| Transamination is required for {alpha}-ketoisocaproate but not leucine to stimulate insulin secretion. | |
| | |
MedLine Citation:
|
PMID: 20736162 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
It remains unclear how α-ketoisocaproate (KIC) and leucine are metabolized to stimulate insulin secretion. Mitochondrial BCATm (branched-chain aminotransferase) catalyzes reversible transamination of leucine and α-ketoglutarate to KIC and glutamate, the first step of leucine catabolism. We investigated the biochemical mechanisms of KIC and leucine-stimulated insulin secretion (KICSIS and LSIS, respectively) using BCATm(-/-) mice. In static incubation, BCATm disruption abolished insulin secretion by KIC, D,L-α-keto-β-methylvalerate, and α-ketocaproate without altering stimulation by glucose, leucine, or α-ketoglutarate. Similarly, during pancreas perfusions in BCATm(-/-) mice, glucose and arginine stimulated insulin release, whereas KICSIS was largely abolished. During islet perifusions, KIC and 2 mM glutamine caused robust dose-dependent insulin secretion in BCATm(+/+) not BCATm(-/-) islets, whereas LSIS was unaffected. Consistently, in contrast to BCATm(+/+) islets, the increases of the ATP concentration and NADPH/NADP(+) ratio in response to KIC were largely blunted in BCATm(-/-) islets. Compared with nontreated islets, the combination of KIC/glutamine (10/2 mM) did not influence α-ketoglutarate concentrations but caused 120 and 33% increases in malate in BCATm(+/+) and BCATm(-/-) islets, respectively. Although leucine oxidation and KIC transamination were blocked in BCATm(-/-) islets, KIC oxidation was unaltered. These data indicate that KICSIS requires transamination of KIC and glutamate to leucine and α-ketoglutarate, respectively. LSIS does not require leucine catabolism and may be through leucine activation of glutamate dehydrogenase. Thus, KICSIS and LSIS occur by enhancing the metabolism of glutamine/glutamate to α-ketoglutarate, which, in turn, is metabolized to produce the intracellular signals such as ATP and NADPH for insulin secretion. |
| | |
Authors:
|
Yingsheng Zhou; Thomas L Jetton; Stephanie Goshorn; Christopher J Lynch; Pengxiang She |
Publication Detail:
|
Type: Journal Article Date: 2010-08-24 |
Journal Detail:
|
Title: The Journal of biological chemistry Volume: 285 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2010 Oct |
Date Detail:
|
Created Date: 2010-10-25 Completed Date: 2010-11-16 Revised Date: 2011-10-31 |
Medline Journal Info:
|
Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
|
Languages: eng Pagination: 33718-26 Citation Subset: IM |
Affiliation:
|
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Adenosine Triphosphate
/
chemistry Animals Female Glucose / chemistry, metabolism Glutamine / chemistry Insulin / metabolism, secretion Islets of Langerhans / cytology Keto Acids / chemistry* Ketoglutaric Acids / chemistry Leucine / chemistry* Mice Mice, Transgenic Mitochondria / enzymology* Oxygen / chemistry Transaminases / genetics*, metabolism |
| Chemical | |
Reg. No./Substance:
|
0/Keto Acids; 0/Ketoglutaric Acids; 11061-68-0/Insulin; 328-50-7/alpha-ketoglutaric acid; 50-99-7/Glucose; 56-65-5/Adenosine Triphosphate; 56-85-9/Glutamine; 61-90-5/Leucine; 7782-44-7/Oxygen; 816-66-0/alpha-ketoisocaproic acid; EC 2.6.1.-/Transaminases; EC 2.6.1.42/branched-chain-amino-acid transaminase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Functional differences of invariant and highly conserved residues in the extracellular domain of the...
Next Document: A novel cytoplasmic adaptor for retinoic acid receptor (RAR) and thyroid receptor functions as a Der...