bluuebunny/crossref_metadata_2025 huggingface dataset:
Empagliflozin and Linagliptin Administered in Combination or as Serial Add-On Therapy Decreases Macrovascular and Microvascular Stiffening and Microalbuminuria in a Mouse Model of Diabetic Nephropathy
Authors: AROOR ANNAYYA R. , HABIBI JAVAD , JIA GUANGHONG , KLEIN THOMAS , MAYOUX ERIC , DEMARCO VINCENT
Published: June 2018

Diabetic individuals are at increased risk for progression of proteinuria and renal fibrosis. There is an urgent need for more effective therapeutic strategies since conventional anti-hyperglycemic therapies may not sufficiently reduce renal injury. Combinations of newer anti-hyperglycemia therapies, such as, DPP-4 and SGLT2 inhibitors, which improve glycemia by differing mechanisms and exhibit cardiovascular and renal protections may show promise in this regard. We tested the hypothesis that targeting SGLT2 and DPP-4 improves aortic and renal vascular stiffening as well as suppression of renal tissue injury. Eleven week old female db/db mice were fed a diet containing LINA (2mg/kg/day) or EMPA (10mg/kg/day) monotherapy for 10 weeks. Additional groups received add-on therapy after 5 weeks on monotherapy (LINA added to EMPA or EMPA added to LINA. One group received LINA and EMPA combination therapy for the entire 10 week test period. A control group received no therapy. Both EMPA and LINA monotherapies decreased diabetes associated aortic and renal vascular stiffening and albuminuria. Improvement by LINA was observed without any significant improvement in glycemic control whereas EMPA significantly reduced both fasting glucose and HbA1c levels accompanied by decrease vascular stiffening and albuminuria. Like the monotherapies, combination therapy or serial add-on therapies afforded cardiovascular and reno-protection, however, these dual therapies had marginal advantage over monotherapy. Taken together, suppression of macrovascular and microvascular stiffening by DPP-4 and SGLT2 inhibitors contribute significantly to vascular health in diabetic patients by both glycemic-dependent and -independent mechanisms.

Disclosure

A.R. Aroor: None. J. Habibi: None. G. Jia: None. T. Klein: Employee; Self; Boehringer Ingelheim GmbH. E. Mayoux: None. V. DeMarco: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc..
Metabolic Markers Predictive of Prediabetes in the Korean Population
Authors: LEE HEUN-SIK , PARK TAE-JOON , KIM BONG-JO
Published: June 2018

Background: Prediabetes (PD) is a high-risk state for type 2 diabetes (T2D), but the risk of progression from PD to T2D can be prevented by early diagnosis and intervention. Metabolomics studies suggest that metabolic biomarkers can shed insight into etiological mechanisms and improve the accuracy of prediction of disease onset.

Objectives: We aimed to identify serum metabolic biomarkers and verify their predictive performance for PD in the Korean population, as compared to the performance of known clinical risk factor (CRF) as well as previously reported metabolites (PRM) in other population studies.

Methods: A targeted metabolomics was carried out to quantify serum metabolites for 1,723 participants from the Korea Association REsource (KARE) cohort from which 500 individuals were followed-up to 6-years. PD-related metabolites were identified at baseline by statistical methods including multivariable regression analysis, and tested their association to incidence of PD during follow-up.

Results: The 12 metabolites were significantly altered in PD (adjusted P<4.07E-04). These metabolites predicted incidence of PD with an area under curve (AUC) of 0.71. The AUC of the metabolic markers was significantly higher than that of the two PRM models (0.56 and 0.64, P<0.005) and the CRF (0.64, P<0.01). The performance of the metabolic markers compared to glucose model was significantly higher among the obese (BMI >= 25 kg/m2, 0.79 vs. 0.58, P<0.001), significantly lower among the female (0.73 vs. 0.85, P<0.002) and the lean (BMI<25 kg/m2, 0.68 vs. 0.78, P<0.01), and not significantly different among the age and the male. The full model with metabolic markers, CRF, glucose yielded the best prediction (AUC=0.84).

Conclusion: Our results revealed that the novel metabolic markers are not only associated with the risk of PD, but also improve the prediction performance in combination with classical approaches. These findings may help understanding causality of diabetes progression and developing preventive strategies for T2D.

Disclosure

H. Lee: None. T. Park: None. B. Kim: None.
Dipeptidyl Peptidase-4 Inhibition with Linagliptin Promotes Angiogenesis/Vasculogenesis in the Hearts of Female Diabetic db/db Mice
Authors: TOEDEBUSCH RYAN , AROOR ANNAYYA R. , HABIBI JAVAD , KLEIN THOMAS , PULAKAT LAKSHMI , DEMARCO VINCENT
Published: June 2018

We have previously reported that the DPP-4 inhibitor linagliptin (LINA) prevents diastolic dysfunction and myocardial fibrosis in a mouse model of diet-induced obesity, a pre-clinical model of prediabetes. LINA suppressed WD-induced pro-inflammatory mediators, such as TRAF3IP2 and downstream signaling intermediates, NF-κB, AP-1 and p38-MAPK in the heart. Herein, we extend that study by testing whether LINA slows progression of diastolic dysfunction in diabetic db/db mice, and improves the underlying maladaptive immune/inflammatory response. To accomplish this, we fed db/db mice normal mouse chow with or without linagliptin (38 mg/kg chow). After performing echocardiography on mice treated or not for 10 weeks, we analyzed expression of 200 cytokines in myocardial extracts and performed Ingenuity Pathway Analysis (IPA) in an effort to determine what signaling pathways are predicted to be differentially activated in the heart. Mice treated with linagliptin had improved diastolic function indicated by lower LV filling pressure compared to untreated mice (E/E’; 35 vs. 50; p<0.05). IPA predicted that LINA activates pathways contributing to cardiovascular development of the vasculature (32 molecules, Activiation z-score = 3.7), angiogenesis (31 molecules, Activation z-score = 3.7) and vasculogenesis (27 molecules, Activation z-score = 3.7). Cardiomyocyte size (i.e., cross-sectional area) was reduced by 23% (533±30 vs. 411±18 μm2; p<0.05) and myocardial capillary density was two-fold higher with LINA treatment compared to untreated mice (p<0.05). In addition, the proteome analysis showed a significant decrease in TNF-α related apoptosis inducing ligand, a cytokine that induces endothelial nitric oxide, in untreated mice, however, this deficiency was prevented by LINA. These data suggest that linagliptin exerts a beneficial immune/inflammatory response in the diabetic heart that confers myocardial vasculoprotection.

Disclosure

R. Toedebusch: None. A.R. Aroor: None. J. Habibi: None. T. Klein: Employee; Self; Boehringer Ingelheim GmbH. L. Pulakat: None. V. DeMarco: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc..
Identification of Novel Transcriptional Regulators of Uncoupling Protein 1 Using a Modified CRISPR-Cas9 Methodology
Authors: DARCY JUSTIN , WANG CHIH-HAO , LUNDH MORTEN , SHAMSI FARNAZ , LYNES MATT , EMANUELLI BRICE , TSENG YU-HUA
Published: June 2018

Obesity is an epidemiological dilemma due to its associated comorbidities such as diabetes, cancer, and heart disease. Because traditional weight loss strategies such as diet and exercise are thus far ineffective at curtailing the growing prevalence of obesity, new therapeutic approaches are being sought after. In this regard, brown adipose tissue (BAT) has garnered attention due to its ability to burn fat as fuel during thermogenesis, which is carried out by the mitochondrial uncoupling protein 1 (UCP1). Since UCP1 is mainly regulated at the level of transcription, our laboratory sought to identify novel transcriptional regulators of UCP1 using a modified CRISPR-Cas9 methodology termed engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) (Fujii and Fujita, 2015). enChIP takes advantage of dCas9, which lacks endonuclease activity while maintaining functional DNA binding activity, fused to a 3xFLAG tag that can be used for immunoprecipitation. For our study, we delivered five guide RNAs (gRNAs) targeting the Ucp1 promoter region in a mouse-derived mature brown adipocyte line that had been modified to endogenously express the dCas9-3XFLAG fusion protein. Following treatment with either vehicle or CL316,243, we immunoprecipitated the resulting Ucp1/dCas9/3XFLAG complex using an anti-FLAG antibody. We then utilized tandem liquid chromatography-mass spectrometry for an unbiased proteomic screen to evaluate proteins enriched by β3-adrenergic stimulation. Three biological replicates revealed 17 enriched proteins in mature adipocytes following β-adrenergic stimulation. These included histone variants and proteins involved in transcriptional regulation, such as H2A.Z and CRIP2, respectively. These identified proteins have the potential to be manipulated to regulate the expression of UCP1, thereby affecting the thermogenic function of BAT and systemic metabolism.

Disclosure

J. Darcy: None. C. Wang: None. M. Lundh: None. F. Shamsi: None. M. Lynes: None. B. Emanuelli: None. Y. Tseng: Other Relationship; Self; Chugai Pharmaceutical Co., Ltd.. Research Support; Self; MedImmune.
Diet-Induced Adipose Tissue Inflammation and Hypoxia Are Reversed by GLP-1 Potentially via Improved Microcirculation
Authors: XU FEN , CHEN ZONGLAN , XIAN YINGXIN , DENG HONG R. , XU WEN , LIANG HUA , WENG JIANPING
Published: June 2018

Obesity is considered as an inflammatory disease. A proposed trigger of the inflammation is hypoxia, which occurs when the enlargement of vascular network is not sufficient to support the expanding adipocytes. Exenatide, a GLP-1 receptor agonist, plays an anti-inflammatory role in obesity, but the mechanisms are poorly understood. The current study investigated the effects of exenatide on inflammation, hypoxia and microcirculation in epididymal fat of high-fat diet induced obese mice. Here, 8-week-old male C57BL/6 mice were randomly divided into 2 groups: NC group (normal control) and HF group (high-fat diet). After 12 weeks diet induction, HF group was further divided into 2 groups: HF group (HF+saline) and HF+EX group (HF+exenatide, 24nmol/kg/day). Compared with NC group, HF group showed significant increases in weight gain and impaired glucose tolerance; serum inflammatory cytokine levels (IL-6, TNF-α, MCP-1) were elevated. Immunohistochemistry staining of F4/80 showed that macrophage infiltration increased in adipose tissue. The mRNA expressions of hypoxia-induced gene (HIF-1a, eNOS) were significantly upregulated. However, laser confocal microscopy showed that capillary density was reduced in HF group. After 4 weeks exenatide treatment, all the obese induced immune disorder (e.g., inflammatory cytokine levels, macrophage infiltration) and hypoxia were significantly ameliorated, leading to an improved energy homeostasis in HF mice when compared with those receiving saline treatment. Proteins levels of PECAM-1 and VEGF-R2 which are indicators of angiogenesis were obviously elevated and capillary density measured by confocal was dramatically increased by exenatide in epididymal fat tissues. As insufficient vasculature may trigger hypoxia and inflammation in obesity, our results indicated that inflammation and hypoxia in obesity could be reversed by GLP-1 potentially via improved angiogenesis and microcirculation in adipose tissue.

Disclosure

F. Xu: None. Z. Chen: None. Y. Xian: None. H.R. Deng: None. W. Xu: None. H. Liang: None. J. Weng: None.
Weight Loss Outcomes with Species-Specific Dual GLP-1R/GCGR Agonists in Animal Models
Authors: ELVERT RALF , BOSSART MARTIN , ZHANG BOB , KANNT AIMO , WAGNER MICHAEL , HAACK TORSTEN , EVERS ANDREAS , DUDDA ANGELA , LORENZ MARTIN , KEIL STEFANIE , LARSEN PHILIP J.
Published: June 2018

Dual agonism of glucagon-like peptide-1 receptor and glucagon receptor (GLP-1 R/GCGR) was shown to reduce body weight. Species-specific dual GLP-1 R/GCGR agonist peptides (SSDA), structurally based on exendin-4 and carrying a fatty acid side-chain for half-life extension, or the selective GLP-1 R agonist liraglutide (lira) were administered to diet-induced obese (DIO) mice twice daily for 32 days, and to DIO and diabetic cynomolgus monkeys once daily for 43 days. Potencies of the SSDA and lira on mouse and monkey GLP-1 receptors were in the single-digit picomolar range. Body weight change was greater with SSDA than with lira in mice (-21.1 ± 2.1% vs. -12.9 ± 1.4%) and monkeys (-8.2 ± 1.2%; p<0.001 vs. -5.1 ± 1.1%; p<0.001; Figure). Indirect calorimetry in mice showed increased total energy expenditure (TEE) in those treated with SSDA, caused not only by increased fat oxidation but also by increased oxidation of carbohydrates. Lira significantly increased TEE, but significantly less than SSDA. These data support the mechanistic view that weight loss with SSDA does not result exclusively from reduced food intake but also from increased energy expenditure induced by GCGR activity. In murine and primate models, dual GLP-1 R/GCGR agonism with SSDA led to greater body weight loss than GLP-1 R alone. This represents a novel dual mechanism of action with potential for the treatment of obesity.

Disclosure

R. Elvert: Employee; Self; Sanofi. M. Bossart: Employee; Self; Sanofi. B. Zhang: None. A. Kannt: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. M. Wagner: Employee; Self; Sanofi. T. Haack: Employee; Self; Sanofi-Aventis Deutschland GmbH. A. Evers: Employee; Self; Sanofi. A. Dudda: Employee; Self; Sanofi. M. Lorenz: None. S. Keil: Employee; Self; Sanofi. P.J. Larsen: Employee; Self; Sanofi.
The Presence of Cerebral White Matter Lesions and Lower Skin Microvascular Perfusion Predict Decline in General Cognitive Ability in Type 1 Diabetes Patients but Not in Healthy Controls
Authors: EMANUEL ANNA L. , DUINKERKEN EELCO VAN , WATTJES MIKE P. , KLEIN MARTIN , BARKHOF FREDERIK , SNOEK FRANK J. , ERINGA ETTO C. , IJZERMAN RICHARD , SERNE ERIK H.
Published: June 2018

Objective: Cognitive impairments in type 1 diabetes may result from hyperglycemia-associated cerebral microangiopathy. In this study we aimed to identify cerebral microangiopathy and skin microvascular dysfunction - as surrogate marker for generalized microvascular function - as predictors of cognitive decline over time.

Research Design and Methods: Twenty-five type 1 diabetes patients and 25 matched healthy controls underwent neurocognitive testing at baseline and after follow-up (mean duration of 3.8±0.8 years). At baseline, 1.5 T cerebral magnetic resonance imaging was used to detect white matter lesions (WML) and cerebral microbleeds. In addition, skin capillary perfusion was assessed by means of capillary microscopy. Multiple linear regression analysis was performed to examine if cerebral microangiopathy and capillary perfusion were associated with changes in cognitive performance.

Results: In type 1 diabetes patients, but not in healthy controls, the presence of WML (ß=-0.419;p=0.037) as well as lower skin capillary perfusion (baseline: ß=0.753;p<0.001; peak hyperemia: ß=0.743;p=0.001; venous occlusion: ß=0.675;p=0.003; absolute capillary recruitment: ß=0.549;p=0.022) at baseline were associated with decline in general cognitive ability over time, independent of age and sex, HbA1c and severe hypoglycemic events. The relationship between WML and cognitive decline was significantly reduced to non-significant levels after adjusting for capillary perfusion.

Conclusions: In type 1 diabetes patients, presence of WML and lower skin capillary perfusion predict poorer general cognitive ability over time. The relationship between WML and cognitive decline was significantly reduced when adjusting for capillary perfusion, suggesting that generalized microvascular dysfunction at least partly underlies WML-associated cognitive decline.

Disclosure

A.L. Emanuel: None. E. van Duinkerken: None. M.P. Wattjes: Consultant; Self; Biogen. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Roche Pharma, Sanofi Genzyme. M. Klein: None. F. Barkhof: None. F.J. Snoek: None. E.C. Eringa: None. R. Ijzerman: Research Support; Self; AstraZeneca. E.H. Serne: None.
Low-Dose FGF-21 Administration Decreases Obesity-Induced Hepatic Steatosis, but Has No Effect on Inflammation in Mice
Authors: SHARMA SHALIGRAM , JUNG SEAN , GRAFF EMILY , GETTYS THOMAS W. , WANDERS DESIREE
Published: June 2018

Pharmacologically, FGF-21 reduces body weight, increases insulin sensitivity, and reduces hepatic lipids in rodents. Preclinical studies suggest that FGF-21 may exert anti-inflammatory effects. We aimed to determine 1) whether endogenous FGF-21 provides protective effects against high-fat diet (HFD)-induced inflammation, and 2) whether low-dose administration of FGF-21 reverses HFD-induced inflammation and hepatic steatosis. In experiment #1, wild type (WT) and FGF-21-/- mice (n=8/group) were fed a HFD for 15 weeks. RT-PCR analysis showed that despite weighing slightly less than the WT mice, the FFG-21-/- mice were more susceptible to HFD-induced inflammation of the liver and white adipose tissue (WAT). To test whether administration of FGF-21 provides protection from HFD-induced inflammation, in Experiment #2, 20 male C57BL/6J mice were fed a HFD for 10 weeks. After 10 weeks of HFD feeding, mice were administered vehicle (saline + 0.1% BSA; n=10) or recombinant human FGF-21 (R and D Systems; n=10; 0.3 mg/kg/day) for 14 days via subcutaneous osmotic minipumps. There was no effect of FGF-21 administration on body weight. Histological analysis of WAT showed no effect of FGF-21 on adipocyte size, and no effect on crown-like structure number. Confirming this lack of effect of FGF-21 on inflammation, RT-PCR analyses of liver and WAT showed comparable mRNA expression of inflammatory markers, including Adgre1, Itgam, Itgax, Ccl2, Il1b, and Tnf in the vehicle- and FGF-21 treated groups. Despite having no effect on inflammation, FGF-21 significantly reduced fasting blood glucose levels. Histological evaluation of liver showed that low-dose FGF-21 administration improved nonalcoholic steatohepatitis score, attributed to decreased microvesicular steatosis.

In conclusion, endogenous FGF-21 confers some protection against obesity-induced inflammation, and low-dose FGF-21 administration decreases hepatic steatosis independent of changes in body weight.

Disclosure

S. Sharma: None. S. Jung: None. E. Graff: None. T.W. Gettys: None. D. Wanders: None.
TLR4-Induced Local Adipose Inflammation Critically Regulates Glucose Homeostasis
Authors: ZHAO SHANGANG , SCHERER PHILIPP E.
Published: June 2018

Acute adipose inflammation is beneficial for adipose tissue remodeling, while chronic unsolved inflammation may lead to systemic insulin resistance. Toll-like receptor 4 (TLR4) may be an important mediator for obesity-associated chronic low grade inflammation and insulin resistance. However, up to date, we do not have a model available that allows us to study systemic consequences of adipose tissue inflammation originating selectively at the level of the adipocyte. Here, using cre-loxP and doxycycline-inducible system, we generated a new mouse model, which exclusively expresses physiological levels of TLR4 in adipocytes of adult mice in the background of an otherwise global TLR4 null mouse (“ATLR4 mice”). Upon LPS injection, ATLR4 mice show modest acute inflammation in local adipose tissue, but no inflammatory response at the systemic level. However, when exposed long-term to a HFD diet, ATLR4 mice show reduced body weight gain as well as improved glucose and insulin tolerance. This beneficial effect may - at least in part - be due to increased browning of subcutaneous white adipocytes. Under thermoneutral conditions (when we minimize the contributions of the browning effects), the ALTR4 mice show a slightly higher body weight gain, but still preserve better glucose tolerance. RNAseq data indicates the beneficial effect of ATLR4 mice may be associated with enhancing acetyl-coA synthesis pathway to promote PPARgamma acetylation and adipogenesis. Based on that, we conclude that adipose tissue inflammation originating in the adipocyte contributes only minimal, if any, effects on systemic inflammation. In contrast, TLR4-induced local inflammation signaling results in improvements in glucose homeostasis.

Disclosure

S. Zhao: None. P.E. Scherer: None.
Insulin Action on Endothelial Cells Limits Leukocyte-Endothelial Interaction through CXCR4 and Counteracts Intestinal Tumor Formation in Obesity
Authors: RATHJEN THOMAS , LI QIAN , PARK KYOUNGMIN , POVLSEN GRO , OLSEN GRITH SKYTTE. , KING GEORGE L. , RASK-MADSEN CHRISTIAN
Published: June 2018

An activated, pro-inflammatory endothelium is a key feature of obesity and type 2 diabetes but little is known about its contribution to the increased cancer risk in these conditions. We recently published that insulin resistance in endothelial cells increases VCAM-1 expression, increases recruitment of tumor-associated neutrophils and promotes intestinal tumor formation. Here, we report that tumor-prone Apc(Min/+) mice have 2.1-fold more intestinal tumors during high-fat feeding. However, gain of insulin signaling specifically in endothelial cells by overexpression of IRS1 prevented 44% of tumors in diet-induced obesity. RNA sequencing in primary human endothelial cells identified 17 genes changed by insulin treatment with a log(2) change of at least ±0.5, among them C-X-C motif chemokine receptor 4 (CXCR4), which was downregulated by 54%. Downregulation of CXCR4 after insulin treatment was completely prevented by pretreatment with wortmannin but not by U0126, an inhibitor of MAPK signaling. Using FACS of enzymatically dissociated tissue, CXCR4 mRNA in CD31+ cells was 77% higher in mice with diet-induced obesity compared to lean controls and 37% higher in db/db mice compared to db/+ controls, consistent with upregulation of CXCR4 in endothelial cell insulin resistance. CXCL12, the ligand for CXCR4, increased leukocyte adhesion to cultured endothelial cells and this was completely prevented by plerixafor, a clinically approved CXCR4 antagonist. In vivo microscopy of mesenteric venules showed an increase in leukocyte rolling and adhesion after intravenous injection of CXCL12 and this change was abrogated in transgenic mice with endothelial overexpression of IRS1. We conclude that endothelial cell insulin signaling limit leukocyte-endothelial cell interaction through downregulation of CXCR4 and that improving insulin signaling in endothelial cells may protect against tumor development in obesity.

Disclosure

T. Rathjen: Employee; Self; Novo Nordisk A/S, Bayer AG. Q. Li: None. K. Park: None. G. Povlsen: Employee; Self; Novo Nordisk A/S. G.S. Olsen: Employee; Self; Novo Nordisk A/S. G.L. King: Research Support; Self; Sanofi-Aventis. C. Rask-Madsen: Research Support; Self; Novo Nordisk A/S.
Silencing of Supramammillary Nucleus (SuMN) Dopaminergic Neuronal Activity Induces the Obese Glucose Intolerant State
Authors: ZHANG YAHONG , TSAI TSUNG-HUANG , EZROKHI MICHAEL , STOELZEL CARL , CINCOTTA ANTHONY
Published: June 2018

The “westernized” diet reduces brain dopamine synthesis and low brain striatal dopamine function has been associated with and implicated in potentiation of metabolic syndrome in animals and humans. However, hypothalamic dopamine function may be a more dominant regulator of peripheral fuel metabolism. The hypothalamic SuMN dopaminergic neurons project to the lateral septum, medial preoptic area, and suprachiasmatic nucleus, areas that prominently regulate both peripheral metabolism and striatal dopamine function. However, a causal role for such hypothalamic dopaminergic circuitry in modulating peripheral metabolism under normal feeding conditions has never been explored. This study therefore tested the impact of SuMN-selective knock-down of tyrosine hydroxylase (TH, the rate-limiting enzyme for dopamine synthesis) gene expression using AAV-mediated shRNA targeting TH (AAV-TH shRNA) on peripheral fuel metabolism in 14 weeks old rats fed standard low fat rodent chow (RC). Rats were micro-infused at the SuMN with either AAV-TH shRNA (N=12) or AAV-scrambled shRNA [control] (N=10) and maintained on RC ad lib for 77 days to assess changes in body weight (BW), glucose tolerance and fat metabolism. SuMN-selective TH knock down increased BW gain (54%, p=0.0005), total white adipose tissue mass (43%, p=0.012), feed efficiency (BW gain /g food) (25%, p= 0.048) and cumulative food consumption (15%, p= 0.0001) vs. control. SuMN-selective TH knock down increased glucose tolerance test glucose area under curve (AUC) by 27% (p=0.009) with no change in insulin AUC (p=0.99) vs. control. Such knock down also reduced adipose tissue mitochondrial fatty acid oxidation (FAO) rate (basal oxygen consumption rate 51%, p< 0.0001; endogenous FAO rate 58%, p< 0.0001; and exogenous FAO 54%, p=0.024). These findings indicate that reduced SuMN dopaminergic neuronal activity facilitates dysglycemia and obesity while reducing fat energy expenditure and increasing food consumption.

Disclosure

Y. Zhang: Employee; Self; VeroScience, LLC. T. Tsai: Employee; Self; VeroScience, LLC. M. Ezrokhi: Employee; Self; VeroScience, LLC. C. Stoelzel: Employee; Self; VeroScience, LLC. A. Cincotta: Employee; Self; VeroScience, LLC.. Stock/Shareholder; Self; VeroScience, LLC..
Increased Glycemic Variability Is Associated with Augmented Brain Glucose Transport amongst Poorly Controlled T1DM Individuals
Authors: HWANG JANICE , JIANG LIHONG , LAM WAI , RANGEL ELIZABETH SANCHEZ , ROTHMAN DOUGLAS L. , MASON GRAEME F. , SHERWIN ROBERT
Published: June 2018

Both hyperglycemia and hypoglycemia have been shown to modulate glucose transport into the brain; however, the impact of glycemic variability remains unknown. This study was undertaken to investigate the impact of glycemic variability on brain glucose transport kinetics amongst T1DM individuals.

Nine individuals with poorly-controlled T1DM (age 6F/3M, age 30±4 years, BMI 27±1.2 kg/m2, HbA1C 8.0±0.3%, duration of DM 17±5 years) underwent 1H magnetic resonance spectroscopy scanning in the occipital lobe to measure the change in intracerebral glucose levels during a 2-hour hyperglycemia clamp (target glucose 220 mg/dl). In addition for 5-6 days prior to scanning, individuals wore a continuous glucose monitor (Dexcom G4) to assess several measures of glycemic variability (EasyGV).

The mean change in brain glucose was 0.99±0.1 mmol/L. There was no significant relationship between HbA1C% and change in intracerebral glucose (P=0.31), which may be due to the narrow range of HbA1C. However, there were significant positive correlations between measures of glycemic variability and change in intracerebral glucose (Figure).

These findings suggest that the degree of glycemic variability can modulate brain glucose transport and highlight the need for future studies to investigate the impact of glycemic variability on brain glucose kinetics.

Disclosure

J. Hwang: None. L. Jiang: None. W. Lam: None. E. Sanchez Rangel: None. D.L. Rothman: None. G.F. Mason: Consultant; Self; UCB, Inc., Sumitomo Dainippon Pharma Co., Ltd. R. Sherwin: Other Relationship; Self; QuintilesIMS, MannKind Corporation. Research Support; Self; Regeneron Pharmaceuticals, Inc.. Other Relationship; Self; ICON plc..
Nr4a1 and Nr4a3 Knock Out Mice Have Impaired Glucose Clearance and Beta-Cell Function under High-Fat Feeding
Authors: SMITH COURTNEY J. , KENER KYLE B. , TESSEM JEFFERY S.
Published: June 2018

We have shown that the orphan nuclear receptors Nr4a1 and Nr4a3 are critical for beta cell mitochondrial respiration and fuel utilization, and that loss of either factor impedes fuel utilization and insulin secretion. We have also demonstrated that prolonged culture of INS-1 832/13 beta cells with progressively increasing concentrations of palmitic acid results in decreased Nr4a1 and Nr4a3 expression, impaired mitochondrial respiration, and reduced insulin secretion. Here we explore the effect of 20-week high fat diet on wild type mice and mice deficient for either Nr4a1 or Nr4a3. Nr4a1 and Nr4a3 knock out mice have greater body weight than wild type animals when on a high fat diet. Mice deficient for Nr4a1 or Nr4a3 have no significant change in non-fasting blood glucose measurements as compared to wild type under normal chow conditions. Non-fasting blood glucose was elevated in both Nr4a1 and Nr4a3 knock out mice under high fat feeding conditions. Fasting glucose tolerance tests also demonstrate that Nr4a1 and Nr4a3 knock out mice have impaired glucose tolerance as compared to wild type animals under high fat feeding. Mitochondrial respiration of muscle, liver, adipose and islets are impaired as compared to wild type controls under high fat feeding. Glucose stimulated insulin secretion is impaired in islets from Nr4a1 or Nr4a3 knock out mice fed a high fat diet. These data demonstrate changes in various metabolic tissues as a result of high fat feeding and deletion of the Nr4a orphan nuclear receptors, demonstrating that they play a critical role in systemic fuel utilization.

Disclosure

C.J. Smith: None. K.B. Kener: None. J.S. Tessem: None.
Preoperative Hemoglobin A1c Predicts Postoperative Weight Loss following Bariatric Surgery in Patients with Diabetes
Authors: ORTEGA CAMILA B. , LEE HUI-JIE , PORTENIER DANA , GUERRON ALFREDO D. , TONG JENNY
Published: June 2018

Consensus on whether preoperative (pre-op) hyperglycemia predicts adverse surgical outcomes is lacking. The objective of the study was to evaluate the relationship between pre-op HbA1c and postoperative (post-op) surgical outcomes in patients with diabetes mellitus (DM). Patients who underwent bariatric surgery between January 2000 and April 2017 and met the diagnostic criteria of DM and had pre-op HbA1c measures were studied. Logistic and GEE linear regression were used to examine the association between pre-op HbA1c and post-op morbidity and mortality and percentage weight loss (%WL) at 30 days and 1 year. A total of 2173 patients (mean age 48.6 ± 10.6, pre-op weight: 297.5 ± 60.3 lb, 75% females) were evaluated. Among them, 49.6% had HbA1c of < 7%, 26.4% had HbA1c 7-8%, and 23.9% had HbA1c > 8%. The incidence of 30-day complications (readmission, reoperation, bleeding, pulmonary embolism, leak) was 6.1% and 30-day mortality was 0.1%. These rates did not differ between HbA1c groups or between Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), gastric band, and duodenal switch (DS) procedures. There was no significant association between pre-op HbA1c and complication rates or %WL at 30 days post-op. However, we detected an association between HbA1c and 1-year %WL (p = 0.014) in that 1% increase in pre-op HbA1c was associated with 0.74% less WL at 1 year after adjusting for confounders (95% CI: -1.08% to -0.41%, p < 0.0001). Females lost less weight than males (p = 0.0009) and patients with ≥ 1 anti-hypertensive medications pre-op lost less weight than those without (p < 0.0001) at 1 year. Furthermore, patients operated with DS lost more while those with SG and banding lost less weight than with RYGB.

In conclusion, pre-op HbA1c was not associated with post-op morbidity or mortality but it is a significant predictor for post-op WL at 1 year. Our data suggest that tighter glycemic control pre-op may lead to better weight loss outcomes after bariatric surgery in patients with DM.

Disclosure

C.B. Ortega: None. H. Lee: None. D. Portenier: Consultant; Self; Medtronic, Allergan, Teleflex, Gore, Intuitive. Research Support; Self; Teleflex. A.D. Guerron: Other Relationship; Self; Medtronic, Gore. Consultant; Self; Mederi, Levita. J. Tong: None.
Insulin Sensitivity Is an Independent Determinant of Bone Mineral Density in Overweight and Obese Individuals
Authors: NADERPOOR NEGAR , MOUSA AYA , COURTEN BARBORA DE
Published: June 2018

Background: Higher BMI and 25-hydroxyvitamin D (25OHD) levels are associated with higher bone mineral density (BMD). However, obese individuals are more likely to be vitamin D-deficient. There is limited data on other factors influencing BMD in the obese population.

Methods: We examined the cross-sectional relationship between BMD and anthropometric, metabolic, biochemical markers, in addition to dietary calcium and phosphate intake and physical activity in 54 overweight or obese but otherwise healthy adults (35 males, 19 females) with 25OHD≤50 nmol/L. BMD, body mass index (BMI), percent body fat (PFAT), fat mass and lean mass (dual energy x-ray absorptiometry), insulin sensitivity (euglycaemic-hyperinsulinaemic clamp, M), 25OHD, calcium and phosphate, PTH, FGF-23, alkaline phosphatase (ALP), high-sensitivity C-reactive protein (hs-CRP), lipid profile were measured and physical activity and dietary calcium and phosphate intake were calculated based on self-report and validated questionnaires.

Results: BMD was correlated with 25OHD (r=0.3, p=0.02), phosphate (r=0.3, p=0.04), M (r=0.4, p=0.006), dietary calcium (r=0.3, p=0.3) and dietary phosphate (r=0.3, p=0.04) after adjustments for age, sex and BMI. There were no differences in BMD, 25OHD, calcium, phosphate, PTH and FGF-23 levels between insulin-sensitive and insulin-resistant groups (insulin sensitivity (M) cut-off of 4.7 mg/kg/min, all p>0.5). However, ALP was significantly higher in the insulin-resistant group (86.28 vs. 72.92 IU/L, p=0.04). In regression analyses, 25OHD (p=0.02), phosphate (p=0.01), BMI (p=0.02) and M (p=0.02) remained independently related to BMD.

Conclusion: Insulin sensitivity and phosphate levels in addition to BMI and 25OHD were related to BMD in this overweight/obese and vitamin D-deficient population. These findings provide further evidence supporting an independent role for insulin sensitivity in bone health.

Disclosure

N. Naderpoor: None. A. Mousa: None. B. de Courten: None.
Efficacy and Safety of HSG4112, a Novel Anti-Obesity Oral Agent in Diet-Induced Obesity (DIO) Mice
Authors: YOO SANG-KU , KIM KYUNGIL , JO IN GEUN , LIM KEUN-WAN
Published: June 2018

HSG4112 is an Investigational New Drug (IND) discovered by Glaceum Inc. through Quantitative Structure-Activity Relationship (QSAR) study on Glabridin and its derivatives. It is currently in Phase 1 study as a treatment for obesity. In nonclinical studies, HSG4112 showed a significant body-weight reduction effect with excellent safety profiles in Diet-Induced Obesity (DIO) mice. The test consisted of a normal control group (normal diet), a vehicle control group (high fat diet), a test group (HSG4112 100mg/kg) and a pair-fed group. HSG4112 was given orally once daily for 7 days for 6 consecutive weeks (qd×7×6). After 6 weeks, the total mean weight loss was 10.2g (-26.0%) in the test group. The contribution made by reduced food intake was 38.0% and the energy expenditure effect was 62.0%. Increase of O2 consuming and CO2 generating rates, and decrease of 5’ Adenosine Monophosphate-activated Protein Kinase (AMPK) activity in hypothalamus after oral administration of HSG4112 to DIO mice were observed. Single oral dose toxicity study of HSG4112 was performed with rat and dog. The Maximum Tolerated Dose (MTD) 2,000mg/kg was observed from both rat and dog.

In conclusion, in nonclinical studies, HSG4112 demonstrated sufficient efficacy and safety as an anti-obesity drug supporting further clinical development.

Disclosure

S. Yoo: Employee; Self; Glaceum. K. Kim: None. I. Jo: Employee; Self; Glaceum Incoporation. K. Lim: Employee; Self; Glaceum Inc..
Laparoscopic Sleeve Gastrectomy Improves Serum Uric Acid Levels and Has Sex Difference in Severely Obese Patients
Authors: ZHU CUILING , GAO JINGYANG , MEI FANGYUN , WANG XINGCHUN , LI LIANG , LU LIESHENG , ZHOU DONGLEI , QU SHEN
Published: June 2018

Introduction: Hyperuricemia (HUA) is associated with multiple metabolic comorbidities. Recent evidence has shown that bariatric surgery may improve major comorbidities including HUA. We aimed to investigate changes of serum uric acid (sUA) and other biomarker parameters in severely obese patients after laparoscopic sleeve gastrectomy (LSG) over a 1-year period.

Methods: A prospective follow-up study of 12 months was conducted with 133 obese patients undergoing LSG. Patients were divided into two groups: normal sUA (NUA) group and HUA group. sUA and relevant metabolic parameters were compared pre and post operation.

Results: At baseline, sUA levels and prevalence of HUA were significantly higher in males than females. Patients with HUA tended to have a worsening metabolic status. After surgery, sUA levels did not exhibit statistically significant changes in NUA group. In HUA group, females showed significantly decreased sUA levels from 3 to 12 months, while in males, sUA significantly increased at 1- and 3-month but decreased at 6- and 12-month after LSG. For HUA patients, we observed gradual reduction in the occurrence of HUA and increase in the resolution rates of HUA, and changes in sUA levels were significantly higher in females than males. Decreased sUA levels correlated significantly with decreased BMI, fasting insulin and HOMA-IR in females, and BMI and HOMA-IR in males.

Conclusion: The sUA levels and rate of HUA were significantly higher in males than females. LSG appears to be effective in reducing sUA levels and occurrence of HUA in patients with HUA prior to the operation, which exhibited earlier and more favorable for female patients. Reduced sUA levels may be potentially mediated by substantial weight loss and improved insulin resistance.

Disclosure

C. Zhu: None. J. Gao: None. F. Mei: None. X. Wang: None. L. Li: None. L. Lu: None. D. Zhou: None. S. Qu: None.
Chemerin and Tissue Inhibitor of Metalloproteinases 2, a Potential Link to Nonalcoholic Fatty Liver Changes in Metabolic Syndrome
Authors: FATIMA SADIA
Published: June 2018

Metabolic syndrome (MetS) in Pakistan affects 18-46% individuals. Over nutrition and sedentary behavior acts as a trigger, yet in many instances normal weight individuals may develop MetS. Adipokine Chemerin modulates glucose and lipid homeostasis. Furthermore remodeling of adipocyte extracellular matrix is affected by proteolytic enzymes and their endogenous regulators known as Tissue inhibitor of metallo-proteinases (TIMPs). Therefore, this study was designed to identify the circulating levels of TIMP2, Chemerin and its polymorphism in metabolically healthy and unhealthy subjects and relate with fatty liver changes. We recruited MetS positive (n=92) vs. negative (n=208) adults diagnosed on the basis of National Cholesterol Education Program Adult Control Panel III criteria. Serum Chemerin, Leptin and TIMP2 levels were measured by enzyme linked immunosorbent assay, lipid profile, blood glucose and insulin were performed by automation. Body fat percentage was measured by bioelectrical impedance analysis. Fatty liver was detected by ultra-sonographic scans. Chemerin rs171736polymorphism was determined by tetra arm polymerase chain reaction. Higher Chemerin and TIMP2 level were observed in MetS positive vs. MetS negative (37.87± 13.60 vs. 24.03 ± 12.32 ng/ml);(199.83 ±12.26 vs. 32.57 ± 2.36 pg/ml) individuals. However, no difference was seen for Leptin level (19.95 ± 13.46; 22.24±12.51ng/ml) in our study. Chemerin and TIMP2 correlated positively with the body fat percent and MetS (p<0.05). Thirty eight (41.3%) MetS positive while seventy seven (37.01%) MetS negative subjects were diagnosed with fatty liver disease and 17.9% subjects were classified as metabolically unhealthy normal weight individuals. The variant rs171736showed association with MetS phenotype (OR 1.841 [1.101-3.078]; p=0.020). Presence of this minor ’G’ allele was seen to increase the risk of developing MetS by 1.567 (p<0.012).

Disclosure

S. Fatima: None.
BMI Z-Score Trajectories in Youth with T1D—An International Comparison
Authors: WU MENGDI , PHELAN HELEN , SCHWANDT ANKE , FOSTER NICOLE C. , COUPER JENNY , STEIGLEDER-SCHWEIGER CLAUDIA , WILLI STEVEN M. , JONES TIM , KROSCHWALD PETER , MAAHS DAVID M. , PRINZ NICOLE , CRAIG MARIA E.
Published: June 2018

Obesity in youth with type 1 diabetes (T1D) has emerged as a challenge in care. Data from the Australasian Diabetes Data Network (ADDN), Diabetes Prospective Follow-up (DPV) in Austria and Germany, and T1D Exchange (T1DX) registry in the U.S. were compared to assess international differences in BMI z-score trajectories in youth with T1D. Longitudinal data from 11,513 participants between ages 8-17 years with T1D duration ≥1 year. and ≥5 aggregated body mass index (BMI) values (ADDN: N=1073, 46% female, mean HbA1c 8.3%; DPV: N=8722, 46% female, mean HbA1c 7.8%; T1DX: N=1718, 45% female, mean HbA1c 8.6%) were analyzed. Participants diagnosed with celiac and/or thyroid disease were excluded. Latent class growth modeling by Nagin was used to identify subgroups following similar BMI z-score trajectories. Five distinct trajectories were identified in ADDN and T1DX participants, and six in DPV (Figure). In all registries most participants in ADDN and T1DX maintained weight status over time. However, obese (BMI z-score ≥2) participants from ADDN achieved weight loss over time, compared to obese participants in T1DX, whose BMI SD increased during the teen years. In DPV, there were trajectories indicating dramatic weight gain/loss during puberty. Further analysis by sex and minority status will help to understand the within-registry and between-registry variation and may help target clinical interventions to achieve healthy weight in youth with T1D.

Disclosure

M. Wu: None. H. Phelan: None. A. Schwandt: None. N.C. Foster: None. J. Couper: None. C. Steigleder-Schweiger: None. S.M. Willi: Advisory Panel; Self; Boehringer Ingelheim GmbH. Other Relationship; Self; Caladrius Biosciences, Inc.. Consultant; Self; GlaxoSmithKline plc., JAEB Center For Health Research. T. Jones: None. P. Kroschwald: None. D.M. Maahs: Advisory Panel; Self; Insulet Corporation. Consultant; Self; Abbott. Research Support; Self; Medtronic, Bigfoot Biomedical, Dexcom, Inc., Insulet Corporation, Roche Diabetes Care Health and Digital Solutions. N. Prinz: None. M.E. Craig: None.
Impact of Laparoscopic Sleeve Gastrectomy on Thyroid Function Profiles in Chinese Euthyroid Obese Patients
Authors: LI LIANG , WANG XINGCHUN , GAO JINGYANG , QU SHEN
Published: June 2018

There exists close relationship between thyroid function and obesity. Laparoscopic sleeve gastrectomy (LSG) is an effective bariatric surgery in weight loss and obesity-associated comorbidities. However, only a few studies involve in the alteration of thyroid hormones after LSG with inconsistent results. This study aimed to investigate the impact of LSG on thyroid function profiles in Chinese euthyroid obese subjects. A retrospective study was performed of prospectively collected data in 36 obese patients (17 males and 19 females) who underwent LSG. Thyroid function profiles (TT4, FT4, TT3, FT3 and TSH, all within normal reference ranges), anthropometric data, and glucose-lipid metabolic parameters were recorded at baseline, 3 and 6 months after LSG (abbreviated as 3M/6M Post-LSG). Correlations between TSH with other parameters were evaluated. In all individuals, BMI was dramatically decreased at 3M/6M Post-LSG accompanied by decreased fasting blood glucose, fasting insulin, fasting C-peptide, triglyceride and increased HDL-c (P<0.01 or P<0.05). FT3, FT4 and TT3 without TT4 levels were gradually declined from baseline to 6M Post-LSG (P<0.01 or P<0.05, with slight changes in numerical values and still within their normal reference ranges). TSH levels remained unchanged at 3M/6M Post-LSG compared with baseline. In females, the TSH decrease (δTSH) was positively correlated with BMI decrease (δBMI, P<0.05), percentage of total weight loss (%TWL, P<0.01), and percentage of excess weight loss (%EWL, P=0.051, approximately significant) at 6M Post-LSG, while no correlation was observed in males.

In summary, we speculate that euthyroid obese subjects are adept at preserving their thyroid function homeostasis despite of morbid obesity at baseline as well as dramatic weight loss and significant improvement of glucose-lipid metabolism after LSG. In addition, δBMI/%TWL/%EWL may be the predictor of improved TSH levels after LSG in female but not male obese patients.

Disclosure

L. Li: None. X. Wang: None. J. Gao: None. S. Qu: None.
Attitudes Regarding Technology and Weight Loss in Patients with Diabetes and Prediabetes in a Military Health System
Authors: BEAUVAIS ALEXIS , WARDIAN JANA L. , SAUERWEIN TOM J.
Published: June 2018

Background: Military dependents and veterans have obesity, prediabetes and diabetes rates similar to the general U.S. population. This project examined the attitudes of patients with prediabetes and diabetes regarding weight loss and the use of technology in weight management.

Method: A survey was distributed to three primary care clinics and a diabetes specialty care clinic in the San Antonio Military Health System (SAMHS) over a two week period in February 2017. Demographics included age, sex, and presence of medical diagnoses including prediabetes and diabetes. Access to and attitudes regarding multiple types of personal technology were assessed. Data analysis was completed using SPSS version 22.

Results: There were 424 surveys collected. Prediabetes was self-reported by 25 (6.6%) respondents and 151 (39.6%) respondents self-reported a diabetes diagnosis. Interest in weight loss was high for patients with prediabetes (100%) and diabetes (73.5%); of those with diabetes that also self-identified as obese, 50 (96%) were interested in losing weight. Patients with prediabetes and diabetes were interested in using fitness trackers (65.5%), online videos (57.1%), receiving text messages (53.9%), fitness apps (53.3%), and the existing patient online portal (52.1%). Access to technology was high; many patients owned a personal computer or tablet (76.6%), used text messaging (75%), or owned a smart phone (64.5%). A majority (59.7%) believed technology was helpful for weight loss, but relatively few had used technology in past weight loss efforts (32.4%).

Conclusions: This survey showed that SAMHS patients with prediabetes and diabetes have significant interest in weight loss, access to personal technology devices, and interest in using technology to assist with weight loss. These results will be used to augment existing weight management and health interventions for people with prediabetes and diabetes.

Disclosure

A. Beauvais: None. J.L. Wardian: None. T.J. Sauerwein: Speaker's Bureau; Self; Merck & Co., Inc., AstraZeneca.