bluuebunny/crossref_metadata_2025_split huggingface dataset:
292-OR: Renin-Angiotensin System Inhibition, Cardiorespiratory Fitness, and Mortality Risk in Diabetic Patients
Authors: KOKKINOS PETER , MYERS JONATHAN N. , SIDOSSIS LABROS , FASELIS CHARLES , NARAYAN PUNEET , NYLEN ERIC , SUI XUEMEI , MOORE HANS , KARASIK PAMELA 
Published: June 2019

Introduction: Patients with type 2 diabetes mellitus (T2DM) have significantly higher risk of cardiovascular events and mortality. Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs) decrease mortality risk in T2DM patients. Cardiorespiratory fitness (CRF) is associated with lower mortality risk in T2DM patients. However, the combined effects of CRF and ACEI/ARBs on mortality risk in T2DM patients has not been assessed.
Methods: We identified 6,888 T2DM patients (age 58.3±10.1 years) with no evidence of ischemia as indicated by a maximal standardized exercise treadmill test. We established two CRF categories based on age-adjusted median peak metabolic equivalents (METs) achieved: Unfit (5.4±1.3 METs; n=3,474) and Fit (9.0±2.3 METs; n=3414). We then formed 2 groups within each CRF category (treated and not treated with ACEI/ARBs) for a total of four CRF-ACEI/ARBs groups. Cox proportional hazards models, adjusted for known risk factors were constructed to assess the CRF-ACEI/ARBs interaction and mortality risk association.
Results: During a follow-up of 14.2±6.9 years, 2,495 patients died, accounting for 25.5 events/1,000 person-years of observation. Patients treated with ACE/ARBs had 25% lower mortality risk compared to those not treated with ACE/ARBs (HR 0.75; 95% CI: 0.69-0.82). When CRF-ACEI/ARBs categories were considered, Unfit individuals not treated with ACEI/ARBs had 24% higher mortality risk compared to those treated with ACEI/ARBs (HR 1.24; 95% CI 1.11-1.38). For Fit individuals, the risk was 26% lower (HR: 0.74; CI: 0.66-0.83) for those not treated with ACEI/ARBs and 45% lower in those treated with ACEI/ARBs (HR 0.55; 95% CI 0.48-0.62).
Conclusions: ACEI/ARBs therapy and increased CRF are effective in lowering mortality risk in in T2DM patients. The combination of ACEI/ARBs and higher CRF was synergistic, resulting in substantially lower mortality risk than either therapy alone.

Disclosure
P. Kokkinos: None. J.N. Myers: None. L. Sidossis: None. C. Faselis: None. P. Narayan: Research Support; Self; AstraZeneca, Eli Lilly and Company. E. Nylen: None. X. Sui: None. H. Moore: None. P. Karasik: None.
299-LB: Endothelial Regulation of Pancreatic ß-Cell Homeostasis in Diabetes
Authors: LI MANNA , QIAN MING , XU JIAN 
Published: June 2019

Diabetes is the result of having an inadequate supply of functional insulin-producing β-cells. Efforts in research and development that focused on using systemic pathway to induce β-cell regeneration have had limited clinical success. Emerging studies implicate local islet molecular and cellular factors in pancreatic β-cell homeostasis. Intraislet endothelial cells (IECs), a key ally of pancreatic β-cells, secrete factors that could affect β-cell survival and insulin production. Fibroblast growth factor (FGF) 21 is an endocrine hormone that regulates energy homeostasis and insulin sensitivity. The function of endogenous FGF-21 derived from ECs is undefined in diabetes. With a loss-of-function approach, this study sought to determine the role of EC-FGF-21 in pancreatic β-cell homeostasis in STZ-induced diabetic mice and high-fat diet (HFD)-induced obese mice. Mice with EC-specific deletion of FGF-21 gene (EC-FKO) were generated by crossing Tie2-Cre mice with FGF-21loxP mice. In 8-to-10-week-old male mice (n=15/group) treated with STZ (50 mg/kg, i.p. for consecutive 5d and killed 4 weeks later), EC-FKO vs. wild type C57BL/6J (WT) mice displayed more severe hyperglycemia, degeneration of insulin-producing β-cells, and expansion of glucagon-producing α-cells. Both groups showed similar changes in pancreatic Glut2 and PARP1 protein levels and vascular density. In 8-to-10-week-old WT male mice (n=15/group) fed an HFD (TestDiet: 60% energy from fat) for 16 weeks, obesity and insulin resistance developed, along with lipid accumulation in the islet and compensatory expansion of β-cell mass, all of which were worsened, except for less β-cell mass expansion, in EC-FKO mice. Our latest immunofluorescent data showed a significant reduction of IEC-FGF-21 protein staining in WT mice treated with STZ or HFD vs. non-treated mice. Our findings suggest that EC-FGF-21 is required to maintain β-cell homeostasis under stress conditions. Loss of IEC-FGF-21 may contribute, at least in part, to β-cell degeneration in diabetes.

Disclosure
M. Li: None. M. Qian: None. J. Xu: None.

Funding
National Institutes of Health
30-OR: Whole Genome Sequence Analysis of Type 2 Diabetes Risk in 44,713 Humans of Diverse Ancestry in the TOPMed Study
Authors: HIGHLAND HEATHER M. , WESSEL JENNIFER , MANNING ALISA ,   TOPMED DIABETES WORKING GROUP
Published: June 2019

Risk of developing type 2 diabetes (T2D) is heritable, with over 403 independent genetic variants having been identified primarily through analysis of common variants in European ancestry populations. To further illuminate the genetic architecture of T2D, we conducted a whole genome sequence (WGS) association study (&gt;38x depth) of common, low frequency, and rare variants in 9,663 individuals with T2D and 35,050 controls of diverse ancestry from NHLBI’s Trans-Omics for Precision Medicine (TOPMed) study. We conducted single variant analyses and SKAT tests of rare variants (MAF &lt;1%) annotated with pancreatic islet specific regulatory annotation to define variant sets. In single variant analyses, a total of 15 regions were significantly associated (α=5e-08) with T2D, seven of which are novel associations (in or near ODF2L, LMAN2, KCNV1, CBR1, VLDLR-AS1, LINC01052 and NKX2-5). These new associations were either ancestry specific or rare variants. For instance, a variant not present in other ancestral groups, near KCNV1, was associated with increased risk of T2D (MAF 5.5%, P= 1.57e-08, OR=1.43) in African ancestry. Set based testing of rare variants identified seven regions associated with T2D in at least one ancestry. Six of these were noncoding: in African ancestry CBR1 gene centric variants (cumulative MAC[cMAC]=623, P = 5.85e-09) and an active promoter region in proximity to MRPL46 and MRPS11 (cMAC=3,218, P = 4.89e-07); and in Asian ancestry an enhancer hub containing NXPH3 (cMAC=3,317, P = 3.42e-05) and an active enhancer region linked to RP11-135A1.2 and HES1 (cMAC=57, P = 4.87e-07) were associated with T2D. KLRC4 predicted deleterious coding variants were associated with T2D in the European ancestry group (cMAC=25, P = 3.63e-06). In large scale WGS analyses, we extended our knowledge of the genetic basis of T2D through the inclusion of ancestrally diverse samples, variant typing without imputation, and use of tissue specific regulatory annotation to identify new T2D loci.

Disclosure
H.M. Highland: None. J. Wessel: Employee; Spouse/Partner; Eli Lilly and Company. A. Manning: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (5U01DK078616-10, K01DK107836)
300-OR: Individualized Hemoglobin A1C: A New Glycemic Marker Determined Using Continuous Glucose Monitoring
Authors: BERGENSTAL RICHARD M. , DUNN TIMOTHY , XU YONGJIN , AJJAN RAMZI 
Published: June 2019

Glycation of hemoglobin (Hb) measured by A1C depends on red blood cell (RBC) lifespan, thus may misrepresent intracellular glucose exposure in other tissues, and may explain observed dissociations between A1C and microvascular complications. A kinetic model that accounts for rates of RBC turnover and intracellular glucose transport was evaluated for A1C individualization using continuous glucose monitoring data (CGM) and laboratory A1C from 58 individuals with diabetes (type 1/type 2 = 5/53, mean age 58 years (range 27 to 77, M/F=38/20). A1C was performed at 0, 3, and 6 months with concurrent CGM for 6 months, having a minimum of 80% coverage and no gaps &gt;36 hours. The adjustment required to calculate individualized A1C is expressed as follows: A1C/(A1C+(1-A1C)*KTR/KT), where KT is the Hb and RBC turnover rate, and KTR is the reference Hb and RBC turnover rate. The mean (±SD) rate of Hb and RBC turnover was 1.18±0.20%/day as depicted in the Figure, showing the individualized A1C calculation. These data suggest that laboratory A1C does not only underestimate cellular glucose exposure in some patients but can also overestimate average glucose levels making the individual prone to hypoglycemia through unnecessary escalation of antidiabetic therapies. Quantitative individualization of A1C derived from A1C and CGM readings has the potential to more accurately assess intracellular glycemic exposure.

Disclosure
R.M. Bergenstal: Research Support; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Dexcom, Inc., Glooko, Inc., Hygieia, JDRF, Johnson & Johnson Medical Devices Companies, Lilly Diabetes, Medtronic MiniMed, Inc., Merck & Co., Inc., National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk Inc., Roche Diabetes Care, Sanofi. Other Relationship; Self; Abbott, Helmsley Charitable Trust, Hygieia, Lilly Diabetes, Novo Nordisk Inc., Onduo LLC, Sanofi, UnitedHealth Group Inc. T. Dunn: Employee; Self; Abbott Laboratories. Y. Xu: Employee; Self; Abbott Laboratories. R. Ajjan: Consultant; Self; Abbott. Research Support; Self; Abbott, LifeScan, Inc.

Funding
Abbott Diabetes Care
301-LB: Effects of Amino Acid Restriction on Development of Type 2 Diabetes in NZO Mice by FGF21 Secretion
Authors: CASTAÑO-MARTINEZ TERESA , JONAS WENKE , WEBER DANIELA , WEIKERT CORNELIA , LAEGER THOMAS 
Published: June 2019

Dietary protein restriction (PR) is emerging as an alternative approach to treat obesity and glucose intolerance since it increases plasma fibroblast growth factor 21 (FGF-21) levels. Also, dietary methionine restriction (MR) is known to mimic the metabolic effects of PR by increasing FGF-21 and inducing beneficial effects. Therefore, we tested in New Zealand Obese (NZO) mice, a model of polygenic obesity and type 2 diabetes, whether a moderate PR or a MR protects against diabetes. Moreover, we investigated whether a decreased methionine intake caused by vegetarian and vegan diets modulates plasma FGF-21 in humans.
NZO mice were placed on high-fat diets that provided protein at control (18 gm%), low levels (4 gm%), or on high-fat diets (protein, 18 gm%) that provided methionine at control (0.86 gm%) or low levels (0.17 gm%) for up to 9 weeks. Changes in glucose homeostasis and energy expenditure were assessed. Among humans, plasma FGF-21 levels were investigated by comparing vegetarians and vegans to omnivores, and the effect of short-term vegetarian diet on FGF-21 induction was evaluated.
PR prevented the onset of hyperglycemia only when protein was substituted by fat. When protein was substituted by carbohydrates, mice developed hyperglycemia two weeks later than the control, despite elevated plasma FGF-21 levels and increased energy expenditure. MR elevated plasma FGF-21 levels and prevented the onset of hyperglycemia. Human plasma FGF-21 levels were higher in vegans and vegetarians compared to omnivores. Interestingly, already a short-term switch to a vegetarian diet increased plasma FGF-21 in omnivores.
Thus, restriction of dietary protein and methionine elevates plasma FGF-21 levels, which protect from hyperglycemia, an effect compromised by high dietary carbohydrates in NZO mice. Patients at high risk of developing type 2 diabetes may benefit from dietary changes in favor of methionine restriction, via increased circulating levels of FGF-21, without protein and calorie restriction.

Disclosure
T. Castaño-Martinez: None. W. Jonas: None. D. Weber: None. C. Weikert: None. T. Laeger: None.

Funding
Deutsche Forschungsgemeinschaft
301-OR: The Impact of Continuous Glucose Monitoring in Youth with Type 1 Diabetes, Aged 16-21
Authors: LEE MYRON , HOLMES-WALKER JANE , FARRELL KAYE 
Published: June 2019

Background: People with T1DM under 21 are eligible for subsidised continuous glucose monitoring (CGM) products under the Australian National Diabetes Services Scheme. There are few “real world” published studies to evaluate the benefits of CGM in young adults.
Aim: To determine whether CGM is associated with improvement in glycaemic markers amongst eligible T1DM patients.
Methods: Patients at the Westmead Hospital young adult diabetes clinic aged 16-21 who commenced CGM prior to July 2018 were followed-up for 6 months after CGM commencement. Differences in HbA1c and glucose metrics at baseline and follow-up are compared between those started on CGM and those who were not.
Results: There were 115 eligible patients, of which 38% (n=44) commenced CGM. There were no differences in age, gender or baseline HbA1c of those started on CGM vs. those who were not. CGM users were more likely to use CSII than MDI (n=27 vs. 17, P=0.02), and came from post code areas which had higher median household incomes, despite fully subsidised CGM costs. At 6 months follow-up, only 41% (n=18/44) were confirmed to still be using CGM, with common reasons for dropout being discomfort, inconvenience, and disruptive alarms. Of those who continued, there was no change from baseline to 6 months in HbA1c (8.2±1.3% vs. 8.3±1.5%, P=0.7), coefficient of variation of glucose (0.39 vs. 0.38, P=0.5), or % time in range (54% vs. 58%, P=0.3), with average CGM wear time 65% in the 4 weeks prior to follow-up visit. At 6 months there was a weak correlation between percentage use of CGM and HbA1c reduction (R=0.46, P=0.07). Mean hypoglycaemia fear scores (worry scale) was significantly decreased from baseline at 6 months (33 vs. 18, P&lt;0.01).
Conclusion: There are high rates of discontinuation in CGM use amongst T1DM patients aged 16-21. At six months of use there was no significant improvement in glycaemic control, although higher CGM usage was weakly correlated with increased time in range. Worry of hypoglycaemia was significantly decreased amongst those who continued CGM.

Disclosure
M. Lee: None. J. Holmes-Walker: None. K. Farrell: None.
308-OR: Genome-Wide Association Study of Food Frequency Questionnaire Single Nutrients and Dietary Patterns Uncover Hundreds of Genetic Associations
Authors: COLE JOANNE B. , LEONG AARON , HIRSCHHORN JOEL , FLOREZ JOSE C. 
Published: June 2019

Unhealthy dietary habits are leading risk factors for type 2 diabetes (T2D) and related traits. However, there has been limited success in the use of traditional dietary measures in genetic, epidemiological, and clinical translation studies thus far, highlighting the potential for exploring complex and genetically based dietary habits. We leveraged quantitative traits and extensive correlation structure from food frequency questionnaires in UK Biobank, one of the largest cohorts of diet and genetics collected to date (N~500K), to derive dietary habits that encompass both single nutrients and principal component (PC) dietary patterns. Dietary patterns summarize correlated food intake into single factors that better represent true dietary habits and thus can translate well into diabetes care and prevention. For example, dietary pattern PC1, similar to “prudent” and “Western” factors as have been previously described, separate individuals that consume more whole meal bread, produce, fish, and water from those that consume more white bread, processed meat, and butter and oil spreads. Overall, we found that 84% of 170 derived dietary habits had a significant genetic component, and genome-wide association studies of 143 significantly heritable dietary habits identified 814 independent genetic loci surpassing genome-wide significance (5.0×10-8). Among these include genetic loci previously associated with T2D, BMI, HDL cholesterol and triglyceride levels, coronary artery disease, physical activity, and macronutrient intake as well as several novel loci. A better understanding of the genetic architecture of diet will undoubtedly be of value to the diabetes community, for which these discoveries lay the foundation for research on biological mechanisms of diet, interaction with known genetic and environmental diabetes risk factors, and advancement on dietary intervention and prevention plans for diabetes.

Disclosure
J.B. Cole: None. A. Leong: None. J. Hirschhorn: Board Member; Self; Camp4 Therapeutics. J.C. Florez: None.

Funding
American Diabetes Association (1-19-PDF-028 to J.B.C.); National Institute of Diabetes and Digestive and Kidney Diseases (5T32DK110919-02)
312-OR: Functional Decline in Brown Adipose Progenitors during BAT Remodeling
Authors: HUANG ZAN , ZHANG ZENGDI , RUAN HAI-BIN 
Published: June 2019

In humans, there is a striking decrease in the prevalence and activity of brown adipose tissue (BAT) with age and obesity; however, the cellular and molecular mechanisms of BAT remodeling are almost completely unknown. Rodent models have been widely used to study BAT but they possess constitutively active BAT throughout life even at thermoneutrality; therefore, complementary animal models that possess characteristics of human BAT remodeling are needed. Here, we found that BAT progressively whitened in rabbits in a similar manner as in humans. As rabbits mature, preadipocytes in BAT displayed reduced capacity to be differentiated into brown adipocytes, when transplanted into immune-deficient mice. RNA-sequencing of brown preadipocytes identified that, during BAT remodeling, genes enriched for muscle contraction and mitochondrial function were down-regulated, while genes involved in lipid and amino acid metabolism were up-regulated. Single-cell RNA sequencing discovered a unique population of stromal vascular fraction cells specifically expressing genes regulating muscle and mitochondrial function. Knocking down these genes in rabbit brown preadipocytes blunted their ability to become mature brown adipocytes. We also identified follistatin like 1 (FSTL1) as a novel “batokine” that is specifically expressed by brown preadipocytes but not mature brown adipocytes. FSTL1 gradually reduced its expression when BAT whitens in rabbits, but was stably expressed in mouse BAT during life. Deleting FSTL1 specifically in the Myf5 lineage in mice reduced BAT size, UCP1 expression, and body temperature in newborns, suggesting the constitutive expression of FSTL1 prevents BAT whitening in mice. Taken together, we identify potential molecular mechanisms underlying functional decline in the browning ability of preadipocytes that contribute to BAT remodeling in rabbits and possibly humans.

Disclosure
Z. Huang: None. Z. Zhang: None. H. Ruan: None.

Funding
American Diabetes Association (1-18-IBS-167 to H-B.R.)
316-OR: Suppressing Adipose Tissue Inflammation Promotes Insulin Resistance in Mice
Authors: ZHU QINGZHANG , SCHERER PHILIPP E. 
Published: June 2019

Obesity is frequently concomitant with chronic adipose inflammation, although its role in the pathophysiology of obesity remains inconclusive. We previously described that constitutively suppressing adipose inflammation indeed impairs adipose development and leads to profound systemic metabolic disturbances. RIDα/β is an adenoviral protein complex that inhibits several inflammatory pathways, including TNFα and IL1β. To avoid developmental issues, we generated a tet-responsive promoter-driven RIDα/β (“TRE-RID”) mouse and crossed it to an adiponectinP-rtTA mouse to achieve doxycycline(dox)-inducible, adipocyte-specific expression of this transgene (referred to as fatRID mice).
We induced RIDα/β expression with dox-chow diet at 8-weeks of age. Upon induction, RIDα/β is specifically expressed in adipocytes, but not in the liver. LPS-stimulated inflammatory markers, such as TNFα, IL1β and Saa3 are significantly decreased in transgenic mice. Under dox-chow fed conditions, fatRID mice display higher levels of glucose and insulin upon refeeding. FatRID mice exhibit glucose intolerance and insulin resistance. Under obesogenic condition with high-fat-diet (HFD, supplement with dox) feeding, fatRID mice gain less weight, but also display insulin resistance. Moreover, to precondition the mice with inflammation and obesity, mice were pre-fed with HFD without dox for 30 days, and then switched to dox-containing HFD. Under these conditions, fatRID mice exhibit similar body weights, but still display glucose intolerance, insulin resistance, massive fatty liver and reduced adiponectin levels. These metabolic impairments were seen despite the fact that inflammatory pathways (including TNFα and IL1β) are effectively reduced.
Combined, suppressing adipose inflammation under either normal or obese conditions promotes insulin resistance, despite beneficial (or minimally no negative) effects on body weight.

Disclosure
Q. Zhu: None. P.E. Scherer: None.

Funding
National Institutes of Health
319-LB: GLP-1 Receptor Agonist Promotes Brown Remodeling in? Human Adipose-Derived Stromal Cells Isolated from Omentum through Foxc2
Authors: HE XIAOYING , LIU LIEHUA , KE WEIJIAN , LI YANBING 
Published: June 2019

Background: Brown adipose tissue (BAT) can disperse stored energy as heat. Promoting BAT-like features in white adipose tissue (WAT) is an attractive therapeutic approach to oppose obesity, glucose intolerance and insulin resistance. Accumulating evidence has revealed the significant role of glucagon-like peptide-1 (GLP-1) in improving insulin resistance in adipose tissue by reducing fat mass and adipocyte hypertrophy. Forkhead box C2 (FOXC2) plays a vital role in the regulation of lipid metabolism.
Objects: Here, we investigated the effect of brown remodeling induced by the GLP-1 receptor (GLP-1R) agonist exenatide (exendin-4) in human adipose-derived stromal cells (hADSCs) isolated from omentum. We also looked at the role of FOXC2 in this process.
Methods: hADSCs were isolated, cultured and differentiated as previously described. The effect of Exendin-4 on brown remodeling during differentiation of hADSCs was examined. The knockdown by siRNA was performed to determine the roles of FOXC2 in brown remodeling during differentiation of hADSCs.
Results: In our study, oil red O test showed that Exendin-4 significantly increased the number of smaller lipid droplets, which is more similar to the morphological characteristics of brown fat. QPCR showed that Exendin-4 treatment could significantly up-regulate mRNA levels of some pro-brown adipogenic genes (UCP-1, FOXC2, PPARGC1A, PRDM16 and DIO2). Western blot also indicated that Exendin-4 could increase the protein levels of FOXC2 and UCP-1. Exendin-4-induced responses were partially blocked by GLP-1 receptor antagonist exendin9-39. The pro-brown adipogenic effects and increased expression of adipocyte specific markers caused by Exendin-4 was significantly reversed by the knockdown of FOXC2.
Conclusions: Our data highlight that a GLP-1R agonist promotes brown remodeling of WAT in a FOXC2-dependent manner, this might be one of the mechanisms underlying its effect on weight loss.

Disclosure
X. He: None. L. Liu: None. W. Ke: None. Y. Li: None.