bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gender and Age Variations in Obesity in the Jackson Heart Study
Authors: CORREA ADOLFO , GAO YAN , BROWN LAVONNE D. , BELL RONNY A. , BERTONI ALAIN 
Published: June 2018

In 2013-2014 in the U.S., the prevalence of obesity (body mass index (BMI)≥30 kg/m2) among African Americans was 38.2% in men and 57.2% in women, decreasing after age 60 in men but not in women. We used data from the Jackson Heart Study (JHS) to examine gender- and age-variations in prevalence of obesity as defined by BMI, waist circumference (WC), and waist-to-height ratio (WHtR). Based on data from JHS Visit 3 (2009-2013), we conducted a cross-sectional analysis of prevalence of obesity defined by BMI (≥30), WC (&gt;88 cm among women and &gt;102 cm among men), and WHtR (&gt;0.5) by age and gender. We used logistic regression to evaluate associations of obesity defined by BMI (ref: BMI&lt;25), WC (ref: ≤88 cm for women and ≤102 cm for men) and WHtR (ref: ≤ 0.5) with gender and age, adjusted for physical activity. JHS Visit 3 participants (n=3680) were 64% female and had a mean age of 62.2 years. Prevalence of obesity defined by BMI for age groups 20-49, 50-59, and ≥60 years was 67%, 67%, and 59%, respectively (p=0.005) among women; and 58%, 48%, and 40% respectively (p&lt;0.001) among men. For the same age groups, the prevalence of obesity defined by WC was 82%, 83%, and 83%, respectively (p=0.732) for women, and 48%, 51% and 47%, respectively (p=0.540) for men; and by WHtR was 91%, 94%, and 94%, respectively (p=0.127) for women, and 87%, 87%, and 89%, respectively (p&lt;0.001) for men. Age- and physical activity-adjusted odds ratio (aORs) for obesity among women compared to men were 2.2 (95% CI: 1.8-2.7) when based on BMI, 5.2 (95% CI: 4.5-6.1) when based on WC, and 2.0 (95% CI: 1.5-2.5) when based on WHtR. For women, physical activity-aOR for obesity per 1-year increment in age was 0.96 (95% CI: 0.95-0.97) when based on BMI but did not differ from the null when based on WC or WHtR. For men, similar physical activity-aORs for obesity per 1-year increment were observed. For both women and men, prevalence of obesity defined by BMI decreased with age but not when defined by WC or WHtR. Age-related decreases in obesity defined by BMI may not reflect decreases in obesity defined by WHtR.

Disclosure
A. Correa: None. Y. Gao: None. L.D. Brown: None. R.A. Bell: None. A. Bertoni: Other Relationship; Self; Merck & Co., Inc..
Constitutively Active Grp1 Promotes Basal Glucose Transport into White Adipose and Enhances Insulin Sensitivity in High-Fat Fed Mice
Authors: COPPS KYLE D. , LI JIAN 
Published: June 2018

Insulin-stimulated phosphorylation of Grp1 (general receptor for phosphoinositides; a.k.a Cyth3, cytohesin3) in cultured adipocytes is known to promote recycling of insulin-regulated glucose transporter (Glut4)-containing vesicles from the endosome to plasma membrane, and to enhance glucose uptake thereafter. We found that Cre-dependent expression of a constitutively active form of Grp1 (caGrp1) specifically increased basal glucose uptake into WAT of young chow-fed mice, without altering Akt phosphorylation or insulin-stimulated uptake. Although early growth and glucose homeostasis in chow-fed caGrp1 mice were normal, caGrp1 mice fed a high fat diet (HFD) became markedly less adipose, and showed improved glucose tolerance and insulin sensitivity vs. Cre-negative controls. Fasting insulinemia in HFD-fed caGrp1 mice was lower, whereas circulating adiponectin was higher, and FGF-21 and leptin were unchanged. Hepatic lipid disposition in HFD-fed caGrp1 mice was comparable to that in controls, though circulating and liver free fatty acids were slightly lower. However, epigonadal WAT from caGrp1 mice showed markedly reduced staining for inflammatory marker CD68, and adipocyte size was also significantly greater. Collectively, these features distinguish caGrp1 mice from those with adipose-specific over-expression of Glut4 described by others, but remain compatible with an adipose-specific basis of improved systemic insulin sensitivity. Given recently improved understanding of the structural/functional changes induced in Grp1 via Akt phosphorylation, drug-based activation of Grp1 in WAT might prove an attractive route by which to favorably alter systemic insulin sensitivity and glycemia.

Disclosure
K.D. Copps: None. J. Li: None.
Regulation of Insulin Sensitivity by Phosphorus
Authors: LIN YI , BERGER LINDSEY , SUN ZHONGJIE 
Published: June 2018

Dietary phosphorus excess as a result of the ever growing consumption of highly processed foods has been associated with developments of ageing related diseases such as diabetes and obesity in the general human population. Insulin resistance is the main feature of aged human population especially in patients with type 2 diabetes and some people with obesity. Thus, the study of a low phosphorus diet on glucose homeostasis such as insulin resistance and glucose tolerance is of great interest. Here, we investigated glucose homeostasis in male and female 129Sv mice fed with low phosphorus diet (0.2% of Pi) vs. control diet (0.4% of Pi). Interestingly, the fasting basal glucose level dropped significantly in male mice after being fed with low Pi diet for 4 weeks. In addition, low Pi diet significantly enhanced insulin sensitivity in both male and female mice. Furthermore, low Pi diet lowered serum Pi levels in mice of both genders without interrupting the growing pattern of body weights during the 10-week feeding period. Examination of proteins with Western Blot revealed that low Pi diet significantly enhanced insulin receptor β (IRβ) levels in skeletal muscles. In vitro experiments indicated that low Pi enhanced and high Pi inhibited insulin signals such as tyrosine phosphorylation of IRβ (Tyr1150/1151) and serine phosphorylation of Akt (Ser473) in primary culture of human skeletal muscle cells (HSkMCs). In addition, low Pi increased and high Pi decreased insulin-induced glucose uptake in HSkMCs. Therefore, these data indicate that low Pi diet regulates glucose homeostasis, partly via enhancing insulin sensitivity through upregulating insulin signals and insulin-induced glucose uptake in skeletal muscles.

Disclosure
Y. Lin: None. L. Berger: None. Z. Sun: None.
Actions of Apolipoprotein A-IV on Insulin-Independent Glucose Control and Activation of Akt in Mouse Liver
Authors: HE JING , ZHAO JING , YANG ZIYU , ZHANG JIANBO , WEI SHUGUANG , LI SHENGBIN , LI XIAOMING 
Published: June 2018

Insulin resistance is a risk factor for type 2 diabetes, fatty liver and metabolic syndrome. We reported previously that apolipoprotein A-IV (ApoA4) increased insulin secretion, insulin sensitivity and improved glucose uptake in adipocytes by PI3K-Akt pathways. Whether insulin sensitivity is improved by ApoA4 in mouse liver remains unclear. Here we used mice as well as hepatocytes to investigate the action of ApoA4 on glucose control and hepatic Akt activation. Liver tissues were from lean mice 2 h after a single ip injection of recombinant mouse ApoA4 (n = 5 per group) and tissue lysates were separated by Western blotting with anti-pAkt antibody. Primary mouse hepatocytes were cultured for glucose-uptake experiment and pAkt analysis after ApoA4 stimulation. Approach to block insulin secretion transiently in insulin-resistant DIO mice (6wk-HFD) and lean mice by propranolol and epinephrine was used by co-administration with glucose after a single ip injection of ApoA4 prior to being sacrificed for the liver. Treatment of the mice with ApoA4 for 2 h increased Akt phosphorylation from liver in dose-dependent in the basal state. In time and dose-dependent manner, direct action of ApoA4 on Akt activation in primary mouse hepatocytes too indicates this effect was insulin independent. ApoA4 treatment also increased [3H]-2-deoxyglucose uptake by primary mouse hepatocytes. The contributions of ApoA4 on insulin-independent glucose disposal was verified with insulin blocking. ApoA4 to an equal extent of direct insulin-independent and insulin-dependent, enhanced blood glucose clearance in both insulin-resistant DIO mice and lean mice. With the glucose challenge, ApoA4 treatment resulted in an increase in Akt phosphorylation in liver, heart and brown adipose tissue in insulin-dependent in lean mice, but which was in insulin-independent only in liver in DIO mice. Data imply ApoA4 as a novel antidiabetic drug to treatments of diabetic diseases.

Disclosure
J. He: None. J. Zhao: None. Z. Yang: None. J. Zhang: None. S. Wei: None. S. Li: None. X. Li: None.
Pharmacologic Uncoupling of Skeletal Muscle Mitochondria Promotes Glucose Metabolism
Authors: HULL MICHAELA E. , AXELROD CHRISTOPHER L. , FITZGERALD KELLY M. , SACKS JESSICA , KIRWAN JOHN P. 
Published: June 2018

Mitochondrial uncoupling was one of the earliest pharmacologic approaches to the treatment of obesity-related diseases. However, low mitochondrial specificity and negative off-target effects limited the viability of such agents. BAM15 is a small molecule recently identified for its potent ability to uncouple mitochondria. Thus, the purpose of this investigation was to explore the physiological effects of BAM15 on skeletal muscle mitochondrial function and glucose metabolism. C2C12 myotubes were incubated with either vehicle or BAM15 at varying concentrations for 16 hours. Cell viability was assessed by detection of dehydrogenase activity. Cytotoxicity was measured by a Caspase 3/7 activity assay. Glucose uptake was measured using [3H]-2-deoxy-D-glucose in the presence and absence of insulin. Oxygen consumption rates were measured using an XF24 extracellular flux analyzer. Cells were harvested for the assessment of plasma membrane GLUT4 and protein signaling via Western blot. Cells treated with BAM15 were viable up to 100 μM, and lacked toxicity up to 50 μM, compared to vehicle. BAM15 significantly increased glucose uptake (P&lt;0.05) at concentrations as low as 6.25 μM. Concentrations of 25 μM and above exhibited a 2-4 fold greater glucose uptake than insulin (P&lt;0.05), which saturated at 50 μM. BAM15 significantly increased basal oxygen consumption (P&lt;0.05), while markedly reducing coupling efficiency (P&lt;0.05). BAM15 upregulated primary energy homeostasis pathways via activation of AKT (t3and s473), AS160 (t642), and AMPK (t172). Additionally, BAM15 increased plasma membrane GLUT4 translocation (P&lt;0.05). BAM15 is a pharmacologically active compound with low toxicity and mitochondrial specificity capable of inducing glucose metabolism in skeletal muscle. These data provide compelling evidence for future investigation of BAM15 as a potential treatment for diabetes and other obesity-related metabolic diseases.

Disclosure
M.E. Hull: None. C.L. Axelrod: None. K.M. Fitzgerald: None. J. Sacks: None. J.P. Kirwan: None.
Isoform-Selective Targeting of Facilitative Glucose Transporters with Small Molecule Inhibitors
Authors: HEITMEIER MONIQUE , HRESKO RICHARD C. , SHANMUGAM MALA , HRUZ PAUL W. 
Published: June 2018

There are currently 14 known mammalian facilitative glucose transporters (GLUTs) that serve a variety of critical roles in maintaining glucose homeostasis. The ability to potently target glucose transport in an isoform-selective manner is of paramount importance to investigate the normal function of these transporter isoforms and their individual contributions to disease pathogenesis. A number of GLUT isoform-selective small molecule inhibitors have been identified. To investigate the structural basis of GLUT inhibition and facilitate further refinement of the efficacy and selectivity of these antagonists, we performed kinetic analysis of the effects of WBZ-117, C-20, BAY-876 and several HIV protease inhibitors, on 3H-2-deoxyglucose uptake into cell lines selectively over-expressing GLUT1, GLUT4 or a T30I H160N GLUT1 mutant transporter. Several important findings were made: 1) based on Ki(app) measurements, indinavir, lopinavir, WZB-117 and C-20 selectively inhibit GLUT4 13-55 fold vs. GLUT1. Although structurally divergent, the potency of these 4 compounds against GLUT1 can be markedly enhanced to levels approximating those for GLUT4 by substituting just two GLUT1 amino acids located in the glucose permeation pathway to those found in GLUT4 (T30I and H160N); 2) nelfinavir is a weak GLUT4 inhibitor but acts as a GLUT1 activator, increasing transport activity 1.4-fold; 3) saquinavir selectively inhibits GLUT4 and the T30I H160N GLUT1 mutant, and exhibits complex kinetic patterns in the mutant cell line consistent with a two site model for partial inhibition; 4) kinetic analysis revealed that selective GLUT1 inhibitor, BAY-876, is a noncompetitive inhibitor of this transporter. Taken together, these data provide key structural insights into the ability of small molecules to alter GLUT function that will aid in the development of novel isoform-selective drugs for glucose-dependent diseases.

Disclosure
M. Heitmeier: None. R.C. Hresko: None. M. Shanmugam: None. P.W. Hruz: None.
Modeling the Spectrum of Human Insulin Resistance Using Induced Pluripotent Stem Cells
Authors: LEBASTCHI JASMIN , BATISTA THIAGO M. , CARCAMO-ORIVE IVAN , KROOK ANNA , ZIERATH JULEEN R. , KNOWLES JOSH , RONALD KAHN C. 
Published: June 2018

Induced pluripotent stem cells (iPSCs) represent a unique model to study the genetic components of insulin resistant states in vitro and can be studied in both the undifferentiated and differentiated state. In prior studies we have shown that iPSCs from patients with insulin receptor mutations exhibit altered insulin signaling with reduced insulin-stimulated phosphorylation of IR, IRS, and AKT in iPS-derived myotubes compared to healthy subjects and have reduced insulin stimulation of proliferation and gene expression. We now use iPSCs to characterize the insulin response of type 2 diabetics (T2D) and nondiabetic individuals before and after differentiation to skeletal muscle. The iPSCs from a subgroup of the nondiabetic individuals were further divided into those in the upper and lower quartiles of insulin resistance as determined using steady-state plasma glucose (SSPG) methodology. We find that iPSCs from insulin sensitive controls, insulin resistant (IR) nondiabetics and from patient with type 2 diabetes exhibited similar levels of pluripotency markers and showed similar changes in markers of muscle differentiation through the satellite cell-like and myoblast/myotube stage. This was true for iPSC derived from blood cells and from muscle biopsies. Insulin-induced activation of early signaling steps including phosphorylation of IR, IRS, AKT, ERK and GSK3 showed dose-responsive phosphorylation in the iPSC, as well as myotube stage with significant 10 nM and 100 nM insulin. Importantly, iPSCs differentiated into satellite-like cells displayed insulin resistance at the level of AKT phosphorylation in both the T2D and IR patients (p=0.0134 and p=0.0352). There was also decreased GSK3 phosphorylation in cells from T2D patients (p=0.0325). Thus, iPSC-derived muscle satellite-like cells from T2D and nondiabetic IR individuals retain defects in AKT and GSK3 phosphorylation indicating a level of a genetic or persistent epigenetic signature of insulin resistance in vitro.

Disclosure
J. Lebastchi: None. T.M. Batista: None. I. Carcamo-Orive: None. A. Krook: None. J.R. Zierath: None. J. Knowles: None. C. Kahn: Advisory Panel; Self; CohBar, ERX Therapeutics, AntriaBio, Inc.. Board Member; Self; Kaleio Biosciences.
DJB Surgery Improved the T2DM Rats Glucose Homeostasis, Elevated the Glucose Utilization, and the GLUT3 Expression in Brain
Authors: PAN RUIYAN , LI NA , ZHAO TINGKUN , WANG HUAIJIE , JIANG BIN , YAN QINGTAO , GAO ZHIQIN , QU MEI-HUA 
Published: June 2018

Duodenal-jejunal bypass surgery (DJB) is a experimental surgical procedure to study the mechanism of gastric surgery in T2DM treatment.
Methods: T2DM rats induced by high glucose high fat food and low dose streptozotocin (STZ) injection were randomly divided into 2 groups: T2DM group and DJB surgery group (T2DM-DJB).Wistar rats were used as normal control. The fasting blood glucose and HbA1C were measured. Glucose utilizationin the brain was detected by small animal positron emission tomography (PET) using [18F]-fluorodeoxyglucose ([18F]-FDG).GLUT1, GLUT3 expression in the brain were measured by Q-RT-PCR.
Results:DJB surgery significantly decreased the fasting blood glucose and Hb1Ac of the T2DM rats. [18F]-FDG uptake (standardized uptake values (SUV)mean)in the brain was elevated siginificantly 4 weeks after DJB (Wistar vs. T2DM vs. T2DM-DJB: SUVmean value 1.30±0.27 vs. 0.59±0.10 vs. 1.55±0.31, P&lt;0.001). Q-RT-PCR showed that GLUT3 expression in the brain significantly increased 4 weeks after DJB while T2DM rats decreased. This study indicates that the improvement of glucose utilization in the brain plays an pivotal role in DJB treatment of T2DM.

Disclosure
R. Pan: None. N. Li: None. T. Zhao: None. H. Wang: None. B. Jiang: None. Q. Yan: None. Z. Gao: None. M. Qu: None.
The Risk of Breast Cancer in Women with Diabetes
Authors: BOTA MARIA , AUTIER PHILIPPE , BOYLE PETER 
Published: June 2018

Some observational studies have suggested an increased risk of breast cancer (BC) among diabetic patients. A meta-analysis was performed to assess the risk of BC in diabetic patients compared to nondiabetic patients. Studies were selected if they had a prospective design. Studies that compared BC incidence in women with diabetes to the incidence in the general population were excluded. Summary relative risks (SRR) were computed using a random-effect model. Eighteen studies were included in the meta-analysis, including 28,230,143 person-years of follow-up and 320,111 BC cases. A significantly increased risk of BC among diabetic patients compared to nondiabetic patients was found: SRR=1.13 (95% CI: 1.04, 1.24). There was a large amount of unexplained heterogeneity of results across studies (I²=95%), but no indication of publication bias. The SRR remained similar when the analysis was restricted to post-menopausal women (SRR=1.12 (95% CI: 0.99, 1.26)). Only two studies reported data in pre-menopausal women. In the 9 studies that adjusted for adiposity, both the SRR and the heterogeneity of results across studies substantially decreased (SRR=1.(95% CI: 0.97, 1.14), I²=21%). In contrast, in the 9 studies that did not adjust for adiposity, both the SRR and the heterogeneity increased (SRR=1.19 (95% CI: 1.01, 1.39), I²=98%). Only two studies included 1,723 and 14 BC cases among type 1 diabetic women. The RR for BC were 0.90 (95% CI: 0.85, 0.94) and RR=1.01 (95% CI: 0.60, 1.71), respectively. This analysis provides evidence for a moderately increased risk of BC in diabetic patients. The effect of the adjustment for BMI on the SRR and on the heterogeneity suggests that the increased BC risk appears to be linked to adiposity, and not to being diabetic. New studies should collect data allowing the assessment of Breast Cancer risk according to the duration of diabetes and treatments that favour weight loss.

Disclosure
M. Bota: None. P. Autier: Other Relationship; Self; Sanofi. P. Boyle: Other Relationship; Self; Sanofi.
Short-Term Weight Loss Undermines Brain Regulation of Food Consumption
Authors: LAM WAI , SEO DONGJU , LACADIE CHERYL , SCHMIDT CHRISTIAN P. , ROSENBERG SAMUEL , HOANG HAI , HWANG JANICE , CONSTABLE TODD , SAVOYE MARY , SINHA RAJITA , SHERWIN ROBERT , BELFORT-DEAGUIAR RENATA 
Published: June 2018

Post-prandial hyperglycemia has been shown to suppress appetite by modulating brain activity. We have observed that after weight loss, obese (OB) individuals exhibit increased hunger and decreased brain responses in regions associated with appetite control during hyperglycemia. This study aimed to investigate whether short-term weight loss can affect brain regulation of food intake during hyperglycemia in obesity.
14 healthy OB subjects (8F/6M, age 46±8 years, BMI 33.4±3.5 kg/m2) underwent functional MRI (fMRI) during a hyperglycemic clamp (200 mg/dl). Blood-oxygen-level-dependent (BOLD) brain activity was assessed while subjects viewed high calorie food pictures. Hunger was rated before and after the scan. Immediately after the scan, subjects had an ad libitum test meal. The study was repeated after an 8 week reduced calorie diet that caused 2.9±2.8 kg weight loss (p=0.002).
Hunger significantly increased during the fMRI-clamp study after the diet (p=0.036), but not before the diet. Total calorie intake at the test meal nearly doubled after weight loss (978±492 vs. 1895±189 kcal, p&lt;0.001). This was associated with a significant decrease in brain activity in regions modulating feeding behavior after the diet (p&lt;0.001, Figure 1). These data suggest that short-term dieting diminishes glucose-induced neural control of appetite and food consumption, which may have important implications for weight loss maintenance.

Disclosure
W. Lam: None. D. Seo: None. C. Lacadie: None. C.P. Schmidt: None. S. Rosenberg: None. H. Hoang: None. J. Hwang: None. T. Constable: None. M. Savoye: None. R. Sinha: None. R. Sherwin: Other Relationship; Self; QuintilesIMS, MannKind Corporation. Research Support; Self; Regeneron Pharmaceuticals, Inc.. Other Relationship; Self; ICON plc. R. Belfort-DeAguiar: Research Support; Self; GlaxoSmithKline plc..
Amygdala Glucose-Sensing Neurons Regulate Glucose Metabolism
Authors: DEVARAKONDA KAVYA , BAYNE MITCHELL , ALVARSSON ALEXANDRA , STANLEY SARAH 
Published: June 2018

Dysfunction of blood glucose produces health problems with profound consequences. In humans, the central nervous system (CNS) plays a vital role in glucose metabolism. The medial and basomedial amygdalar nuclei contain neurons that alter their firing in response to physiological changes in glucose concentrations and express glucokinase (GK), an enzyme thought to act as a glucose sensor in the CNS. However, little is known about the anatomy and function of these neurons. We have found that amygdala neurons express cfos, a marker of neuronal activation, in response to changes in blood glucose. Using a transgenic mouse with Cre recombinase expression in GK neurons and the retrograde tracer pseudorabies virus (PRV), we have also found that GK-expressing neurons in the amygdala are part of a polysynaptic circuit to peripheral endocrine organs. Finally, modulating the activity of amygdala neurons alters both feeding and glucose metabolism. Together, these data support a role for amygdala glucose-sensing neurons in the regulation of glucose metabolism and behaviors that restore circulating glucose levels to normal.

Disclosure
K. Devarakonda: None. M. Bayne: None. A. Alvarsson: None. S. Stanley: None.