title: Mitochondrial pyruvate carrier 2 hypomorphism in mice leads to defects in glucose-stimulated insulin secretion.
abstract: Carrier-facilitated pyruvate transport across the inner mitochondrial membrane plays an essential role in anabolic and catabolic intermediary metabolism. Mitochondrial pyruvate carrier 2 (Mpc2) is believed to be a component of the complex that facilitates mitochondrial pyruvate import. Complete MPC2 deficiency resulted in embryonic lethality in mice. However, a second mouse line expressing an N-terminal truncated MPC2 protein (Mpc2(Δ16)) was viable but exhibited a reduced capacity for mitochondrial pyruvate oxidation. Metabolic studies demonstrated exaggerated blood lactate concentrations after pyruvate, glucose, or insulin challenge in Mpc2(Δ16) mice. Additionally, compared with wild-type controls, Mpc2(Δ16) mice exhibited normal insulin sensitivity but elevated blood glucose after bolus pyruvate or glucose injection. This was attributable to reduced glucose-stimulated insulin secretion and was corrected by sulfonylurea KATP channel inhibitor administration. Collectively, these data are consistent with a role for MPC2 in mitochondrial pyruvate import and suggest that Mpc2 deficiency results in defective pancreatic β cell glucose sensing.
authors.affiliation: Division of Geriatrics and Nutritional Sciences, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Vigueira
authors.affiliation: Division of Geriatrics and Nutritional Sciences, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Kyle S
authors.initials: KS
authors.lastname: McCommis
authors.affiliation: Division of Geriatrics and Nutritional Sciences, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: George G
authors.initials: GG
authors.lastname: Schweitzer
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Remedi
authors.affiliation: Division of Geriatrics and Nutritional Sciences, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Kari T
authors.initials: KT
authors.lastname: Chambers
authors.affiliation: Advanced Imaging Research Center and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Fu
authors.affiliation: Metabolic Solutions Development Company, Kalamazoo, MI 49007, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: McDonald
authors.affiliation: Metabolic Solutions Development Company, Kalamazoo, MI 49007, USA.
authors.forename: Serena L
authors.initials: SL
authors.lastname: Cole
authors.affiliation: Metabolic Solutions Development Company, Kalamazoo, MI 49007, USA.
authors.forename: Jerry R
authors.initials: JR
authors.lastname: Colca
authors.affiliation: Metabolic Solutions Development Company, Kalamazoo, MI 49007, USA.
authors.forename: Rolf F
authors.initials: RF
authors.lastname: Kletzien
authors.affiliation: Advanced Imaging Research Center and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Shawn C
authors.initials: SC
authors.lastname: Burgess
authors.affiliation: Division of Geriatrics and Nutritional Sciences, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Brian N
authors.initials: BN
authors.lastname: Finck
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins; D005260:Female; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D019344:Lactic Acid / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D033681:Mitochondrial Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; D012636:Secretory Rate / Q000187:drug effects
chemical_list: D027321:Anion Transport Proteins; D007328:Insulin; C000595573:MPC1 pyruvate carrier protein, mouse; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; D019344:Lactic Acid; D005947:Glucose