title: Studies with leucine, beta-hydroxybutyrate and ATP citrate lyase-deficient beta cells support the acetoacetate pathway of insulin secretion.
abstract: We hypothesized that contrasting leucine with its non-metabolizable analog 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid (BCH) might provide new information about metabolic pathways involved in insulin secretion. Both compounds stimulate insulin secretion by allosterically activating glutamate dehydrogenase, which enhances glutamate metabolism. However, we found that leucine was a stronger secretagogue in rat pancreatic islets and INS-1 cells. This suggested that leucine's metabolism contributed to its insulinotropism. Indeed, we found that leucine increased acetoacetate and was metabolized to CO(2) in pancreatic islets and increased short chain acyl-CoAs (SC-CoAs) in INS-1 cells. We then used the leucine-BCH difference to study the hypothesis that acyl groups derived from secretagogue carbon can be transferred as acetoacetate, in addition to citrate, from mitochondria to the cytosol where they can be converted to SC-CoAs. Since BCH cannot form sufficient acetoacetate from glutamate, transport of any glutamate-derived acyl groups to the cytosol in BCH-stimulated cells must proceed mainly via citrate. In ATP citrate lyase-deficient INS-1 cells, which are unable to convert citrate into cytosolic acetyl-CoA, insulin release by BCH was decreased and adding beta-hydroxybutyrate or alpha-ketoisocaproate, which increases mitochondrial acetoacetate, normalized BCH-induced insulin release. This strengthens the concept that acetoacetate-transferred acyl carbon can be converted to cytosolic SC-CoAs to stimulate insulin secretion.
authors.affiliation: Childrens Diabetes Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. mjmacdon@wisc.edu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Macdonald
authors.forename: Noaman M
authors.initials: NM
authors.lastname: Hasan
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Longacre
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism* / Q000494:pharmacology; D001275:ATP Citrate (pro-S)-Lyase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000090:Acetoacetates / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D005969:Glutamate Dehydrogenase / Q000032:analysis; D005973:Glutamine / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology; D007656:Ketoglutaric Acids / Q000032:analysis; D007930:Leucine / Q000378:metabolism* / Q000494:pharmacology; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000090:Acetoacetates; D007328:Insulin; D007656:Ketoglutaric Acids; D005973:Glutamine; C016635:acetoacetic acid; D005969:Glutamate Dehydrogenase; D001275:ATP Citrate (pro-S)-Lyase; D007930:Leucine; D005947:Glucose; D020155:3-Hydroxybutyric Acid