bluuebunny/crossref_metadata_2025_split huggingface dataset:
NFκB Regulation of Mitochondrial Function in Skeletal and Cardiac Muscle
Authors: VALENTINE JOE , LI MENGYAO E. , ZHANG NING , SHOELSON STEVEN E. , MUSI NICOLAS 
Published: June 2018

NFκB is a transcription factor that controls immune and inflammatory processes. In muscle, NFκB has been implicated in regulation of muscle mass/function, metabolism, and mitochondrial function. Yet, NFκB’s role in aging-related changes to skeletal muscle and heart remains less defined. To investigate the role of NFκB in aging skeletal muscle and heart, we study a mouse model (MISR mice) with suppressed NFκB signaling in these tissues. Recently we found that these mice have exacerbated loss of skeletal muscle mass during aging. Here, we report that NFκB suppression caused reductions in skeletal muscle mass as early as 1 month of age. Aging per se (in WT mice) lead to a global downregulation of mitochondrial function (reduced respiration and enhanced reactive oxygen species production) and expression of mitochondrial biogenesis genes in skeletal muscle. Furthermore, suppression of NFκB signaling in skeletal muscle resulted in mitochondrial function defects in early life (4 months old), whereas in aged mice (30-33 months old) it had the opposite effect. Contrary to findings in skeletal muscle, in the heart aging increased mitochondrial respiration and reactive oxygen species production (in WT mice) and NFκB suppression protected against the aging related changes to reactive oxygen species production. We conclude that suppression of the canonical NFκB pathway has antagonistic pleiotropic effects (detrimental in early life and advantageous in aging animals) on mitochondrial function in skeletal muscle, but is beneficial throughout the lifespan in the heart. Furthermore, canonical NFκB signaling regulates muscle development and cellular metabolism at the transcriptional and functional levels.

Disclosure
J. Valentine: None. M.E. Li: None. N. Zhang: None. S.E. Shoelson: Consultant; Self; Par Pharmaceuticals. Stock/Shareholder; Self; Catabasis Pharmaceuticals. N. Musi: None.
Assessment of Proinflammatory Mediators of Beta-Cell Circadian Clock Dysfunction in Diabetes
Authors: JAVEED NAUREEN , RAKSHIT KUNTOL , MATVEYENKO ALEKSEY 
Published: June 2018

Both type 1 and type 2 diabetes are characterized by a decline in β-cell function and mass partly attributed to exposure of β-cells to proinflammatory cytokines. The molecular mechanisms underlying this process are not well understood, however several lines of evidence have linked the circadian clock with regulation of the deleterious proinflammatory effects in diabetes. Therefore, in this study, we assessed the effect of known proinflammatory mediators of β-cell failure in diabetes (IL-1β, TNFα, IL-6, and IFNγ) on the β-cell circadian clock. Through real-time bioluminescence tracking of islets from Per2:luciferase (a key circadian clock gene reporter) knock-in mice, our data revealed that IL-1β (2 ng/ml) diminished β-cell circadian rhythmicity via impairment of the amplitude and the phase of oscillations (p&lt;0.vs. vehicle). This was in contrast to TNFα, IL-6, and IFNγ, which showed either mild suppression or no effect on the β-cell clock. We next assessed the ability of proinflammatory cytokines to modulate Bmal1 and Clock (two main transcription factors in the circadian pathway) gene and protein expression. Interestingly, studies using INS-1 832/13 cells and cadaveric human islets revealed that IL-1β addition (0.2-5 ng/ml) for 24 h significantly reduced Bmal1 (but not Clock) at both the mRNA (∼40-50%, p&lt;0.05) and protein (10-65%, p&lt;0.05) level in a dose dependent manner. In contrast, other cytokines (IL-6, TNFα, and IFNγ) only modestly diminished Bmal1 expression after 24 h. In assessing a molecular link between IL-1β and the β-cell clock, Bmal1 promoter activity was determined using a BMAL1:luciferase expressing INS-1 832/13 stable-transfected cell line. Importantly, IL-1β (0.01-5 ng/ml) showed a dose dependent decrease in Bmal1 promoter activation (up to 90%). This body of work provides the first novel connection between diabetogenic inflammatory cytokines, specifically IL-1β, as the dominant mediator of β-cell clock dysfunction in diabetes.

Disclosure
N. Javeed: None. K. Rakshit: None. A. Matveyenko: None.
Mitophagy Receptor FUNDC1 Links Mitochondrial Quality Control to Muscle–Adipose Dialogue in Alleviating Dietary Obesity
Authors: FU TINGTING , XU ZHISHENG , LIU LIN , LIANG XIJUN , ZHOU DANXIA , GUO QIQI , XIAO LIWEI , GAN ZHENJI 
Published: June 2018

The quality of mitochondria in skeletal muscle is essential for maintaining metabolic homeostasis during adaptive stress responses. However, the precise control mechanism of muscle mitochondrial quality and its physiological impacts remain unclear. Here, using two independent skeletal muscle-specific knockout mouse lines, we demonstrate that FUNDC1, a mediator of mitophagy, plays an essential role in controlling muscle mitochondrial quality as well as metabolic homeostasis. Mice with FUNDC1 deficiency in skeletal muscle (FUNDC1 mKO) showed decreased muscle fat utilization and endurance capacity (∼40%) compared to WT littermates during exercise. Analysis of biochemical markers of mitophagy revealed a marked decrease in mitochondrial localization of LC3-II and P62 protein levels, and this caused impaired mitochondrial respiration capacity. FUNDC1 loss-of-function studies in primary skeletal myocyte recapitulated defective mitophagy and impaired mitochondrial energetic as observed in FUNDC1 mKO muscle. Surprisingly, mice lacking muscle FUNDC1 were resistant to high fat diet (HFD) induced obesity despite reduced muscle mitochondrial energetics. Moreover, glucose and insulin tolerance tests demonstrated that HFD-fed FUNDC1 mKO mice were more tolerant to glucose challenge and more sensitive to insulin stimulation compared to HFD-fed WT controls. This seemingly paradoxical phenotype was due to enhanced fat burning in in adipose tissue. HFD-fed FUNDC1 mKO mice had markedly elevated expression of key thermogenic genes such as Ucp1 (17-fold), Cidea (13-fold), and Dio2 (9-fold) in white adipose. Mechanistically, FUNDC1 deficiency elicited a retrograde response in muscle that upregulated FGF-21 expression, thereby promoting the thermogenic remodeling of adipose tissue. Thus, these findings reveal a pivotal role of FUNDC1-dependent mitochondrial quality-control in mediating the muscle-adipose dialogue to regulate systemic metabolism.

Disclosure
T. Fu: None. Z. Xu: None. L. Liu: None. X. Liang: None. D. Zhou: None. Q. Guo: None. L. Xiao: None. Z. Gan: None.
Reduced ß Cell SPCA1 Leads to Impaired Calcium Oscillations and Decreased Autophagy
Authors: BONE ROBERT N. , KONO TATSUYOSHI , EVANS-MOLINA CARMELLA 
Published: June 2018

The β-cell Golgi, an important site of proinsulin maturation, is a significant store of intracellular Ca2+. However, the contribution of Golgi Ca2+ to diabetes pathophysiology is unknown. The Golgi primarily utilizes the Secretory Pathway Ca2+ ATPase (SPCA1) to maintain intra-Golgi Ca2+ stores. SPCA1 expression was measured in islets from Akita and db/db mice and cadaveric human islets from donors with T1D and T2D. In all cases, SPCA1 levels were significantly lower compared to nondiabetic controls. Proteomics and Reverse Phase Protein Array performed in INS-1 β-cells lacking SPCA1 (SPCA1KO) indicated dysregulated cell death, cell growth, and proliferation pathways compared to WT INS-1 cells. Consistent with this, SPCA1KO cells exhibited increased caspase-3/7 following tunicamycin treatment. SPCA1KO cells also had elevated basal cytosolic Ca2+ levels, decreased organelle Ca2+ reuptake following organelle Ca2+ store depletion, and accelerated Golgi collapse. Despite a significant reduction in GSIS, SPCA1KO cells exhibited a 12-fold insulin content increase. Autophagy has been reported as a key regulator in maintaining β-cell insulin homeostasis. Immunoblot revealed reduced expression of the autophagy marker LC3-II and the autophagosome Atg5/Atg12 complex in SPCA1KO cells, following autophagy induction with Torin. Islets from mice haploinsufficient for SPCA1 (SPCA1+/-) exhibited elevated cytosolic Ca2+ levels and impaired Ca2+ oscillations as reflected by increased phase 1 amplitude and period, compared to WT littermates. In islets, restoration of SPCA1 to normal levels rescued the oscillatory defect. Interestingly, islets from SPCA1+/- mice did not exhibit increased insulin content, however, SPCA1+/- islets had decreased insulin secretion and increased numbers of immature insulin granules. Taken together, we find that β-cell SPCA1 plays an important role in the maintenance of Golgi Ca2+ levels, while loss of SPCA1 led to dysregulated β-cell Ca2+ homeostasis.

Disclosure
R.N. Bone: None. T. Kono: None. C. Evans-Molina: None.
The Association between the Adipokine C1QTNF1 and Type 2 Diabetes Is Significantly Modulated by Obesity
Authors: GEIGER KATHRIN , MUENDLEIN AXEL , LEIHERER ANDREAS , SAELY CHRISTOPH H. , EBNER JANINE , BRANDTNER EVA-MARIA , LARCHER BARBARA , MADER ARTHUR , FRAUNBERGER PETER , DREXEL HEINZ 
Published: June 2018

C1q and tumor necrosis factor related protein 1 (C1QTNF1) is an adipokine which has recently captured attention as a modulator of various metabolic pathways. As shown in animal and in vitro studies C1QTNF1 enhances glucose and fatty acid oxidation and improves insulin sensitivity. Paradoxically, C1QTNF1 serum levels were found to be elevated in patients with type 2 diabetes (T2DM). To further elucidate the role of serum C1QTNF1 in T2DM, we investigated its association with metabolic parameters linked to T2DM in 542 patients undergoing coronary angiography for the evaluation for established or suspected stable coronary artery disease. In the total study cohort, C1QTNF1 was significantly (p-values &lt;0.001 for all comparisons) increased in patients with T2DM, the metabolic syndrome (MetS), as well as in obese patients (defined as BMI ≥30 kg/m2). Further, C1QTNF1 was positively correlated with BMI, fasting glucose, HbA1c, CRP, and the homeostatic model assessment (HOMA) index of insulin resistance (all p-values &lt;0.001), but not with the HOMA index of beta-cell function (p&gt;0.05). Subgroup analyses with respect to obesity revealed that the association between C1QTNF1 and T2DM was highly significant in obese patients (p&lt;0.001), but not in non-obese subjects (p=0.076). An interaction term obesity x C1QTNF1 was significant (p = 0.018), indicating a significantly stronger association between C1QTNF1 and T2DM in obese patients than in non-obese subjects. Similarly, the association between C1QTNF1 and the MetS was significant only in obese patients (p=0.009), but not in non-obese subjects (p=0.074), We conclude that obesity significantly influences the association between C1QTNF1 serum levels and T2DM and should be considered in further studies evaluating the relationship of C1QTNF1 with metabolic traits.

Disclosure
K. Geiger: None. A. Muendlein: None. A. Leiherer: None. C.H. Saely: None. J. Ebner: None. E. Brandtner: None. B. Larcher: None. A. Mader: None. P. Fraunberger: None. H. Drexel: None.
Exenatide and Saxagliptin Do Not Attenuate NFkB-Induced Inflammation in Prediabetic Humans
Authors: GUTIERREZ ABSALON D. , BERMUDEZ KARLA , HAMIDI VALA , RIGGS KAYLA , COVERDALE SARA , DURSTELER AMY , KUMAR NITYA K. , RUSCHEINSKY MONIKA 
Published: June 2018

Incretin mimetic medications acutely downregulate inflammation via the NfkB pathway during the fasting state in humans with type 2 diabetes mellitus. Free fatty acids (FFAs) activate TLR4, stimulating NFkB and the production of IL-6, which downregulates insulin signaling via SOCS3. We investigated this pathway in the acute postprandial state—utilizing a high-fat meal and incretin mimetic therapies—in humans with prediabetes. Sixteen humans with prediabetes (age 50 ± 2 years, BMI 32.5 ± 0.4 kg/m2, HbA1c 5.96 ± 0.05%) participated in a randomized, crossover, double-blinded trial comparing exenatide, saxagliptin, and placebo. Blood was drawn at baseline (fasting) and 2 hours for the collection of peripheral blood mononuclear cells (PBMCs) and plasma. After baseline blood draw, subjects were given study medication followed by high-fat test meal. Procedures were repeated for all study arms. Subsequently, seven of these subjects (age 51 ± 2 years, BMI 33.3 ± 0.6 kg/m2, HbA1c 5.86 ± 0.17%) participated in an open-label extension study after the administration of exenatide extended-release (EXR) for six weeks. The above procedures were repeated. In the randomized trial, plasma FFA decreased in all groups (p&lt;0.05), though the magnitude of decrease was smaller for exenatide. Plasma IL6 levels increased in all groups except the saxagliptin (p&lt;0.05). Western blots of PBMCs showed no significant changes in levels of NFkB, TLR4, or SOCS3. Plasma insulin did not change in the exenatide group but increased in other groups. In the extension study with EXR, plasma FFA decreased between 0 and 2 hours (p&lt;0.05), and to a greater extent than the prior exenatide group. Plasma IL6 levels decreased (p&lt;0.05) and insulin levels increased (p&lt;0.05). Western blots showed no significant changes in levels of NFkB, TLR4, or SOCS3. These data show that six weeks of EXR significant reduced postprandial FFA levels and IL-6 without any noted changes in NFkB pathway between 0 and 2 hours.

Disclosure
A.D. Gutierrez: Speaker's Bureau; Self; AstraZeneca, Med Learning Group. K. Bermudez: None. V. Hamidi: None. K. Riggs: None. S. Coverdale: None. A. Dursteler: None. N.K. Kumar: None. M. Ruscheinsky: None.
SGLT1 in Pancreatic a Cells Regulates Glucagon Secretion in Mice, Possibly Explaining the Distinct Effects of SGLT2 Inhibitors on Plasma Glucagon Levels
Authors: SUGA TAKAYOSHI , KIKUCHI OSAMU , KOBAYASHI MASAKI , MATSUI SHO , HASHIMOTO HIROMI H. , SASAKI TSUTOMU , KAKIZAKI SATORU , YAMADA MASANOBU , KITAMURA TADAHIRO 
Published: June 2018

A recent report described that sodium glucose cotransporter (SGLT) 1 and 2 were expressed in α cells, and dapagliflozin which is a specific SGLT2 inhibitor, increased plasma glucagon levels by inhibiting SGLT2 in α cells. However, it is still controversial whether SGLT2 inhibitors increase plasma glucagon levels in vivo. Here, we showed that dapagliflozin, but not canagliflozin which is a SGLT2/low-potency-SGLT1 inhibitor, increased plasma glucagon levels in mice fed a high-fat, high-sucrose diet (HFHSD) and diabetic db/db mice. A glucose clamp study revealed that the plasma glucagon increase associated with dapagliflozin could be explained as a response to acute declines in blood glucose. RT-PCR and whole RNA sequencing revealed that SGLT1 and glucose transporter 1 (GLUT1), but not SGLT2, were expressed in αTC1 cells and mouse islets. We showed that canagliflozin suppressed glucagon secretion by inhibiting SGLT1 in α cells; consequently, plasma glucagon did not increase with canagliflozin, even though blood glucose declined. We also showed that the SGLT1 effect on glucagon secretion depended on sodium/glucose cotransport, but not on metabolic effect of glucose. Islets from HFHSD and db/db mice displayed higher SGLT1 expression and lower GLUT1 expression than the islets from control mice. These expression levels were associated with glucagon secretion levels. Furthermore, SGLT1 inhibitor and siRNA against SGLT1 suppressed glucagon secretion in isolated islets. These data suggested that a novel mechanism regulated glucagon secretion, through SGLT1, in α cells. This finding explained the distinct effects of dapagliflozin and canagliflozin on plasma glucagon levels in mice.

Disclosure
T. Suga: None. O. Kikuchi: None. M. Kobayashi: None. S. Matsui: None. H.H. Hashimoto: None. T. Sasaki: None. S. Kakizaki: None. M. Yamada: None. T. Kitamura: None.
GLP-1 Integrates the Innate Immune System to Glucose Homeostasis
Authors: DAVIS ELLEN M. , HUTCH CHELSEA , KIM KI-SUK , MAERZ BASMA , ROELOFS KAREN J. , LEHRKE MICHAEL , SANDOVAL DARLEEN A. 
Published: June 2018

Glucagon-like peptide-1 (GLP-1) is a gut peptide that increases post prandially and functions to increase insulin secretion and improve glucose homeostasis. GLP-1 is coded by the preproglucagon gene (Gcg) and is expressed by intestinal and pancreatic cells. Interestingly, GLP-1 is also increased during sepsis, which is the most common cause of death in intensive care units (ICU). The goal of this study was to determine in a preclinical model of sepsis if the increase in GLP-1 was from intestinal or pancreatic cells. In order to model sepsis, we administered lipopolysaccharide (LPS) to Cre-control mice, to mice devoid of Gcg, and thus GLP-1 (Gcg null), to mice with Gcg expression reactivated only in the intestine (GcgRAδIntestine), and to mice with Gcg expression reactivated only in the pancreas (GcgRAδPancreas). LPS significantly increased GLP-1 in the control mice, as well as in the two reactivated genotypes compared to saline. However, the degree of the increase in both GcgRAδIntestine and GcgRAδPancreas mice was about 50% of control animals. LPS first increased, then significantly decreased blood glucose in control, pancreatic and intestinal reactivated mice but was significantly lower across all time points in Gcg null mice. These data suggest that both intestinal and pancreatic sources contribute to the increase in plasma GLP-1 seen in our model of sepsis. However, either pancreatic or intestinal sources of GLP-1 are sufficient to maintain glucose responses to LPS.

Disclosure
E.M. Davis: None. C. Hutch: None. K. Kim: None. B. Maerz: None. K.J. Roelofs: None. M. Lehrke: Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Novo Nordisk A/S. Advisory Panel; Self; Sanofi, Amgen Inc., Bayer AG, MSD K.K. D.A. Sandoval: Research Support; Self; Novo Nordisk A/S, Zafgen, Ethicon US, LLC..
Chronic Fractalkine Administration Exerts Durable Effects to Improve Glucose Tolerance with Specific Effects to Pancreatic Endocrine Function
Authors: LEE YUN SOK 
Published: June 2018

Previously we reported that the fractalkine (FKN)/CX3CR1 system represents a novel regulatory mechanism for insulin secretion and beta cell function. In this study, we examined whether chronic administration of FKN can exert durable effects to improve glucose tolerance in obese rodent models and performed a series of comprehensive mechanistic studies. Chronic administration of a long acting form of FKN (FKN-Fc fusion protein) into obese and insulin resistant mice improved glucose tolerance with improved beta cell function. Unexpectedly, FKN-Fc administration also led to decreased plasma glucagon levels. At the molecular level, FKN inhibited ATP-sensitive potassium channel conductance by an ERK-dependent mechanism in both alpha and beta cells. This led to enhanced glucose-stimulated action potential (AP) firing in beta cells, while it decreased alpha cell AP amplitude. Consistent with these results, FKN-Fc treatment increased GSIS and decreased glucagon secretion in beta and alpha cells, respectively. In addition to these effects in islet cells, chronic FKN-Fc treatment also decreased hepatic glucose production. In vitro and ex vivo experiments with normal and obese hepatocytes demonstrated that FKN treatment decreases glucagon-stimulated cAMP levels and CREB phosphorylation in a pertussis toxin-sensitive manner. Taken together, these results raise the possibility of use of FKN-based therapy to improve type 2 diabetes by increasing both insulin secretion and insulin sensitivity.

Disclosure
Y. Lee: None.
Improvement of Insulin Resistance and Cardiovascular Risk Factors with Treatment of Subclinical Hypothyroidism in Patients with Autoimmune Thyroiditis
Authors: NEVES CELESTINO , OLIVEIRA SOFIA C. , NEVES JOÃO SÉR , PEREIRA MIGUEL G. , SOKHATSKA OKSANA , OLIVEIRA ANA , MEDINA JOSÉ LUIZ , DELGADO LUIS , CARVALHO DAVIDE M. 
Published: June 2018

Introduction: Subclinical hypothyroidism (SCH) seems to be associated with increase in cardiovascular risk factors and insulin resistance. The effect of the treatment of SCH with L-thyroxine on cardiovascular profile is not yet clear.
Methods: We evaluated the effects of L-thyroxine therapy in 120 patients (mean age 45.7 ± 12.2 years, 80 women) with SCH due to autoimmune thyroiditis that had no prior treatment for thyroid or cardiovascular disease. The treatment was titrated to TSH levels between 0.4 and 4.0mIU/L. The laboratory data obtained, before and at least 6 months after thyroid function normalization, included thyroid function, antithyroid antibodies, lipid profile, and HOMA-IR (Homeostasis Model Assessment for insulin resistance), HISI (Hepatic Insulin Sensitivity Index), and IGI (Insulinogenic Index). Statistical analysis was performed with Mann-Whitney test, and Spearman’s correlation coefficient.
Results: After treatment L-thyroxine, we observed a significant decrease of TSH (6.43±0.53 to 1.23±0.42 mIU/L, p=0.03) and a significant increase of fT4 (0.74±0.12 to 1.25±0.14 ng/mL, p&lt;0.05). We also observed a decrease of LDL (116.1±34.2 to 91.2±16.3 mg/dL, p&lt;0.01) and Lp(a) (32.0 ±19.1 mg/dL to 21.4±18.1 mg/dl, p&lt;0,01). HDL and Apo A1 increased significantly after treatment (45.2±15.2 to 58.5±18.1 mg/dL, p &lt;0.01; 124.5±43.3 vs. 136.5±56.4 mg/dL, p&lt;0.01, respectively). Treatment with L-thyroxine significantly reduced HOMA-IR (0.24±0.17 to 0.17±0.10, p=0.03) and HISI (334.9±92.9 to 703.8±97.1, p=0.02). At baseline, TSH was positively correlated with total cholesterol (r=0.38, p=0.01), LDL (r=0.38, p=0.01), TG (r=0.28, p=0.01) and IGI (r=0.22, p=0.05). FT3 was negatively correlated with Lp(a) (r =-0.41, p=0.04).
Conclusions: The treatment of SCH in patients with autoimmune thyroiditis is associated with a significant improvement of insulin resistance and cardiovascular risk.

Disclosure
C. Neves: None. S.C. Oliveira: None. J. Neves: None. M.G. Pereira: None. O. Sokhatska: None. A. Oliveira: None. J. Medina: None. L. Delgado: None. D.M. Carvalho: None.