Lower succinyl-CoA:3-ketoacid-CoA transferase (SCOT) and ATP citrate lyase in pancreatic islets of a rat model of type 2 diabetes: knockdown of SCOT inhibits insulin release in rat insulinoma cells.
Succinyl-CoA:3-ketoacid-CoA transferase (SCOT) is a mitochondrial enzyme that catalyzes the reversible transfer of coenzyme-A from acetoacetyl-CoA to succinate to form acetoacetate and succinyl-CoA. mRNAs of SCOT and ATP citrate lyase were decreased 55% and 58% and enzyme activities were decreased >70% in pancreatic islets of the GK rat, a model of type 2 diabetes. INS-1 832/13 cells were transfected with shRNAs targeting SCOT mRNA to generate cell lines with reduced SCOT activity. Two cell lines with >70% knockdown of SCOT activity showed >70% reduction in glucose- or methyl succinate-plus-beta-hydroxybutyrate-stimulated insulin release. Less inhibition of insulin release was observed with two cell lines with less knockdown of SCOT. Previous studies showed knockdown of ATP citrate lyase in INS-1 832/13 cells does not lower insulin release. The results further support work that suggests mitochondrial pathways involving SCOT which supply acetoacetate for export to the cytosol are important for insulin secretion.
Hasan
Noaman M
NM
Childrens Diabetes Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Longacre
Melissa J
MJ
Seed Ahmed
Mohammed
M
Kendrick
Mindy A
MA
Gu
Harvest
H
Ostenson
Claes-Goran
CG
Fukao
Toshiyuki
T
MacDonald
Michael J
MJ
D001275:ATP Citrate (pro-S)-Lyase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D015256:Coenzyme A-Transferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000503:physiopathology*; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000201:enzymology* / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000201:enzymology; D008954:Models, Biological; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar
D007328:Insulin; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D001275:ATP Citrate (pro-S)-Lyase; D015256:Coenzyme A-Transferases; C021460:3-ketoacid CoA-transferase
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