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dc.contributor.authorChakera, Ali J
dc.contributor.authorHurst, Paul S
dc.contributor.authorSpyer, Gill
dc.contributor.authorOgunnowo-Bada, Emmanuel O
dc.contributor.authorMarsh, William J
dc.contributor.authorRiches, Christine H
dc.contributor.authorYueh, Chen-Yu
dc.contributor.authorMarkkula, S Pauliina
dc.contributor.authorDalley, Jeffrey W
dc.contributor.authorCox, Roger D
dc.contributor.authorMacdonald, Ian A
dc.contributor.authorAmiel, Stephanie A
dc.contributor.authorMacLeod, Kenneth M
dc.contributor.authorHeisler, Lora K
dc.contributor.authorHattersley, Andrew T
dc.contributor.authorEvans, Mark L
dc.date.accessioned2018-09-05T12:51:09Z
dc.date.available2018-09-05T12:51:09Z
dc.date.issued2018-11
dc.identifier.issn2212-8778
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/279641
dc.description.abstractOBJECTIVE: Appropriate glucose levels are essential for survival; thus, the detection and correction of low blood glucose is of paramount importance. Hypoglycemia prompts an integrated response involving reduction in insulin release and secretion of key counter-regulatory hormones glucagon and epinephrine that together promote endogenous glucose production to restore normoglycemia. However, specifically how this response is orchestrated remains to be fully clarified. The low affinity hexokinase glucokinase is found in glucose-sensing cells involved in glucose homeostasis including pancreatic β-cells and in certain brain areas. Here, we aimed to examine the role of glucokinase in triggering counter-regulatory hormonal responses to hypoglycemia, hypothesizing that reduced glucokinase activity would lead to increased and/or earlier triggering of responses. METHODS: Hyperinsulinemic glucose clamps were performed to examine counter-regulatory responses to controlled hypoglycemic challenges created in humans with monogenic diabetes resulting from heterozygous glucokinase mutations (GCK-MODY). To examine the relative importance of glucokinase in different sensing areas, we then examined responses to clamped hypoglycemia in mice with molecularly defined disruption of whole body and/or brain glucokinase. RESULTS: GCK-MODY patients displayed increased and earlier glucagon responses during hypoglycemia compared with a group of glycemia-matched patients with type 2 diabetes. Consistent with this, glucagon responses to hypoglycemia were also increased in I366F mice with mutated glucokinase and in streptozotocin-treated β-cell ablated diabetic I366F mice. Glucagon responses were normal in conditional brain glucokinase-knockout mice, suggesting that glucagon release during hypoglycemia is controlled by glucokinase-mediated glucose sensing outside the brain but not in β-cells. For epinephrine, we found increased responses in GCK-MODY patients, in β-cell ablated diabetic I366F mice and in conditional (nestin lineage) brain glucokinase-knockout mice, supporting a role for brain glucokinase in triggering epinephrine release. CONCLUSIONS: Our data suggest that glucokinase in brain and other non β-cell peripheral hypoglycemia sensors is important in glucose homeostasis, allowing the body to detect and respond to a falling blood glucose.
dc.description.sponsorshipYousef Jameel Fund Sir Jukes Thorn Trust Elmore Fund Chang Gung University College of Medicine
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherElsevier BV
dc.rightsAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAnimals
dc.subjectMice, Inbred BALB C
dc.subjectHumans
dc.subjectMice
dc.subjectDiabetes Mellitus
dc.subjectHyperinsulinism
dc.subjectHypoglycemia
dc.subjectDisease Models, Animal
dc.subjectEpinephrine
dc.subjectGlucagon
dc.subjectInsulin
dc.subjectGlucokinase
dc.subjectGlucose
dc.subjectBlood Glucose
dc.subjectHypoglycemic Agents
dc.subjectGlucose Clamp Technique
dc.subjectAdult
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectInsulin-Secreting Cells
dc.titleMolecular reductions in glucokinase activity increase counter-regulatory responses to hypoglycemia in mice and humans with diabetes.
dc.typeArticle
prism.endingPage27
prism.publicationDate2018
prism.publicationNameMol Metab
prism.startingPage17
prism.volume17
dc.identifier.doi10.17863/CAM.27010
dcterms.dateAccepted2018-08-02
rioxxterms.versionofrecord10.1016/j.molmet.2018.08.001
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-11
dc.contributor.orcidDalley, Jeffrey [0000-0002-2282-3660]
dc.contributor.orcidEvans, Mark [0000-0001-8122-8987]
dc.identifier.eissn2212-8778
rioxxterms.typeJournal Article/Review
pubs.funder-project-idSir Jules Thorn Charitable Trust (unknown)
pubs.funder-project-idDiabetes Research & Wellness Foundation (DRWF) (DRWF/MO/STUDENTSHIP/2005)
pubs.funder-project-idJuvenile Diabetes Research Foundation Ltd (JDRF) (1-2006-29)
pubs.funder-project-idDiabetes UK (BDA:RD05/0003059)
pubs.funder-project-idWellcome Trust (100574/Z/12/Z)
pubs.funder-project-idDiabetes UK (None)
pubs.funder-project-idWellcome Trust (089942/Z/09/A)
pubs.funder-project-idMedical Research Council (G1000183)
pubs.funder-project-idWellcome Trust (093875/Z/10/Z)
pubs.funder-project-idWellcome Trust (098012/Z/11/Z)
cam.issuedOnline2018-08-13


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Attribution 4.0 International (CC BY 4.0)
Except where otherwise noted, this item's licence is described as Attribution 4.0 International (CC BY 4.0)