bluuebunny/crossref_metadata_2025_split huggingface dataset:
251-OR: Relationship of Short-Term HbA1c Change with Vascular Events, Severe Hypoglycaemia, and Mortality
Authors: NANAYAKKARA NATALIE , OHKUMA TOSHIAKI , WOODWARD MARK , CHALMERS JOHN , ZOUNGAS SOPHIA 
Published: June 2019

Objective: To examine the effects of change in glycaemic control on clinical outcomes in patients with type 2 diabetes.
Research Design and Methods: Data were obtained from 9981 participants of the ADVANCE trial and ADVANCE-ON follow-up. Participants were categorized into 3 groups by glycated haemoglobin (HbA1c) change from baseline to 6 months, &gt;0.25% decrease, &gt;0.25% increase and minimal change (±0.25%). Adjusted Cox and logistic regression analyses examined relationships between HbA1c change and all-cause mortality, macrovascular events, microvascular events and severe hypoglycaemia.
Results: Mean (±SD) age was 65.8±6.4 years, diabetes duration 7.9±6.4 years and HbA1c 7.5±1.6% at baseline. In the first 6 months, 48%, 22% and 30% of participants had an HbA1c decrease, minimal change or increase respectively. Median (IQR) follow-up was 9.4 (5.1-10.4) years. Compared to those with minimal HbA1c change at 6 months, participants with an HbA1c increase at 6 months had greater risk of risk of all-cause mortality [1.26 (1.11-1.43)], macrovascular events [1.26 (1.10-1.44)] and microvascular disease [1.36 (1.09-1.70) whereas participants with an HbA1c decrease did not have greater risk of all-cause mortality [0.99 (0.87-1.12)], macrovascular events [1.06 (0.93-1.21)] or microvascular disease [0.97 (0.77-1.21)]. Neither HbA1c increase [1.05 (0.83-1.33)] or decrease [1.16 (0.91-1.47)] was associated with greater risk of severe hypoglycaemia. These effects were similar when HbA1c change at 3 months was considered and in subgroup analyses by age, gender, diabetes duration, or baseline HbA1c.
Conclusions: Increased rather than decreased HbA1c at 6 months was associated with increased risks of death and vascular events in type 2 diabetes.

Disclosure
N. Nanayakkara: None. T. Ohkuma: None. M. Woodward: Consultant; Self; Amgen Inc., Kirin. J. Chalmers: Research Support; Self; Idorsia. S. Zoungas: None.
259-OR: Magnetic Resonance Imaging of Transplanted Islets Labeled with Exendin-4-Conjugated Manganese Magnetism-Engineered Iron Oxide Nanoparticles
Authors: JUANG JYUHN-HUARNG , SHEN CHIA-RUI , WANG JIUN-JIE , WU SHU-TING , CHEN CHEN-YI , KAO CHEN-WEI , LIN SUNG-HAN , WANG YUN-MING 
Published: June 2019

To detect and trace transplanted β-cells by magnetic resonance imaging (MRI), we conjugated manganese magnetism-engineered iron oxide (MnMEIO) nanoparticles with exendin-4 (MnMEIO-Ex4) which can specifically bind glucagon-like peptide-1 receptors on β-cells. Incubation of MIN6 β-cells and MnMEIO showed MnMEIO with iron content 5-40 μg/mL had no adverse effect on MIN6 β-cells assessed by the fluorescence of propidium iodide and insulin secretory response to glucose. Positive iron staining by Prussian blue was found in the MIN6 loaded with MnMEIO-Ex4 but not with MnMEIO. A transmission electron microscope with elementary mapping of iron and manganese demonstrated MnMEIO-Ex4 nanoparticles distributed in the cytoplasm of MIN6 β-cells. In vitro 7.0 T MR image showed loss of intensity in MIN6 β-cells loaded with MnMEIO-Ex4 but not with MnMEIO. With addition of poly-L-lysine, only MIN6 β-cells incubated with MnMEIO-Ex4 but not MnMEIO stimulated proinsulin mRNA expression and insulin secretion. On day 1, 6, 15, 22 and 29 after syngeneic transplantation of 700 C57/B6 mouse islets labeled with MnMEIO-Ex4, the islet graft under left kidney capsule could be visualized on 7.0 T MRI as persistent hypodense areas (indicated by arrows in Figure). Our results indicate MnMEIO-Ex4 nanoparticles are safe and effective for the detection and monitoring of islet grafts by MRI.

Disclosure
J. Juang: None. C. Shen: None. J. Wang: None. S. Wu: None. C. Chen: None. C. Kao: None. S. Lin: None. Y. Wang: None.

Funding
Chang Gung Memorial Hospital
260-LB: Continuous Glucose Monitoring Metrics in Islet Transplant Recipients with Long-Term Insulin Independence
Authors: BAIDAL DAVID , ALVAREZ GIL ANA M. , PADILLA NATHALIA , RICORDI CAMILLO , ALEJANDRO RODOLFO 
Published: June 2019

Continuous glucose monitoring (CGM) following islet transplantation (ITx) has shown improved time-in-range, reduced glycemic variability (GV) and hypoglycemia prevention despite subnormal beta-cell function. However, it is unclear if improvement by CGM persists long-term in insulin independent (Ifree) ITx recipients. We evaluated 5 ITx recipients who remained Ifree for &gt;5 years. Subjects completed 7-day non-blinded CGM (Dexcom G4 Platinum). HbA1c, 90min C-peptide, Clarke score, and BETA-2 score (composite measure of beta-cell function after ITx) were obtained. Before ITx, mean age was 47.2±4.0 years, diabetes duration 34.6±9.4 years, HbA1c 7.0±1.2%, insulin/Kg/day 0.44±0.08 units and Clarke score 5 (range 4-7). Subjects received 1-2 islet infusions. Induction immunosuppression consisted of ATG or daclizumab and dual maintenance with sirolimus, tacrolimus or mycophenolate mofetil. At time of CGM, subjects were Ifree and 10.7±3.5 years post-ITx (range 7.7-16.0). Two subjects were on non-insulin adjunct therapies. CGM and metabolic data, BETA-2 and Clarke scores are shown in Table 1. In Ifree ITx recipients with very good long-term graft function (BETA-2 score&gt;15) and restoration of hypoglycemia awareness, CGM shows near-normalization of time-in-range and GV with minimal time-in-hypoglycemia. ITx is a successful long-term cellular therapy for T1D in a selected group of patients.

Disclosure
D. Baidal: None. A.M. Alvarez Gil: None. N. Padilla: None. C. Ricordi: Advisory Panel; Self; Zone Labs. R. Alejandro: None.

Funding
National Institute of Allergy and Infectious Diseases/National Institute of Diabetes and Digestive and Kidney Diseases (U01-DK-070460); Immune Tolerance Network (NIS01); Diabetes Research Institute Foundation; State of Florida; University of Miami Clinical and Translational Science Institute (1UL1TR000460); JDRF International (4-2004-361)
268-OR: Insulin Resistance in the Liver, but Not Muscle or Adipose, Is Essential for Remission from Newly Diagnosed Type 2 Diabetes by Short-Term Insulin Intensive Therapy
Authors: WAN XUESI , HUANG ZHIMIN , LI YANBING 
Published: June 2019

To clarify the effects of insulin resistance from different tissues on the remission from newly diagnosed type 2 diabetes (T2DM) following short-term insulin intensive therapy (SIIT). This study enrolled 37 healthy controls and 160 patients with newly diagnosed type 2 diabetes mellitus (n=160, HbA1c11±2.1%). They were randomly divided to four groups, CSII alone for 2 weeks, or combination with an insulin sensitizer (CSII + metformin or CSII + rosiglitazone), or an antioxidant (CSII + α-lipoic acid). HOMA-IR, Adipo-IR and intramyocellular lipid (IMCL), were compared before and after termination of CSII. After short-term intensive treatment, 77.5% patients achieved normal HOMA-IR but little change in the Adipo-IR. The IMCL were nearly normalized except for those in metformin group, impacted by the lower insulin dose. The improvement of HOMA-IR and FFA, not IMCL or Adipo-IR, statistically related to the percentage declines of FPG (r=0.317 and 0.275), while only the HOMR-IR was associated with ΔPPG% (r=0.284). And 40.6% patients achieved sustained normal HOMA-IR in the first 3 months after CSII and attained 50% remission rate at the 5-year, far beyond 8.9% in the other patients (HR = 2.82 95% CI is1.813-4.388, p&lt;0.001). Besides, slight superiority has occurred with HOMA-IR, Adipo-IR and IMCL in the CSII+ rosiglitazone group. In brief, short-term CSII therapy, with or without insulin sensitizers, is extremely effective in improving insulin resistance, even normalizing the HOMA-IR and IMCL. Sustained normal hepatic insulin resistance is essential for remission from T2DM. Insulin reversed ectopic fat in muscle with dose effect and the combination therapy with rosiglitazone is superior.

Disclosure
X. Wan: None. Z. Huang: None. Y. Li: None.
276-LB: Constitutive Activation of PKA Signaling in POMC-Expressing Cells Improves Systemic Glucose Metabolism
Authors: CHOI JONG HAN , MIN SE HEE , KANG GIL MYOUNG , KIM JI YE , KIM MIN-SEON 
Published: June 2019

Constitutive Proopiomelanocortin (POMC)-expressing cells are mainly found in the hypothalamic arcuate nucleus, brainstem solitary tract nucleus, and pituitary gland. The cAMP-dependent protein kinase A (PKA) critically transduces signaling pathways of many important hormones and neurotransmitters including glucagon, GLP-1, α-MSH, dopamine and catecholamine. We generated the mice deleting PKA regulatory subunit R1A (Prkar1a) in POMC-expressing cells to induce constitutive activation of PKA signaling in POMC cells. These mice exhibited interesting phenotypes similar to human Cushing's syndrome; thin skin, hair loss, increased fat mass but reduced muscle and bone mass, female infertility, retarded linear growth, hump and insulin resistance. Moreover, they had increased corticosterone levels both in urine and plasma along with adrenal cortical hypertrophy. Interestingly, despite severe insulin resistance and obesity, plasma glucose concentrations were significantly lower in both fasting and post-glucose loading conditions. These mice showed enhanced insulin-independent glucose disposal. FDG-PET scanning and 2DG uptake tests revealed increased glucose uptake in the brain and the kidney. Normalization of corticosteroid levels by bilateral adrenalectomy and corticosteroid replacement could not normalize blood glucose. Collectively, our hypothesis is that abnormal activation of PKA signaling in pituitary POMC cells causes human Cushing’s syndrome-like phenotype whereas unusual activation of PKA signaling in hypothalamic POMC neurons enhances glucose disposal in the brain and the kidney.

Disclosure
J. Choi: None. S. Min: None. G. Kang: None. J. Kim: None. M. Kim: None.

Funding
National Research Foundation of Korea
276-OR: Rethinking Metabolically Healthy Obesity: What Is the Underlying Risk?
Authors: AXELROD CHRISTOPHER L. , HARI ADITHYA , MEY JACOB T. , BEYL ROBBIE A. , KIRWAN JOHN P. 
Published: June 2019

Introduction: Type 2 diabetes (T2D) is a multifactorial disease with both heritable and environmental origins. Overweight and obesity are the primary risk factors, present in 90% of persons with T2D. However, little is known of the intrinsic risk carried by individuals with moderate to severe obesity. The purpose of this study was to identify and analyze risk factors in obese individuals with and without clinical metabolic risk factors. We hypothesized that the insulin sensitivity of metabolically healthy obese individuals would be similar to their BMI matched counterparts.
Methods: Eighty-seven sedentary adults underwent an inpatient stay consisting of anthropometric measurements, blood chemistries, body composition (DXA), aerobic capacity (VO2MAX), and insulin sensitivity testing (glucose clamp). Subjects were first stratified by BMI (&lt;25 and &gt;30). Those with a BMI &gt;30 were further stratified based upon a composite metabolic health score consisting of: BMI, VO2MAX, HOMA-IR, triglycerides, and cholesterol levels. Group differences were assessed using a one-way ANOVA with multiple comparisons.
Results: Individuals with obesity had elevated HDL, LDL, blood pressure, waist-to-hip ratio and body fat (ALL P&lt;0.05) compared to lean controls, with no differences between metabolically healthy and unhealthy individuals. Metabolically unhealthy individuals had elevated fasting insulin (P&lt;0.05) and glucose (P&lt;0.05) levels compared to both lean controls and metabolically healthy obese individuals. However, both the metabolically healthy and unhealthy obese individuals had reduced insulin sensitivity (lean to obese P&lt;0.01, interaction P=0.40) compared to lean controls.
Conclusions: Metabolically healthy obese individuals retain the risk associated with T2D, most notable being reduced insulin sensitivity. Furthermore, we posit that safe and effective treatments for T2D, such as insulin sensitizing therapy or bariatric surgery, may be warranted in metabolically healthy obese individuals alike.

Disclosure
C.L. Axelrod: None. A. Hari: None. J.T. Mey: None. R.A. Beyl: None. J.P. Kirwan: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging; Louisiana Clinical & Translational Science Center
277-LB: LRP1 Mediates the Transport of Leptin Across the Blood-CSF Barrier at the Choroid Plexus
Authors: SEO JI A , KANG MIN-CHEOL , MENDES NATALIA FERREIRA , ARAUJO THIAGO , YANG WON-MO , KIM YOUNG-BUM 
Published: June 2019

Leptin is an adipocyte-derived hormone that reduces food intake and stimulates energy expenditure. In order to achieve its physiological actions, it needs to enter the brain. The precise routes of brain entry of many metabolic signals have not been identified, but most studies suggest that transport across the BBB and CSF barrier are required. This study was designed to test the hypothesis that LRP1 mediates leptin’s transport across the blood-CSF barrier at the choroid plexus (ChP). To address this, we have first generated Foxj1-Cre; tdTomato mice to see the expression pattern of Foxj1 in the brain. The expression of tdTomato is restricted to the epithelial cells of the ChP and the ependymal cells of the ventricles. Mice lacking LRP1 in the epithelial cells and ependymal cells of the brain were thus generated and studied. Here we show that deletion of LRP1 in the epithelial cells of the ChP and the ependymal cells of the ventricles causes hyperleptinemia. This effect is independent of body weight and adiposity. In addition, mice lacking LRP1 in the epithelial cells of the ChP and the ependymal cells of the ventricles are insulin-resistant. Most importantly, leptin-induced food intake and hypothalamic Stat3 phosphorylation were significantly impaired in Foxj1-Cre; LRP1lox/lox mice compared with LRP1lox/lox mice. However, ICV leptin decreased food intake and increased hypothalamic Stat3 phosphorylation in Foxj1-Cre; LRP1lox/lox mice. There were no differences in both food intake and Stat3 phosphorylation between LRP1lox/lox mice and Foxj1-Cre; LRP1lox/lox mice. These data clearly demonstrate that LRP1 in the epithelial cells of the ChP mediates leptin transport across the blood-CSF barrier at the ChP and further implicate that defective leptin transport may not contribute to the regulation of body weight homeostasis.

Disclosure
J. Seo: None. M. Kang: None. N. Ferreira Mendes: None. T. Araujo: None. W. Yang: None. Y. Kim: None.

Funding
National Institutes of Health (R01DK106076); National Research Foundation of Korea (2018R1D1A1B07049123)
279-OR: How to Use rtCGM Data to Predict Future Severe Hypoglycemia?
Authors: HERMANNS NORBERT , EHRMANN DOMINIC , CALHOUN PETER , FRECKMANN GUIDO , HEINEMANN LUTZ 
Published: June 2019

We combined rtCGM-baseline-data of the HypoDE and DIAMOND study to predict future severe hypoglycemia (SH; third party assistance for recovery). At baseline, in both studies, the rtCGM system (Dexcom G4) was masked. We analyzed the data of 127 study participants in the control groups with type 1 diabetes (age 46.0 ±11.5 years; diabetes duration 22.4 ±14.1 years, A1c 7.9 ±1.0%) using SMBG during the trials. According to the consensus statement we used the following hypoglycemia-specific predictors: % of glucose values &lt; 70mg/dl and &lt;54 mg/dl, the number of such events, Low Blood Glucose Index (LBGI), and the coefficient of variation (CV). After baseline, a total of 44 severe hypoglycemic events were observed during the following 6-months; with 12.6% affected participants. We analyzed the area under the Receiver Operating Characteristics (ROC) curves and determined cut-off values with an optimal sensitivity and specificity (Table). All hypoglycemia-related parameters, except CV, were able to predict SH during the next 6 months significantly better than prediction by chance; e.g., if ≥ 7% of glucose values were &lt; 70 mg/dl, the probability for SH in the next 6-months was 23.4%. CGM-derived hypoglycemic outcome parameters might help to identify people with diabetes who have an increased risk for future hypoglycemia. These results should be corroborated by non-masked use of rtCGM but might also be useful in patients using SMBG.

Disclosure
N. Hermanns: Advisory Panel; Self; Abbott. Board Member; Self; Eli Lilly and Company. Research Support; Self; Abbott, Berlin-Chemie AG, Dexcom, Inc., Roche Diabetes Care. Speaker's Bureau; Self; Berlin-Chemie AG, Dexcom, Inc., Novo Nordisk A/S. D. Ehrmann: Advisory Panel; Self; Medtronic. Speaker's Bureau; Self; Abbott, Berlin-Chemie AG, Dexcom, Inc. P. Calhoun: Stock/Shareholder; Self; Dexcom, Inc. G. Freckmann: Advisory Panel; Self; Abbott, Novo Nordisk Pharma GmbH, Sensile Medical AG. Consultant; Self; Metronom Health Europe, Roche Diabetes Care, Sanofi. Speaker's Bureau; Self; Ascensia Diabetes Care, Dexcom, Inc., Ypsomed AG. L. Heinemann: Consultant; Self; Roche Diabetes Care. Research Support; Self; Dexcom, Inc. Stock/Shareholder; Self; Profil Institute for Metabolic Research, ProSciento.

Funding
Dexcom, Inc.
285-LB: Short-Term Effect of Saturated and Monounsaturated Fatty Acids on Hepatic Energy Metabolism
Authors: BEDNARSKI TOMASZ , RAHIM MOHSIN , YOUNG JAMEY 
Published: June 2019

Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease affecting about 30% of the U.S. population. The prognosis for simple liver steatosis is relatively benign; however, chronic inflammation and progressive fibrosis may lead to nonalcoholic steatohepatitis (NASH) and later to cirrhosis and hepatocellular carcinoma. There is no established treatment to stop progression from NAFLD to NASH to date. Therefore, we developed a protocol to investigate the acute impact of saturated (SFA) and monounsaturated (MUFA) fatty acids on liver energy metabolism and their potential lipotoxic effects. Conscious, unrestrained, overnight fasted 12 weeks old male C57Bl/6J mice were given continuous, intravenous infusions of either saline, 20% lard oil or 20% olive oil emulsions (as described in Stein DT et al. J Clin Invest. 1997; 100 (2): 398-403) for 5 hrs. Lipid infusion was accompanied by primed, continuous infusion of [6,6-2H2] glucose (16mg/kg/min for 5 min and 0.8 mg/kg/min continuously) and sodium [13C3]lactate (200 μM/kg/min 5 min and 40 μM/kg/min continuously) intravenously for 4 and 2 hrs, respectively. Both plasma and liver free fatty acids were upregulated in SFA and MUFA groups. However, liver triglycerides, alanine aminotransferase (ALT) and aspartate transaminase (AST) were significantly increased, whereas plasma insulin and glucose levels significantly decreased, only in the MUFA group. 13C and 2H-enrichment of plasma glucose and liver alanine, glutamate, lactate and urea obtained at the end of the study were measured by GC-MS and used to regress liver metabolic fluxes using a flexible flux modeling platform (INCA). We observed that both SFA and MUFA increased the absolute rate of dihydroxyacetone phosphate (DHAP) flux from glycerol. Absolute flux of acetyl-CoA production was shifted from synthesis through pyruvate dehydrogenase toward increased contribution from fatty acid oxidation. On the other hand, only MUFA decreased the gluconeogenesis rate.

Disclosure
T. Bednarski: None. M. Rahim: None. J. Young: Consultant; Self; Pfizer Inc. Stock/Shareholder; Self; Metalytics.

Funding
National Institutes of Health (R01DK106348)
287-LB: Autophagic Degradation of CRY1 and Control of Gluconeogenesis
Authors: SOLER MIRIAM TOLEDO , SINGH RAJAT 
Published: June 2019

Cryptochrome 1 (CRY1) is a core clock repressor that maintains clock periodicity. CRY1 robustly suppresses hepatic gluconeogenesis by regulating CREB/cAMP and glucocorticoid receptor signaling and by reducing levels of FoxO1—a transcription factor that drives gluconeogenesis. Autophagy degrades cytoplasmic contents in lysosomes for maintenance of quality control and provision of energy. Since the liver clock and autophagy are each regulated by insulin and glucagon, we hypothesized that the control of autophagy, the circadian clock, and glucose homeostasis are interlinked. We have shown that induction of circadian autophagy between 3pm-7pm degrades CRY1, which releases its inhibition of gluconeogenesis and promotes glucose production. Acutely blocking autophagy or inactivating the LC3-Interacting-Region (LIR) motifs of CRY1, which allow it to interact with the autophagy marker LC3, led to accumulation of CRY1 and suppression of gluconeogenesis. Thus, autophagy drives glucose production in liver by timed degradation of CRY1. Interestingly, high-fat feeding accelerates the autophagic degradation of CRY1, which contributes to obesity-associated hyperglycemia. Since phosphorylation of CRY1 triggers its proteasomal degradation, and since phosphorylation in the vicinity of LIRs is thought to facilitate interaction with LC3, we hypothesized that phosphorylation of CRY1 leads to its degradation through autophagy and increases glucose production. Accordingly, we generated specific phosphorylation-resistant and constitutively-phosphorylated CRY1 mutants that were delivered to the liver. While the phosphorylation-resistant CRY1 mutant accumulated in liver and lowered blood glucose levels, the constitutively-phosphorylated CRY1 mutation that favors its rapid degradation resulted in increased blood glucose. Our results show that CRY1 phosphorylation couples its turnover by autophagy to regulation of gluconeogenesis—revealing novel targets to prevent obesity-associated hyperglycemia.

Disclosure
M. Toledo Soler: None. R. Singh: None.

Funding
American Diabetes Association (1-18-IBS-062 to R.S.)
287-OR: Acute Exercise Enhances the Differentiation Rate of Human Adipocyte Precursor Cells
Authors: VARSHNEY PALLAVI , GUTH LISA M. , ANDERSON CARA M. , RAAJENDIRAN ARTHE , WATT MATTHEW J. , HOROWITZ JEFFREY F. 
Published: June 2019

The direct effects of exercise on white adipose tissue morphology and metabolic function remain unclear, due in large part to confounding effects of the reduction in fat mass that often accompanies exercise training. The purpose of this study was to determine if a session of endurance exercise could impact the rate of adipogenesis. Eight lean, healthy human subjects performed a single session of exercise (1 hour of endurance exercise at 65% of their maximal aerobic capacity; VO2max). Blood samples were collected without prior exercise (No-EX) and immediately after exercise (EX). Serum was extracted, and human adipocyte precursor cells were incubated for 72 hours in vitro in either the No-EX or EX serum. This serum preincubation was immediately followed by a standard 14-day differentiation protocol. On both days 3 and 9 of differentiation, mRNA expression levels of differentiation markers, PPARG and FABP4, were significantly greater (P&lt;0.01) in cells preincubated in the EX vs. No-EX serum (e.g., Day 3 PPARG expression: 11.4±0.6 vs. 8.3±0.4 2-∆Ct; P=0.005, and Day 9 FABP4 expression: 2185±82 vs. 1619±98 2-∆Ct; P&lt;0.0001). In addition, after 14 days of differentiation, we also found significantly greater protein abundance of important lipolytic and esterification regulators, G0S2, ATGL, HSL and GPAT1 (all P&lt;0.05). As expected, compared with No-EX, the EX sera had greater concentrations of IL-6, lactate, fatty acids, epinephrine, and growth hormone, some of which may contribute to the enhanced adipogenic signaling after exercise.
In summary, factors released into the circulation during and/or immediately after a session of endurance exercise can accelerate the rate of differentiation in human adipocyte precursor cells. Enhanced adipogenic signaling in response to exercise may have metabolic health benefits by priming adipose tissue for a more effective energy storage during periods of weight gain.

Disclosure
P. Varshney: None. L.M. Guth: None. C.M. Anderson: None. A. Raajendiran: None. M.J. Watt: None. J.F. Horowitz: Research Support; Self; American Diabetes Association.

Funding
National Institutes of Health (R01DK077966, T32DK101357)