisory Panel; Spouse/Partner; Merck Sharp & Dohme Corp.. Speaker's Bureau; Spouse/Partner; AstraZeneca. Advisory Panel; Spouse/Partner; AstraZeneca. Speaker's Bureau; Spouse/Partner; Boehringer Ingelheim GmbH, Pfizer Inc.. G.M. Kilmartin: None. N. Wischer: None. S. Zoungas: Advisory Panel; Self; AstraZeneca.
Sclerostin Resistance Protects Bone Mass and Retards the Onset of Metabolic Abnormalities in a Mouse Model of Type 1 Diabetes
Authors: LEANZA GIULIA , STROLLO ROCKY , POZZILLI PAOLO , CIVITELLI ROBERTO , NAPOLI NICOLA
Published: June 2018

Type 1 diabetes (T1D) is characterized by bone fragility and increased risk of fracture. In humans and preclinical models of T1D, serum markers of bone formation are decreased suggesting reduced bone turnover rates. In a preliminary study, we found high circulating levels of the Wnt inhibitor sclerostin (Scl) in T1D patients. To test the potential role of Scl and Wnt in T1D bone disease, we introduced the Scl-resistant Lrp5A214V mutation, associated with high bone mass (HBM), in mice carrying the Ins2Akita mutation (Akita), which causes hypoinsulinemia and hyperglycemia at age 4-5 week. Both Akita and Akita/HBM mutants developed diabetes (non-fasting blood glucose >300 mg/dl), albeit with different onset timing. At 6 weeks, only 30% of Akita/HBM mice had developed hyperglycemia, compared to 90% of Akita mice (n=10); and at 8 weeks only 40% of Akita/HBM were hyperglycemic vs. 90% in the Akita group. Only at 12 weeks was the majority of Akita/HBM mice hyperglycemic, as the Akita group. Furthermore, Akita mice exhibited a significant impairment in glucose tolerance in an intraperitoneal glucose tolerance test relative to Akita/HBM mice at 6 and 8 weeks (p<0.for difference in areas under the curve; n=3-6). Thus, Wnt signaling hyperactivation in Scl resistant mice may slow the onset of T1D, although it does not prevent it. No significant differences in weight and nose-tail length were found in Akita/HBM mutants and controls. Importantly, bone mass was 18% higher in Akita/HBM relative to Akita littermates at 12 weeks (p<0.001; n=3-6), a difference that persisted up until at least 18 weeks of age, despite prolonged hyperglycemia. Bone mass in compound mutants was not different relative to HBM mice. Thus, the metabolic changes caused by T1D do not alter the consequence of Scl resistance and Wnt hyperactivation on bone.

In summary, even though we have not yet measured bone strength, Wnt stimulation protects bone mass and may retard the onset of metabolic abnormalities in T1D.

Disclosure

G. Leanza: None. R. Strollo: None. P. Pozzilli: Research Support; Self; Sanofi. Speaker's Bureau; Self; Eli Lilly and Company. Research Support; Self; Merck Sharp & Dohme Corp.. R. Civitelli: None. N. Napoli: None.
Functional Evaluation of RNLS, a Gene Harboring Risk Variants for Type 1 Diabetes in European and African Ancestry Subjects
Authors: ONENGUT-GUMUSCU SUNA , VOGLER NOAH , FAIDAS MARIA , PICKIN REBECCA R. , GERSZ ELAINE , RICH STEPHEN S.
Published: June 2018

Genetic studies of type 1 diabetes (T1D) have identified more than 40 risk loci, yet the causative genes in each locus is widely unknown. Here, we investigated a candidate gene in the 10q23.31 risk locus—FAD-dependent amine oxidase (RNLS). Variants in RNLS gene are associated with T1D risk in both European and African ancestry populations, indicating common genetic contributions to T1D. Currently, our understanding of the function of RNLS is very limited and primarily within the context of a few human diseases, most notably hypertension, kidney disease, cardiovascular disease, and cancer. In previous studies a positive RNLS-STAT3 feedback loop has been suggested. With consideration to these reports, and the importance of JAK-STAT signalling in immune-mediated diseases we evaluated if RNLS functions in activation of STAT3. An IFN-β time course was conducted to understand if overexpression of RNLS affects STAT3 levels and phosphorylation levels of STAT3. While we observed no difference in steady-state levels of STAT3 in cells overexpressing RNLS, we did observe increased levels of phospho-STAT3 upon IFN-β stimulation (p: 0.0051). In addition, to understand the function of RNLS in the immune system, we used RNAseq to compare transcriptomes of Jurkat cells expressing endogenous RNLS vs. ones overexpressing RNLS. RNAseq analysis identified 390 genes that were differentially expressed, by more than two-fold, of which 74.1 (289/390) of genes were up-regulated and 25.9 (101/390) were down-regulated in cells overexpressing RNLS. Tissue specific gene network analysis revealed that genes that were up-regulated mainly functioned in pathways related to chromosome segregation and cell division while genes that were down-regulated by RNLS were involved in IFN and NF-kappa B signaling pathways. Overall our results established a role for RNLS in cell-cycle related pathways and immune signaling pathways, providing new mechanistic insights of the role of RNLS in T1D.

Disclosure

S. Onengut-Gumuscu: None. N. Vogler: None. M. Faidas: None. R.R. Pickin: None. E. Gersz: None. S.S. Rich: None.
Mendelian Randomization Suggests Causal Influence of Glycemic Traits on DNA Methylation
Authors: DICORPO DANIEL A. , LENT SAMANTHA , GUAN WEIHUA , HIVERT MARIE-FRANCE , PANKOW JAMES S. ,   CHARGE EPIGENETICS WORKING GROUP,   CHARGE DIABETES WORKING GROUP
Published: June 2018

Type 2 diabetes (T2D) is caused by interactions between genetic predisposition and environmental exposure. DNA methylation, a key epigenetic mark, is one measure of the molecular impact of environmental factors on DNA. We tested for associations between glycemic traits and peripheral blood cell DNA methylation in 473,669 CpG sites across the genome in individuals from multiple ancestries, and tested for causal relationships at these loci.

We conducted an epigenome-wide fixed effects meta-analysis for 3 glycemic traits-fasting glucose (FG), log fasting insulin (FI), and HbA1c—in 13,543 nondiabetic individuals of African (N=3,746), European (N=9,254), and Hispanic (N=543) ancestry across 16 cohorts. All analyses were adjusted for age, sex, smoking status, cell types, BMI, and technical covariates. We used Mendelian randomization (MR) analyses to determine whether glycemic traits causally influence methylation at the CpG sites identified in the meta-analysis. We performed MR analyses in Framingham Heart Study individuals (N=6,472), using separate genetic risk scores (GRS) as instruments for each of the 3 glycemic traits.

In the epigenome-wide meta-analysis of all ancestries, there were 43 CpG sites associated with FG, 89 with FI, and 54 with HbA1c, using a Bonferroni threshold of P<1.1×10-7. In addition to detecting many novel candidate loci for each trait, we found associations with all 3 glycemic traits at previously reported T2D methylated loci SREBF1, LINC00649, and ABCG1. In MR analyses, we showed that a higher GRS for FI was associated with greater methylation at cg17058475 in CPT1A (P=4×10-4) and higher GRS for HbA1c with greater methylation at cg05779219 near THBD (P=4×10-4).

We identified many novel candidate methylation loci associated with glycemic traits and 2 CpG sites where MR analysis indicated that methylation is causally influenced by glycemic traits. These findings support the hypothesis that variation in glycemia influences peripheral blood DNA methylation.

Disclosure

D.A. DiCorpo: None. S. Lent: None. W. Guan: None. M. Hivert: None. J.S. Pankow: None.
Targeted Metabolomics Identifies Elevated Serotonin Levels in Carriers of a TCF7L2 Diabetes Risk Allele
Authors: LEIHERER ANDREAS , MUENDLEIN AXEL , GEIGER KATHRIN , SAELY CHRISTOPH H. , BRANDTNER EVA-MARIA , EBNER JANINE , LARCHER BARBARA , MADER ARTHUR , FRAUNBERGER PETER , DREXEL HEINZ
Published: June 2018

The transcription factor 7-like 2 (TCF7L2) is part of the Wnt signaling pathway. Its polymorphism rs7903146 is associated with risk for metabolic diseases, primarily diabetes, whereas the molecular mechanisms explaining how TCF7L2 impacts metabolism have remained unsolved. We evaluated the metabolic profile of a total of 394 angiographied patients with respect to their rs7903146 genotype (C/T) using targeted metabolomics in a discovery (n=154) and a validation (n=240) study. We identified serotonin as the top ranked metabolite to be increased in carriers of the diabetes risk allele (T) in both studies. For all 394 patients fold change was 44.6% (p=2.e-5), and in multivariate logistic regression analyses, serotonin concentration was significantly associated with the rs7903146 genotype even after full adjustment including diabetes (stand. adj. OR 2.69[1.23-5.87]; p=0.013). In a larger cohort of 1660 similar patients, we found that risky allele carriers had a significantly higher fasting glucose (116 vs. 109 mg/dl, p=0.007), post-challenge glucose (147 vs. 135 mg/dl, p=0.036), HbA1c (6.2 vs. 6.0 %, p<0.001), and prevalence of T2DM (30.8 vs. 25.8 %, p=0.022) than patients without the risky allele. Apart from rs7903146, analyzing the whole gene, we found that 9 out of 19 unlinked SNPs in TCF7L2 were significantly associated with serotonin as well.

In conclusion, this study identifies a significant association between elevated serotonin concentrations and the diabetes risk allele of the TCF7L2 rs7903146 polymorphism. Recently, Wnt-signalling has been suggested to be involved in serotonin expression and serotonin has been shown to regulate glucose homeostasis, to increase the risk of diabetes, and to be elevated in diabetic subjects. Together, these new findings suggest that serotonin may be, at least in part, involved in the impact of Wnt/TCF7L2-signalling on metabolic homeostasis and diabetes.

Disclosure

A. Leiherer: None. A. Muendlein: None. K. Geiger: None. C.H. Saely: None. E. Brandtner: None. J. Ebner: None. B. Larcher: None. A. Mader: None. P. Fraunberger: None. H. Drexel: None.
Quantitative Trait Loci G×E and G×G for Glycemic Traits—Response to Metformin and Placebo in the Diabetes Prevention Program (DPP)
Authors: MAXWELL TAYLOR J. , JABLONSKI KATHLEEN A. , FRANKS PAUL W. , KAHN STEVEN E. , KNOWLER WILLIAM C. , MATHER KIEREN J. , FLOREZ JOSE C. ,   DPP RESEARCH GROUP
Published: June 2018

The complex genetic architecture of type 2 diabetes (T2D) includes gene-by-environment (G×E) and gene-by-gene (G×G) interactions. To identify genetic markers for G×E and G×G, we screened individual markers for patterns indicative of interactions (rQTL and vQTL). rQTL exist when the correlation between multiple glycemic traits varies by genotype and vQTL occur when the variance of a glycemic trait varies by genotype (potentially flagging G×G and G×E interactions). In the metformin and placebo arms of the DPP (n=1,762) we screened 280,965 exomic and intergenic SNPs with minor allele frequency >0.01, for rQTL and vQTL patterns in year one changes from baseline in glycemic traits (insulinogenic index [IGI], insulin sensitivity index [ISI], fasting glucose and fasting insulin). Covariates included baseline age and BMI, sex, and ancestry. Significant (P<1.8×10-7) vQTL and rQTL generated a priori hypotheses for G×G screens and individual G×E tests for a SNP × metformin treatment interaction. All P values were obtained via parametric bootstrapping. Several unique vQTL and rQTL were identified, leading to 6 nominally significant metformin treatment × SNP interactions (4 IGI, 1 insulin, 1 glucose) and 12 G×G interactions (all IGI) that exceeded experiment-wide significance (P<4.1×10-9). Of these loci, some are directly associated with incident diabetes, others act as rQTL to modify a glycemic trait’s risk relationship with diabetes (2 diabetes/glucose, 2 diabetes/insulin, 1 diabetes/IGI). rs3197999, an ISI/Insulin rQTL, is a possibly gene damaging missense mutation in MST1, a gene affecting β-cell apoptosis and insulin secretion that in DPP and other studies is associated with diabetes and other glycemic traits. This rQTL may also link MST1 with insulin sensitivity where ISI and insulin responses differentially vary by genotype. This study demonstrates evidence for context-dependent effects (G×G and G×E) and complexity of these T2D-related traits.

Disclosure

T.J. Maxwell: None. K.A. Jablonski: None. P.W. Franks: Research Support; Self; Eli Lilly and Company, Sanofi, Novo Nordisk A/S, Servier, Boehringer Ingelheim GmbH. Consultant; Self; Zoe Ltd. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim GmbH, Elcelyx Therapeutics, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Research & Development, Merck & Co., Inc., Novo Nordisk A/S. W.C. Knowler: None. K.J. Mather: Research Support; Self; Merck & Co., Inc., Sanofi-Aventis, Novo Nordisk A/S, Abbott. Advisory Panel; Self; Merck & Co., Inc. J.C. Florez: Consultant; Self; Intarcia Therapeutics, Inc.. Consultant; Spouse/Partner; Santen. D. Research Group: None.
Association of CREBRF Variants with BMI and Diabetes in Pacific Islanders
Authors: HANSON ROBERT L. , SAFABAKHSH SAIED , CURTIS JEFFREY , MAHKEE DARIN K. , BAIER LESLIE , KNOWLER WILLIAM C. , NELSON ROBERT , HSUEH WEN-CHI
Published: June 2018

A recent genome-wide association study (GWAS) in Samoans (a Polynesian population) identified strong associations of CREBRF variants with BMI. The G allele at rs12513649 (frequency=25.8%) was associated with ∼1.3 kg/m2 higher BMI per copy, as was the Gln allele at rs373863828 (which codes for an ArgGln substitution). The Gln allele at rs373863828 has frequency of 25.9% in Samoans and is rare in most global populations, although it has been observed at low frequency in some other Oceanic populations. The alleles associated with higher BMI were suggestively associated with lower risk of type 2 diabetes [T2D, odds ratio (OR)=0.69 per copy, P=4.7×10-7]. We investigated the associations of rs12513649 and rs373863828 with BMI and T2D in 2029 Pacific Islanders from Guam and Saipan, who participated in a GWAS. Frequencies of the G allele at rs12513649 and the Gln allele at rs373863828 were 8.1 and 5.4% respectively in full-heritage Chamorros (N=928), 4.1 and 0.2% in Filipinos (N=249), 6.1 and 3.7% in Chuukis (N=153), 2.2 and 1.1% in Carolinians (N=43), and 20.7 and 2.2% in Palauans (n=45). Using a genomic control procedure with adjustment for age, sex, end-stage renal disease and the first four genetic principal components, the G allele at rs12513649 and the Gln allele at rs373863828 were associated with higher BMI (β=1.60 kg/m2, P=0.002 and β=1.36 kg/m2, P=0.058 respectively). They were also modestly associated with taller height (β=0.8 cm, P=0.11, and β=1.5 cm, P=0.019). The alleles conferring higher BMI were associated with lower prevalence of T2D (OR=0.62, P=0.0and OR=0.45, P=0.001). When combined with previously published results for Samoans via meta-analysis, the association of rs373863828 with T2D achieved genome-wide statistical significance (OR=0.67, P=2.9×10-8). These results suggest that CREBRF variants may be important contributors to obesity in Oceanic populations, and they confirm the associations of the allele conferring higher BMI with lower risk of T2D.

Disclosure

R.L. Hanson: None. S. Safabakhsh: None. J. Curtis: None. D.K. Mahkee: None. L. Baier: None. W.C. Knowler: None. R. Nelson: None. W. Hsueh: None.
The Different Effect of Sucrose on Transcriptomic Profile in Adipose and Muscle Tissues in Model of Metabolic Syndrome and Insulin Resistance
Authors: HÜTTL MARTINA , MARKOVÁ IRENA , MALINSKA HANA , KAZDOVA LUDMILA , SEDA ONDREJ
Published: June 2018

The development and progression of insulin resistance is driven by genetic and enviromental factors and their interactions. Sucrose belongs to nutrition factors with lipogenic impact, induces de novo lipogenesis, reduces fatty acid oxidation and can deteriorate insulin sensitivity. The aim of study was to investigate transcriptome profile in adipose and muscle tissues under standard or high sucrose diet (HSD) (70 kcal% as sucrose) in two strains of rats - Wistar and a strain of hereditary hypertriglyceridemic rats (HHTg) as a polygenic model of metabolic syndrome and insulin resistance. The transcriptome analysis was evaluated in the context of development and progression of insulin resistance. HSD feeding in 2 weeks increased epididymal adipose tissue (EAT) weight in both strains (P diet<0.05), but not body weight. In addition, HSD feeding resulted in elevated levels of fasting glucose (P diet<0.05), insulin (P diet<0.01) and FFA (P diet<0.05, P strain<0.05), but adiponectin was decreased only in HHTg rats (P<0.01). Insulin sensitivity of EAT was significantly reduced (P diet<0.05, P strain<0.05), but HSD did not change triglycerides or insulin sensitivity in muscle. In skeletal muscle, HSD significantly changed expression (FDR<0.05) of 20 transcripts in HHTg and 21 in Wistar (only 2 common). In EAT, HSD significantly changed expression of 810 transcripts in HHTG and 1823 in Wistar (344 common). The most affected pathways were insulin receptor signaling in HHTg and mitochondrial dysfunction and oxidative phosphorylation in Wistar rats. Major regulator nodes of the mechanistic networks included insulin, SCD and miR-27 for HSD effect in HHTg and LIPE, miR-27 and VEGF in Wistar strain.

In conclusion, HSD feeding impaired insulin sensitivity in both rat strains. Transcriptomic alterations in adipose tissue precede muscle changes caused by HSD and show distinct patterns in genetically susceptible HHTg model of metabolic syndrome.

Disclosure

M. Hüttl: None. I. Marková: None. H. Malinska: None. L. Kazdova: None. O. Seda: None.
Chronic Low Grade Inflammation in Type 2 Diabetes—Activation of the Inflammasomes by Circulating Metabolites
Authors: MONLUN MARIE , RIGALLEAU VINCENT , BLANCO LAURENCE , MOHAMMEDI KAMEL , BLANCO PATRICK
Published: June 2018

Type 2 diabetes (T2D) is associated with chronic low-grade inflammation. We studied its mechanisms by addressing the role of inflammasomes in monocytes and their activation by circulating metabolites to produce inflammatory cytokines IL1β and IL18. Blood samples were collected from patients with T2D. Serum was filtered at 3 kDa to remove macromolecules. Inflammasome activation was analyzed by gene expression of various Nod Like Receptors by RT-quantitative PCR as well as IL1β and IL18 secretion from these monocytes in culture (ELISA). Twenty-one patients (38% women) were included in 2016. They were 57±10 years old, BMI were 33.1±6.3 kg/m2. They had T2D for 14±9 years and HbA1c at 9.5±1.2%. Their C Reactive Protein levels was 8.1±8.0 mg/L. Each subject was sampled twice at 4 days of interval: in hyperglycemia (2.56±0.86g/L) then in normoglycemia (1.23±0.41g/L). Two inflammasomes were transcripted: NLRP1 and NLRC4, with significant high level whether in normoglycemia (fold-change 1.47, p=0.01 and 1.33, p=0.02) and hyperglycemia (fold-change 1.41, p=0.02 and 1.31, p=0.04). This transcriptional priming seems to have a functional consequence with IL1β production by monocytes of some T2D patients. Healthy monocytes were collected from voluntary blood donors (Glycaemia: 0.97±0.17g/L). Incubation of them with filtered serum of T2D patients recapitulated the priming signal. The same two inflammasomes were transcripted: NLRP1 and NLRC4, whether in normoglycemia (fold-change 1.35, p=0.002 and 1.23, p=0.02) and hyperglycemia (fold-change 1.31, p=0.01 and 1.30, p=0.052). Although it did not induce activation of mature cytokines. We have shown the activation of NLRP1 and NLRC4 inflammasomes and their secretion of inflammatory cytokine in T2D patients. Some soluble serum metabolites seem directly involved in this inflammatory cascade. Our next objective will be to identify these molecules, which are potential biomarkers of predictive of chronic immune activation in T2D.

Disclosure

M. Monlun: None. V. Rigalleau: None. L. Blanco: None. K. Mohammedi: Speaker's Bureau; Self; Novo Nordisk Inc.. Other Relationship; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Sanofi. Other Relationship; Self; Sanofi, Takeda Development Centre Europe Ltd., Boehringer Ingelheim Pharmaceuticals, Inc.. P. Blanco: None.
New 2017 ACC/AHA Hypertension Guidelines—Cost-Effectiveness among U.S. Adults with Type 2 Diabetes
Authors: SHAO HUI , LAXY MICHAEL , ROLKA DEBORAH B. , GREGG EDWARD W. , ZHANG PING
Published: June 2018

Introduction: The new 2017 American College of Cardiology (ACC) and American Heart Association (AHA) hypertension guideline defines hypertension as either systolic blood pressure (SBP) > 130 mmHg or diastolic blood pressure (DBP) > 80 mmHg, compared with the old guideline of SBP >140 mmHg or DBP > 90 mmHg. The new definition would increase number of persons eligible for hypertension treatment. Our objectives were to estimate how many more persons with type 2 diabetes would be eligible for hypertension treatment under the new guideline and to assess the cost-effectiveness (CE) of treating this newly eligible population.

Method: Data from the 2011-2016 National Health and Nutrition Examination Survey and the 2015 Census were used to estimate the numbers of persons with diabetes who would be eligible for hypertension treatment under the new and old guidelines. The CDC-RTI cost-effectiveness diabetes simulation model was used to project the lifetime health and cost (2017 USD) consequences of treating newly eligible persons. Two hypertension treatments were modeled: moderate BP treatment as defined in the guidelines and intensive BP treatment using multiple antihypertensive drugs as implemented in the UK Prospective Diabetes Study trial. The CE of the new guideline was measured using costs per quality-adjusted life year (QALY).

Results: The number of persons with diabetes eligible for hypertension treatment would increase from 8.4 (27.7%) to 15.7 million (51.9%) under the new ACC/AHA guideline. Treating hypertension persons defined by new guideline would result in $3038/QALY if the moderate BP treatment were implemented and would be cost-saving if intensive BP treatment were implemented, compared to treating persons defined through old guideline.

Conclusion: The new ACC/AHA hypertension guideline would nearly double the number of persons with diabetes who would be eligible for hypertension treatment. Treating those newly eligible is likely to be cost-effective or even cost-saving.

Disclosure

H. Shao: None. M. Laxy: None. D.B. Rolka: None. E.W. Gregg: None. P. Zhang: None.
Measure Real-Time cAMP Signaling in the Living Cell
Authors: LIU XIPING , HONG SEAN , WU SHIJUAN , YAO ZHIWEN , YAO QIANG X.
Published: June 2018

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that plays a key role in regulating glucose homeostasis via its activity at the GLP-1 receptor (GLP-1R). To date, GLP-1R has become an attractive therapeutic target for type 2 diabetes (T2D). Several GLP-1R agonists have been developed or are in clinical trials such as: Exenatide, Liraglutide, Lixisentide, Dulagutide, Semiglutide, Efpeglenatide, and Albenatide. These drugs stimulate G-protein-coupled receptors (GPCR) resulting in adenylated cyclase activation and consequently cyclic adenosine mono-phosphate (cAMP) production. This makes the cAMP assay platform is useful for identifying GLP-1 functional activities. However, current cAMP assays have two major limitations: 1) low accuracy with infeasibility of real time measurements of cAMP levels and 2) low precision among separate sample preparation from live cells. In order to overcome those restrictions and design a rapid and homogeneous protocol, a living cell based real-time potency assay has been developed for measuring bioactivity of GLP-1r agonists such as Albenatide. This assay, which combines the stimulating cell, lysis, and cAMP measurement in-situ, provides fast, accurate, reproducible, and highly sensitive results. The assay linearity has been tested with the proportionality of concentration/amount of analyte. The r2 of the linear curve in measuring relative potency (RP) vs. nominal RP was >0.99 and the recovery of the expected relative potency in the range of 50∼200% were 102.6∼112.4%. Compared with the traditional ELISA-based assay, this assay requires less sample volume (20ul vs. 100ul), low matrix effect with wide assay window (5 fold higher), high sensitivity (pM vs. nM), and shorter procedure time (hours vs. days). Thus, applications of this novel cell-based cAMP assay can be extended to high-throughput screening for the potency of GLP-1r agonists, and more specifically characterizing the anti-drug antibody (ADA) capabilities.

Disclosure

X. Liu: None. S. Hong: None. S. Wu: None. Z. Yao: None. Q.X. Yao: None.
Change in Circulating Monocyte Profile with Foot Ulcer Healing in Diabetic Patients
Authors: MIN DANQING , NUBE VANESSA L. , TAO ANH , YUAN XIN , BROOKS BELINDA , WONG JENCIA , TWIGG STEPHEN M. , MCLENNAN SUSAN
Published: June 2018

Poor wound healing in diabetes is associated with increased chronic inflammation and alterations in macrophage accumulation. Chronic inflammation can alter the phenotype of macrophage precursors, monocytes but whether their phenotype is changed in association with wound healing is not known. Blood was obtained from 21 patients (14 male: 7 female) attending the High Risk Foot Clinic at RPA Hospital at their initial visit (V1), week 4 (V2) and week 8 (V3). Wound area was measured and wound type was assessed by a podiatrist. Monocyte number (CD14+), phenotype as classical (CD16−), non-classical (CD16++), and intermediate (CD16+), anti-inflammatory (CD163+) subset and expression of receptors CCR2, CCR5 and TLR2, TLR4 were determined by flow cytometry. The MMPs and TIMP-1 were measured in plasma by zymography and ELISA. Over the 8 weeks, 6 ulcers healed (H) and 15 failed to heal (NH). The age, duration of diabetes, HbA1c, wound size and duration at V1 were not different between the groups but the % CD16++ monocytes was higher in H vs. NH at V1 (23.5 vs. 8.3) and V3 (17.4 vs. 7.2) and monocyte CCR2+ was lower in H at V3 (P<0.05). Interestingly plasma MMP-3 and MMP-9/TIMP-1 ratio were higher in H at V1 but MMP-9 was lower in H at V3 (P<0.05). The wound area at V1 was not associated with wound closure rate (WCR: r=0.39, P=0.08). However for all samples at V2+V3, the WCR correlated with monocyte %CD16++ (r=0.42), CD16+ (r=0.39), CD163+ (r=0.37), and CD14+ (r=-0.39), CD16- (r=-0.52), as well as plasma MMP-2 (r=-0.67) and MMP-9 (r=-0.41)(P<0.05). At either V2 or V3, the relationship was maintained for monocyte %CD16++and CD16- and plasma MMP-2 (P<0.05). These results in people with diabetic foot ulcers suggest that circulating monocyte phenotype is altered as the wound heals. The positive relationship in WCR with monocyte anti-inflammatory profile suggests a predictive role for these markers. Whether the transition of monocytes from a pro- to an anti-inflammatory phenotype plays a mechanistic role in wound healing remains to be elucidated.

Disclosure

D. Min: None. V.L. Nube: None. A. Tao: None. X. Yuan: None. B. Brooks: None. J. Wong: Speaker's Bureau; Self; Novo Nordisk A/S, AstraZeneca, Eli Lilly and Company. S.M. Twigg: Advisory Panel; Self; Abbott. Consultant; Self; Abbott. Advisory Panel; Self; Novo Nordisk Inc., Sanofi-Aventis, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. Speaker's Bureau; Self; AstraZeneca, Merck Sharp & Dohme Corp.. Other Relationship; Self; Abbott. S. McLennan: None.
Glycolysis-Dependent Inflammasome Activation by Carbon Monoxide
Authors: KIM DAEYEON , CHUN SUNG WAN , KIM YEOJOO , KIM SANG JIN , MOON JONG-SEOK
Published: June 2018

Low dose of carbon monoxide (CO) has anti-inflammatory role through various signaling pathways. Cellular metabolism has been implicated in the activation of inflammation in immune cells.

Here we show that CO-dependent metabolic pathway regulates the activation of the nucleotide-binding domain, leucine-rich-repeat-containing receptor (NLR), pyrin-domain-containing 3 (NLRP3) inflammasome. CO-releasing molecule-3 (CORM-3) resulted in reduced glycolysis-dependent NLRP3 inflammasome activation in macrophages. The reduced mTORC1 activation by CORM-3 resulted in less glycolysis during NLRP3 inflammasome activation. CORM-3 suppressed caspase-1 activation and the secretion of IL-1β and IL-18 in macrophages in response to LPS and ATP. Moreover, CORM-3 inhibits the oligomerization of the adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which is required for NLRP3-dependent caspase-1 activation. Furthermore, CORM-3-treated mice showed substantial reduction in IL-1β production by hyperglycemia in a mouse model of STZ-induced diabetes.

Our results suggest that CO regulates glycolysis-dependent NLRP3 inflammasome activation and may provide a therapeutic approach for inflammation in metabolic diseases.

Figure. CORM-3 Treatment Suppresses NLRP3 Inflammasome Complex Formation During NLRP3 Inflammasome Activation.

Disclosure

D. Kim: None. S. Chun: Research Support; Self; Handok Inc.. Other Relationship; Self; Daiichi Sankyo Company, Limited, Novo Nordisk Inc., Eli Lilly and Company. Y. Kim: None. S. Kim: None. J. Moon: None.
Pax4 Gene Transfer Induces α-to-ß Transdifferentiation and Improves the Therapeutic Efficacy of Islet Transplantation
Authors: PARAJULI KESHAB R. , ZHANG YANQING , WU HONGJU
Published: June 2018

Pax4 is a transcriptional factor which plays a critical role in the generation of insulin producing β-cells during embryonic development. Our group previously demonstrated that Pax4 delivered by adenoviral vector induces insulin expression and reduces glucagon in αTC1.9 cells and primary human islets. The purpose of the present study was to determine whether Pax4 gene expression induces pancreatic α-cells to become β-cell using lineage tracing techniques and confers therapeutic benefits in the context of islet transplantation. In this study, we generated α mouse model in which their α cells are labelled with YFP, namely αYFP mouse. Using this mouse model, we found that Ad5.Pax4 induced glucagon secreting α-cells to become insulin secreting β-cells in isolated αYFP islets. Quantification of YFP+/Pax4+/insulin+ cells confirmed that Pax4 induced α-to-β cell conversion as assessed by the presence of YFP reporter in new β-cells. In addition, these Pax4-treated islets increased glucose-stimulated insulin secretion compare to control group. Furthermore, we transplanted Pax4-treated primary mouse islets into kidney capsule of the streptozotocin-induced diabetic mice and found that they significantly reduced the blood glucose and improved glucose tolerance compared to control groups. These data indicate that Pax4 induced α- to functional β-cell conversion, and proved therapeutic benefits for islet transplantation.

Disclosure

K.R. Parajuli: None. Y. Zhang: None. H. Wu: None.
Development of Perfluorodecalin Contained Microcapsules for Islet Survival and Function
Authors: KIM JIWON , PARK HEON SEOK , YOON KUN-HO , LEE EUN YOUNG
Published: June 2018

Hypoxic injury of islets is a major obstacle for encapsulated islet transplantation into the peritoneal cavity. To improve oxygen delivery to encapsulated islets, we integrated 20% of the oxygen carrier material, perfluorodecalin (PFD) contained alginate capsules with islets (PFD-alginate). Integration of PFD clearly improved islet viability and decreased reactive oxygen species production compared with islets encapsulated with alginate only (alginate) and naked islets exposed to hypoxia in vitro. In PFD-alginate capsules, HIF-1α expression was minimal, also insulin expression was well secreted. Furthermore, the best islet function represented by glucose-stimulated insulin secretion was observed for the PFD-alginate capsules. In vivo study, the marginal number naked islets and encapsulated islets (alginate and PFD-alginate) were transplanted into streptozotocin-induced diabetic mice. Non-fasting blood glucose levels and intraperitoneal glucose tolerance tests in the PFD-alginate group was lower than in the alginate group. The harvested islets stained positive for insulin in all groups, but the ratio of dead cell area was 4 times higher in the alginate group was than in the PFD-alginate group.

In conclusion, PFD contained alginate microcapsules improved islet function and survival by minimizing the hypoxic damage of islets after intraperitoneal transplantation.

Disclosure

J. Kim: None. H. Park: None. K. Yoon: None. E. Lee: None.
Ten-Year Trends in Consumer-Directed Health Plan Enrollment and Out-of-Pocket Costs among Commercially Insured Members with Diabetes
Authors: GARABEDIAN LAURA F. , ROSS-DEGNAN DENNIS , ZHANG FANG , CALLAHAN MATTHEW X. , LECATES ROBERT , WALLACE JAMIE , SOUMERAI STEPHEN B. , WHARAM JAMES F.
Published: June 2018

Background: Diabetes is a major cause of morbidity and mortality and a driver of escalating health care costs in the U.S. In attempts to reduce costs, U.S. employers are increasingly offering consumer-directed health plans (CDHPs) that include Health Savings Accounts (HSA) or Health Reimbursement Arrangements (HRA) and high annual deductibles. Recent research has found that CDHPs are associated with concerning impacts on diabetes patients, but growth in CDHP enrollment and their out-of-pocket (OOP) cost trends in this vulnerable population are unknown.

Methods: We used a time series design to assess 2005-2014 annual trends among ∼70 million unique members of all ages insured by a large national commercial insurer from 2005-2014. We analyzed mutually exclusive populations of interest, identified by ACG, comprising: (1) diabetes mellitus with no cardiovascular disease (DM), (2) diabetes with co-morbid cardiovascular disease (DM+CVD), and (3) “healthy” (i.e., ACG score <=1). We used linear models, t-tests and chi-square tests to assess (a) CDHP and non-CDHP prevalence and (b) total annual OOP costs in 2014 dollars.

Results: CDHP prevalence among DM members increased by 2.5% per year (p<0.001), from 1.3% in 20to 23.2% in 2014. DM+CVD members had a similar increase. In 2014, 19.5% of DM+CVD members and 28.7% of healthier members were in CDHPs (p<0.001 for both compared to DM). Annual OOP costs for non-CDHP members were significantly lower than for CDHP members throughout the study period. For example, in 2014, CDHP DM members had average OOP costs of $2103.62 compared to $1379.87 for non-CDHP DM members (p<0.001).

Conclusions: CDHP enrollment has increased markedly over the last 10 years among members with and without diabetes. However, diabetes members were less likely than healthier members to be in CDHPs, particularly if they had co-morbid CVD. Among diabetes patients, OOP costs were significantly higher for CDHP than non-CDHP members.

Disclosure

L.F. Garabedian: Other Relationship; Self; Harvard Pilgrim Health Care. D. Ross-Degnan: None. F. Zhang: None. M.X. Callahan: None. R. LeCates: None. J. Wallace: None. S.B. Soumerai: None. J.F. Wharam: None.
Fibroblast Growth Factor-21 Maintains Glucose Homeostasis through Influencing the Expansion and Function of Subcutaneous Adipose Tissue
Authors: LI HUATING , QIAN LINGLING , WU LIANG
Published: June 2018

Fibroblast growth factor 21 (FGF-21) has been extensively studied in recent years due to its multiple therapeutic benefits for a cluster of obesity-related cardiometabolic complications. However, an unsolved puzzle is that despite its pleiotropic metabolic benefits, FGF-21 is paradoxically elevated in obesity and diabetes in both animals and humans. Its pathophysiological relevance in response to excess energy intake remains poorly understood. Here we provide both clinical and animal evidences demonstrating that elevated endogenous FGF-21 in obesity serves as a defense mechanism against systemic insulin resistance. Serum FGF-21 levels were positively associated with subcutaneous fat area in subjects with insulin-sensitive overweight/obesity. Furthermore, FGF-21 knockout mice (FGF-21KO) showed much less subcutaneous adipose tissue (SAT) mass and were more insulin resistant when fed with high-fat diet. Replenishment of recombinant FGF-21 to a level equivalent to those occurring in diet-induced obesity restored SAT mass and reversed insulin resistance in FGF-21KO but not in adipose-specific βklotho knockout mice. Moreover, transplantation of SAT from wild type to FGF-21KO mice improved insulin sensitivity in the recipient mice. Mechanistically, circulating FGF-21 acts in an endocrine manner on subcutaneous fat to promote the healthy expansion. FGF-21 upregulates adiponectin in subcutaneous adipose tissue, accompanied with an increase of M2 macrophage polarization. This study raises the possibility that targeting subcutaneous fat through manipulation of FGF-21 may represent a promising therapeutics to combat insulin resistance.

Disclosure

H. Li: None. L. Qian: None. L. Wu: None.