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Institution

Eli Lilly and Company

CompanyIndianapolis, Indiana, United States
About: Eli Lilly and Company is a company organization based out in Indianapolis, Indiana, United States. It is known for research contribution in the topics: Population & Agonist. The organization has 17826 authors who have published 22835 publications receiving 946714 citations. The organization is also known as: Eli Lily.
Topics: Population, Agonist, Insulin, Placebo, Olanzapine


Papers
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Journal ArticleDOI
TL;DR: It is found that FGF21 acts directly on the liver to stimulate phosphorylation of fibroblast growth factor receptor substrate 2 and ERK1/2 and the direct effects examined are not dependent on PGC-1α.
Abstract: Fibroblast growth factor (FGF21) plays an important role in regulating hepatic oxidation of fatty acids and gluconeogenesis in response to fasting and during consumption of a ketogenic diet. However, the metabolic pathways through which FGF21 regulates hepatic function are not well defined. To identify the effects of FGF21 on the liver in vivo, we administered FGF21 to mice and analyzed acute effects on signaling and gene expression. We found that FGF21 acts directly on the liver to stimulate phosphorylation of fibroblast growth factor receptor substrate 2 and ERK1/2. Acute FGF21 treatment induced hepatic expression of key regulators of gluconeogenesis, lipid metabolism, and ketogenesis including glucose-6-phosphatase, phosphoenol pyruvate carboxykinase, 3-hydroxybutyrate dehydrogenase type 1, and carnitine palmitoyltransferase 1α. In addition, injection of FGF21 was associated with decreased circulating insulin and free fatty acid levels. FGF21 treatment induced mRNA and protein expression of peroxisome proliferator-activated receptor-γ coactivator (PGC-1α), suggesting that PGC-1α may play a role in regulating FGF21 action. However, studies using mice with liver-specific ablation of PGC-1α revealed the same regulation of gluconeogenic gene expression by FGF21 as seen in wild-type mice, indicating that PGC-1α is not necessary for the effect of FGF21 on glucose metabolism. These data demonstrate that FGF21 acts directly on the liver to modulate hepatic metabolism. The direct effects we examined are not dependent on PGC-1α. In addition, FGF21 treatment is associated with decreased serum insulin levels that my affect hepatic function.

219 citations

Journal ArticleDOI
TL;DR: FGF21 regulates fatty acid activation and oxidation in livers of mice, and in the absence of FGF21, accumulation of inactivated fatty acids results in lipotoxic damage and increased steatosis.

218 citations

Journal ArticleDOI
TL;DR: An overview of the statistical and operational attributes of several currently used methods and their strengths and limitations and points to consider in integration of safety data mining with traditional pharmacovigilance methods are provided.
Abstract: In the last 5 years, regulatory agencies and drug monitoring centres have been developing computerised data-mining methods to better identify reporting relationships in spontaneous reporting databases that could signal possible adverse drug reactions. At present, there are no guidelines or standards for the use of these methods in routine pharmacovigilance. In 2003, a group of statisticians, pharmacoepidemiologists and pharmacovigilance professionals from the pharmaceutical industry and the US FDA formed the Pharmaceutical Research and Manufacturers of America-FDA Collaborative Working Group on Safety Evaluation Tools to review best practices for the use of these methods. In this paper, we provide an overview of: (i) the statistical and operational attributes of several currently used methods and their strengths and limitations; (ii) information about the characteristics of various postmarketing safety databases with which these tools can be deployed; (iii) analytical considerations for using safety data-mining methods and interpreting the results; and (iv) points to consider in integration of safety data mining with traditional pharmacovigilance methods. Perspectives from both the FDA and the industry are provided. Data mining is a potentially useful adjunct to traditional pharmacovigilance methods. The results of data mining should be viewed as hypothesis generating and should be evaluated in the context of other relevant data. The availability of a publicly accessible global safety database, which is updated on a frequent basis, would further enhance detection and communication about safety issues.

218 citations

Journal ArticleDOI
TL;DR: Current findings on the physiological role of the five known muscarinic acetylcholine receptors (mAChRs) as shown by gene targeting technology were reported and new activities were discovered.
Abstract: In this review we report recent findings on the physiological role of the five known muscarinic acetylcholine receptors (mAChRs) as shown by gene targeting technology. Using knockout mice for each mAChRs subtype, the role of mAChRs subtypes in a number of physiological functions was confirmed and new activities were discovered. The M1 mAChRs modulate neurotransmitter signaling in cortex and hippocampus. The M3 mAChRs are involved in exocrine gland secretion, smooth muscle contractility, pupil dilation, food intake, and weight gain. The role of the M5 mAChRs involves modulation of central dopamine function and the tone of cerebral blood vessels. mAChRs of the M2 subtype mediate muscarinic agonist-induced bradycardia, tremor, hypothermia, and autoinhibition of release in several brain regions. M4 mAChRs modulate dopamine activity in motor tracts and act as inhibitory autoreceptors in striatum. Thus, as elucidated by gene targeting technology, mAChRs have widespread and manifold functions in the periphery and brain.

218 citations


Authors

Showing all 17866 results

NameH-indexPapersCitations
Mark J. Daly204763304452
Irving L. Weissman2011141172504
Eric J. Topol1931373151025
Tony Hunter175593124726
Xiang Zhang1541733117576
Jerrold M. Olefsky14359577356
Stephen F. Badylak13353057083
George A. Bray131896100975
Lloyd Paul Aiello13150685550
Levi A. Garraway12936699989
Mark Sullivan12680263916
James A. Russell124102487929
Tony L. Yaksh12380660898
Elisabetta Dejana12243048254
Hagop S. Akiskal11856550869
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Performance
Metrics
No. of papers from the Institution in previous years
YearPapers
20236
202287
2021815
2020868
2019732
2018742