Richard Kibbey, MD/PhD
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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
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MIMOSA
Selected Publications
- Childhood Pancreatitis and Risk for Incident Diabetes in Adulthood.Bendor CD, Bardugo A, Zucker I, Cukierman-Yaffe T, Lutski M, Derazne E, Shohat T, Mosenzon O, Tzur D, Sapir A, Pinhas-Hamiel O, Kibbey RG, Raz I, Afek A, Gerstein HC, Tirosh A, Twig G. Childhood Pancreatitis and Risk for Incident Diabetes in Adulthood. Diabetes Care 2020, 43: 145-151. PMID: 31694859, PMCID: PMC7011197, DOI: 10.2337/dc19-1562.
- Mitochondrial Proton Leak Regulated by Cyclophilin D Elevates Insulin Secretion in Islets at Nonstimulatory Glucose Levels.Taddeo EP, Alsabeeh N, Baghdasarian S, Wikstrom JD, Ritou E, Sereda S, Erion K, Li J, Stiles L, Abdulla M, Swanson Z, Wilhelm J, Bellin MD, Kibbey RG, Liesa M, Shirihai O. Mitochondrial Proton Leak Regulated by Cyclophilin D Elevates Insulin Secretion in Islets at Nonstimulatory Glucose Levels. Diabetes 2020, 69: 131-145. PMID: 31740442, PMCID: PMC6971491, DOI: 10.2337/db19-0379.
- N-acyl taurines are endogenous lipid messengers that improve glucose homeostasis.Grevengoed TJ, Trammell SAJ, McKinney MK, Petersen N, Cardone RL, Svenningsen JS, Ogasawara D, Nexøe-Larsen CC, Knop FK, Schwartz TW, Kibbey RG, Cravatt BF, Gillum MP. N-acyl taurines are endogenous lipid messengers that improve glucose homeostasis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2019, 116: 24770-24778. PMID: 31740614, PMCID: PMC6900532, DOI: 10.1073/pnas.1916288116.
- Distinct Hepatic PKA and CDK Signaling Pathways Control Activity-Independent Pyruvate Kinase Phosphorylation and Hepatic Glucose Production.Gassaway BM, Cardone RL, Padyana AK, Petersen MC, Judd ET, Hayes S, Tong S, Barber KW, Apostolidi M, Abulizi A, Sheetz JB, Kshitiz, Aerni HR, Gross S, Kung C, Samuel VT, Shulman GI, Kibbey RG, Rinehart J. Distinct Hepatic PKA and CDK Signaling Pathways Control Activity-Independent Pyruvate Kinase Phosphorylation and Hepatic Glucose Production. Cell Reports 2019, 29: 3394-3404.e9. PMID: 31825824, PMCID: PMC6951436, DOI: 10.1016/j.celrep.2019.11.009.
- Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma.Chung KM, Singh J, Lawres L, Dorans KJ, Garcia C, Burkhardt DB, Robbins R, Bhutkar A, Cardone R, Zhao X, Babic A, Vayrynen SA, Dias Costa A, Nowak JA, Chang DT, Dunne RF, Hezel AF, Koong AC, Wilhelm JJ, Bellin MD, Nylander V, Gloyn AL, McCarthy MI, Kibbey RG, Krishnaswamy S, Wolpin BM, Jacks T, Fuchs CS, Muzumdar MD. Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma. Cell 2020, 181: 832-847.e18. PMID: 32304665, PMCID: PMC7266008, DOI: 10.1016/j.cell.2020.03.062.
- Glucose Response by Stem Cell-Derived β Cells In Vitro Is Inhibited by a Bottleneck in Glycolysis.Davis JC, Alves TC, Helman A, Chen JC, Kenty JH, Cardone RL, Liu DR, Kibbey RG, Melton DA. Glucose Response by Stem Cell-Derived β Cells In Vitro Is Inhibited by a Bottleneck in Glycolysis. Cell Reports 2020, 31: 107623. PMID: 32402282, PMCID: PMC7433758, DOI: 10.1016/j.celrep.2020.107623.
- Pyruvate Kinase Controls Signal Strength in the Insulin Secretory Pathway.Lewandowski SL, Cardone RL, Foster HR, Ho T, Potapenko E, Poudel C, VanDeusen HR, Sdao SM, Alves TC, Zhao X, Capozzi ME, de Souza AH, Jahan I, Thomas CJ, Nunemaker CS, Davis DB, Campbell JE, Kibbey RG, Merrins MJ. Pyruvate Kinase Controls Signal Strength in the Insulin Secretory Pathway. Cell Metabolism 2020, 32: 736-750.e5. PMID: 33147484, PMCID: PMC7685238, DOI: 10.1016/j.cmet.2020.10.007.
- Multi-Tissue Acceleration of the Mitochondrial Phosphoenolpyruvate Cycle Improves Whole-Body Metabolic Health.Abulizi A, Cardone RL, Stark R, Lewandowski SL, Zhao X, Hillion J, Ma L, Sehgal R, Alves TC, Thomas C, Kung C, Wang B, Siebel S, Andrews ZB, Mason GF, Rinehart J, Merrins MJ, Kibbey RG. Multi-Tissue Acceleration of the Mitochondrial Phosphoenolpyruvate Cycle Improves Whole-Body Metabolic Health. Cell Metabolism 2020, 32: 751-766.e11. PMID: 33147485, PMCID: PMC7679013, DOI: 10.1016/j.cmet.2020.10.006.
- NLRX1 Deletion Increases Ischemia-Reperfusion Damage and Activates Glucose Metabolism in Mouse Heart.Zhang H, Xiao Y, Nederlof R, Bakker D, Zhang P, Girardin SE, Hollmann MW, Weber NC, Houten SM, van Weeghel M, Kibbey RG, Zuurbier CJ. NLRX1 Deletion Increases Ischemia-Reperfusion Damage and Activates Glucose Metabolism in Mouse Heart. Frontiers In Immunology 2020, 11: 591815. PMID: 33362773, PMCID: PMC7759503, DOI: 10.3389/fimmu.2020.591815.
- Mitochondrial Fission Governed by Drp1 Regulates Exogenous Fatty Acid Usage and Storage in Hela Cells.Song JE, Alves TC, Stutz B, Šestan-Peša M, Kilian N, Jin S, Diano S, Kibbey RG, Horvath TL. Mitochondrial Fission Governed by Drp1 Regulates Exogenous Fatty Acid Usage and Storage in Hela Cells. Metabolites 2021, 11 PMID: 34069800, PMCID: PMC8157282, DOI: 10.3390/metabo11050322.
- Development of a Bioartificial Vascular Pancreas.Han EX, Wang J, Kural M, Jiang B, Leiby KL, Chowdhury N, Tellides G, Kibbey RG, Lawson JH, Niklason LE. Development of a Bioartificial Vascular Pancreas. Journal Of Tissue Engineering 2021, 12: 20417314211027714. PMID: 34262686, PMCID: PMC8243137, DOI: 10.1177/20417314211027714.
- Dyrk1b promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice.Bhat N, Narayanan A, Fathzadeh M, Kahn M, Zhang D, Goedeke L, Neogi A, Cardone RL, Kibbey RG, Fernandez-Hernando C, Ginsberg HN, Jain D, Shulman G, Mani A. Dyrk1b promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice. The Journal Of Clinical Investigation 2022, 132 PMID: 34855620, PMCID: PMC8803348, DOI: 10.1172/JCI153724.
- Comprehensive Analysis of Metabolic Isozyme Targets in Cancer.Marczyk M, Gunasekharan V, Casadevall D, Qing T, Foldi J, Sehgal R, Shan NL, Blenman KRM, O'Meara TA, Umlauf S, Surovtseva YV, Muthusamy V, Rinehart J, Perry RJ, Kibbey R, Hatzis C, Pusztai L. Comprehensive Analysis of Metabolic Isozyme Targets in Cancer. Cancer Research 2022, 82: 1698-1711. PMID: 35247885, DOI: 10.1158/0008-5472.CAN-21-3983.
- Citrullination of glucokinase is linked to autoimmune diabetes.Yang ML, Horstman S, Gee R, Guyer P, Lam TT, Kanyo J, Perdigoto AL, Speake C, Greenbaum CJ, Callebaut A, Overbergh L, Kibbey RG, Herold KC, James EA, Mamula MJ. Citrullination of glucokinase is linked to autoimmune diabetes. Nature Communications 2022, 13: 1870. PMID: 35388005, PMCID: PMC8986778, DOI: 10.1038/s41467-022-29512-0.
- β Cell-specific deletion of Zfp148 improves nutrient-stimulated β cell Ca2+ responses.Emfinger CH, de Klerk E, Schueler KL, Rabaglia ME, Stapleton DS, Simonett SP, Mitok KA, Wang Z, Liu X, Paulo JA, Yu Q, Cardone RL, Foster HR, Lewandowski SL, Perales JC, Kendziorski CM, Gygi SP, Kibbey RG, Keller MP, Hebrok M, Merrins MJ, Attie AD. β Cell-specific deletion of Zfp148 improves nutrient-stimulated β cell Ca2+ responses. JCI Insight 2022, 7 PMID: 35603790, DOI: 10.1172/jci.insight.154198.