bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of Different Methods for Carbohydrate Disorder Detection
Authors: DASKALOVA IVONA , TOTOMIROVA TZVETELINA , PETROV NIKOLAY 
Published: June 2018

Measurement of fasting glucose and prandial glucose, as well as glycated haemoglobin (HbA1c) and oral glucose tolerance test (OGTT) could confirm diabetes or impaired glucose tolerance but they are invasive and time consuming methods. Some new technologies assessing dermal changes in perspiration like EZscan are used for defining carbohydrate state. We compare common methods used for detecting carbohydrate disorders with EZscan methodology assessing their potency to reveal diabetic and prediabetic patients. We studied 124 patients (64 males, 60 females, mean age 43.4±8.9years) with very high risk for diabetes. In these patients we measured HbA1c and performed OGTT and diagnosis diabetes or prediabetes was based on general recommendations. In addition patients underwent EZscan test in which diagnosis is based on measurement of electrochemical skin conductance. Only in 37 patients (29.8%) HbA1c was above 6.5% and in another 38 patients (30.6%) HbA1c was between 6.0-6.49%. After performing OGTT 22 patients (17.7%) were defined with increased fasting glucose (IFG) and 37 patients (29.8%) were with impaired glucose tolerance (IGT), 58 patients (46.7%) were with diabetes. Results from EZscan test show that 65 patients (52.4%) are with IFG/IGT and 55 patients (44.3%) are with diabetes. Age and gender did not have influence on the results. We conclude that EZscan could be used as test with similar to OGTT power for diagnosis of diabetes. HbA1c shows least potency for diagnosis. EZscan presents with some additional advantages being noninvasive method, taking no more than five minutes, with no need of special condition.

Disclosure
I. Daskalova: None. T. Totomirova: None. N. Petrov: None.
Air Pollution–Induced Diabetes Is Mediated via the Gastrointestinal Tract
Authors: BOSCH ANGELA J.T. , ROHM THERESA V. , ALASFOOR SHEFAA , DERVOS THOMAS , CAVELTI-WEDER CLAUDIA 
Published: June 2018

Background: Epidemiological studies show an association between air pollution and increased diabetes risk. However, the causal mechanism remains poorly understood. While it is believed that air pollution particles inhaled into the lungs cause diabetes via local and systemic inflammation, these particles also reach the gastrointestinal (GI) tract by swallowing and mucociliary clearance and could thereby initiate diabetes.
Research Design and Method: To differentiate between the effects of air pollution particles reaching the lungs vs. the GI tract, male C57B6/N mice were exposed to diesel exhaust particles (DEP; weekly dose 60µg) either by oral gavage (5 days/week) or intratracheal instillation (twice/week) for up to 6 months and glycemia monitored by glucose tolerance tests.
Results: Mice orally treated with DEP showed impaired glucose tolerance with reduced insulin secretion already after two months of treatment, while insulin sensitivity was not affected. Furthermore, orally treated mice showed a distorted balance of pro- and anti-inflammatory intestinal macrophages with a specific loss of the anti-inflammatory subpopulation, which normally constitutes the majority of intestinal macrophages in the healthy gut. Although mice receiving DEP by intratracheal instillation had increased monocyte recruitment to the lungs, they did not show any impairment in glucose tolerance up to 5 months.
Conclusion: Exposure of DEP to the GI tract but not the lungs causes impaired glucose tolerance and a concomitant decrease in anti-inflammatory intestinal macrophages. Our results provide new insights into the mechanism of air pollution-induced diabetes with the gut as the primary organ mediating the disease and thus could be targeted by potential prevention and therapeutic strategies.

Disclosure
A.J.T. Bosch: None. T.V. Rohm: None. S. AlAsfoor: None. T. Dervos: None. C. Cavelti-Weder: None.
Urocortin-2 Gene Transfer Effectively Treats Type 1 Diabetes in Mice
Authors: GAO MEI HUA , LAI NGAI CHIN , GIAMOURIDIS DIMOSTHENIS , GUO TRACY Y. , XIA BING , KIM YOUNG CHUL , ESTRADA MONICA V. , NGUYEN HUU VIET ANH , SKOWRONSKA-KRAWCZYK DOROTA , KIRK HAMMOND H. 
Published: June 2018

Type 1 diabetes (T1D) affects 1.3 million U.S. patients. Tight glucose control reduces microvascular complications and adverse cardiovascular events. Insulin therapy is essential but has shortcomings: a) only 1 in 3 patients achieve targeted glucose control; b) aggressive insulin use increases hypoglycemia; c) 25% of T1D patients develop insulin resistance. We previously reported that urocortin-2 (UCn2) gene transfer increases insulin sensitivity and release in mouse models of type 2 diabetes. In the present study, 3m-old male Akita mice with T1D (due to Ins2 mutation) received IV saline, AAV8. Null or AAV8.UCn2 (2x1012 gc/kg). Ten weeks after UCn2 gene transfer we saw normalization of fasting glucose, HbA1c and glucose tolerance (Table). Increased body weight and reduced water intake was seen after UCn2 gene transfer. Hyperinsulinemic euglycemic clamps showed increased insulin sensitivity and skeletal muscle glucose uptake. There was reduced nephropathy and retinopathy and increased survival (Table). Echocardiography showed improved ejection fraction (p&lt;.001), end-systolic dimension (p&lt;.001) and diastolic function (p&lt;.0001). Data acquisition and analyses were blinded. The mechanisms for beneficial effects include increased insulin release and sensitivity. Thus, UCn2 gene transfer may be a viable therapy both for new onset T1D with detectable endogenous insulin, and for later stage T1D to reduce exogenous insulin needs.
UCn2 Gene Transfer in Akita Mice (Type 1 Diabetes)Saline or AAV8.Null (n)AAV8.UCn2 (n)pPlasma UCn2 (ng/mL)1±.2 (14)12±.9 (14)&lt;.0001Urine Output (ml/hr).43±.06 (8).24±.06 (8).0412hr Fasting Glucose (mg/dL)272±25 (8)106±12 (8)&lt;.0001HbA1c (%)8.2±.4 (5)5.5±.4 (5)&lt;.002Glucose Tolerance Test (AUC)3128±215 (8)2062±286 (8)&lt;.0001Insulin Release 2h post gluc (ng/ml).15±.01 (8).29±.4 (8).004Glucose Infusion Rate (mg/kg/min)12±2.89 (6)33.6±5.3 (5).001Vast Lat Glu Uptake (µM/m/100g)8.2±.4 (7)23.2±2.6 (6)&lt;.0001Glomerulus Expansion Score1.7±.04 (8)1.5±.04 (8).01Urine Albumin/Creatinine (3hr)28±3 (8)17±3 (8).01Retinal Vascular Leak (%)43±1 (5)19±5 (4).001200-day Survival (%)0 (17 of 17 died)82 (3 of 17 died)&lt;.0001Mean ± SE; p from Student’s t-test (unpaired, 2 tails); AAV8, Adeno-Associated Virus Type 8

Disclosure
M. Gao: None. N. Lai: None. D. Giamouridis: None. T.Y. Guo: None. B. Xia: None. Y. Kim: None. M.V. Estrada: None. V. Nguyen Huu: None. D. Skowronska-Krawczyk: None. H. Hammond: Stock/Shareholder; Self; Renova Therapeutics.
The Tyrosine Phosphatase LMPTP Is a Key Promoter of Adipogenesis
Authors: STANFORD STEPHANIE , ZHANG VIDA , BOTTINI NUNZIO 
Published: June 2018

The low molecular weight protein tyrosine phosphatase (LMPTP), encoded by the ACP1 gene, acts as a regulator of insulin signaling by dephosphorylating the activation motif of the insulin receptor. Multiple human genetics studies suggest that high LMPTP catalytic activity promotes metabolic syndrome and severity of obesity. We recently reported that LMPTP is a critical promoter of insulin resistance in obesity through an action on the liver and that pharmacological inhibition of LMPTP reverses obesity-associated diabetes in mice. Since LMPTP is highly expressed in adipose tissue but little is known about its function in these tissues, we examined the role of LMPTP in adipocyte biology. Intriguingly, we found that LMPTP acts as a critical promoter of adipogenesis. Our data indicate a novel role for LMPTP in promoting adipocyte differentiation and suggest that there may be additional signaling pathways under control of LMPTP in these cells.

Disclosure
S. Stanford: None. V. Zhang: None. N. Bottini: None.
Some Indicators of Carbohydrate Metabolism in Individuals after the Abolition of the Use of Anabolic Androgenic Steroids
Authors: LYKHONOSOV MYKOLA P. , BABENKO ALINA Y. 
Published: June 2018

Background: The use of anabolic androgenic steroids to form a sports figure is widespread. Anabolic androgenic steroids (AAS) are used in higer doses than in therapeutic practice. Studies of the side effects of AAS on carbohydrate metabolism are hampered due to the self-over-the-counter use of AAS.
Hypothesis: We assumed that with the abolition of AAS, the effect of high doses of testosterone (Ts) and nandrolone decanoate on the utilization of glucose is reduced.
Methods: After informational lectures among visitors in sports clubs in St. Petersburg on the impact of the AAS application on health, patients who expressed desire were included in the study. The inclusion criterion was the use of preparations of 19-nortestosterone with a course of 6 to 8 weeks in a weekly dosage of 300 to 700 mg in combination with Ts propionate and Ts enanthate, as well as the rejection of the subsequent use of anabolic steroids. BMI, HbA1c, immunoreactive insulin (IRI) and Fasting plasma glucose (FG), homeostatic model assessment-insulin resistance HOMA-IR were compared before and 3 months after the abolition of all AAS, while maintaining the previous physical activity and eating habits.
Results: We examined 24 pts (18M), age 27 ± 3.6. The average period of use of AAS is 7.3 weeks. After the abolition of the AAS, the IMB increased (mean difference = 4.7 kg, p = 0.012). The metabolism of glucose has changed in the direction of an increase in all the indicators considered: FG (mean difference = 1.02 mmol / l, p = 0.047), IRI (mean difference = 9.83, p = 0.023), HOMA-IR (mean difference = 7.31, p = 0.015) and HbA1c (mean difference = 0.25%, p = 0.031). However, no violations of glucose metabolism were detected in any case.
Conclusions: The abolition of AAS in athletes caused an increase in body weight and a shift in all glucose metabolism rates closer to the upper normal values, this trend deserves further study.

Disclosure
M.P. Lykhonosov: None. A.Y. Babenko: None.
Membrane sn-1,2 Diacylglycerol Mediates Lipid-Induced Hepatic Insulin Resistance In Vivo
Authors: LYU KUN , ZHANG DONGYAN , NOZAKI YUICHI , ZHANG YE , BHANOT SANJAY , CLINE GARY , SAMUEL VARMAN , SHULMAN GERALD I. 
Published: June 2018

Diacylglycerol (DAG) has been proposed to mediate lipid-induced hepatic insulin resistance. Accumulated hepatic DAG activates PKCε which phosphorylates insulin receptor kinase (IRK) at T1160 to inhibit IRK activation and cause insulin resistance. However, the importance of DAG in lipid-induced hepatic insulin resistance remains controversial. To test the physiological effect of acute DAG accumulation on hepatic insulin sensitivity, we used antisense oligonucleotide (ASO) to specifically inhibit hepatic diglyceride acyltransferase 2 (DGAT2) which catalyzes the conversion of DAG to triglyceride. Previously, chronic DGAT2 inhibition was shown to paradoxically decrease hepatic DAG content due to decreased SREBP-1c-mediated lipogenesis and improve hepatic insulin sensitivity. However, we hypothesized that acute DGAT2 inhibition might provide a narrow window to transiently increase hepatic DAG content and allow us to identify the association between DAG, PKCε activation/translocation and hepatic insulin resistance. As hypothesized, an acute (2-day) DGAT2 inhibition increased hepatic DAG content and PKCε activation (cytosol to membrane translocation). DGAT2 ASO-treated rats on regular chow diet displayed impaired insulin-mediated suppression of hepatic glucose production. This defect of hepatic insulin action was at the level of IRK as indicated by impaired insulin-stimulated IRK Y1158/1162 phosphorylation. Furthermore, measured by a novel LC-MS/MS method, hepatic sn-1,2 DAG, which is the DAG stereoisomer capable of activating PKCε, was increased in the subcellular membrane compartment with DGAT2 ASO treatment.
Conclusion: These data support the importance of membrane sn-1,2 DAG in mediating lipid-induced hepatic insulin resistance through “increased membrane sn-1,2 DAG content -&gt; PKCε activation/translocation -&gt; increased IRK T1160 phosphorylation -&gt; decreased IRK Y1158/1162 phosphorylation -&gt; decreased IRK activity” in vivo.

Disclosure
K. Lyu: None. D. Zhang: None. Y. Nozaki: None. Y. Zhang: None. S. Bhanot: Employee; Self; Ionis Pharmaceuticals, Inc.. G. Cline: None. V. Samuel: None. G.I. Shulman: Advisory Panel; Self; AstraZeneca, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc.. Research Support; Self; Gilead Sciences, Inc..
Pancreatic Adipose Tissue in Diet-Induced Type 2 Diabetes
Authors: GARCIA BELEN CHANCLON , WU YANLING , NORDBECK ELIN BANKE , MUSOVIC SALIHA , OLOFSSON CHARLOTTA S. , RORSMAN PATRIK , ASTERHOLM INGRID WERNSTEDT 
Published: June 2018

Obesity represents one of the most important health problems. Proper adipose tissue expandability is crucial for avoiding metabolic disorders. Furthermore, not all fat depots are functionally equal. Our previous work indicates that the expansion of the mesenteric adipose tissue (MWAT) plays a role in the intestinal barrier. Whether pancreas-associated adipose tissue (PAT) has a specific function is currently unknown. We hypothesize that storage of excess nutrients in PAT and PAT-derived adipokines (such as adiponectin) protect the pancreas against metabolic dysfunction during weight gain/obesity. An initial morphological study showed that PAT has an increased number of small, but fewer large adipocytes relative the adjacent MWAT. We compared the response to a 16-week high-fat diet (HFD)/obesity between PAT, other fat depots and pancreas. We found higher mRNA expression of inflammation markers in MWAT, inguinal (IWAT) and gonadal fat (GWAT), but not in PAT in response to HFD/obesity. HFD also downregulated the expression of insulin receptor and adiponectin in all fat depots, but not in PAT. The pancreas showed an increase in inflammatory and insulin resistance markers only after long-term (16 weeks) HFD exposure, a time point when also PAT displayed a reduction in insulin receptor and adiponectin expression. Smaller adipocytes are typically more functional than large adipocytes. Thus, these data suggest that PAT have an increased capacity for energy storage. This in turn may protect the pancreas against ectopic lipid accumulation and lipotoxicity. Moreover, our data show that PAT is protected against the deleterious effects of HFD, maintaining normal mRNA levels of adiponectin, insulin receptor and markers of inflammation.
In summary, we believe that PAT protects the pancreatic beta-cells from lipotoxicity through its increased capacity for energy storage, sustained insulin sensitivity and possibly also increased insulin exposure because of its anatomical location.

Disclosure
B. Chanclon Garcia: None. Y. Wu: None. E. Banke Nordbeck: None. S. Musovic: None. C.S. Olofsson: None. P. Rorsman: None. I. Wernstedt Asterholm: None.
Berberine Improves Mitochondrial Function in Colon Epithelial Cells to Protect L-Cells from Necrosis in Preservation of GLP-1 Secretion
Authors: YE JIANPING , LE JIAMEI , SUN YONGNING 
Published: June 2018

Berberine (BBR) was reported to preserve the colon function in GLP-1 secretion in obese rodents through the butyrate-GPR43 pathway. However, the mechanism remains largely unknown except the pathway. Here, we tested BBR activity in the inhibition of clone epithelial necrosis in diet-induced obese mice. BBR was administrated in DIO mice through dietary supplementation for 8 weeks. Energy balance, insulin sensitivity and intestine mucosal function were monitored. Mitochondria were examined in the large intestine epithelial cells for structure and function to understand cell death. Mitochondrial structure was examined under the transmission electron microscopy and the function was determined using Seahorse XF24. Gut microflora was examined by Miseq sequencing and the fecal short chain fatty acids (SCFAs) were examined using gas chromatograph (GC). An increase in epithelial necrosis was observed in the colon mucosa together with a reduction in GLP-1 secretion and expression in DIO mice. Cristae loss and membrane rupture were observed in the mitochondrial structure of the colon epithelial cells. A disbalance of mitochondrial complexes was observed with an elevation in the complex I activity, and a fall in the complex II and IV activities. The abundance of short chain fatty acids were decreased along with the dysbiosis in the DIO mice. All of those alterations were corrected in DIO mice together with glucose disorder by the BBR treatment. The data suggest that BBR may protect the colon epithelial cells from necrosis in DIO mice to preserve GLP-1 secretion function. The effect was mediated by restoration of mitochondrial function from the disbalance among the complex I, II and IV. The direct and indirect effects of BBR are discussed.

Disclosure
J. Ye: None. J. Le: None. Y. Sun: None.
Association between Vitamin D and Metabolic Indexes in Patients with Polycystic Ovary Syndrome
Authors: SHANMEI SHEN , JIAYI LIU , YIKUN LI , CHENGCHENG QIAO , JIAMIAO YANG , BI YAN , ZHU DALONG 
Published: June 2018

Objective: The aim of this study was to investigate the effect of vitamin D on the metabolic characteristics of polycystic ovary syndrome(PCOS) and its mechanism.
Methods and Results: 155 cases of PCOS patients and 74 non-PCOS women withmatched age and BMI were enrolled in this study.Data were collected from May 2016 to November 2017. Plasma 25-hydroxyvitamin D[25(OH)D], metabolic markers, and sex hormones were measured. Homeostasis model assessment(HOMA-IR), triglyceride(TG), testosterone(T), free androgen index(FAI) and uric acid(UA) were significantly increased(P&lt;0.05) while 25-(OH)D, high-density lipoprotein cholesterol (HDL-C) and sex hormone binding globulin(SHBG) were lower(P&lt;0.05) in PCOS than non-PCOS. Body mass index(BMI), fasting plasma insulin(FINS), HOMA-IR, TG, total cholesterol(TC) and T,FAI were higher(P&lt;0.05) in Low-Vitamin D group than High-Vitamin D group. Postprandial plasma glucose(PPG) and postprandialplasma insulin(PINS) were higher(P&lt;0.05) in Low-Vitamin D group than both High-Vitamin D group and Middle-Vitamin D group. Vitamin D was associated with BMI(r=-0.265, P=0.002), SBP(systolic blood pressure)(r=-0.267, P=0.002), HOMA-IR(r=-0.265, P=0.001),PINS(r=-0.252, P=0,002), TG(r=-0.265, P=0.001) and FAI(r=-0.211, P=0.027) in women with PCOS. However, after BMI was adjusted, vitamin D was no longer associated with these indexes. Vitamin D inoverweight/obese women with PCOS was lower than normal-weight women(P&lt;0.05). Vitamin D was associated with DBP(r=-0.746,P=0.021) in overweight women with PCOS and was associated with PINS(r=-0.405,P=0.001)in obese women with PCOS.
Conclusion: Serum level of vitamin D was lower in women with PCOS than controls. Vitamin D in overweight/obese women with PCOS was lower than normal-weight women with PCOS. Vitamin D is associated with insulin resistance and cardiovascular disease risk in overweight/obese women with PCOS.

Disclosure
S. Shanmei: None. L. Jiayi: None. L. Yikun: None. Q. Chengcheng: None. Y. Jiamiao: None. Y. Bi: None. D. Zhu: None.
Effect of High-Glucose Concentration on the E3 Ubiquitin Ligase Activity of Mdm2
Authors: GERONIMO RAUL BARZALOBRE 
Published: June 2018

The degradation of p53 occurs via ubiquitin-26S proteosome, after Mdm2 (murine double minute 2) marks p53 with ubiquitins. The concentration and phosphorylation of Mdm2 and p53, greatly affect the ubiquitination rate of p53, by avoiding the recognition and physical interaction between p53 and Mdm2. Phosphorylation of Mdm2 in Ser395 by ATM decreases its ability to direct the degradation of p53. Therefore, we aim to study the effects of high glucose concentrations on the RING domain of Mdm2 and its ubiquitin E3 ligase activity.
We cultured RINm5F cells in RPMI-1640 medium supplemented with 10% fetal bovine serum (v / v) at two concentrations of glucose 5 and 30 mM for up to 72 h, in a humid atmosphere at 37 ° C and 5% CO2. At the end of the treatment the cells were lysed to separate the nuclear and cytosolic fraction. After quantifying the proteins, they were visualized on SDS-PAGE and transferred to a PVDF membrane. Primary antibodies against Mdm2, Mdm2 p-Ser395, ATM, Arf, c-Abl, and ubiquitin were used and revealed using an amplified fluorescence kit from GE.
The results show that the stress caused by high concentrations of glucose stimulates the phosphorylation of Mdm2 in Ser 395 by ATM activation. The phosphorylation of Ser395 alters the RING domain of Mdm2 and decreases its ubiquitin E3 ligase activity, ubiquitination and degradation of p53. Therefore, stress due to increased glucose decreases the ubiquitin E3 ligase activity of Mdm2 by inducing the phosphorylation of this residue, which leads to the stabilization and increase of p53 and the subsequent activation of apoptotic events.
The Ser 395 residue of the RING domain is important for the efficient function of ubiquitin ligase of Mdm2 in β cells under conditions of hyperglycemia.

Disclosure
R. Barzalobre Geronimo: None.
Fetuin A—A Major Player in Lipid-Induced Islet Dysfunction and ß-Cell Apoptosis
Authors: KUNDU RAKESH , MUKHUTY ALPANA 
Published: June 2018

Fetuin-A is a glycoprotein that is secreted from both liver and adipose tissue. Circulating Fetuin-A (FetA) is elevated in type 2 diabetes and causes impaired insulin sensitivity. Few recent findings suggested that FetA is responsible for palmitate induced inflammatory injury to the β-cell via TLR4 pathway. Yet it is unknown whether FetA is associated with β-cell death and reduction of functional islet mass that causes dearth of circulatory insulin in chronic hyperlipidemic condition. To validate this hypothesis MIN6 cells (mice insulinoma cells) were treated with various concentrations of palmitate and /or FetA for 48h and subjected to MTT assay and flowcytometry analysis. The results depicted higher mortality of cells (30-40%) with increasing dose of palmitate (0.25-0.75 mM) and/ or FetA (5-20 mM). Palmitate-FetA treated cells demonstrated substantial reduction in the cell proliferative markers (Akt, cyclin D1) while higher expression of apoptotic markers (Bax, caspase 3 and PARP). Silencing of NF-kB or TLR4 in MIN6 cells restore cell viability on palmitate-FetA treatment indicating significance of TLR4-NF-kB axis in β-cell mortality. Our recent findings demonstrated FetA secretion from MIN6 cells on stimulation of palmitate. Silencing of fetA in MIN6 cells, reduced cell mortality with improved GSIS (1.5 fold). Treatment of MIN6 cells or mice islets with cytokines, such as IL-1β and TNF-α, results β-cell apoptosis mimicking the inflamed conditions of the islets. Co-culture experiments of MIN6 cells with adipocytes or macrophages in presence of palmitate showed elevated levels of cytokines (IL-1β, IL6, TNF-α) in the media and significant number of apoptotic MIN6 cells (20-30%). In vivo analysis of islets structure and function in high fat diet (HFD) fed mice model for a period of 20 weeks demonstrated atrophied islets and accumulation of macrophages. Our present investigation therefore indicated FetA to be a major player in lipid induced pancreatic-β cell death and dysfunction in type 2 diabetes.

Disclosure
R. Kundu: None. A. Mukhuty: None.