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INFORMATION FOR

Richard Kibbey, MD/PhD

Associate Professor of Medicine; Faculty Director, Core in Chemical Metabolism; Associate Director, Yale Program for Translational Biomedicine; Associate Chief of Research, Endocrinology

Contact Information

Richard Kibbey, MD/PhD

Lab Location

Office Location

Mailing Address

  • Endocrinology

    PO Box 208020, 300 Cedar Street

    New Haven, CT 06520-8020

    United States

Research Summary

Dr. Kibbey is a clinically-active physician scientist dedicated to the treatment of diabetes and other metabolic diseases. Mitochondria, as the primary sites of consumption and production of metabolites and energy, are central to regulation of insulin secretion, glucose production, nerve transmission, muscular contraction and normal and cancer cell growth. Mitochondria, therefore, require mechanisms to ‘sense’ their own metabolic environment in order to efficiently respond to supply and demand termed ‘metabolic equilibrioception.’ In order to better understand these and other important mitochondrial metabolic fluxes, methods to discriminate between oxidative, exchange, anaplerotic, and cataplerotic fluxes were developed. Consequently, the LC/MS/MS method Mass Isotopomeric Multi-Ordinate Spectroscopic Analysis (MIMOSA) follows the step-wise flow of mass isotopomers along these intersecting metabolic pathways. It captures both steady state and dynamic metabolic fluxes by resolving positional isotopomers of the TCA cycle. As a consequence, MIMOSA not only can determine the rates of individual intracellular fluxes but, when more than one pathway compete for a reaction, the relative flow of each contribution.

From the study of a rare condition of congenital hypoglycemia, the Kibbey lab identified mitochondrial GTP (mtGTP) as an important equilibrioceptive indicator involved in glucose homeostasis and ascribed the first physiological activity of the mitochondria GTP cycle as a “metabolic tachometer.” In tissues such as pancreatic b-cells and hepatocytes, the mtGTP is hydrolyzed by the mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) to generate PEP that is essential for insulin secretion, while in hepatocytes it catalyzes this crucial step of gluconeogenesis. Finally, it also regulates glucagon secretion from a-cells.

His laboratory has developed a unique experience with mitochondrial, cellular, tissues-specific and whole body metabolism needed to advance mtGTP understanding. It is strongly vested in both understanding intracellular and inter-tissue metabolic flux associated with metabolic human disease. Differences in equilibrioception and responses to pharmacologic therapy are used to identify defects in metabolism as novel therapeutic targets for humans. While Dr. Kibbey’s graduate studies were NMR protein structure, his expertise now lies in 13C mass spectrometry, insulin resistance and secretion, bioenergetics, and applications to cellular, cancer and animal preclinical models.

Extensive Research Description

Dr. Kibbey is a clinically-active physician scientist dedicated to the treatment of diabetes and other metabolic diseases. Mitochondria, as the primary sites of consumption and production of metabolites and energy, are central to regulation of insulin secretion, glucose production, nerve transmission, muscular contraction and normal and cancer cell growth. Mitochondria, therefore, require mechanisms to ‘sense’ their own metabolic environment in order to efficiently respond to supply and demand termed ‘metabolic equilibrioception.’ In order to better understand these and other important mitochondrial metabolic fluxes, methods to discriminate between oxidative, exchange, anaplerotic, and cataplerotic fluxes were developed. Consequently, the LC/MS/MS method Mass Isotopomeric Multi-Ordinate Spectroscopic Analysis (MIMOSA) follows the step-wise flow of mass isotopomers along these intersecting metabolic pathways. It captures both steady state and dynamic metabolic fluxes by resolving positional isotopomers of the TCA cycle. As a consequence, MIMOSA not only can determine the rates of individual intracellular fluxes but, when more than one pathway compete for a reaction, the relative flow of each contribution.

From the study of a rare condition of congenital hypoglycemia, the Kibbey lab identified mitochondrial GTP (mtGTP) as an important equilibrioceptive indicator involved in glucose homeostasis and ascribed the first physiological activity of the mitochondria GTP cycle as a “metabolic tachometer.” In tissues such as pancreatic b-cells and hepatocytes, the mtGTP is hydrolyzed by the mitochondrial isoform of phosphoenolpyruvate carboxykinase (PEPCK-M) to generate PEP that is essential for insulin secretion, while in hepatocytes it catalyzes this crucial step of gluconeogenesis. Finally, it also regulates glucagon secretion from a-cells.

His laboratory has developed a unique experience with mitochondrial, cellular, tissues-specific and whole body metabolism needed to advance mtGTP understanding. It is strongly vested in both understanding intracellular and inter-tissue metabolic flux associated with metabolic human disease. Differences in equilibrioception and responses to pharmacologic therapy are used to identify defects in metabolism as novel therapeutic targets for humans. While Dr. Kibbey’s graduate studies were NMR protein structure, his expertise now lies in 13C mass spectrometry, insulin resistance and secretion, bioenergetics, and applications to cellular, cancer and animal preclinical models.

Coauthors

Research Interests

Diabetes Mellitus, Type 2; Endocrinology; Glucose; Insulin; Metabolism; Mitochondria; Physiology; Mass Spectrometry

Research Image

Selected Publications

  • Abstract C050: Elucidating mechanisms of endocrine-exocrine signaling in obesity-driven pancreatic cancerGarcia C, Lawres L, Agabiti S, Singh J, Tong A, Venkat A, Burkhardt D, Cardone R, Kibbey R, Krishnaswamy S, Muzumdar M. Abstract C050: Elucidating mechanisms of endocrine-exocrine signaling in obesity-driven pancreatic cancer Cancer Research 2022, 82: c050-c050. DOI: 10.1158/1538-7445.panca22-c050.
  • Biomarkers of autoimmunity and beta cell metabolism in type 1 diabetesYang M, Kibbey R, Mamula M. Biomarkers of autoimmunity and beta cell metabolism in type 1 diabetes Frontiers In Immunology 2022, 13: 1028130. PMCID: PMC9647083, DOI: 10.3389/fimmu.2022.1028130.
  • 784 Metabolic crosstalk in the wound bed: How adipocytes and immune cells communicate during wound healingForni M, Xu T, Krause W, Pannone R, Kibbey R, Rudolph M, Horsley V. 784 Metabolic crosstalk in the wound bed: How adipocytes and immune cells communicate during wound healing Journal Of Investigative Dermatology 2022, 142: s136. DOI: 10.1016/j.jid.2022.05.797.
  • 316-OR: Genetic Deletion of Beta-Cell Pkm1, Pkm2, and Pck2 Identifies PEP as an Essential Signal for Compartmentalized KATP Closure and Cycling of the Insulin Secretory PathwayFOSTER H, HO T, POTAPENKO E, CARDONE R, KIBBEY R, MERRINS M. 316-OR: Genetic Deletion of Beta-Cell Pkm1, Pkm2, and Pck2 Identifies PEP as an Essential Signal for Compartmentalized KATP Closure and Cycling of the Insulin Secretory Pathway Diabetes 2022, 71 DOI: 10.2337/db22-316-or.
  • Abstract P5-17-01: Targeting Acetyl-CoA carboxylase in pre-clinical breast cancer modelsFoldi J, Marczyk M, Gunasekharan V, Qing T, Sehgal R, Shan N, Muthusamy V, Umlau S, Surovtseva Y, Kibbey R, Pusztai L. Abstract P5-17-01: Targeting Acetyl-CoA carboxylase in pre-clinical breast cancer models Cancer Research 2022, 82: p5-17-01-p5-17-01. DOI: 10.1158/1538-7445.sabcs21-p5-17-01.
  • 127-OR: In Vivo Genetic Evidence That the Pyruvate Kinase Isoforms PKM1 and PKM2 Differentially Control Beta-Cell Fuel SensingFOSTER H, HO T, POTAPENKO E, LEWANDOWSKI S, SDAO S, VANDEUSEN H, CARDONE R, KIBBEY R, MERRINS M. 127-OR: In Vivo Genetic Evidence That the Pyruvate Kinase Isoforms PKM1 and PKM2 Differentially Control Beta-Cell Fuel Sensing Diabetes 2021, 70 DOI: 10.2337/db21-127-or.
  • A Single Virtual Consult Reduces Severe Hyperglycemia in Patients Admitted with COVID19 InfectionAthonvarangkul D, Gunawan F, Gunawan F, Nagel K, Nagel K, Bak L, Bak L, Herold K, Hwang J, Jastreboff A, Kibbey R, Shulman G, Vatner D, Alausa J, Alausa J, Subair L, Subair L, Inzucchi S. A Single Virtual Consult Reduces Severe Hyperglycemia in Patients Admitted with COVID19 Infection Journal Of The Endocrine Society 2021, 5: a335-a335. PMCID: PMC8089507, DOI: 10.1210/jendso/bvab048.683.
  • Abstract LT013: Endocrine-exocrine signaling is a driver of obesity-associated pancreatic ductal adenocarcinomaGarcia C, Singh J, Lawres L, Agabiti S, Burkhardt D, Tong A, Cardone R, Kibbey R, Krishnaswamy S, Muzumdar M. Abstract LT013: Endocrine-exocrine signaling is a driver of obesity-associated pancreatic ductal adenocarcinoma Cancer Research 2021, 81: lt013-lt013. DOI: 10.1158/1538-7445.tme21-lt013.
  • 120-LB: Small Molecule Activator of Pyruvate Kinase Regulates In Vivo Glucose HomeostasisABULIZI A, CARDONE R, SIEBEL S, KUNG C, KIBBEY R. 120-LB: Small Molecule Activator of Pyruvate Kinase Regulates In Vivo Glucose Homeostasis Diabetes 2020, 69 DOI: 10.2337/db20-120-lb.
  • 369-OR: [1,2-13C2]-L-Glutamine Mass Isotopomers Map Hepatic Mitochondrial Metabolism without Tracer InterferenceSIEBEL S, CARDONE R, ABULIZI A, RAAISA R, WILLIAMS R, SEHGAL R, BUTRICO G, CLINE G, ROTHMAN D, MASON G, KIBBEY R. 369-OR: [1,2-13C2]-L-Glutamine Mass Isotopomers Map Hepatic Mitochondrial Metabolism without Tracer Interference Diabetes 2020, 69 DOI: 10.2337/db20-369-or.
  • Cyclophilin D-Dependent Mitochondrial Proton Leak in ß Cells Promotes Basal Insulin SecretionALSABEEH N, TADDEO E, WIKSTRÖM J, RITOU E, STILES L, KIBBEY R, LIESA M, SHIRIHAI O. Cyclophilin D-Dependent Mitochondrial Proton Leak in ß Cells Promotes Basal Insulin Secretion Diabetes 2018, 67 DOI: 10.2337/db18-312-lb.
  • PEPCK-MKibbey R. PEPCK-M 2018, 3864-3873. DOI: 10.1007/978-3-319-67199-4_101756.
  • PEPCK-MKibbey R. PEPCK-M 2016, 1-9. DOI: 10.1007/978-1-4614-6438-9_101756-1.
  • GLP‐2 reprograms glucose metabolism in intestinal stem cellsShi X, Alves T, Zeng X, Kibbey R, Estes M, Guan X. GLP‐2 reprograms glucose metabolism in intestinal stem cells The FASEB Journal 2015, 29 DOI: 10.1096/fasebj.29.1_supplement.851.4.