bluuebunny/crossref_metadata_2025_split huggingface dataset:
272-OR: Metabolically Healthy Obesity Is Not So Healthy
Authors: COMMODORE-MENSAH YVONNE , LAZO MARIANA , TANG OLIVE , ECHOUFFO TCHEUGUI JUSTIN B. , NDUMELE CHIADI E. , NAMBI VIJAY , BALLANTYNE CHRISTIE M. , WANG DAN , SELVIN ELIZABETH 
Published: June 2019

Background: It is unclear whether the “metabolically healthy” obese phenotype has low cardiovascular disease (CVD) risk. High-sensitivity cardiac troponin T (hs-cTnT), a biomarker of myocardial damage, characterizes subclinical CVD risk. We categorized obesity phenotypes and studied their cross-sectional and prospective associations with subclinical and clinical CVD.
Methods: We included 11,844 adults in the Atherosclerosis Risk in Communities (ARIC) Study. We used ATP III metabolic syndrome criteria and BMI to define obesity phenotypes as metabolically healthy non-obese (MHNO), metabolically unhealthy non-obese (MUNO), metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO).
Results: At baseline (1990-1992), mean age was 56 years, 56% were female and 23% black. The MHO group was more likely to have detectable hs-cTnT (≥ 6 ng/L) than the MHNO (OR 1.23, 1.02-1.49). During over 26 years of follow-up, 3,560 participants developed CVD. The metabolically unhealthy and obese phenotypes had higher CVD risk than MHNO (Table). Detectable hs-cTnT was associated with higher CVD risk in all phenotypes; MHO had CVD risk, which was intermediate between MHNO and MUO regardless of hs-cTnT (Table).
Conclusion: Our results show that metabolically “healthy” obesity is associated with substantial excess burden of subclinical and clinical CVD. Lifestyle modification among obese adults, regardless of metabolic status, is vital to prevent CVD.

Disclosure
Y. Commodore-Mensah: None. M. Lazo: None. O. Tang: None. J.B. Echouffo Tcheugui: None. C.E. Ndumele: None. V. Nambi: Other Relationship; Self; Dynamed, Merck & Co., Inc., Roche Diagnostic USA. C.M. Ballantyne: Consultant; Self; Abbott, Akcea Therapeutics, Amarin Corporation, Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Esperion, Gilead Sciences, Inc., Matinas BioPharma, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Roche Diagnostic USA, Sanofi. Research Support; Self; Abbott, Akcea Therapeutics, Amarin Corporation, Amgen Inc., Esperion, Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals, Roche Diagnostic USA, Sanofi. Other Relationship; Self; Roche Diagnostic USA. D. Wang: None. E. Selvin: None.

Funding
National Institutes of Health (5KL2TR001077-05)
273-OR: Intrapancreatic Adipose Tissue of Nondiabetic and Type 2 Diabetic Subjects and Relationships with Islet Morphometry
Authors: SULEIMAN MARA , LUCA CARMELA DE , SIMONE PAOLO DE , BOGGI UGO , GRANO FRANCESCA , BUGLIANI MARCO , MARCHETTI PIERO , MARSELLI LORELLA 
Published: June 2019

Little information is available on adipose tissue features in the human pancreas (AdTP). In the present study we performed morphologic and morphometric studies on AdTP of 9 overweight/obese nondiabetic (ND, age: 65±5 years; 4M/5F; BMI: 31.3±0.4 Kg/m2, mean±SEM) and 13 matched type 2 diabetic (T2D, age: 70±2 years, 8M/5F; BMI: 30.0±0.8 kg/m2) organ donors. Adipocytes were identified and quantified on a fluorescence DM5500 Leica microscope, using the MetaMorph v 1.8.0 software with a tresholded mask applied in exclusive mode. Macrophages were identified by immunohistochemistry using anti-CD68 (Dako) antibody. Assessment of insulin (Abcam Ab) and glucagon (Sigma Ab) positive cells was also performed. The number of adipocytes trended higher (+32.8%) in T2D (8.9±1.4/mm2) compared to ND (6.7±2.1/mm2) and their size was greater in T2D (9,319±1,028 μm2) than ND (5,639±639 μm2, p=0.01). AdTP area in relation to acinar tissue was 90.4% higher (p=0.07) in T2D (7.6±1.3%) than ND (3.9±1.5%). The amount of adipocytes with adjacent ≥ 3 CD68+ cells was higher (p=0.048) in T2D (31/281, 11%) than ND (7/147, 5%). Insulin positive area (T2D: 0.49±0.06%; ND: 0.55±0.09%) as well as glucagon positive area (T2D: 0.24±0.03%; ND: 0.32±0.07%) did not differ significantly between the two groups. Adipocyte size was negatively associated with islet number in ND+T2D (p=0.06) and positively with insulin area in ND (p=0.058); there was a significant, positive relationship between the amount of adipocytes and the number of islets in T2D (p=0.017).
In conclusion, we found significant differences in the AdTP of T2D as compared to ND, including increased adypocite size and presence of adipocyte adjacent CD68+ cells; some of these parameters correlated with islet morphometric indices.

Disclosure
M. Suleiman: None. C. De Luca: None. P. De Simone: None. U. Boggi: None. F. Grano: None. M. Bugliani: None. P. Marchetti: None. L. Marselli: None.

Funding
Innovative Medicines Initiative 2 Joint Undertaking (115881); European Union; European Federation of Pharmaceutical Industries and Associations; Swiss State Secretariat for Education, Research and Innovation (16.0097-2)
275-OR: Higher Liver Fat and Whole-Body Insulin Sensitivity in Newly Diagnosed Type 2 Diabetes Patients with a Variant in Transmembrane 6 Superfamily Member 2 Protein
Authors: BODIS KALMAN , SZENDROEDI JULIA , AHLERS JULIANE MARIA , KARUSHEVA YANISLAVA , ZAHARIA OANA P. , ANTONIOU SOFIA , KNEBEL BIRGIT , KUPRIYANOVA YULIYA , HWANG JONG-HEE , BURKART VOLKER , MUESSIG KARSTEN , AL-HASANI HADI , RODEN MICHAEL , MARKGRAF DANIEL F. 
Published: June 2019

Knockdown of the gene encoding transmembrane 6 superfamily member 2 protein (TM6SF2) in mice increases hepatocellular lipid content (HCL) and decreases very low-density lipoprotein secretion. Humans with TM6SF2 mutations are at higher risk of nonalcoholic fatty liver disease, but lower risk of cardiovascular disease. The relevance of TM6SF2 mutations for HCL and insulin sensitivity in type 2 diabetes is less clear. This study aimed at elucidating the relevance of the E167K (SNP rs58542926) mutation in the gene encoding TM6SF2 for HCL, hepatic insulin sensitivity and whole-body insulin sensitivity in type 2 diabetes.
We compared male patients with recently diagnosed type 2 diabetes with (n=16) or without (n=16) E167K mutation, matched for age and BMI (50±1 vs. 48±3 years; 32±1 vs. 32±2 kg/m2) from the German Diabetes Study. Whole-body and hepatic insulin sensitivity were assessed by Botnia-clamp tests with [6,6-2H2]glucose, HCL by 1H magnetic resonance spectroscopy and hepatic fibrosis by the fibrosis-4 index (FIB4).
Patients with and without TM6SF2 mutation had comparable levels of HbA1c (6.2±0.2 vs. 5.9±0.1%) and serum triglycerides (136±14 vs. 149±14 mg/dl). Carriers of TM6SF2 mutation had higher HCL (9.0±1.9 vs. 4.6±0.4%, p&lt;0.05) and whole-body insulin sensitivity (7.1±0.6 vs. 5.4±0.2 mg/(kg*min), p&lt;0.05), but similar hepatic insulin sensitivity (1.6±0.1 vs. 1.6±0.1 mg/(kg*min)) and fibrosis score (1.2±0.1 vs. 1.0±0.1).
In conclusion, the E167K mutation of the TM6SF2 gene dissociates liver steatosis from whole-body insulin sensitivity. This may result from favored trapping of triglycerides within the liver, which would in turn protect peripheral tissues from insulin resistance induced by liver-derived lipids.

Disclosure
K. Bodis: None. J. Szendroedi: None. J.M. Ahlers: None. Y. Karusheva: None. O.P. Zaharia: None. S. Antoniou: None. B. Knebel: None. Y. Kupriyanova: None. J. Hwang: None. V. Burkart: None. K. Muessig: None. H. Al-Hasani: None. M. Roden: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Poxel SA, Servier. Board Member; Self; Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker's Bureau; Self; Novo Nordisk Inc. D.F. Markgraf: Research Support; Self; Sanofi.
28-OR: Genetic Landscape of Diabetes in the Swiss Population
Authors: SCHWITZGEBEL VALERIE , BLOUIN JEAN-LOUIS , SANTONI FEDERICO 
Published: June 2019

Background/Introduction: Diabetes represents a heterogeneous group of metabolic disorders and monogenic diabetes is thought to affect 1- 5% of the diabetes population. Monogenic diabetes causes neonatal diabetes (ND), maturity-onset diabetes of the young (MODY), and syndromic diabetes. The identification of the gene underlying diabetes remains crucial. In many cases, it will instruct a personalized treatment regime, thus improving metabolic control. The aim of the study was to identify mutations causing genetic diabetes.
Methods: Inclusion criteria for testing were ND, autoantibody negative type 1 diabetes (T1D), presumed MODY, type 2 diabetes (T2D) diagnosed before the age of forty-five without metabolic features and syndromic diabetes. Haloplex technology was used to perform targeted next-generation sequencing (NGS) for 323 genes known to be involved in glucose homeostasis.
Results: We have analyzed 234 diabetic individuals (137 females, 97 males) living in Switzerland by NGS. The mean age at diabetes diagnosis was 27.7 ±15.4 years. We identified variants in the MODY genes 1-13 in 41% (95/234) of the patients, of which 7 had variants in two, and one in three genes. The most frequent variants involved GCK in 58% (55/95), followed by HNF1A 19%, HNF4A 7%, ABCC8 6%, HNF1B/KCNJ11/KLF11 3%, NEUROD1 2% and PAX4 1%. When mapped to age at diabetes onset, MODY variants were most frequent in the neonatal group (50%, 2/4), and declined with age to reach 36% (13/36) in the &gt;45 year group. In the group with variants in other than MODY genes (n=111) diabetes onset was 30 ±16 years; in 39% of the individuals we identified one genetic variant with a maximum of up to six in 1.8% of the probands.
Conclusion: NGS is now a feasible method to diagnose monogenic diabetes, as we identified variants in MODY genes in 41% of probands in our cohort. We detected potential digenic and oligogenic diabetes forms in 61% of the probands with variants in other than MODY genes. The discovery of additional diabetes genes may lead to novel, rational treatment strategies.

Disclosure
V. Schwitzgebel: None. J. Blouin: None. F. Santoni: None.

Funding
Swiss National Science Foundation
283-OR: Structured Nurse-Led Intervention following Ambulance Call Out for Hypoglycemia Reduces Cardiovascular Mortality in Type 2 Diabetes
Authors: PEARSON SAM , KULAVARASALINGAM KAVITA , BAXTER PAUL , MITCHELL-GEARS AMELIA K. , WHITTAM BEVERLEY ANN , AJJAN RAMZI 
Published: June 2019

Aims: The aim of this work is to provide in depth characterization of patients with type 2 diabetes (T2D) with severe hypoglycemia and assess the role of structured nurse-led intervention on clinical outcome.
Methods: Individuals with T2D and severe hypoglycemia requiring ambulance services assistance were recruited into the study. Participants were randomized into standard arm (n=64), managed using existing pathways, or intervention arm (n=60), receiving nurse-led support for a period of 90 days. A third group did not wish to participate in the interventional study but consented for their data to be collected and were analyzed separately (observational arm; n=36).
Results: Of the 160 participants, 88 were men and median age was 77.0 (IQR 69.3-82.0) years. Mean HbA1c±SD was 59.7±16.1 mmol/mol and capillary glucose levels at ambulance crew arrival was 2.2±0.75 mmol/L. HbA1c, smoking status, age and presenting glucose were similar in the standard and intervention arms. 9 participants withdrew or lost to follow-up and were excluded from analysis. Individuals were followed-up for a median of 1350 days (IQR 870-1627) and mortality occurred in 67 participants (44.4%), with cardiovascular events as the leading cause (34%) followed by infections (27%). The number of deaths in the intervention arm was 17 (32%) compared with 31 (50%) in conventionally managed individuals (p=0.047), mainly due to a reduction in cardiovascular mortality [1 (2%) and 11 (18%), respectively; p&lt;0.01]. Individuals in the observational and standard arms had similar mortality rate.
Discussion: This pilot study demonstrates that cardiovascular events and infections are the main cause of mortality following severe hypoglycemia in the community requiring ambulance services assistance. A structured nurse-led intervention for 3 months reduces mortality primarily due to a decrease in cardiovascular events.

Disclosure
S. Pearson: Speaker's Bureau; Self; Novo Nordisk Inc. K. Kulavarasalingam: None. P. Baxter: None. A.K. Mitchell-Gears: Other Relationship; Self; Heart Research UK. B.A. Whittam: None. R. Ajjan: Consultant; Self; Abbott. Research Support; Self; Abbott, LifeScan, Inc.
289-OR: Aerobic Exercise Counteracts Mitochondrial Dysfunction in the Insulin Resistant Brain
Authors: RUEGSEGGER GREGORY , VANDERBOOM PATRICK M. , DASARI SURENDRA , KLAUS KATHERINE , NAIR K. SREEKUMARAN 
Published: June 2019

Insulin resistance increases the risk for Alzheimer’s disease and other dementias; however, the underpinning mechanisms for this increased risk remain to be fully defined. Insulin resistance impairs mitochondrial oxidative metabolism and increases reactive oxygen species (ROS) in skeletal muscle, both of which are counteracted by aerobic exercise (AE). Therefore, we considered whether similar events occur in the brain, specifically in regions such as cerebrum and hippocampus which are rich in insulin receptors and mitochondria. We determined whether AE would counteract mitochondrial deficits in hippocampal and cerebral mitochondrial function in high fat diet (HFD) induced insulin resistance. Four weeks of HFD in mice induced hippocampal insulin resistance which was corrected by AE. HFD decreased ATP production and increased ROS emission in isolated cerebral mitochondria, which were rescued with AE. Impairments in mitochondrial function with HFD were paralleled by reductions in mtDNA copy number, mRNA expression of mitochondrial genes, and oxidative enzyme activities (e.g., citrate synthase, COX) in the hippocampus, which were corrected by AE. We also observed excessive mitochondrial fission in the hippocampus following HFD, which was prevented by AE. Proteomic analysis of the hippocampus showed that HFD led to oxidative post-translational modifications (PTMs) of mitochondrial proteins; however, this increase in oxidative PTMs to mitochondrial proteins with HFD was almost completely reversed by AE. Further, intranasal administration of the insulin receptor antagonist S961 prevented AE-induced improvements in ATP production and ROS emission in isolated cerebral mitochondrial during HFD, demonstrating that AE enhances cerebral mitochondrial function during HFD by resensitizing brain insulin signaling.

Disclosure
G. Ruegsegger: None. P.M. Vanderboom: None. S. Dasari: Consultant; Self; The Binding Site. K. Klaus: None. K. Nair: None.
290-LB: Repeated Neonatal Oral Sucrose Treatment Affects Growth and Insulin-Like Growth Factor-1 in Mice
Authors: CONTRERAS CYNTHIA YAMILKA RAMIREZ , MUSSAI EI-XIA , WIEDEMAN ALEJANDRA M. , MEHRAN ARYA , SALEHZADEH MELODY , BOONPATTRAWONG NICHA , RANGER MANON , SOMA KIRAN K. , HOLSTI LIISA , DEVLIN ANGELA M. 
Published: June 2019

Premature infants (&lt;;37 weeks of gestation) often require hospitalization in the neonatal intensive care unit, where they may experience painful procedures due to medical care. Oral sucrose is the non-pharmacological standard of care for minor procedural pain relief; 0.5-2mL of a 24% sucrose solution is administered orally prior to each painful procedure. Throughout hospitalization infants can be exposed to high and cumulative volumes of sucrose; however, little is known about the long-term effects of oral sucrose on growth and development. The objective of this study was to determine the long-term effects of repeated neonatal oral sucrose treatment on growth, adiposity, and glucose homeostasis. Neonatal female and male mice (C57BL/6J) were randomly assigned to one of five treatment groups (n=6-10 mice/group/sex): sham (only handled), sterile water, sucrose, fructose, or glucose. Pups were treated 10 times/day for the first six days of life with 0.2g/kg weight of respective treatments (1-4 μl/dose; 24% solutions) orally to mimic what is given to preterm babies. At 3 weeks (weeks), mice were weaned onto a control diet and fed until euthanasia, at 16 weeks. There were no effects of neonatal oral sucrose treatment on glucose and insulin tolerance, and glucose stimulated insulin secretion at weaning or during adulthood. Female sucrose-treated compared to water-treated mice gained less weight (15.4±1.60 vs. 17.4±1.90g), had smaller tibias (15.9± 0.35 vs. 16.67±0.24mm), and lower serum insulin-like growth factor 1 (IGF-1) (378± 98.0 vs. 661±196ng/ml) at 16 weeks. No differences in growth were found in males. However, IGF-1 levels were lower in sucrose-treated vs. sham male mice (401± 143 vs. 641±165ng/ml). Our findings suggest that repetitive neonatal sucrose treatment may affect growth in females through an IGF-1-dependent pathway.

Disclosure
C.Y. Ramirez Contreras: None. E. Mussai: None. A.M. Wiedeman: None. A. Mehran: None. M. Salehzadeh: None. N. Boonpattrawong: None. M. Ranger: None. K.K. Soma: None. L. Holsti: Other Relationship; Self; Provincial Health Services Association. A.M. Devlin: None.

Funding
British Columbia Children's Hospital Research Institute
290-OR: High-Intensity Interval Training and Moderate-Intensity Continuous Training Induce Similar Modifications to Factors Regulating Skeletal Muscle Lipolysis
Authors: RYAN BENJAMIN J. , SCHLEH MICHAEL W. , VARSHNEY PALLAVI , LUDZKI ALISON , GILLEN JENNA B. , FOUG KATIE , CARR BENJAMIN D. , HOROWITZ JEFFREY F. 
Published: June 2019

Abnormalities in muscle lipid metabolism in obesity have been linked to insulin resistance. Exercise training alters skeletal muscle lipid abundance and localization, but the direct effects of exercise training (independent of weight loss) on skeletal muscle lipolytic proteins are not clearly understood, and data are lacking regarding influence of training intensity on factors regulating muscle lipid metabolism in obesity. Our aim was to examine the effects of high-intensity interval training (HIIT) vs. moderate-intensity continuous training (MICT) on skeletal muscle lipolytic proteins in obese humans. Eighteen sedentary, obese adults completed 12 weeks (4 sessions weekly) of either HIIT (10 x 1 min at 90% HRmax, 1 min recovery; n=8) or MICT (45 min at 70% HRmax; n=10). Muscle biopsies (vastus lateralis) were collected before and after training. Subjects maintained body weight and fat mass and the post-training biopsy occurred 3 days after the final exercise session. Both exercise training programs increased aerobic capacity (VO2max) by ~10% (p=0.003), with no significant difference between HIIT and MICT. In muscle samples, hormone-sensitive lipase (HSL) protein abundance increased ~2-fold after training in HIIT (P&lt;0.05), but not MICT. Training did not affect muscle abundance of adipose triglyceride lipase (ATGL) in either group but interestingly, the abundance of both CGI-58 (a positive regulator of ATGL lipolytic activity) and G0S2 (a negative regulator of ATGL lipolytic activity) increased ~15-20% after training (p&lt;0.02), with no difference between HIIT and MICT.
In summary, HIIT and MICT result in similar modifications to lipolytic proteins in skeletal muscle, although our findings suggest that HIIT may be a more potent stimulus for increasing HSL abundance. Future work is needed to determine if the concomitant increases in protein abundance of CGI-58 and G0S2 with training may improve lipid handling in obesity.

Disclosure
B.J. Ryan: None. M.W. Schleh: None. P. Varshney: None. A. Ludzki: None. J.B. Gillen: None. K. Foug: None. B.D. Carr: None. J.F. Horowitz: Research Support; Self; American Diabetes Association.

Funding
National Institutes of Health (R01DK077966, P30DK089503, T32DK007245); Canadian Institutes of Health Research (DFS146190)
295-OR: User Acceptance of the Eversense® CGM System in a Home Use Setting: The House Study
Authors: LONDAHL MAGNUS , LANDIN-OLSSON MONA , ATTVALL STIG 
Published: June 2019

Background: The Eversense® CGM System is the first implantable CGM available for long-term continuous glucose measurement with a single sensor. The small sensor is indicated for subcutaneous wear in the upper arm. This study was conducted to assess usability and preference for arm or abdominal sensor wear.
Methods: HOUSE was a prospective, single-arm, two-center study conducted in two sequential 90-day periods in subjects with T1D. During the first period, subjects were inserted with 2 sensors: one in upper arm and one in abdomen. After 90 days, both sensors were removed and subjects chose either the upper arm or abdominal location for the next sensor. Study visits occurred every 30 d up to 180 d for device downloads/safety assessment. At the 90-day and 180-day visit, subjects filled out a custom-designed questionnaire on their experience with the CGM system.
Results: Eighteen subjects participated (83% male, age 40±12.5 years, BMI 25.6±4.4kg/m2, 23 years from diabetes diagnosis; mean±SD). Sixty-one percent were on MDI and 89% had prior CGM experience. Two subjects withdrew consent due to personal reasons and 100% of the remaining sensors lasted each 90-day cycle. Ninety-four percent preferred to wear the sensor in the upper arm with 72% highly agreed/agreed that the transmitter was comfortable on the arm and 23% highly agreed/agreed that the transmitter was comfortable on the abdomen. The majority of subjects reported that sensor insertion was painless (69%) and that they were able to wear the transmitter in their everyday setting (94%). Product likeability scores were high: 94% on displaying readings on a smartphone and 75% on predicted hypo-/hyperglycemic alerts. The median wear time was 23.4 hours/day and 88% of subjects reported reviewing their CGM glucose values at least every other hour while awake.
Conclusion: In a home-use setting with experienced CGM users, subjects preferred wearing the Eversense on the arm compared to the abdomen. The system was rated high for usability on either the arm or abdomen.

Disclosure
M. Londahl: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi. M. Landin-Olsson: None. S. Attvall: None.
305-LB: BRD7 Deficiency Leads to the Development of Obesity
Authors: LEE JUNSIK M. , KIM YOO , SALAZAR HERNANDEZ MARIO A. , PARK SANG 
Published: June 2019

Elevated endoplasmic reticulum (ER) stress is tightly associated with the development of obesity and insulin resistance. Previous reports showed that haploinsufficiency of X-box binding protein 1 (XBP1), one of the master regulators of ER protein folding function, results in obesity and type 2 diabetes. In our previous work, we showed that bromodomain-containing protein 7 (BRD7) regulates the nuclear translocation of XBP1 through its interaction with the regulatory subunits of phosphatidylinositol 3 kinase (PI3K), p85s. We reported that the expression levels of BRD7 are significantly reduced in the liver of obese mice and acute upregulation of hepatic BRD7 in obese and type 2 diabetic mice improves glucose homeostasis. In our current unpublished work, we show that nuclear translocation of BRD7 is independent of PI3K activity and p110, the catalytic subunit of PI3K, is not involved in the degradation of BRD7. We show that both whole-body reduction and liver-specific deletion of BRD7 lead to increased weight gain. We also show that sustained restoration of BRD7 in the liver starting at an early age protects mice from developing obesity, glucose intolerance, and insulin resistance even when challenged with a high-fat diet.

Disclosure
J.M. Lee: None. Y. Kim: None. M.A. Salazar Hernandez: None. S. Park: None.

Funding
American Diabetes Association (1-17-IBS-104 to S.P.); National Institutes of Health