bluuebunny/crossref_metadata_2025_split huggingface dataset:
267-LB: Diabetes-induced Insulin Resistance and DPP-4 Activity Can Be Alleviated through the Reduction of M1 Polarization of Adipose Tissue
Authors: CHEN LEE-WEI 
Published: June 2019

Dysregulation of M1/M2 polarization in adipose tissues is emerging as a central mechanism underlying the pathogenesis of obesity and comorbidities such as insulin resistance and nonalcoholic fatty liver disease. To define the involvement of dysregulation of M1/M2 polarization of adipose tissues in diabetes and the effect of nondiabetic plasma on M1/M2 polarization of adipose tissue and liver as well as dipeptidyl peptidase-4 (DPP-4) activity in plasma, we purified stromal vascular fractions (SVFs) from diabetic and nondiabetic mice and analyzed their M1/M2 polarization with or without the treatment of nondiabetic plasma. SVF of diabetic mice (Lep-/-) demonstrated a significant increase of M1 but decrease of M2 signature as compared with nondiabetic mice (Lep+/-). Treatment of SVF from adipose tissue of Lep-/- mice with plasma of Lep-/- mice in vitro significantly increased M1 gene signature. Treatment of SVF from adipose tissue of Lep-/- mice with plasma of nondiabetic mice (Lep+/- mice) increased M2 gene signature. Moreover, injection of plasma of nondiabetic mice (Lep+/-) to adipose tissue of diabetic mice (Lep-/-) induces M2 expression of SVF and decreases inflammation of liver and DPP-4 activity of diabetic (Lep-/-) mice. These data suggest that plasma of diabetic mice can induce M1 expression and plasma of nondiabetic mice can induce M2 expression of adipose tissue of diabetic mice.
In conclusion, diabetes and obesity-induced insulin resistance, glucose intolerance, and systemic inflammation can be alleviated through the reduction of M1 polarization of adipose tissue.

Disclosure
L. Chen: None.

Funding
Taiwan Ministry of Science and Technology (MOST 107-2314-B-010-043-MY3)
27-OR: Simplifying Detection of Large Scale Deletions Causing MODY5
Authors: BERBERICH AMANDA J. , WANG JIAN , CAO HENIAN , MCINTYRE ADAM D. , ROBINSON JOHN F. , YANG PING , KNOLL JOAN , HEGELE ROBERT 
Published: June 2019

Maturity Onset Diabetes of the Young (MODY) 5, also known as renal cysts and diabetes syndrome, is a rare autosomal dominant form of monogenic diabetes caused by mutations in the HNF1B gene encoding hepatocyte nuclear factor 1 homeobox beta. Whole gene deletions of one copy of HNF1B are the most common mutation underlying MODY5, with more extensive deletions encompassing HNF1B and several surrounding genes, known as 17q12 deletion syndrome, present in a sub-set of individuals with MODY5, who present with additional clinical features. Historically, these large scale deletions are not identified using Sanger or targeted next generation sequencing (NGS) panels, and require other tools, such as microarray-based genomic hybridization or multiplex ligation probe amplification to detect. Incorporating such tests to targeted sequencing adds significantly to cost and labor.
Recent advances in bioinformatics allow for identification of large-scale copy number variation (CNV) from NGS output data without requiring additional laboratory methods. The NGS data from 57 patients suspected to have MODY by their physicians but who were negative for pathogenic mutations using a targeted NGS approach were thus re-examined using a CNV calling tool (CNV Caller, VarSeq v1.4.3).
Three unrelated patients were found to have large scale deletions spanning HNF1B. These deletions were verified using whole exome sequencing data as well as microarray analysis (CytoScan, Affymetrix), which confirmed the presence of 17q12 deletion in all three individuals. The deletions varied in size from 1.46 to 1.85 million base pairs. Clinical correlation revealed a history of genitourinary abnormalities in all three probands.
These results confirm the utility of the CNV Caller tool in identifying large-scale deletions causing MODY5, as well as 17q12 deletion syndrome. This may represent an easier, more cost-effective approach to making this diagnosis, ultimately improving case detection and allowing for more personalized care for affected individuals.

Disclosure
A.J. Berberich: None. J. Wang: None. H. Cao: None. A.D. McIntyre: None. J.F. Robinson: None. P. Yang: None. J. Knoll: Stock/Shareholder; Self; Cytognomix Inc. R. Hegele: Consultant; Self; Aegerion Pharmaceuticals, Akcea Therapeutics, Amgen Inc., Regeneron Pharmaceuticals, Sanofi.
270-LB: Amelioration of Hepatic Insulin Resistance by Brown Adipocyte Secretion
Authors: BHUSHAN ABHINAV , TANATAWEETHUM NIDA , LEE CHAEEUN , ZHONG FRANKLIN , TRANG ALLYSON , BUDIMAN ANDREW 
Published: June 2019

Insulin resistance (IR) is a hallmark of T2D. In the IR state, insulin fails to inhibit hepatic glucose production yet promotes lipogenesis. Although thiazolidinediones can partially reinstate insulin sensitivity, there are concerns about long-term usage. Recent studies have shown positive effects of paracrine signaling from BAT transplant on metabolic homeostasis. Transplant of embryonic BAT into diabetic mice can improve glucose tolerance. However, the mechanisms are unclear. In this study, we show that brown adipocyte secretions can partially resolve hepatic IR. We cultured primary hepatocytes in a microfluidic organ-on-chip device. IR was induced by cytokine exposure and the cells were treated with brown adipocyte secretions among other controls. The group treated with brown adipocytes had restored insulin sensitivity. This was verified by an increased Akt phosphorylation (Figure 1), lowered glucose production, increased glucose uptake, and increased glycogen synthesis. We finally confirmed that genes important for glucose production (G6pc, PEPCK) and lipogenesis (SREBP1) were downregulated in the treated cells. We will present results from ongoing mechanistic studies. Our data imply that brown adipocyte secretions contain factors that regulate hepatic insulin sensitivity and could be potential targets for drug development.

Disclosure
A. Bhushan: None. N. Tanataweethum: None. C. Lee: None. F. Zhong: None. A. Trang: None. A. Budiman: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (DK095984NIH, P30DK020595)
278-OR: Increased Cortisol Excretion in Morbid Obesity Is Associated with Higher Body Weight but More Favorable Glucose Metabolism Parameters
Authors: BRIX JOHANNA , KRZIZEK EVA-CHRISTINA , TURA ANDREA , PACINI GIOVANNI , LUDVIK BERNHARD 
Published: June 2019

Cortisol levels might be increased in obesity leading to enhanced gluconeogenesis and inhibited glucose utilization. Subsequent release of catecholamines might additionally promote obesity. In morbid obesity, the association of cortisol excretion to metabolic parameters is not well characterized. We included 1249 patients with MO (76.8% females, mean BMI 45.6± 6.2 kg/m², mean age 40±12 years). Anthropometric data and cardiovascular risk factors were assessed and a glucose tolerance test (oGTT) for calculation of Insulin Resistance and Sensitivity indices was performed. All patients collected 24h hour urine specimens to assess cortisol excretion on two consecutive days. Regarding cortisol excretion, patients were divided into three tertiles (fist&lt; 39.1 µg/24h, second between 39.1and 139.9 µg/24h and third &gt;139.9 µg/24h. Patients in the highest tertile had a higher BMI (p= 0.015) and waist circumference (p= 0.029), however, exhibited a lower diastolic blood pressure (p=0.001), 1-hour (p=0.001) and 2-hour glucose (p= 0.003) as well as HbA1c (p=0.047) values. Area under curve (AUC) for glucose (p&lt;0.001) as well as insulin (p= 0.018) were lower, and HOMA-beta was increased (p=0.006). We did not find any differences regarding OGIS or QUICKI. In a correlation analysis, cortisol levels were inversely associated with glucose-AUC (r=-0.206; p&lt;0.001), HOMA beta (r= 0.084; p= 0.005), BMI r= 0.099; p=0.002), glucose 1-hour (r=-0.107; p&lt;0.001) and glucose 2-hour levels (r=-0.107; p&lt;0.001). Despite being more obese, patients with higher cortisol excretion present with a more favorable metabolic profile compared to those with lower cortisol excretion. These results deserve further attention regarding the respective potential mechanisms.

Disclosure
J. Brix: None. E. Krzizek: None. A. Tura: None. G. Pacini: None. B. Ludvik: Advisory Panel; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Sanofi, Takeda Development Centre Europe Ltd. Research Support; Self; Akebia Therapeutics, Eli Lilly and Company, Novartis AG, Novo Nordisk A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.
283-LB: Dissociating Insulin Signaling and SREBP1c Action from the Lipogenic Drive Seen in Human and Murine Hepatic Insulin Resistance
Authors: VATNER DANIEL F. , TER HORST KASPER W. , GOEDEKE LEIGH , ZHANG DONGYAN , SAMUEL VARMAN , SERLIE MIREILLE J. , SHULMAN GERALD I. 
Published: June 2019

The ongoing debate regarding pathway selective hepatic insulin resistance (IR) focuses on potential insulin signaling branchpoints beyond which regulation of glucose metabolism is attenuated and regulation of de novo lipogenesis (DNL) remains intact. These models suggest that impaired insulin receptor kinase activity, proximal to any potential branchpoint, only plays a minor role in clinical hepatic IR. We compared insulin signaling in liver biopsies from human subjects with nonalcoholic fatty liver disease (NAFLD) and hepatic IR vs. weight matched controls, using glucose ingestion to drive insulin secretion and fructose ingestion as a low insulin comparator. Insulin signaling through phosphorylation of insulin receptor β, Akt, and GSK3β was suppressed in NAFLD (all P &lt; 0.05). Insulin regulation of mTORC1 via PRAS40 phosphorylation was absent in NAFLD subjects; no differences were seen between controls and NAFLD subjects in AMPK dependent RAPTOR phosphorylation. Pathway selective IR implies SREBP1c is primarily responsible for DNL in the insulin resistant liver; we probed the transcriptional regulation of DNL by assessing the in vivo occupancy of lipogenic target gene promoters by SREBP1c and ChREBP using ChIP experiments in mice with diet-induced IR. Fasted-refed mice were refed with high fat diet (HFD) and 1% dextrose drinking water. Mice with hepatic IR (9 day HFD fed) or hepatic and peripheral IR (4 week HFD fed) were compared with more insulin sensitive 2 day HFD fed mice. SREBP1c was not bound to the Fasn promoter in insulin resistant livers, while ChREBP was bound to the Fasn promoter equally in all three groups of mice.
Conclusions: There is a proximal block in insulin signaling in humans with hepatic IR and NAFLD, dissociating previously measured changes in DNL rates from insulin signaling. SREBP does not mediate DNL in insulin resistant mice while ChREBP action can explain the maintenance of the transcriptional program of lipogenesis.

Disclosure
D.F. Vatner: None. K.W. ter Horst: None. L. Goedeke: None. D. Zhang: None. V. Samuel: None. M.J. Serlie: Advisory Panel; Self; Fresenius Medical Care. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc. Advisory Panel; Spouse/Partner; Merck & Co., Inc. Board Member; Self; Novo Nordisk A/S. Consultant; Self; Aegerion Pharmaceuticals, IMetabolic BioPharma Corporation, Longitude Capital, Nimbus Discovery, Inc., Staten Biotechnology B.V.

Funding
National Institutes of Health
291-OR: Exercise Modulates Glucose Metabolism in Part through Changes in the Gut Microbiome
Authors: BRANDAO BRUNA , LI MENGYAO E. , CAI WEIKANG , BATISTA THIAGO M. , HIRSHMAN MICHAEL F. , GOODYEAR LAURIE J. , KAHN C. RONALD 
Published: June 2019

Exercise is one of the most prescribed interventions in the treatment/prevention of diabetes and metabolic disease. It is well established that different diets affect the distribution of gut microbiota. It has recently been shown that exercise may also modify the gut microbome and these modifications may differ depending on the obesity status of the individual. In this work we investigated whether metabolic changes triggered by exercise are transferable via cecum microbiota transplantationand how this would impact on the obesity response to high fat diet (HFD). Ten-week old, B6J male mice, on chow diet, were reared under either standard sedentary conditions or with access to a running wheel for 4 weeks. Under these conditions the latter mice ran an average of 6 Km per day. Mice were scarified, fecal DNA were sequenced and the cecum microbiota were transplanted into germ-free mice in the presence/absence of HFD. As expected, exercise improved insulin sensitivity and glucose tolerance in the donor mice. Shotgun metagenomic analysis of gut microbiota revealed that exercise was associated with decreased relative abundance of Parasutterella_excrementihominis and Bacteroides_thetaiotaomicron and increased Clostridium clostridioforme CAG:511 and Lactobacillus murinus ASF361. Functional composition of the bacterial metagenome indicated these changes resulted in an upregulation of microbial pathways of valine and methionine metabolism. More importantly, transplant of cecum microbiota from exercised donors to non-exercise donors improved running capacity in lean mice and improved glucose tolerance in mice on HFD. In both groups, this was associated with increased glucose uptake in skeletal muscle soleus and BAT.
In summary, exercise reshapes the gut microbiome to improve whole body glucose metabolism, and this effect can be transferred by microbiome transplant. This provides an new opportunity in the treatment of obesity-related insulin resistance.

Disclosure
B. Brandao: None. M.E. Li: None. W. Cai: None. T.M. Batista: None. M.F. Hirshman: Stock/Shareholder; Self; Abbott Laboratories, AbbVie Inc., Amgen Inc., Colgate-Palmolive Company, Medtronic. L.J. Goodyear: None. C. Kahn: Advisory Panel; Self; MedImmune. Board Member; Self; Kaleido Biosciences. Consultant; Self; AntriaBio, Inc., Cobalt Therapeutics, Flagship Pioneering. Research Support; Self; Alnylam.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases
294-LB: Transcriptome-Wide Signals Converge Upon Mitochondrial Function in Developmental Stages of Type 2 Diabetes in Human Skeletal Muscle
Authors: SZCZERBINSKI LUKASZ , NIEMIRA MAGDALENA , SZCZERBINSKI KAROL , PUCHTA URSZULA , SIEWIEC ELWIRA , CITKO ANNA , ZAPOLSKA JOANNA , TAYLOR MARK , LARSEN STEEN , GORSKA MARIA , KRETOWSKI ADAM 
Published: June 2019

Skeletal muscle is a major contributor to overall glucose homeostasis in the body and together with the liver is chiefly responsible for the whole-body insulin sensitivity. However, few studies have investigated the transcriptional signature of insulin resistance in skeletal muscles, at different stages of T2D development. Thus, the aim of this study was to identify the transcriptional signature of dysregulated glucose metabolism in skeletal muscle in humans by profiling the transcriptome with next-generation sequencing (NGS). We selected 40 sedentary males, aged 40-65 years, with BMI 26-33 kg/m2, diagnosed into three groups: 18 normoglycemics, 14 prediabetics and 8 subjects with type 2 diabetes. mRNA was extracted from biopsied Vastus lateralis muscles and sequenced with Illumina HiSeq 4000.Comparing normoglycemic and diabetic subjects revealed 4404 significantly differentially expressed (DE) genes, which represents around 30% of all mapped genes in studied samples. For the comparison between type 2 diabetics and prediabetics, the number of DE genes was 4055 genes. Interestingly we found no significantly DE genes between normoglycemics and prediabetics. KEGG enrichment analysis revealed that DE pathways between diabetics vs. nondiabetics were enriched for pathways related to oxidative phosphorylation, thermogenesis, nonalcoholic fatty liver disease and neurological diseases, which share the same underlying mechanism: mitochondrial dysfunction.These results indicate that skeletal muscle contributes most to overt T2D, with a possible indication that the liver contributes most to early stages the disease development. Differences observed between type 2 diabetics and the two remaining groups, occurring primarily in oxidative phosphorylation and electron transport chain pathways suggests that mitochondrial dysfunction plays the predominant role in the pathogenesis of T2D.

Disclosure
L. Szczerbinski: None. M. Niemira: None. K. Szczerbinski: None. U. Puchta: None. E. Siewiec: None. A. Citko: None. J. Zapolska: None. M. Taylor: None. S. Larsen: None. M. Gorska: None. A. Kretowski: None.
295-LB: Metformin Biphasic Effect on Human Cardiac Mitochondria
Authors: EMELYANOVA LARISA , BAI XIAOWEN , RUDIC THEODORE , WARNER CATHERINE , RIZVI FARHAN , ROSS GRACIOUS , KRESS DAVID , JAHANGIR ARSHAD 
Published: June 2019

Mechanisms by which metformin (Mtf) protects human heart in type 2 diabetes remain debated. We hypothesize that Mtf has a biphasic effect on mitochondria: it causes activation of respiration at low doses via AMPK signaling and inhibition at high doses by directly affecting the activity of complex I and reducing oxidative stress. Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) and mitochondria isolated from human cardiac tissue were exposed to different doses of Mtf (0-20 mM) for 24h and acutely. Oxygen consumption rate (OCR) was assessed in the cells and mitochondria energized by glutamate and malate (complex I substrates) using XF96 Extracellular Flux Analyzer. Superoxide production was measured by monitoring changes in fluorescence intensity of dihydroethidium (DHE). At low doses (0.1 - 1 mM), Mtf significantly increased OCR in hiPSC-CMs (Fig. 1A). The highest OCR was observed at 0.5 mM Mtf. This effect was abrogated by compound C, an inhibitor of AMP-kinase (Fig. 1A). Mtf did not increase OCR in isolated mitochondria (Fig. 1B). At higher doses (1-20 mM), it inhibited OCR both in the cells and isolated mitochondria. This was associated with reduction of superoxide production in the mitochondria (Fig. 1C). In the human heart, Mtf improves cardioprotection due to its biphasic effect on mitochondria. This can be a beneficial alternative to patients with impaired endogenous cardioprotective responses.

Disclosure
L. Emelyanova: None. X. Bai: None. T. Rudic: None. C. Warner: None. F. Rizvi: None. G. Ross: None. D. Kress: None. A. Jahangir: None.

Funding
Aurora Health Care (N-570-3657)
298-OR: Sustained Improvement in Glycaemia following Flash Glucose Monitoring: An Expanded Worldwide Analysis
Authors: JANGAM SUJIT , LANG JORDAN , DUNN TIMOTHY , XU YONGJIN , HAYTER GARY 
Published: June 2019

Flash glucose monitoring (FreeStyle LibreTM system) has shown sustained significant improvement in glycaemia over several months in clinical trials and the real world. Our aim was to re-evaluate the system in a longitudinal observational study with an expanded dataset. De-identified glucose data from 30,703 users over 6 months were analysed. The population was divided into tertiles of low, medium and high risk using time in hyperglycaemia (&gt;240 mg/dl) and time in hypoglycaemia (&lt;70 mg/dl) during the first two weeks. Each group was further sub-divided into tertiles of lower, medium and higher scanning frequency. Comparing the first and last bi-weekly periods, individuals in high risk tertile for hyperglycaemia showed reduced time &gt;240 mg/dl (mean±SE) from 8.2±0.1 to 6.2±0.1 h/day in higher frequency scanners (p&lt;0.0001) and 9.4±0.1 to 7.7±0.1h/day in lower frequency scanners (p&lt;0.0001). Higher and lower frequency scanners in high risk tertile for hypoglycaemia showed reduced time &lt;70 mg/dl (169±2 to 127±2min; p&lt;0.0001 and 174±2 to 125±2min; p&lt;0.0001). Time≤54mg/dL was also reduced in higher and lower frequency scanners (70±1 to 51±1min and 82±1 to 59±1min; p&lt;0.0001 for both). Using an expanded dataset, we have confirmed that Freestyle Libre system use in real life settings is associated with sustained improvement in time spent in hyperglycaemia, hypoglycaemia and serious hypoglycaemia.

Disclosure
S. Jangam: Employee; Self; Abbott Laboratories. Employee; Spouse/Partner; Abbott Laboratories. J. Lang: Employee; Self; Abbott. T. Dunn: Employee; Self; Abbott Laboratories. Y. Xu: Employee; Self; Abbott Laboratories. G. Hayter: Employee; Self; Abbott.

Funding
Abbott Diabetes Care
3-OR: Differential Effects of Novel Antidiabetic Agents on Vascular Function Indices in Patients with Type 2 Diabetes Mellitus
Authors: SIASOS GERASIMOS , BLETSA EVANTHIA , STAMPOULOGLOU PANAGIOTA K. , BATZIAS KONSTANTINOS , PASCHOU STAVROULA A. , ANTONOPOULOS ALEXIOS , TSIGKOU VASILIKI , GOULIOPOULOS NIKOLAOS , MAZARIS SAVVAS , OIKONOMOU EVANGELOS , THANOPOULOU ANASTASIA , POLITOU MARIANNA , VRYONIDOU ANDROMACHI , TOUSOULIS DIMITRIS , TENTOLOURIS NIKOLAS 
Published: June 2019

Background: Arterial stiffness is a well-established surrogate marker of vascular properties in patients with type 2 diabetes mellitus (DM2). We aimed to investigate whether optimization of DM2 therapy with novel antiglycemic agents additional to metformin, may improve arterial wall properties.
Methods: We enrolled 99 consecutive patients (male gender=63.3%) receiving metformin and still not achieving the therapeutic targets. Subjects were assigned to age and sex matched equal groups (n=33/group) of an additional antiglycemic agent; either DPP-4i, SGLT2i (n=28) or GLP-1 agonists. Applanation tonometry was used to assess non-invasively augmentation index (AIx) and aortic pulse wave velocity (PWV) as a measure of arterial stiffness at baseline and at 3-month follow-up. Among other demographics data, hemoglobin A1c (HbA1c) was measured.
Results: There was no difference for male gender (p=0.10) or age (64.92 ± 8.30 years, p=0.27) between the 3 study groups. Interestingly, baseline values improved significantly after SGLT2i and DPP-4i administration both for PWV (11.46 ± 2.77 vs. 9.83 ± 2.19 m/s and 10.89 ± 2.35 vs. 9.68 ± 1.77 m/s respectively, p=0.01 for both) and AIx (28.81 ± 8.55 vs. 25.82 ± 7.40 and 27.91 ± 13.05 vs. 24.91 ± 12.70 respectively, p=0.01 for both), when compared to those at follow-up time. In contrast, GLP-1A administration decreased PWV (12.82 ± 3.00 m/s at baseline vs. 11.67 ± 2.77 m/s during follow-up, p&lt;0.001) but not AIx (31.64 ± 6.21 vs. 30.18 ± 6.03, p= 0.18). HbA1c at baseline was uniformly decreased in all study groups when compared to follow-up (7.52% vs. 6.72% for SGLT2i, 7.76% vs. 6.92% for DPP-4i and 8.19% vs. 6.85% for GLP-1A, p&lt;0.001 for all).
Conclusion: The optimization of DM2 treatment with SGLT2i, DPP-4i or GLP-1A, added to metformin, not only helps to achieve better glycemic control but significantly ameliorates arterial stiffness indices and achieves therapeutic targets in patients with DM2.

Disclosure
G. Siasos: None. E. Bletsa: None. P.K. Stampouloglou: None. K. Batzias: None. S.A. Paschou: None. A. Antonopoulos: None. V. Tsigkou: None. N. Gouliopoulos: None. S. Mazaris: None. E. Oikonomou: None. A. Thanopoulou: None. M. Politou: None. A. Vryonidou: None. D. Tousoulis: None. N. Tentolouris: None.