bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aquaporins-1 and -3 Play Novel, Distinct Roles in Normal Balanced Insulin Signaling
Authors: WU XIANGDONG , WILLIAMS KEVIN JON 
Published: June 2018

Patients with overnutrition, obesity, the atherometabolic syndrome, and type 2 diabetes exhibit imbalanced insulin action, also called pathway-selective insulin resistance. To control glycemia, they require hyperinsulinemia that then overdrives ERK and hepatic de-novo lipogenesis (DNL).
We discovered an oxide transport chain that is required for balanced insulin action (Atherosclerosis 2016;247:225). The chain, abbreviated “NSAPP”, begins when insulin stimulates NOX4 to generate O2•-. NOX4 hands O2•- to SOD3 for conversion into H2O2. Aquaporins (AQPs) channel this H2O2 to inactivate PTEN. Disruption of any component, from NOX4 up to PTEN, leaves PTEN persistently active, thereby producing the same deadly pattern of imbalanced insulin action seen clinically.
We now sought to identify which aquaporins mediate balanced insulin signaling in hepatocytes.
Four AQPs had been reported to act as pores for H2O2: AQP1, 3, 8, and 9. We found that global inhibition of all APQs with low-dose AgNO3 recapitulated the clinical pattern of imbalanced insulin signaling, i.e., full two-site phosphorylation of ERK (pT202/Y204-ERK); monophosphorylation of AKT (pT308-AKT) with only weak phosphorylation at Ser473; robust phosphorylation of AKT targets leading to DNL; but impaired AKT-mediated phosphorylation of FOXO1 (needed to suppress hepatic gluconeogenesis).
Our knockdown of AQP3 recapitulated this pattern of imbalanced insulin signaling. Knockdown of AQP1 produced the mirror-image: strongly inhibited pT202/Y204-ERK and pT308-AKT, but intact pS473-AKT. Knockdowns of AQP8 or AQP9 did not affect insulin signaling to either site on ERK or AKT. Importantly, immunoprecipitation of AQP3 brought down PTEN, a previously unknown partner of any aquaporin.
Thus, AQP3 participates in the NSAPP oxide transport chain. AQP1 plays an unexpected role, perhaps as a scaffold. Our findings will facilitate unraveling the molecular basis for NSAPP dysfunction in overnutrition and hence imbalanced insulin action.

Disclosure
X. Wu: None. K. Williams: Stock/Shareholder; Self; Hygieia, Gemphire, Inc.. Advisory Panel; Self; Gemphire, Inc..
Dissection of Insulin-Dependent Pathways in Skeletal Muscle under Physiological and Diabetic Conditions
Authors: BATISTA THIAGO M. , MARTIN RUBEN GARCIA , CAI WEIKANG , SUK SUJIN , NOH HYE LIM , KIM JASON K. , RONALD KAHN C. 
Published: June 2018

Insulin signaling regulates growth and metabolism, in part, by regulation of gene expression. To gain more insight into transcriptional pathways activated by physiological levels of insulin in vivo we performed euglycemic insulin clamp in mice at low (4 mU.kg-1.min-1) and high (12 mU.kg-1.min-1) concentrations of insulin and analyzed changes in gene expression in skeletal muscle by RNA-sequencing. At 3 h, low insulin regulated 451 genes while high insulin regulated 1771 genes by at least 1.5-fold (FDR&lt;0.25). Interestingly, the most up regulated pathways in muscle were potential targets of estrogen-related receptor alpha (Esrra) and were related to TCA cycle and oxidative phosphorylation, while the most suppressed genes were targets of FoxO1 involved in autophagy. Insulin also inhibited the expression of over 40 genes involved in mRNA processing/splicing, mostly within the U2 ribonucleoprotein complex, which regulates the assembly and catalytic activity of the spliceosome. To determine how these insulin-dependent pathways might be altered in diabetes, we intersected the clamp gene expression data with gene expression data in streptozotocin (STZ) or high fat diet (HFD) obesity-induced diabetes focusing on genes oppositely regulated by insulin and diabetes. This approach revealed 93 insulin-regulated genes that were dysregulated in STZ and HFD muscle. Most related to TCA cycle and oxidative phosphorylation, however, changes in mRNAs involved in RNA processing/splicing also overlapped in HFD samples, thus indicating potential insulin resistance-specific gene expression signatures. Together these data demonstrate that insulin is a potent regulator of gene expression in vivo altering mRNA diversity through both changes in expression and dysregulation of the spliceosome, with the latter being most prominent in states of insulin resistance. These differences provide unique targets for therapeutic approaches to type 1 and type 2 diabetes involving muscle.

Disclosure
T.M. Batista: None. R. Garcia Martin: None. W. Cai: None. S. Suk: None. H. Noh: None. J.K. Kim: None. C. Kahn: Advisory Panel; Self; CohBar, ERX Therapeutics, AntriaBio, Inc.. Board Member; Self; Kaleio Biosciences.
Adipocyte Overexpression of p55alpha Subunit of Pi3k Improves Systemic Glucose Metabolism in Lean Mice
Authors: CLAYTON ZACHARY S. , MCCURDY CARRIE 
Published: June 2018

Phosphatidylinositol 3-kinase (PI3K), a heterodimeric enzyme composed of a regulatory subunit (p85α/β, p55α/γ, p50α) and a catalytic subunit (p110α/β), is an essential component of the canonical insulin signaling cascade in adipose tissue. Insulin-stimulated PI3K activity is decreased in obese adipose tissue in parallel with a 4-fold increase in p55α abundance; heterozygous deletion of Pik3r1 limits regulatory subunit expression and enhances adipocyte insulin signaling. Additionally, genetic deletion of p55α/p50α in mice has been shown to increase adipocyte glucose uptake and systemic insulin sensitivity. Therefore, we hypothesized that adipocyte-specific p55α overexpression (OX) would reduce adipocyte insulin signaling and decrease systemic glucose tolerance. To test this hypothesis, we generated mice with p55α knock-in at the endogenous ROSA26 locus. The recombination cassette was made by flanking the p55α cDNA and a floxed 4x SV40 polyA STOP signal with FRT and F3. The insertion of Pik3r1 at the ROSA26 locus mediated by Flp-recombinase in ES cells targeted with FRT-PGK-neo-F3 at the ROSA26 locus. The polyA STOP signal was removed by crossing the p55α flox (Fl/Fl) mice with mice carrying Adipoq-cre recombinase (OX). At 12 weeks of age, the metabolic phenotype, glucose tolerance and adipocyte insulin signaling were measured in Fl/FL and OX mice. In adipose tissue, p55α abundance was 7-fold higher in OX compared to FL/FL controls with no difference detected in p85α abundance. Body weight and adiposity was not different between FL/FL and OX mice. Food intake, energy expenditure and the respiratory quotient were not different in OX vs. FL/FL, despite a decrease in total activity in OX mice. Contrary to our hypothesis, glucose AUC calculated from oral glucose tolerance tests was 40% lower (P=0.005) in OX vs. FL/FL. Overall these data suggest that increased expression of the p55α regulatory subunit, in contrast to p85α, enhances PI3K activity and insulin signaling in adipocytes.

Disclosure
Z.S. Clayton: None. C. McCurdy: None.
MEDI0382, a GLP-1/Glucagon Receptor Dual Agonist, Enhances Leptin-Mediated pSTAT3 Induction in Key Neuronal Regions That Regulate Metabolism
Authors: JOUIHAN HANI , BARKHOLT PERNILLE , GRÔNLUND RIKKE , TREVASKIS JAMES 
Published: June 2018

MEDI0382 is a potent GLP-1 and glucagon receptor dual agonist peptide that decreases body weight of obese mice by reducing food intake and enhancing energy expenditure. Here we explored whether MEDI0382 may, in part, mediate its effects on metabolism by enhancing leptin action. Diet-induced obese mice were administered vehicle, MEDI0382 (10 nmol/kg; s.c., q.d.) or vehicle and pair-fed to MEDI0382-treated mice for 10 days (n=15-16/group). During this period MEDI0382 induced 11% body weight loss (p&lt;0.01 vs. vehicle), whereas pair-fed mice lost a similar amount of body weight as MEDI0382 group for first 5 days, but rebounded such that final weight loss was 3% from baseline (p&lt;0.vs. vehicle and MEDI0382). On day 10, half of each group was administered vehicle (PBS) or murine leptin (10 mg/kg) and the mice sacrificed 45 min later. Leptin administration increased circulating leptin levels 20-25-fold above endogenous levels. Levels of phosphorylated STAT3 (pSTAT3), a key marker of leptin signaling, were determined in discrete nuclei of the hypothalamus known to regulate energy homeostasis. Within the arcuate nucleus of the hypothalamus pSTAT3 levels were not significantly stimulated by leptin in vehicle or pair-fed mice (indicative of leptin resistance), but were increased in MEDI0382-treated animals. Furthermore, in the dorsomedial, ventromedial and lateral hypothalamic nuclei leptin was able to stimulate pSTAT3 in vehicle and pair-fed mice, but in MEDI0382-treated mice pSTAT3 levels were even further enhanced (p&lt;0.vs. other leptin-treated groups). While we cannot exclude weight loss per se as a factor, these data support the notion that MEDI0382 may mediate its effects on body weight and glycemic control via enhancing central leptin action.

Disclosure
H. Jouihan: None. P. Barkholt: Employee; Self; Gubra. R. Grônlund: None. J. Trevaskis: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca.
TAp63 in Mature POMC Neurons Regulates Glucose and Energy Homeostasis
Authors: WANG CHUNMEI , HE YANLIN , XU PINGWEN , YANG YONGJIE , XU YONG 
Published: June 2018

TAp63 is a transcription factor that has been reported to be important for energy and glucose homeostasis. However, where and how TAp63 functions is unclear. Chow-fed mutant mice with TAp63 deleted from pro-opiomelanocortin (POMC) neurons showed normal body weight and glucose metabolism in both sex. However, HFD fed male and female mice that lack TAp63 from POMC neurons both showed glucose intolerance (GTT) and insulin resistance independent of body weight. Strikingly, deletion of TAp63 in POMC neurons confers “male-like” diet-induced obesity (DIO) to female mice, but does not affect DIO phenotypes in male mice. In contrast, overexpression of TAp63 in POMC neurons partially prevents DIO in male mice but not in female mice. Here we show that POMC neurons in female mice display higher neural activities and express higher POMC mRNAs compared to male counterparts, and both these enhancements in female POMC neurons are correlated to higher expression levels of TAp63. Further, we found that the deletion of TAp63 reduced POMC neuronal activity and diminished the sexual dimorphism of POMC neural activity by decreasing the responsiveness of ERα-positive POMC neurons to the ERα agonist. Finally, we found that TAp63 binds to the promoter of POMC gene and regulate POMC gene expression in POMC neurons. In addition, the expression of energy homeostasis related genes like SRC-1, ERα and TAp63 target genes Sirt1, AMPKα2, LKB1 were also decreased in mice lacking TAp63 in POMC neurons. Collectively, TAp63 in mature POMC neurons regulates glucose homeostasis and TAp63 is one key molecular driver for the sexual dimorphism in energy homeostasis.

Disclosure
C. Wang: None. Y. He: None. P. Xu: None. Y. Yang: None. Y. Xu: None.
Gemigliptin, a Dipeptidyl Peptidase-4 Inhibitor, Protects against Cardiovascular System in Cardiac I/R Injury and Hypertensive Rats
Authors: PARK JIN-SOOK , NAM DAE-HWAN , BAEK EUN-BOK 
Published: June 2018

Cardiovascular disease (CVD) is implicated in the high morbidity and mortality in diabetic patients. Improvement in cardiovascular complications with maintaining glucose level and managing cardiovascular risk factors is important role. Currently, the impact of hypoglycemic medications on CVD is of increasing importance. Although dipeptidyl peptidase-4 inhibitors (DPP-4), a class of antidiabetic drugs, have pleiotropic protective effects on CVD in experimental studies, it remains undetermined whether gemigliptin has a beneficial effect on ischemia reperfusion (I/R)-induced myocardial injury and hypertension. Therefore, this study was performed to evaluate the effects of gemigliptin in the rat model of myocardial I/R injury and spontaneously hypertensive rats (SHR). Gemigliptin (20 and 100 mg/kg/day) was administered per oral to Sprague-Dawley rats for four weeks before I/R operation. Gemigliptin pretreatment improved hemodynamic function and limited infarction size against I/R injury. Additionally, gemigliptin (0.03% and 0.15%) was mixed into the powdered feed and fed to SHR. Gemigliptin treatment with SHR reversed hypertrophy and improved diastolic function. These results suggest that gemigliptin exerts beneficial effect not only on blood glucose but also on cardiovascular system in cardiac I/R injury and hypertensive rats.

Disclosure
J. Park: Employee; Self; LG Chem. D. Nam: Employee; Self; Korea Institute of Toxicology (KIT). E. Baek: Employee; Self; LG Chem.
Hypothalamic Spexin and Galanin Receptor 2 Are Novel Regulators of Energy Balance in Mice
Authors: HA NA-HEE , KIM NAM HOON , KIM CHANG-HOON , SONG MUN-GYU , LEE HYE-JIN , JIN BO-YEONG , PARK MI-RAE , SEONG JAE YOUNG , KIM SIN GON , KIM DONG-HOON 
Published: June 2018

Spexin is a novel neuropeptide discovered by bioinformatics and has been proposed as a regulator of energy balance. However, its precise role and underlying mechanisms remain unclear. In this study, we investigated the role of spexin and its receptor, galanin receptor 2 (GALR2), in regulation of energy balance in the mediobasal hypothalamus of mice. Administration of spexin into the third ventricle near the hypothalamus (I3V) significantly decreased food intake and body weight with no change in energy expenditure in mice. The central spexin-induced anorexia and weight loss were reinstated by pre-I3V administration of GALR2 antagonist, M871, indicating hypothalamic GALR2-mediated action of spexin in the regulation of energy balance. In addition, we showed that I3V administration of spexin-based selective GALR2 agonist significantly reduced food intake and body weight in a dose-dependent manner with no signs of illness assessed by a conditioned taste aversion test, suggesting a novel role of hypothalamic GALR2 in the regulation of energy balance. Furthermore, we found that activation of GALR2 induced by spexin increased phosphorylation of CREB in the mediobasal hypothalamus of mice and cells overexpressing GALR2 different from galanin, suggesting a ligand-dependent switch of G protein coupled with GALR2. Taken together, these results suggested a critical role of hypothalamic spexin and GALR2 in the regulation of energy balance in mice.

Disclosure
N. Ha: None. N. Kim: None. C. Kim: None. M. Song: None. H. Lee: None. B. Jin: None. M. Park: None. J. Seong: None. S. Kim: None. D. Kim: None.
Novel Function of Increased Ventromedial Hypothalamus (VMH) Norepinephrine (NE) to Block Local VMH Hyperglycemia Sensing Coupled to Increased Insulin Action
Authors: STOELZEL CARL , CINCOTTA ANTHONY 
Published: June 2018

It is well established that local glucoprivation at the VMH stimulates glucose inhibitory neurons and acute noradrenergic activity (NA) therein necessary for the sympathoadrenal counter regulatory response to such glucoprivation. However, paradoxically a wide variety of insulin resistant, glucose intolerant, hyperglycemic animal models exhibit chronic elevation of NA at the VMH. Further, chronic VMH infusion of NE to normal animals leads to insulin resistance and glucose intolerance similar to that observed following sustained exposure to a high fat diet. Since VMH glucose excitatory neurons are activated by physiological postprandial increase in local glucose level to increase peripheral insulin action, these VMH NA findings suggest a novel function of elevated VMH NA to block normal postprandial glucose sensing of VMH glucose excitatory (GE) neurons that potentiate postprandial insulin sensitivity. To test this postulate multi-barreled pipettes with carbon fiber recording electrodes were lowered into the VMH of anesthetized rats (N=10) (age 12 weeks, maintained on standard low fat rodent chow diet) and multi-unit responses (MURs) from the central recording electrode (∼.5 Mω) before and during glucose electro-osmotic injection into the VMH (to preferentially activate GE neurons) were obtained. Changes in MURs to such glucose administration (that were at least 15% above baseline, P&lt;0.05) were compared when such glucose was co-administered with micro-iontophoretically injected NE and such NE treatment significantly and consistently reduced such glucose-induced MURs by 46% (P&lt;0.05). Among those glucose-induced MURs greater than 100% above baseline, this NE inhibition was even greater (50%, P&lt;0.05). These findings are the first to identify a novel role for increased VMH NA in the blockade of normal postprandial VMH glucose sensing that is involved in increasing subsequent post-meal peripheral insulin action.

Disclosure
C. Stoelzel: Employee; Self; VeroScience, LLC. A. Cincotta: Employee; Self; VeroScience, LLC.. Stock/Shareholder; Self; VeroScience, LLC..
Glucagon Regulates Energy Balance via FGF-21 Signaling in the Brain
Authors: NASON SHELLY , KIM TEAYOUN , ANTIPENKO JESSICA P. , PAUL JODI , FINAN BRIAN , DIMARCHI RICHARD , HABEGGER KIRK M. 
Published: June 2018

Glucagon is an essential regulator of glucose and lipid metabolism that also promotes weight loss. Thus, novel therapeutics that stimulate glucagon-receptor (GcgR) signaling are promising for treatment of obesity and diabetes; however, the mechanism(s) underlying these effects are yet to be fully elucidated. We previously identified that hepatic glucagon signaling increases the secretion of another fasting hormone, Fibroblast Growth Factor 21 (FGF-21), also known to be involved in regulating energy balance. We have recently observed that mice deficient for liver FGF-21 (FGF-21δLiver) are partially resistant to the anti-obesity effects of GcgR agonism, clearly implicating hepatic FGF-21 as an essential component of the glucagon’s weight-loss effects. FGF-21 signals through an obligate co-receptor (βKlotho, Klb), with expression limited to adipose tissue, liver, and brain, specifically within the suprachiasmatic nucleus (SCN) of the hypothalamus and the hindbrain. As the hypothalamus has known roles in regulating energy balance, we hypothesized that the anti-obesity action of the glucagon-FGF-21 system signals through a central mechanism. Mice deficient for neuronal Klb (KlbδCNS) are less susceptible to diet-induced obesity than wild type mice (P&lt;0.01), with no observed differences in food intake or energy expenditure. Following chronic GcgR activation via the selective agonist IUB288, KlbδCNS mice exhibit a partial reduction in body weight (12%) in comparison to control mice (19%), suggesting that FGF-21 mediates glucagon’s anti-obesity properties through central action. Consistent with GcgR-stimulated, neuronal FGF-21 signaling, we found that neuronal activation, measured via immunohistochemical analysis of cFos expression, was increased in the SCN following IUB288 injection. Taken together, these data suggest that glucagon mediates part of its anti-obesity properties through FGF-21-KLB signaling in the SCN, and has implications for future treatments against obesity and the metabolic syndrome.

Disclosure
S. Nason: None. T. Kim: None. J.P. Antipenko: None. J. Paul: None. B. Finan: Employee; Self; Novo Nordisk Inc. R. DiMarchi: Employee; Self; Novo Nordisk Inc. K.M. Habegger: Consultant; Self; Glyscend, Inc.. Research Support; Self; Glyscend, Inc.. Consultant; Self; Intarcia Therapeutics, Inc..
Blood Pressure and Mortality in U.S. Adults with Diabetes
Authors: RAGHAVAN SRIDHARAN , HO YUK-LAM , RHEE MARY , VASSY JASON L. , GAGNON DAVID R. , CHO KELLY , WILSON PETER W. , PHILLIPS LAWRENCE S. 
Published: June 2018

Recent clinical trials have led to revised hypertension guidelines, but the relationship between blood pressure (BP) control and mortality in diabetes patients receiving routine care has not been described in a contemporary national U.S. cohort. We studied 130,192 primary care patients in the Veterans Health Administration with diabetes (ICD-9 codes 250.xx + outpatient diabetes prescription), newly started on a BP medication in 2003-2005, and with a mean systolic BP (SBP) &gt;130 mmHg in the year prior to BP drug initiation. Mean on-treatment outpatient SBP in the 2nd year after BP drug initiation was the primary exposure. All-cause and cardiovascular (CV) mortality through 2014 were the primary outcomes; mean follow-up was 9 years. We estimated associations between SBP and mortality using multivariable Cox proportional hazards regression, adjusting for age, sex, race, comorbidities, HbA1c, number of BP drugs, and CV risk factors. Relative to SBP 121-130 mmHg, all-cause and CV mortality were significantly higher in those with an SBP of 100-120 mmHg or &gt;160 mmHg on treatment. All-cause mortality was lowest in those with an SBP of 131-140 mmHg; CV mortality did not differ significantly between those with an SBP between 121 and 160 mmHg.
Conclusions: There was only minor variation in mortality rates for BPs from 121 to 160 mmHg in patients with diabetes and hypertension in routine clinical care, but mortality was higher in those with treated BP &lt;120 mmHg or &gt;160 mmHg.

Disclosure
S. Raghavan: None. Y. Ho: None. M. Rhee: None. J.L. Vassy: None. D.R. Gagnon: None. K. Cho: None. P.W. Wilson: None. L.S. Phillips: Other Relationship; Self; DIASYST Inc.. Research Support; Self; Amylin Pharmaceuticals, Eli Lilly and Company, Novo Nordisk Inc., Sanofi-Aventis, PhaseBio Pharmaceuticals, Inc., Roche Diabetes Care Health and Digital Solutions, AbbVie Inc., Vascular Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., GlaxoSmithKline plc., Pfizer Inc.. Other Relationship; Self; Novartis Pharmaceuticals Corporation, Merck & Co., Inc..