title: Differences between human and rodent pancreatic islets: low pyruvate carboxylase, atp citrate lyase, and pyruvate carboxylation and high glucose-stimulated acetoacetate in human pancreatic islets.
abstract: Anaplerosis, the net synthesis in mitochondria of citric acid cycle intermediates, and cataplerosis, their export to the cytosol, have been shown to be important for insulin secretion in rodent beta cells. However, human islets may be different. We observed that the enzyme activity, protein level, and relative mRNA level of the key anaplerotic enzyme pyruvate carboxylase (PC) were 80-90% lower in human pancreatic islets compared with islets of rats and mice and the rat insulinoma cell line INS-1 832/13. Activity and protein of ATP citrate lyase, which uses anaplerotic products in the cytosol, were 60-75% lower in human islets than in rodent islets or the cell line. In line with the lower PC, the percentage of glucose-derived pyruvate that entered mitochondrial metabolism via carboxylation in human islets was only 20-30% that in rat islets. This suggests human islets depend less on pyruvate carboxylation than rodent models that were used to establish the role of PC in insulin secretion. Human islets possessed high levels of succinyl-CoA:3-ketoacid-CoA transferase, an enzyme that forms acetoacetate in the mitochondria, and acetoacetyl-CoA synthetase, which uses acetoacetate to form acyl-CoAs in the cytosol. Glucose-stimulated human islets released insulin similarly to rat islets but formed much more acetoacetate. β-Hydroxybutyrate augmented insulin secretion in human islets. This information supports previous data that indicate beta cells can use a pathway involving succinyl-CoA:3-ketoacid-CoA transferase and acetoacetyl-CoA synthetase to synthesize and use acetoacetate and suggests human islets may use this pathway more than PC and citrate to form cytosolic acyl-CoAs.
authors: Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA. mjmacdon@wisc.edu
authors: Michael J
authors: MJ
authors: MacDonald
authors: Melissa J
authors: MJ
authors: Longacre
authors: Scott W
authors: SW
authors: Stoker
authors: Mindy
authors: M
authors: Kendrick
authors: Ansaya
authors: A
authors: Thonpho
authors: Laura J
authors: LJ
authors: Brown
authors: Noaman M
authors: NM
authors: Hasan
authors: Sarawut
authors: S
authors: Jitrapakdee
authors: Toshiyuki
authors: T
authors: Fukao
authors: Matthew S
authors: MS
authors: Hanson
authors: Luis A
authors: LA
authors: Fernandez
authors: Jon
authors: J
authors: Odorico
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000378:metabolism*; D000090:Acetoacetates / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007515:Islets of Langerhans / Q000201:enzymology*; D051379:Mice; D011766:Pyruvate Carboxylase / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013549:Sweetening Agents / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000090:Acetoacetates; D013549:Sweetening Agents; C016635:acetoacetic acid; D019289:Pyruvic Acid; D001275:ATP Citrate (pro-S)-Lyase; D011766:Pyruvate Carboxylase; D005947:Glucose