Document Detail


Insulin secretion profiles are modified by overexpression of glutamate dehydrogenase in pancreatic islets.
MedLine Citation:
PMID:  14689183     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
AIMS/HYPOTHESIS: Glutamate dehydrogenase (GDH) is a mitochondrial enzyme playing a key role in the control of insulin secretion. However, it is not known whether GDH expression levels in beta cells are rate-limiting for the secretory response to glucose. GDH also controls glutamine and glutamate oxidative metabolism, which is only weak in islets if GDH is not allosterically activated by L-leucine or (+/-)-2-aminobicyclo-[2,2,1]heptane-2-carboxylic acid (BCH). METHODS: We constructed an adenovirus encoding for GDH to overexpress the enzyme in the beta-cell line INS-1E, as well as in isolated rat and mouse pancreatic islets. The secretory responses to glucose and glutamine were studied in static and perifusion experiments. Amino acid concentrations and metabolic parameters were measured in parallel. RESULTS: GDH overexpression in rat islets did not change insulin release at basal or intermediate glucose (2.8 and 8.3 mmol/l respectively), but potentiated the secretory response at high glucose concentrations (16.7 mmol/l) compared to controls (+35%). Control islets exposed to 5 mmol/l glutamine at basal glucose did not increase insulin release, unless BCH was added with a resulting 2.5-fold response. In islets overexpressing GDH glutamine alone stimulated insulin secretion (2.7-fold), which was potentiated 2.2-fold by adding BCH. The secretory responses evoked by glutamine under these conditions correlated with enhanced cellular metabolism. CONCLUSIONS/INTERPRETATION: GDH could be rate-limiting in glucose-induced insulin secretion, as GDH overexpression enhanced secretory responses. Moreover, GDH overexpression made islets responsive to glutamine, indicating that under physiological conditions this enzyme acts as a gatekeeper to prevent amino acids from being inappropriate efficient secretagogues.
Authors:
S Carobbio; H Ishihara; S Fernandez-Pascual; C Bartley; R Martin-Del-Rio; P Maechler
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2003-12-20
Journal Detail:
Title:  Diabetologia     Volume:  47     ISSN:  0012-186X     ISO Abbreviation:  Diabetologia     Publication Date:  2004 Feb 
Date Detail:
Created Date:  2004-03-01     Completed Date:  2005-01-14     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0006777     Medline TA:  Diabetologia     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  266-76     Citation Subset:  IM    
Affiliation:
Division of Clinical Biochemistry, University Medical Center, Geneva, Switzerland.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / metabolism
Amino Acids / drug effects,  metabolism
Amino Acids, Cyclic / pharmacology
Animals
Blotting, Western
Cell Line
Cell Line, Tumor
Glucose / pharmacology
Glutamate Dehydrogenase / metabolism*
Glutamine / pharmacology
Humans
Immunohistochemistry
Insulin / metabolism,  secretion*
Islets of Langerhans / drug effects,  metabolism*
Leucine / analogs & derivatives,  pharmacology
Male
Membrane Potentials / drug effects,  physiology
Mice
Mice, Inbred BALB C
Mitochondria / chemistry,  drug effects,  metabolism
Oxidation-Reduction / drug effects
Potassium Chloride / pharmacology
Rats
Rats, Wistar
Chemical
Reg. No./Substance:
0/Amino Acids; 0/Amino Acids, Cyclic; 11061-68-0/Insulin; 20448-79-7/2-aminobicyclo(2,2,1)heptane-2-carboxylic acid; 50-99-7/Glucose; 56-65-5/Adenosine Triphosphate; 56-85-9/Glutamine; 61-90-5/Leucine; 7447-40-7/Potassium Chloride; EC 1.4.1.2/Glutamate Dehydrogenase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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