Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase.

Abstract:

:Metformin is considered to be one of the most effective therapeutics for treating type 2 diabetes because it specifically reduces hepatic gluconeogenesis without increasing insulin secretion, inducing weight gain or posing a risk of hypoglycaemia. For over half a century, this agent has been prescribed to patients with type 2 diabetes worldwide, yet the underlying mechanism by which metformin inhibits hepatic gluconeogenesis remains unknown. Here we show that metformin non-competitively inhibits the redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase, resulting in an altered hepatocellular redox state, reduced conversion of lactate and glycerol to glucose, and decreased hepatic gluconeogenesis. Acute and chronic low-dose metformin treatment effectively reduced endogenous glucose production, while increasing cytosolic redox and decreasing mitochondrial redox states. Antisense oligonucleotide knockdown of hepatic mitochondrial glycerophosphate dehydrogenase in rats resulted in a phenotype akin to chronic metformin treatment, and abrogated metformin-mediated increases in cytosolic redox state, decreases in plasma glucose concentrations, and inhibition of endogenous glucose production. These findings were replicated in whole-body mitochondrial glycerophosphate dehydrogenase knockout mice. These results have significant implications for understanding the mechanism of metformin's blood glucose lowering effects and provide a new therapeutic target for type 2 diabetes.

journal_name

Nature

journal_title

Nature

authors

Madiraju AK,Erion DM,Rahimi Y,Zhang XM,Braddock DT,Albright RA,Prigaro BJ,Wood JL,Bhanot S,MacDonald MJ,Jurczak MJ,Camporez JP,Lee HY,Cline GW,Samuel VT,Kibbey RG,Shulman GI

doi

10.1038/nature13270

subject

Has Abstract

pub_date

2014-06-26 00:00:00

pages

542-6

issue

7506

eissn

0028-0836

issn

1476-4687

pii

nature13270

journal_volume

510

pub_type

杂志文章

相关文献

NATURE文献大全
  • The interaction landscape between transcription factors and the nucleosome.

    abstract::Nucleosomes cover most of the genome and are thought to be displaced by transcription factors in regions that direct gene expression. However, the modes of interaction between transcription factors and nucleosomal DNA remain largely unknown. Here we systematically explore interactions between the nucleosome and 220 tr...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/s41586-018-0549-5

    authors: Zhu F,Farnung L,Kaasinen E,Sahu B,Yin Y,Wei B,Dodonova SO,Nitta KR,Morgunova E,Taipale M,Cramer P,Taipale J

    更新日期:2018-10-01 00:00:00

  • Robotics: self-reproducing machines.

    abstract::Self-reproduction is central to biological life for long-term sustainability and evolutionary adaptation. Although these traits would also be desirable in many engineered systems, the principles of self-reproduction have not been exploited in machine design. Here we create simple machines that act as autonomous modula...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/435163a

    authors: Zykov V,Mytilinaios E,Adams B,Lipson H

    更新日期:2005-05-12 00:00:00

  • Offshore fresh groundwater reserves as a global phenomenon.

    abstract::The flow of terrestrial groundwater to the sea is an important natural component of the hydrological cycle. This process, however, does not explain the large volumes of low-salinity groundwater that are found below continental shelves. There is mounting evidence for the global occurrence of offshore fresh and brackish...

    journal_title:Nature

    pub_type: 杂志文章,评审

    doi:10.1038/nature12858

    authors: Post VE,Groen J,Kooi H,Person M,Ge S,Edmunds WM

    更新日期:2013-12-05 00:00:00

  • Self-renewal of embryonic-stem-cell-derived progenitors by organ-matched mesenchyme.

    abstract::One goal of regenerative medicine, to use stem cells to replace cells lost by injury or disease, depends on producing an excess of the relevant cell for study or transplantation. To this end, the stepwise differentiation of stem cells into specialized derivatives has been successful for some cell types, but a major pr...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature11463

    authors: Sneddon JB,Borowiak M,Melton DA

    更新日期:2012-11-29 00:00:00

  • Progenitor identification and SARS-CoV-2 infection in human distal lung organoids.

    abstract::The distal lung contains terminal bronchioles and alveoli that facilitate gas exchange. Three-dimensional in vitro human distal lung culture systems would strongly facilitate the investigation of pathologies such as interstitial lung disease, cancer and coronavirus disease 2019 (COVID-19) pneumonia caused by severe ac...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/s41586-020-3014-1

    authors: Salahudeen AA,Choi SS,Rustagi A,Zhu J,van Unen V,de la O SM,Flynn RA,Margalef-Català M,Santos AJM,Ju J,Batish A,Usui T,Zheng GXY,Edwards CE,Wagar LE,Luca V,Anchang B,Nagendran M,Nguyen K,Hart DJ,Terry JM,Belgrad

    更新日期:2020-12-01 00:00:00

  • Splicing factor Sub2p is required for nuclear mRNA export through its interaction with Yra1p.

    abstract::The yeast nuclear protein Yra1p is an essential export factor for mRNA. Yra1p interacts directly with the mRNA transport factor Mex67p/Mtr2p, which is associated with the nuclear pore. Here, we report a genetic interaction between YRA1 and SUB2, the gene for a DEAD box helicase involved in splicing. Mutation of SUB2 a...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/35098113

    authors: Strässer K,Hurt E

    更新日期:2001-10-11 00:00:00

  • eIF5B gates the transition from translation initiation to elongation.

    abstract::Translation initiation determines both the quantity and identity of the protein that is encoded in an mRNA by establishing the reading frame for protein synthesis. In eukaryotic cells, numerous translation initiation factors prepare ribosomes for polypeptide synthesis; however, the underlying dynamics of this process ...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/s41586-019-1561-0

    authors: Wang J,Johnson AG,Lapointe CP,Choi J,Prabhakar A,Chen DH,Petrov AN,Puglisi JD

    更新日期:2019-09-01 00:00:00

  • Structural relaxation in supercooled water by time-resolved spectroscopy.

    abstract::Water has many kinetic and thermodynamic properties that exhibit an anomalous dependence on temperature, in particular in the supercooled phase. These anomalies have long been interpreted in terms of underlying structural causes, and their experimental characterization points to the existence of a singularity at a tem...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature02409

    authors: Torre R,Bartolini P,Righini R

    更新日期:2004-03-18 00:00:00

  • Ban bullying in science.

    abstract:: ...

    journal_title:Nature

    pub_type: 社论

    doi:10.1038/d41586-018-07529-0

    authors:

    更新日期:2018-11-01 00:00:00

  • The mammalian sodium channel BNC1 is required for normal touch sensation.

    abstract::Of the vertebrate senses, touch is the least understood at the molecular level The ion channels that form the core of the mechanosensory complex and confer touch sensitivity remain unknown. However, the similarity of the brain sodium channel 1 (BNC1) to nematode proteins involved in mechanotransduction indicated that ...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/35039512

    authors: Price MP,Lewin GR,McIlwrath SL,Cheng C,Xie J,Heppenstall PA,Stucky CL,Mannsfeldt AG,Brennan TJ,Drummond HA,Qiao J,Benson CJ,Tarr DE,Hrstka RF,Yang B,Williamson RA,Welsh MJ

    更新日期:2000-10-26 00:00:00

  • Regenerative medicine and human models of human disease.

    abstract::Recent advances in stem-cell technology are now allowing the mechanisms of human disease to be studied in human cells. A new era for regenerative medicine is arising from such disease models, extending beyond early cell-based therapies and towards evaluating genetic variation in humans and identifying the molecular pa...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature07037

    authors: Chien KR

    更新日期:2008-05-15 00:00:00

  • US genetic regulations: bacterial field trial to go ahead.

    abstract::The National Institutes of Health's Recombinant DNA Advisory Committee (RAC) has approved a commercial proposal by Advanced Genetic Sciences Inc. to field-test recombinant ice-nucleating bacteria. Its decision came two weeks after a federal judge halted a similar trial by researchers from the University of California...

    journal_title:Nature

    pub_type: 新闻

    doi:10.1038/309483a0

    authors: Budiansky S

    更新日期:1984-06-07 00:00:00

  • The confinement of Neptune's ring arcs by the moon Galatea.

    abstract::Neptune has five narrow ring arcs, spanning about 40 degrees in longitude, which are apparently confined against the rapid azimuthal and radial spreading that normally results from inter-particle collisions. A gravitational resonance based on the vertical motion of the nearby neptunian moon Galatea was proposed to exp...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/417045a

    authors: Namouni F,Porco C

    更新日期:2002-05-02 00:00:00

  • Induction and organization of Ca2+ waves by enteric neural reflexes.

    abstract::The motility of the gastrointestinal tract consists of local, non-propulsive mixing (pendular or segmental) and propulsive (peristaltic) movements. It is generally considered that mixing movements are produced by intrinsic pacemakers which generate rhythmic contractions, and peristalsis by intrinsic excitatory and inh...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/19973

    authors: Stevens RJ,Publicover NG,Smith TK

    更新日期:1999-05-06 00:00:00

  • Emergence of vancomycin tolerance in Streptococcus pneumoniae.

    abstract::Streptococcus pneumoniae, the pneumococcus, is the most common cause of sepsis and meningitis. Multiple-antibiotic-resistant strains are widespread, and vancomycin is the antibiotic of last resort. Emergence of vancomycin resistance in this community-acquired bacterium would be catastrophic. Antibiotic tolerance, the ...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/21202

    authors: Novak R,Henriques B,Charpentier E,Normark S,Tuomanen E

    更新日期:1999-06-10 00:00:00

  • Resolving the fibrotic niche of human liver cirrhosis at single-cell level.

    abstract::Liver cirrhosis is a major cause of death worldwide and is characterized by extensive fibrosis. There are currently no effective antifibrotic therapies available. To obtain a better understanding of the cellular and molecular mechanisms involved in disease pathogenesis and enable the discovery of therapeutic targets, ...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/s41586-019-1631-3

    authors: Ramachandran P,Dobie R,Wilson-Kanamori JR,Dora EF,Henderson BEP,Luu NT,Portman JR,Matchett KP,Brice M,Marwick JA,Taylor RS,Efremova M,Vento-Tormo R,Carragher NO,Kendall TJ,Fallowfield JA,Harrison EM,Mole DJ,Wigmore SJ

    更新日期:2019-11-01 00:00:00

  • Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors.

    abstract::The epidermal growth factor receptor (EGFR)-directed tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib and afatinib are approved treatments for non-small cell lung cancers harbouring activating mutations in the EGFR kinase, but resistance arises rapidly, most frequently owing to the secondary T790M mutation withi...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature17960

    authors: Jia Y,Yun CH,Park E,Ercan D,Manuia M,Juarez J,Xu C,Rhee K,Chen T,Zhang H,Palakurthi S,Jang J,Lelais G,DiDonato M,Bursulaya B,Michellys PY,Epple R,Marsilje TH,McNeill M,Lu W,Harris J,Bender S,Wong KK,Jänne PA

    更新日期:2016-06-02 00:00:00

  • A computational theory for the perception of coherent visual motion.

    abstract::When we see motion, our perception of how one image feature moves depends on the behaviour of other features nearby. In particular, the Gestaltists proposed the law of shared common fate, in which features tend to be perceived as moving together, that is, coherently. Recent psychophysical findings, such as the coopera...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/333071a0

    authors: Yuille AL,Grzywacz NM

    更新日期:1988-05-05 00:00:00

  • The mariner transposable element is widespread in insects.

    abstract::The mariner transposable element is a small member of the short inverted terminal repeat class thought to transpose through a DNA intermediate. Originally described in Drosophila mauritiana, it is now known in several species of the family Drosophilidae, and in a moth Hyalophora cecropia. Here I use primers designed t...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/362241a0

    authors: Robertson HM

    更新日期:1993-03-18 00:00:00

  • Schwann cells induce morphological transformation of sensory neurones in vitro.

    abstract::Cell-cell interactions are thought to play a crucial part in determining the developmental fate of vertebrate cells and regulating their subsequent differentiation. In the peripheral nervous system, for example, signals from neuronal axons determine whether or not some Schwann cells wrap their plasma membrane concentr...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/309367a0

    authors: Mudge AW

    更新日期:1984-05-24 00:00:00

  • Structural basis for sequestration and autoinhibition of cGAS by chromatin.

    abstract::Cyclic GMP-AMP synthase (cGAS) is an innate immune sensor for cytosolic microbial DNA1. After binding DNA, cGAS synthesizes the messenger 2'3'-cyclic GMP-AMP (cGAMP)2-4, which triggers cell-autonomous defence and the production of type I interferons and pro-inflammatory cytokines via the activation of STING5. In addit...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/s41586-020-2748-0

    authors: Michalski S,de Oliveira Mann CC,Stafford CA,Witte G,Bartho J,Lammens K,Hornung V,Hopfner KP

    更新日期:2020-11-01 00:00:00

  • Imaging cortical correlates of illusion in early visual cortex.

    abstract::Exploring visual illusions reveals fundamental principles of cortical processing. Illusory motion perception of non-moving stimuli was described almost a century ago by Gestalt psychologists. However, the underlying neuronal mechanisms remain unknown. To explore cortical mechanisms underlying the 'line-motion' illusio...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature02396

    authors: Jancke D,Chavane F,Naaman S,Grinvald A

    更新日期:2004-03-25 00:00:00

  • Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms.

    abstract::Acquired uniparental disomy (aUPD) is a common feature of cancer genomes, leading to loss of heterozygosity. aUPD is associated not only with loss-of-function mutations of tumour suppressor genes, but also with gain-of-function mutations of proto-oncogenes. Here we show unique gain-of-function mutations of the C-CBL (...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/nature08240

    authors: Sanada M,Suzuki T,Shih LY,Otsu M,Kato M,Yamazaki S,Tamura A,Honda H,Sakata-Yanagimoto M,Kumano K,Oda H,Yamagata T,Takita J,Gotoh N,Nakazaki K,Kawamata N,Onodera M,Nobuyoshi M,Hayashi Y,Harada H,Kurokawa M,Chiba

    更新日期:2009-08-13 00:00:00

  • A nucleotide regulatory site for somatostatin inhibition of adenylate cyclase in S49 lymphoma cells.

    abstract::The cyc- variants of S49 lymphoma cells have served as powerful tools for studying the components and mechanisms of hormone-induced adenylate cyclase stimulation, as these cells are deficient in the guanine nucleotide regulatory site (Ns) mediating hormone, guanine nucleotide, cholera toxin and fluoride-induced stimul...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/303177a0

    authors: Jakobs KH,Aktories K,Schultz G

    更新日期:1983-05-12 00:00:00

  • Auditory cortical responses in the cat to sounds that produce spatial illusions.

    abstract::Humans and cats can localize a sound source accurately if its spectrum is fairly broad and flat, as is typical of most natural sounds. However, if sounds are filtered to reduce the width of the spectrum, they result in illusions of sources that are very different from the actual locations, particularly in the up/down ...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/21424

    authors: Xu L,Furukawa S,Middlebrooks JC

    更新日期:1999-06-17 00:00:00

  • A protein kinase homologue controls phosphorylation of ganciclovir in human cytomegalovirus-infected cells.

    abstract::Human cytomegalovirus (HCMV) is a major pathogen in immunosuppressed individuals, including patients with acquired immune deficiency syndrome. The nucleoside analogue ganciclovir (9-(1,3-dihydroxy-2-propoxymethyl)-guanine) is one of the few drugs available to treat HCMV infections, but resistant virus is a growing pro...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/358162a0

    authors: Sullivan V,Talarico CL,Stanat SC,Davis M,Coen DM,Biron KK

    更新日期:1992-07-09 00:00:00

  • A per-cent-level determination of the nucleon axial coupling from quantum chromodynamics.

    abstract::The axial coupling of the nucleon, gA, is the strength of its coupling to the weak axial current of the standard model of particle physics, in much the same way as the electric charge is the strength of the coupling to the electromagnetic current. This axial coupling dictates the rate at which neutrons decay to proton...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/s41586-018-0161-8

    authors: Chang CC,Nicholson AN,Rinaldi E,Berkowitz E,Garron N,Brantley DA,Monge-Camacho H,Monahan CJ,Bouchard C,Clark MA,Joó B,Kurth T,Orginos K,Vranas P,Walker-Loud A

    更新日期:2018-06-01 00:00:00

  • Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean.

    abstract::Members of the muscarinic acetylcholine receptor family (M1-M5) have central roles in the regulation of many fundamental physiological functions. Identifying the specific receptor subtype(s) that mediate the diverse muscarinic actions of acetylcholine is of considerable therapeutic interest, but has proved difficult p...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/35065604

    authors: Yamada M,Miyakawa T,Duttaroy A,Yamanaka A,Moriguchi T,Makita R,Ogawa M,Chou CJ,Xia B,Crawley JN,Felder CC,Deng CX,Wess J

    更新日期:2001-03-08 00:00:00

  • How a simple 'thank you' could improve clinical trials.

    abstract:: ...

    journal_title:Nature

    pub_type: 社论

    doi:10.1038/d41586-018-07410-0

    authors:

    更新日期:2018-11-01 00:00:00

  • Synthesis of epothilones A and B in solid and solution phase.

    abstract::Epothilones A and B, two compounds that have been recently isolated from myxobacterium Sorangium cellulosum strain 90, have generated intense interest among chemists, biologists and clinicians owing to the structural complexity, unusual mechanism of interaction with microtubules and anticancer potential of these molec...

    journal_title:Nature

    pub_type: 杂志文章

    doi:10.1038/387268a0

    authors: Nicolaou KC,Winssinger N,Pastor J,Ninkovic S,Sarabia F,He Y,Vourloumis D,Yang Z,Li T,Giannakakou P,Hamel E

    更新日期:1997-05-15 00:00:00