bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene Calorie Hypothesis—Proposed to Decode T2DM Pathogenesis
Authors: SHINDE SURESH N. , SHINDE RITUPARNA S. 
Published: June 2018

Insulin and glucose parabolas of OGTT were studied in 1030 subjects, not previously diagnosed as having T2DM. The parabola shape was mainly influenced by adiposity, peripheral Insulin resistance (PIR), beta cell(BC) mass and glucose dose. Fasting hyperinsulinemia(HI) was strongly related to body mass index(BMI). Continued calorie excess(CCE) and BMI along with increase in insulin area under curve, which suggested recruitment of new insulin receptors, acted as BC stressor leading to HI. Fasting HI appears to be a physiological response to incremental BMI, independent of PIR. The rate of rise of insulin (RIR) sustained an angle theta with baseline and both were related to BMI and PIR. The RIR was directly related to rising BMI, fasting insulin and glucose but was inversely related to PIR, 120 min insulin and glucose. CCE affected the Degree of HI whereas PIR affected the Duration of HI (Fig 1). From NoDM category as CCE begins, RIR and theta increase until PIR becomes unmasked. RIR, which is related to PIR, can not rise further. As CCE continues, at variable maximum level of insulin, the individual’s BC capacity, betamax, is reached. The RIR and theta start falling hereafter, until the final values for DM category. Gene-Calorie hypothesis proposes that PIR is an inherited predisposing factor where as CCE with adiposity is an acquired precipitating factor which together cause continuous BC stress and subsequent BC failure leading to T2DM.

Disclosure
S.N. Shinde: Advisory Panel; Self; USV Private Limited, Alkem Laboratories, Lupin Laboratories, Troikka Ltd, IPCA laboratories. R.S. Shinde: None.
Nutritional Regulation of Hunger Circuits in Awake, Behaving Mice
Authors: KNIGHT ZACHARY 
Published: June 2018

Food intake is controlled by specialized neural circuits that monitor nutritional signals from the body, but how nutritional state is represented in the dynamics of these circuits is unknown. I will describe recent work from my lab investigating the dynamics of AgRP neurons, a key neural population that controls hunger. To understand how these cells are regulated by physiologic signals, we have developed a preparation that enables recording of AgRP neuron activity during intragastric feeding of awake, behaving mice. Using this approach, we have shown that AgRP neurons are rapidly inhibited by gastrointestinal nutrients on a timescale of minutes. This rapid feedback is proportional to the number of calories infused, independent of macronutrient identity, and mediated by a combination of hormonal signals. I will discuss general principles of gut-brain communication that have been suggested by these findings as well as key questions that remain to be answered.

Disclosure
Z. Knight: None.
Cell Type–Specific Transcriptional and Epigenetic Profiles from a Rare Neuronal Population within the Arcuate Nucleus
Authors: HEYWARD FRANKIE D. , ROSEN EVAN 
Published: June 2018

The arcuate nucleus (ARC) of the hypothalamus is home to a wide assortment of cell types, many of which uniquely contribute to the regulation of energy homeostasis. Given the high degree of cellular heterogeneity present within the ARC, solutions are needed to achieve a better appreciation for the distinct molecular characteristics of relevant cell types. Past approaches enabling cell type specificity are beset with limitations involving time- and labor-intensiveness, low cellular throughput, and processing-induced changes in cellular state. Moreover, to-date, there exist a paucity of techniques that allow for epigenetic profiling of rare cell types within the brain. The recently developed Nuclear tagging and Translating Ribosome Affinity Purification (NuTRAP) provides an unprecedented ability to obtain either cell type-specific transcriptional or epigenetic profiles. Here we examine the capacity of NuTRAP to obtain cell type specific transcriptional and epigenetic profiles in a relatively small population of energy state-sensitive neurons within the ARC.

Disclosure
F.D. Heyward: None. E. Rosen: None.
Role of ERK in IRF3-Mediated Immune Responses
Authors: CHANG PHOEBE F. , ACEVEDO DANIEL , REYNA SARA M. 
Published: June 2018

Insulin resistance precedes and contributes to the development of type 2 diabetes mellitus, and it is now believed that chronic inflammation is a major contributor to insulin resistance. Both cellular and secreted factors participate in the pathological and physiological changes that occur to promote inflammation. However, the molecular signaling pathways that drive these processes remain elusive. The mitogen activated protein kinase, extracellular signal-regulated kinase 1 and 2 module (ERK1/2), and the transcription factor, interferon regulatory factor-3 (IRF3), are both activated downstream of Toll-like receptor 4 and associated with the development of insulin resistance. We examined whether inhibition of ERK activity blocked IRF3-mediated immune responses. ERK1 and ERK2 isoforms can have different cellular functions; thus, to determine which ERK isoform is involved in the regulation of IRF3 activity, we performed siRNA to knockdown either ERK1, ERK2, or both in RAW 264.7 macrophages and saw 70% knockdown of each ERK1 and ERK2. Knockdown of ERK1 or ERK2 or both blocked IRF3 translocation to the nucleus with LPS treatment (100 ng/ml, 1 hour), as determined by immunofluorescence using an antibody specific for nuclear IRF3. Because phosphorylated and dimerized IRF3 translocates to the nucleus to regulate the transcription of interferon (IFN)-beta expression, we investigated whether ERK1 or ERK2 inhibited IFN-beta release. Macrophages were treated with LPS (100 ng/ml, 6 hour). LPS induced an IFN-beta production of 791±18.0 pg/ml, but knockdown of either ERK1 or ERK2 decreased the release of IFN-beta to 199±12.3 and 282±32.7 pg/ml, respectively. However, double knockdown of ERK1 and ERK 2 had the greatest inhibition of IFN-beta release (121±15.2 pg/ml).
In summary, both ERK1 and ERK2 regulate IRF3 nuclear translocation and signaling in macrophages. We propose that ERK positively regulates IRF3-mediated immune responses and inhibition of ERK signaling will protect against insulin resistance.

Disclosure
P.F. Chang: None. D. Acevedo: None. S.M. Reyna: None.
Glucagon Regulates Hepatic Mitochondrial Biogenesis and Function through Foxo1
Authors: YANG WANBAO , YAN HUI , PAN QUAN , SHEN ZHENG , DAHANAYAKA SUDATH A. , WU CHAODONG , SUN YUXIANG , GUO SHAODONG 
Published: June 2018

The liver is an important organ regulating the energy metabolism, which is tightly governed by multiple hormones. Glucagon secreted from the alpha-cell of the pancreatic islets is a counterregulatory hormone contrary to the action of insulin. In addition to promoting hepatic glucose production, glucagon also plays multiple roles in the liver via its G protein-coupled glucagon receptor. In this study, we found that glucagon attenuated the mitochondrial oxygen consumption and ATP production in primary mouse hepatocytes and decreased hepatic mitochondrial copy numbers. To investigate the molecular mechanisms, we found that glucagon increased the expression of Foxo1 in protein level, which controls the expression of genes responsible for heme biosynthesis, frataxin (FXN) and uroporphyrinogen decarboxylase (UROD). The lower production of heme by glucagon impaired the integrity of electron transport chain (ETC), reducing the heme-dependent complex III (Uqcrc1) and complex IV (mt-Co1). Furthermore, glucagon downregulated mitochondrial transcription factor A (TFAM) and nuclear transcription factors 1 (NRF-1), impairing the mitochondrial biogenesis, which was abolished in Foxo1 deficient primary hepatocytes. These results demonstrate that glucagon inhibits mitochondrial biogenesis and function in a Foxo1-dependent manner.

Disclosure
W. Yang: None. H. Yan: None. Q. Pan: None. Z. Shen: None. S.A. Dahanayaka: None. C. Wu: None. Y. Sun: None. S. Guo: None.
Betatrophin Is Associated with Type 2 Diabetes and Markers of Insulin Resistance
Authors: LEIHERER ANDREAS , MUENDLEIN AXEL , GEIGER KATHRIN , SAELY CHRISTOPH H. , BRANDTNER EVA-MARIA , EBNER JANINE , LARCHER BARBARA , MADER ARTHUR , FRAUNBERGER PETER , DREXEL HEINZ 
Published: June 2018

Betatrophin, also known as ANGPTL8, is secreted by the liver, and its expression is upregulated by nutrition. However, conflicting reports exist on the association of betatrophin with insulin resistance, type 2 diabetes (T2DM) and coronary artery disease (CAD). We therefore measured betatrophin in 553 patients undergoing coronary angiography for the evaluation of established or suspected CAD. T2DM patients (n=161) had higher betatrophin than those without T2DM (12.9±19.0 vs. 9.3±9.0 ng/ml; p=0.005). Betatrophin however did not differ significantly between patients with significant CAD (n=347) and those who did not have significant CAD (10.5±13.5 ng/ml vs. 10.2±11.8 ng/ml; p=0.654). Betatrophin was positively correlated with waist circumference (r=0.150, p=0.001), BMI (r=0.142, p=0.001), fasting glucose (r=0.133, p=0.002), HbA1c (r=0.125, p=0.003), serum insulin (r=0.221, p&lt;0.001), the HOMA index of insulin resistance (r=0.226, p&lt;0.001) and the fatty liver index (r=0.231, p&lt;0.001). In multivariate analysis betatrophin proved to be an independent predictor of diabetes, with a standardized adjusted odds ratio of 1.23 [95% CI 1.01-1.51], p=0.043. We conclude that betatrophin is associated with T2DM and markers of insulin resistance.

Disclosure
A. Leiherer: None. A. Muendlein: None. K. Geiger: None. C.H. Saely: None. E. Brandtner: None. J. Ebner: None. B. Larcher: None. A. Mader: None. P. Fraunberger: None. H. Drexel: None.
Mitogenic Insulin Receptor A Increases in the Rodent Pituitary at the Onset of Puberty
Authors: SALEH FARRAH , TAYLOR HUGH S. , FLANNERY CLARE 
Published: June 2018

Physiological insulin resistance and hyperinsulinemia occurs at the onset of puberty, and is thought to contribute to peri-pubertal growth and development. However, in contrast to IGF-1, little is known about how insulin affects the hypothalamic-pituitary-ovarian (HPO) axis in peri-pubertal girls. Insulin has mitogenic and metabolic activity through splice-variant isoform receptors IR-A and IR-B, respectively. We hypothesize that insulin signaling in HPO tissues contributes to the initiation of puberty, and sought to determine whether IR isoform expression is differentially regulated during puberty.
We evaluated female, FVB/NJ mice: pre-pubertal, 3-4 week old mice (n=4) and peri-pubertal mice (n=7) identified within 24 hours of vaginal opening, an external marker of puberty. IR-A, IR-B, IGF-1R were quantified using a qRT-PCR assay previously validated for receptor comparison. Receptor expression was analyzed by Student’s t-test after log transformation.
IR-A was the predominant IR isoform in the prepubertal hypothalamus, pituitary, and ovary, in a 20:1, 10:1, and 2:1 ratio with IR-B, respectively (p&lt;0.05, all). At puberty, IR-A did not change in the hypothalamus, whereas IR-A increased by 3.6-fold (p=0.059) in the pituitary. IR-B remained largely unchanged during puberty in both the hypothalamus and pituitary (p=NS, respectively). Interestingly, in the peripubertal ovary which has active folliculogenesis and steroid hormone synthesis, both IR-A and IR-B decreased by 33% and 68%, respectively (p&lt;0.03). As expected, IGF-1R levels were higher than IR isoforms in HPO tissues, at both developmental stages. Similar to mitogenic IR-A, IGF-1R increased in the pituitary (p&lt;0.059) during puberty.
An increase in pituitary IR-A expression at the onset of puberty suggests a role for insulin signaling in regulating pituitary hormone production related to puberty. Obesity, a known risk factor for early puberty development in girls, may alter normal insulin signaling in the HPO axis.

Disclosure
F. Saleh: None. H.S. Taylor: None. C. Flannery: None.
Insulin Resistance and Weight Loss in Obese Women with Polycystic Ovary Syndrome Treated with Liraglutide—Single Institution Experience
Authors: CRAWFORD ANDREW , COONEY LAURA G. , JOCHYM NICOLE , DOKRAS ANUJA , AMARO ANASTASSIA 
Published: June 2018

Background: Insulin resistance contributes to the pathogenesis of polycystic ovary syndrome (PCOS) in obese women, but its predictive value for weight loss with liraglutide treatment is unknown.
Methods: Retrospective cohort study of 16 obese (BMI ≥30 kg/m2), nondiabetic women aged 18-42 with PCOS who were seen in a weight loss clinic between November 2014 and November 2016 and prescribed liraglutide (either 1.8 mg/day or 3.0 mg/day based on insurance coverage) and metformin. Maximum weight loss achieved from baseline until 2 to 13 months post-liraglutide initiation was compared. Spearman’s rank correlation was used to establish the relationship between pre-treatment Homeostatic Model for Insulin Resistance (HOMA-IR) and % weight loss. The University of Pennsylvania Institutional Review Board approved the study.
Results: Overall median weight loss was 4.4 kg (-3.4% of initial weight). Median weight loss was -4.7 kg (-3.7%) in women treated with 3.0 mg daily (n=6) and -2.5 kg (-2.0%) in women treated with 1.8 mg (n=10). 6/16 (37.5%) of women experienced &gt;5% weight loss: 2/6 women treated with 3.0 mg daily dosing, and 4/10 women treated with 1.8 mg daily. HOMA-IR at baseline was not associated strongly with % weight loss achieved for all subjects (rs= -0.31, p=0.24), or when stratified to examine those subjects receiving 3.0 mg daily (rs= -0.20; p=0.70) or 1.8 mg daily (rs= -0.36, p=0.31).
Conclusions: In this small study, our findings suggest that insulin resistance at baseline does not strongly correlate with maximum weight loss achieved using liraglutide. Furthermore, our study suggests that liraglutide is an effective tool for weight loss. Overall, 37.5% of women achieved &gt;5% weight loss from baseline, meeting the FDA’s categorical efficacy target for weight loss medications.

Disclosure
A. Crawford: None. L.G. Cooney: None. N. Jochym: None. A. Dokras: Consultant; Self; Fractyl Laboratories, Inc. A. Amaro: Consultant; Self; Novo Nordisk Inc., Andrew Technologies, LLC.
Gut Microbiota as a Potential Target for Treatment of Polycystic Ovary Syndrome
Authors: ZHANG BINGJIE , SHEN SHANMEI , BI YAN , ZHU DALONG 
Published: June 2018

Objective: Emerging evidence has linked the gut microbiota with human metabolic diseases. This study is aimed at investigating the role of gut microbiota and the potential effect of gut microbiota modulation in polycystic ovary syndrome (PCOS).
Methods: We performed an observational study in a cohort of reproductive women with and without PCOS. Subjects with previous history of gastrointestinal surgery or diseases (such as inflammatory bowel disease), taking antibiotics within 3 months prior to the study were excluded. Diagnosis of PCOS was done according to Rotterdam criteria. A total of 78 women were finally included, information regarding their clinical history, symptoms, anthropometric measurements and laboratory data were collected. Fecal bacteria profiling was conducted using 16S rRNA sequencing method. Individuals with PCOS were then randomized to metformin or probiotics (containing Lactobacillus and Bifidobacterium) treatment for 3 months.
Results: We identified that women with PCOS had lower fecal bacteria gene counts, lower bacterial diversity and higher β diversity, indicating lower gene richness and a more heterogeneous gut microbiota community structure. In addition, serum lipid profiles (including total cholesterol, HDL-cholesterol), androgen levels and indexes of insulin resistance (HOMA-IR, Matsuda insulin sensitivity index) were closely correlated with Prevotellaceae, Ruminococcaceae and Lachnospiraceae, which are dominant bacteria in energy metabolism. Furthermore, treating PCOS patients with metformin or probiotics both improved their menstruation cycles, decreased androgen levels and alleviated insulin resistance. Meanwhile, there were significant correlations between changes in metabolic parameters and shifted bacterial populations.
Conclusion: Our findings identify the gut microbiota dysbiosis in PCOS and suggest that it may be possible to intervene in PCOS by targeting the gut microbiota.

Disclosure
B. Zhang: None. S. Shen: None. Y. Bi: None. D. Zhu: None.
Serum Retinol Binding Protein 4 Was Positively Associated with Insulin Resistance and Decreased after Laparoscopic Sleeve Gastrectomy in Chinese Obese Patients
Authors: WANG XINGCHUN , LI LIANG , ZHU CUILING , GAO JINGYANG , QU SHEN 
Published: June 2018

Retinol binding protein 4 (RBP4) is implicated in the regulation of energy metabolism and insulin sensitivity. Laparoscopic sleeve gastrectomy (LSG) has been proven effectively in treating T2DM and other obesity-related comorbidities. We aimed to investigate the association between RBP4 with insulin resistance and the change of RPB4 levels after laparoscopic sleeve gastrectomy (LSG) in Chinese obese patients. Eighty-two obese patients (34 males and 48 females) were enrolled and 30 subjects (10 males and 20 females) underwent LSG in this study. Anthropometric and glucose metabolic parameters were measured. Serum RBP4 levels were detected by enzyme-link immunosorbent assay. In all subjects, serum RBP4 levels were positively associated with BMI, OGTT blood glucose at 0, 30, 120, 180mins, fasting insulin, fasting C-peptide and HOMA-IR at baseline (all P&lt;0.05). Moreover, HOMA-IR was significantly decreased at 3 and 6 months after LSG (all P&lt;0.001). Intriguingly, serum RBP4 levels were also reduced from baseline to 3 and 6 months after LSG (from 43.20±14.27mg/l to 33.00±12.35mg/l to 31.87±9.90mg/l, all P&lt;0.01).
In conclusion, RBP4 is closely associated with glucose metabolism and insulin resistance in Chinese obese patients. The decreased RBP4 levels may partly account for the improved insulin sensitivity in obese subjects after LSG.

Disclosure
X. Wang: None. L. Li: None. C. Zhu: None. J. Gao: None. S. Qu: None.
Association between IGF1/IGFBP3 with Lipid Metabolism and Chronic Low-Grade Inflammation and Alteration after Laparoscopic Sleeve Gastrectomy in Chinese Obese Subjects
Authors: LI LIANG , WANG XINGCHUN , GAO JINGYANG , QU SHEN 
Published: June 2018

Some studies have demonstrated the disturbance of IGF1/IGFBP3 axis in endocrine-metabolic diseases. We aimed to investigate the association between IGF1/IGFBP3 with glucose-lipid metabolism and chronic low-grade inflammation and the changes after laparoscopic sleeve gastrectomy (LSG) in Chinese obese patients. Thirty-six obese subjects were enrolled. Anthropometric data, routine laboratory biochemical parameters and IGF1/IGFBP3 levels were evaluated at baseline and 3 months after LSG. Serum total IGF1 and IGFBP3 levels were measured by enzyme-link immunosorbent assay and molar ratio of IGF1/IGFBP3 is represented as free IGF1 levels. In all subjects, total IGF1 was positively correlated with HDL-c (P&lt;0.05), negatively with weight, BMI, waistline, hipline, waist/hip ratio, C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α) (P&lt;0.or P&lt;0.01). Free IGF1 was negatively correlated with hipline, triglyceride (TG), CRP and TNF-α (P&lt;0.or P&lt;0.01). IGFBP3 was positively correlated with TG and free fatty acids (FFA) (P&lt;0.or P&lt;0.01). Both total IGF1 and IGFBP3 levels were significantly decreased after LSG (from 166.54±64.44ng/ml to 143.02±69.09ng/ml, P=0.048 and from 2556.54±756.99ng/ml to 2051.89±618.61ng/ml, P&lt;0.001, respectively, and more reduction in IGFBP3 levels of 19.74%), while an increased tendency of free IGF1 levels was observed. In addition, changes of total IGF1/free IGF1 were negatively related to changes of CRP and TNF-α (P&lt;0.or P&lt;0.01), and change of IGFBP3 was positively related to change of FFA (P&lt;0.05).
In conclusion, the IGF1/IGFBP3 axis is closely associated with lipid metabolism and chronic low-grade inflammation in Chinese obese patients. Decreased IGFBP3 and increased free IGF1 may partly account for the improved lipid metabolic and chronic low-grade inflammatory profiles after LSG.

Disclosure
L. Li: None. X. Wang: None. J. Gao: None. S. Qu: None.
Glycemic and Metabolic Effects of Liraglutide as Additive Treatment to Different Therapeutic Regimens in Type 2 Diabetes Patients Followed in Primary Care Clinics
Authors: ALHARBI TURKI , TOURKMANI AYLA , ALTWAIJRI SULAIMAN , KOFI MOSTAFA 
Published: June 2018

Background: Liraglutide improved metabolic derangement in type 2 diabetes (T2D). The study aimed to measure changes in glycemic and metabolic parameters after addition of liraglutide in obese insulin-resistant T2D patients
Methods: liraglutide was added to 45 Adult T2D patients, who were on 4 regimens as follows:18 on Sulphonylurea(SU), 9 on SU and Basal insulin, 3 on basal insulin and 15 on multiple daily insulin injections(MDIs). Five patients had history of cardiovascular diseases (CVD).The cohort was followed for 6 months and Liraglutide dose 0.6 escalated to 1.2 mg based on patient tolerance. Glycemic, metabolic and anthropometric parameters were measured every 3 months
Results: Mean age and T2D duration were 51.5±12.9 and 11.6±1.6 years, respectively. Body weight significantly reduced from 98.7kg to 96.0kg, p&lt; 0.001, with a mean difference of 3.39kg ± 5.6kg. Systolic blood pressure reduced from 131.7mmHg to 126.6mmHg (Diff. 6.1mmHg), p = 0.015 while Diastolic blood pressure reduced from 73.3mmHg to 68.6mmHg (Diff. 4.7mmHg), p = 0.026. Most HbA1c reduction observed in the liraglutide 1.2 mg dose group with changes from 9.8% to 8.2% (Diff. 1.6%); and also the most weight reduction observed in the 1.2 mg liraglutide dose group with changes from 103.3kg to 99.7kg (Diff. 3.6kg) compared to 0.6 and 1.8 mg dose groups. HbA1c reduction was largest in MDIs group from 10.2 to 8.6% (Diff. 1.6%). Meanwhile, the most weight reduction noticed in the treatment group on SU and Basal insulin from 97.2kg to 92.8kg (Diff. 4.4kg). Interestingly, patients with CVD had improved HbA1c with changes from 10.62% to 9.77% (Diff. 0.85%) and weight from 86.96kg to 85.72kg (Diff. 1.24kg) without evident hypoglycemia.
Conclusions: Addition of liraglutide to different T2D therapeutic regimen in obese Insulin- resistant patients showed significant improvement in HbA1c, weight, and Blood pressure. These results support the use in primary care clinics.

Disclosure
T. Alharbi: None. A. Tourkmani: None. S. Altwaijri: None. M. Kofi: None.