bluuebunny/crossref_metadata_2025_split huggingface dataset:
212-OR: Testosterone Deficiency Increases Hypothalamic Gliosis and Metabolic Risk
Authors: DORFMAN MAURICIO D. , FREY JEREMY , NESS KELLY M. , NIRAULA ANZELA , KANTER JENNY E. , BORNFELDT KARIN , RUBINOW KATYA , SCHUR ELLEN , THALER JOSHUA 
Published: June 2020

Obesity is associated with metabolic syndrome and gliosis, the activation of microglia (brain macrophages) and astrocytes, in the mediobasal hypothalamus (MBH) of humans and rodents. Similarly, hypogonadism in males is associated with increased susceptibility to weight gain, metabolic syndrome and MBH gliosis. Interventions that reduce glial activation in rodents result in protection from diet-induced obesity. Thus, we hypothesize that the combination of low testosterone and western diet causes gliosis, which in turn increases obesity susceptibility. To test this hypothesis in a rodent model, we combined gonadectomy (GDX) or sham surgery with high-fat diet (HFD) feeding in adult male mice. GDX and HFD feeding synergistically induced a striking activation of MBH astrocytes along with increased numbers of MBH microglia. This gliosis response was reversed to sham levels by testosterone replacement. After only 4 weeks of HFD feeding, differences in adiposity between GDX and sham groups were minimal with only a mild worsening of glucose tolerance. Thus, testosterone deficiency combined with HFD exposure elicits gliosis prior to substantial weight gain, suggesting a direct impact on glial cell function. To characterize the transcriptional response to testosterone deprivation and HFD exposure, we have developed mouse strains with GFP-tagged ribosomes (L10A) in astrocytes and microglia to allow purification of glial cell-specific mRNA from whole hypothalamic tissue samples (tagged ribosome affinity purification (TRAP)). In preliminary analyses, we have confirmed &gt;10-fold enrichment of cell-specific mRNAs with de-enrichment of neuronal transcripts. These studies help reveal novel mechanisms by which hypogonadism increases the predisposition to metabolic disease.

Disclosure
M.D. Dorfman: None. J. Frey: None. K.M. Ness: None. A. Niraula: None. J.E. Kanter: None. K. Bornfeldt: None. K. Rubinow: None. E. Schur: None. J. Thaler: None.

Funding
American Heart Association (16SDG27010018); Diabetes Research Center (P30DK017047); Novo Nordisk (A116079); National Institutes of Health (R01DK119754)
2131-P: BET Bromodomain Inhibition Upregulates SIRT1 In Pancreatic ß-Cells
Authors: JONES LIPINSKI RACHEL A. , WYNIA-SMITH SARAH , NORD JOSHUA , SMITH BRIAN C. 
Published: June 2020

Diabetes develops as a result of both genetic and environmental influences; however, low concordance rates of type 1 diabetes between monozygotic twins and increased penetrance of type 2 diabetes during aging suggests an, as yet, poorly understood epigenetic role in diabetes development and progression. The epigenetic code, of which lysine acetylation (Kac) is a major histone post-translational modification, regulates the structure and dynamics of chromatin leading to epigenetically-controlled changes in gene accessibility toward transcription factors. Histone acetylation is regulated by histone acetyltransferases and deacetylases which write and erase sites of histone acetylation, respectively. SIRT1 is a key protein deacetylase in the control of glucose homeostasis. Decreased SIRT1 can lead to impaired insulin signaling, therefore drugs that enhance either SIRT1 expression or enzymatic activity may treat insulin resistance. Bromodomains are epigenetic readers that interpret the complex pattern of histone acetylation by binding Kac residues on histones and other nuclear proteins. Of particular interest are the bromodomain and extraterminal domain (BET) family of bromodomain-containing proteins, which have recently emerged as a potential target to treat or prevent diabetes. Interestingly, we recently found that treatment of β-cells with BET bromodomain inhibitors leads to increased SIRT1 expression levels, although the underlying mechanism was unclear. Here, we use an insulinoma β-cell line (INS832/13) and primary rat islets to determine the mechanism through which BET proteins suppress SIRT1 expression. To modulate SIRT1 and BET protein levels and activity, we used a combination of small molecules that either inhibit or degrade BET proteins, in conjunction with CRISPR/Cas9 knockout β-cell lines of both SIRT1 and the individual BET proteins.
In summary, BET inhibitors may provide an indirect means to increase SIRT1 activity in β-cells and improve β-cell function in the context of diabetes.

Disclosure
R.A. Jones Lipinski: None. S. Wynia-Smith: None. J. Nord: None. B.C. Smith: None.

Funding
American Diabetes Association (1-18-IBS-068 to B.C.S.); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK119359)
2133-PUB: D10 vs. D50 for Treatment of Inpatient Hypoglycemia
Authors: JONES-RYAN MADELINE L. , ADDASI NOOR , KNEZEVICH JON T. , SAMSON KAELI , DRINCIC ANDJELA T. 
Published: June 2020

Hypoglycemia is a common, difficult to prevent adverse outcome of inpatient diabetes care, which is associated with increased morbidity, mortality and length of stay. ADA standards of care 2020 recommend institutional adoption of evidence-based hypoglycemia management protocols. However, little data is available assessing the efficacy of common hypoglycemia treatment modalities utilized.
The aim of this retrospective study was to evaluate efficacy and safety of 4 hypoglycemia treatment modalities based on initial blood glucose; 50 ml of D50 (T1), 250 ml of D10 (T2), 25 ml of D50 (T3) and 125 ml of D10(T4). Chart review was done on 4,626 admitted to a tertiary medical center between 6/1/16 - 2/28/17 and 6/1/17 - 2/28/18, with 1 or more episodes of hypoglycemia. Patients included in the analysis were non-pregnant adults treated with insulin or oral glucose lowering agents who needed treatment with IV Dextrose. 618 patients met the inclusion criteria. Comparisons were made between the 4 treatment modalities after adjusting for baseline blood glucose; standard protocols recommend T1 and T2 for ADA level 2 hypoglycemia, vs. T3 and T4 for level 1 hypoglycemia. Mean blood sugars were : 48+/13 (T1), 4 8+/-12 (T2), 60 +/-7 (T3), and 61 +/-6 (T4). A difference in resolution of hypoglycemia at time 1 (a median of 21 minutes after treatment) was noted; 96.8% in T1, 94.5% in T2, 97.3% in T3 and 98.6% in T4 (P&lt;0.0001). At time 2 (a median of 2.3 hours after the treatment), recurrent hypoglycemia was 25.8% in T1, 17.6% in T2, 15% in T3 and 16.5% in T4 (p=0.005). Hyperglycemia (&gt;180 mg/dL) at time 2 was higher in T1 and T2, 11.7% and 11% respectively, compared with 6.3% in T3 and only 2.9% in T4 (P=0.005). 50 ml of D50 was associated with the highest rate of recurrent hypoglycemia. Across all arms, recurrent hypoglycemia was common at 2 hours after initial treatment, with time widely varied (19 minutes to 12 hours). Protocols should include ongoing monitoring after initial hypoglycemia.

Disclosure
M.L. Jones-Ryan: None. N. Addasi: None. J.T. Knezevich: Speaker’s Bureau; Spouse/Partner; Valeritas, Inc. K. Samson: None. A.T. Drincic: None.
2135-PUB: Identifying the Anthropometric Measurement and Lipid and Glucose Indexes That Best Correlate with Metabolic Syndrome in a Chinese Population
Authors: XIN ZHONG 
Published: June 2020

In this investigation, we compared the performance of various parameters including Waist-to-Height Ratio (WHtR), Waist-Hip Ratio (WHR), Waist Circumference (WC), Body Mass Index (BMI), and triglycerides glucose related Index including TyG index, TyG-BMI, TyG-WC in detecting Metabolic Syndrome (MS). (TyG index: TG× FPG, TyG-BMI: TyG index × BMI, TyG-WC: TyG index × WC) In 2013, 2972 registered permanent residents in a rural satellite town of Beijing, aged ≥ 20 years, were invited to participate in the study. MS patients were identified with the criteria of Chinese Diabetes Society (CDS). The receiver-operating characteristics (ROC) curve analyses and the respective area under the ROC curves (AUC) were used to compare the association of the different index with MS.In men, the AUC was 0.81 (0.78-0.84) for BMI, 0.77 (0.74-0.81) for WHtR, 0.68 (0.63-0.72) for WHR, 0.77 (0.74-0.80) for WC in detecting MS, respectively. In women, the AUC was 0.78 (0.76-0.81), 0.76 (0.73-0.78), 0.66 (0.64-0.68), 0.76(0.74-0.78), respectively. The correlation between BMI and MS was higher than other indicators by comparing AUCs (P&lt;0.05). In men, the AUC was 0.88 (0.86-0.90) for TyG index, 0.89 (0.87-0.92) for TyG-BMI, 0.88 (0.86-0.90) for TyG-WC, respectively. In women, the AUC was 0.88 (0.86-0.90), 0.88 (0.86-0.92), 0.87 (0.85-0.89), respectively. There were no significant differences for these three indexes. However, the correlation between TyG index and MS was higher than BMI (P&lt;0.05).The cut-off points for BMI evaluating MS were 25.0 Kg/m2 in men and 25.3 Kg/m2 in women, and for TyG index were 8.87 in men and 8.80 in women. BMI is an efficient surrogate marker in the evaluation of MS in Chinese people. It can be used to screen MS patients and self-assess the risk in common people easily. TyG index is better than BMI in the evaluation of MS. This will help general practitioners to assess the risks of their patients quickly.

Disclosure
Z. Xin: None.

Funding
Expert Promotion Program of Beijing Health Systems (2015-3-017)
2140-PUB: Effect of Metformin on Incretin Secretion in Patients with Diabetes and Chronic Heart Failure
Authors: KOPECKY JAN , HOŠKOVÁ EVA , VELEBA JIRI , MELENOVSKY VOJTECH , PELIKANOVA TEREZIE 
Published: June 2020

Aim: Metformin (MET) is a mainstay for treatment of type 2. diabetes (DM). Its use in patients with chronic heart failure (HF) patients is recent, associated with lower frequency of cardiovascular events and with better survival, but mechanisms of action are unclear. GLP-1 incretin is reported to have cardioprotective effects. Our aim was to assess the effects of MET on glucose metabolism, incretin secretion and cardiac function in patients with DM and HF.
Methods: A randomized, double-blind, placebo-controlled, crossover study testing the effect of 3 - month usage of metformin vs. placebo. Treatment naive patients with DM and HF were randomized to metformin (2 g/day) or to placebo group. At the beginning and the end of each intervention period (baseline, after MET and after placebo) panel of various metabolic tests including meal test and cardiac function tests (echocardiography, cardiopulmonary exercise test) was done.
Results: Metformin significantly reduced HbA1c. During meal test, metformin significantly reduced AUC of glucose, insulin and amylin; and increased GLP-1 and peptide YY. Details in Table. There was no change in cardiac function as assessed by echocardiography and spiroergometry.
Conclusions: Metformin therapy in patients with HF improves diabetes compensation and has no significant effect on cardiac function. Improvement might be partly mediated by alteration of gut endocrine function.

Disclosure
J. Kopecky: None. E. Hošková: None. J. Veleba: None. V. Melenovsky: None. T. Pelikanova: None.

Funding
VZ 00023001 IKEM
215-LB: Ablation of Nos-1 Neurons in the PVH Reveals an Essential Role in Sustaining Metabolic Homeostasis, Independent of Melanocortin Function
Authors: FAULKNER LATRICE D. , GONZALEZ IAN E. , OLSON DAVID , MEEK THOMAS H. 
Published: June 2020

The paraventricular hypothalamus (PVH) is vital for energy balance regulation, as developmental or mechanical lesions targeting the PVH lead to massive obesity. We have shown that activation of PVH neurons expressing nitric oxide synthase-1 (Nos1PVH) suppresses food intake and increases energy expenditure. This differentiates these neurons from the well-studied melanocortin 4 receptor-expressing population (Mc4RPVH), as activation of Mc4RPVH neurons suppresses feeding but does not alter energy expenditure. In situ hybridization studies in our laboratory show that Mc4R and Nos1 mRNAs do not overlap in the PVH, suggesting that these cell populations may regulate energy balance independently. We hypothesize that the contributions of Nos1PVH neurons to maintaining metabolic homeostasis are independent of Mc4RPVH neurons. To test this hypothesis, we used established Nos1 and Mc4R Cre-expressing lines to create a Nos1Cre+Mc4RCre dual recombinase model. Then, we inactivated Nos1PVH and Mc4RPVH neurons alone or in combination. Several metabolic parameters were monitored for 8 weeks post-injection. These experiments allowed us to examine the interdependency of Nos1 and Mc4R PVH populations in energy balance control. Silencing the Nos1PVH population alone resulted in the acute onset of obesity without affecting feeding behavior. This phenotype was exacerbated when we simultaneously silenced both Nos1 and Mc4R PVH neurons. This suggests an additive interaction between the two groups; although a synergistic effect cannot be excluded. Future studies will focus on the effects of Nos1PVH inactivation on energy expenditure and defining the Nos1 neurocircuitry that facilitates PVH-mediated metabolic regulation. Our overall goal is to unravel the cellular and neurobiological mechanisms engaged by Nos1PVH neurons and open new avenues for treating obesity.

Disclosure
L.D. Faulkner: None. I.E. Gonzalez: None. D. Olson: Research Support; Self; MedImmune, Inc, Novo Nordisk A/S. T.H. Meek: Employee; Self; Novo Nordisk Inc.
215-OR: Silencing CCKBR Containing Neurons in the VMN Restrains Hepatic Glucose Production to Ameliorate Diabetes in Mice
Authors: AFFINATI ALISON , FLAK JONATHAN , BOZADJIEVA NADEJDA , KODUR NANDAN , CRAS-MÉNEUR CORENTIN M. , SANDOVAL DARLEEN A. , MYERS MARTIN G. 
Published: June 2020

Optimal glucose control remains elusive for many patients with diabetes despite current therapies, necessitating the development of novel therapeutic modalities. While the central nervous system (CNS) plays a crucial role in glucose homeostasis, specific CNS targets for therapeutic intervention in diabetes have remained elusive. We recently demonstrated that the cholecystokinin b receptor (CCKbR)-expressing subpopulation of ventromedial hypothalamic nucleus (VMN; VMNCCKBR) neurons not only mediate the counter-regulatory response, but also elevate blood glucose by insulin-independently modulating hepatic glucose production under normal physiologic conditions. To test the potential therapeutic utility of these neurons for the treatment of diabetes, we cre-dependently expressed tetanus toxin in the VMN of Cckbrcre mice to silence VMNCCKBR neurons in streptozotocin (STZ)-induced (insulinopenic; Type 1 model) and leptin-deficient (ob/ob; obese Type 2 model) mice. While STZ-treated control mice became hyperglycemic and lost approximately 20% of their body weight over two weeks, VMNCCKBR-silenced mice were protected from these effects of STZ, despite similar hormone levels in STZ-treated control and CCKBRTTmice. Similarly, silencing of VMNCCKBR neurons in ob/ob mice normalized fasting and ad libitum-fed blood glucose despite identical food intake, body weight and body composition in control and VMNCCKBR-silenced mice. While VMNCCKBR-silenced ob/ob mice exhibited no alterations in glucose or insulin tolerance compared to controls, glucose clamps demonstrated decreased hepatic glucose output in the VMNCCKBR-silenced animals. These data suggest that VMNCCKBR neurons represent potential targets to reduce hepatic glucose production and ameliorate hyperglycemia in diabetes.

Disclosure
A. Affinati: Research Support; Self; Novo Nordisk Inc. J. Flak: None. N. Bozadjieva: None. N. Kodur: None. C.M. Cras-Méneur: None. D.A. Sandoval: Research Support; Self; MedImmune, Novo Nordisk A/S. M.G. Myers: Research Support; Self; AstraZeneca, Novo Nordisk Inc.

Funding
National Institutes of Health (5T32DK7245-42, 1F32DK122660-01)
2151-PUB: Association of Homocysteine with Early Nephropathy in Patients with Type 2 Diabetes
Authors: LI JIANBO , LV QING , LU HUAN , ZHANG HONGMAN , ZHOU JUN 
Published: June 2020

Early predication and intervention of diabetic nephropathy is increasingly imperative. Hyperhomocysteinemia is common and chronically induces arteriolar thickening, and tubulointerstitial and podocyte injury, therefore, could play a causative role in early renal injury in the kidney in type 2 diabetes. In this study, we for the first time investigated the relation of plasma total homocysteine concentration to early nephropathy in type 2 diabetes. We enrolled 183 type 2 diabetic patients in a cross-sectional study. Early diabetic nephropathy status was diagnosed by presence of microalbuminuria. Plasma total homocysteine levels were measured using fluorescence polarization immunoassay. Variables for diabetic nephropathy were obtained from fasting blood samples and interviewer- questionnaire. We found that plasma total homocysteine concentrations were elevated in subjects with early diabetic nephropathy than without (13.3±2.9)µmol/l vs. (8.5 ± 1.4)μmol/l, p &lt; 0.01). The association of homocysteine with the diabetic nephropathy was independent of major traditional risk factors for diabetic nephropathy (duration of diabetes, HbA1c, and blood pressure) and determinants of higher homocysteine concentration (age, sex, serum folate and vitamin B12, Biguanide use, and serum cystatin or creatinine levels,) (OR: 1.36 (1.08-1.74), p &lt; 0.05). Furthermore, per increase of 5.0 μmol/l plasma homocysteine was related to early nephropathy (OR: 1.15 (1.04-1.29), p &lt; 0.05), after controlling for per unit increase of other factors: per 5 year increase of duration of diabetes, per 1% increase of HbA1c, per 10 nmol/l increase of serum folate, per 100 pmol/l increase of serum B12, per 0.1 mg/L increase of serum cystatin or per 10 μmol/l increase of creatinine, and per 10 or 5 mmHg increase of systolic or diastolic blood pressure. We concluded that plasma total homocysteine concentration was independently associated with occurrence of early diabetic nephropathy. Future prospective studies are warranted.

Disclosure
J. Li: None. Q. Lv: None. H. Lu: None. H. Zhang: None. J. Zhou: None.

Funding
National Natural Science Foundation of China (81070655); Jiangsu Provincial Natural Science Foundation of China (BK2009441)
2156-PUB: Diabetic Foot Ulcers: Correlation of Nutritional Status of Type 2 Diabetic Patients of Hyderabad Sindh, Pakistan
Authors: SHAIKH IMRAN ALI 
Published: June 2020

Objectives: To know the correlation of foot ulcers to the nutritional status of type 2 Diabetic patients of Hyderabad.
Study Design: Cross sectional study.
Place of Study: Private clinics of consultants of Hyderabad, Sindh, Pakistan.
Duration of Study: February 2015 to June 2016.
Methodology: 387 diabetic type 2 patients were selected from different clinics of physicians, orthopedics and diabetic consultants of sadder Hyderabad Sindh Pakistan. The mean age was 40±11.5 years. All patients were enrolled on prescribed proforma. Thorough clinical examination was done. Wagner’s classification was used to categorize diabetic foot ulcers. Nutritional status was classified on Mini Nutritional Assessment score and patients were divided into three groups according to Mini nutritional score. Blood samples were obtained for Hemoglobin%, blood sugar, serum calcium and serum albumin estimation. All patients were assessed radiologically by x-rays of involved foot. ANOVA test was used and p value &lt;0.05 was considered statically significant.
Results: There was linear correlation in between Mini nutritional assessment and severity of diabetic foot ulcer (p &lt;0.03). Biochemical parameter were also significantly associated with the severity of ulcers. Serum albumin was decreased in grade 4 ulcer significantly (p value &lt;0.04), while hemoglobin was also decreased in grade 4 ulcer, p value (&lt;0.05). There was no association of serum calcium to severity of foot ulcer, (p value &gt;0.07).
Conclusion: Diabetic foot ulcers are common in type 2 diabetic patients and nutritional status is strongly associated with grade of severity. It is important to assess nutritional status of all diabetic patients.

Disclosure
I. Shaikh: None.
2159-PUB: Factors Associated with Health-Related Quality of Life among Diabetic Foot Ulcer Patients: A Cross-Sectional Survey from Saudi Arabia
Authors: ALDAWISH MOHAMMED , AL-AYED MOUSAB 
Published: June 2020

Objective: To estimate the Health-Related Quality of Life (HRQOL) related risk factors in Diabetic Foot Ulcer (DFU) patients.
Methods: This cross-sectional study was performed using 81 type 2 diabetes patients with DFU, from January 2019 to May 2019, at one of the chief tertiary hospitals in Riyadh, Saudi Arabia. The study population was chosen with purpose and convenience, based on patient availability during their regular and customary outpatient clinic visits. Using the Arabic version of the Short-Form 36-Item Survey (SF-36) these patients were interviewed and the HRQOL was assessed.
Results: From the univariate analysis preformed, it was evident that the independent factors mentioned induced vital variations in the patients’ physical functions viz., age, gender, education, occupation, smoking, duration of diabetes, hypertension, dyslipidemia, body mass index (BMI) and the number of diabetes-associated complications, hypertension and dyslipidemia. The physical health of the patient was strongly influenced by gender, education, occupation, income, BMI and number of complications. The emotional health of the patient was affected by dyslipidemia, deformity and prior amputations, as well as BMI and glycosylated hemoglobin (HbA1c). The social standing of the patient was impacted by age, income, education, and occupation. The degree of pain experienced by the patient varied with age and number of complications, as well as with the notable differences in their general health. The factors of age, education, occupation, income and number of complications induced several health changes to differing degrees.
Conclusion: The DFU patients generally revealed low HRQOL. However, prospective and large-scale studies are required, in the future, to support these findings.

Disclosure
M. Aldawish: None. M. Al-Ayed: None.
216-OR: O-GlcNAc Transferase in the Ventromedial Hypothalamus Regulates Lipid Metabolism through Fat Depot–Specific Sympathetic Innervation
Authors: WANG QI , ZHANG BICHEN , YANG YUNFAN , MI JIA , TIAN GENG , ONG QUNXIANG , YANG XIAOYONG 
Published: June 2020

The ventromedial hypothalamus (VMH) is a primary site that initiates counter-regulatory response and regulates food intake, maintaining glucose and lipid homeostasis. Known as a nutrient sensor and metabolic regulator, O-linked β-D-N-acetylglucosamine modification (O-GlcNAcylation) of intracellular proteins is catalyzed by O-GlcNAc transferase (OGT). How O-GlcNAc signaling in the VMH regulates whole-body metabolism remains unknown. Here, using the mouse model with VMH neuron-specific OGT deletion (VOK), we report that OGT is a nutrient sensor in VMH neurons that primarily regulates lipid metabolism. VOK mice show increased body weight and adiposity as well as reduced energy expenditure. OGT deletion in VMH neurons has no significant effects on food intake, physical activity, substrate utilization, glucose tolerance or insulin sensitivity. Lipolysis in subcutaneous and visceral white adipose tissues (WATs) is reduced in VOK mice, indicated by reduced activation of hormone-sensitive lipase (HSL) via cAMP-dependent protein kinase (PKA). In addition, VOK mice have lower serum glucagon and norepinephrine levels and show impaired depot-specific sympathetic innervation to WATs. These data reveal that O-GlcNAc signaling in VMH neurons specifically controls lipid metabolism through depot-specific sympathetic innervation.

Disclosure
Q. Wang: None. B. Zhang: None. Y. Yang: None. J. Mi: None. G. Tian: None. Q. Ong: None. X. Yang: None.

Funding
American Diabetes Association (1-19-IBS-119 to X.Y.); National Institutes of Health (R01DK089098, R01DK102648)