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
- Loss of ZNF148 enhances insulin secretion in human pancreatic β cells.de Klerk E, Xiao Y, Emfinger C, Keller M, Berrios D, Loconte V, Ekman A, White K, Cardone R, Kibbey R, Attie A, Hebrok M. Loss of ZNF148 enhances insulin secretion in human pancreatic β cells. JCI Insight 2023, 8 PMID: 37288664, DOI: 10.1172/jci.insight.157572.
- Loss of ZNF148 enhances insulin secretion in human pancreatic ß cells.71. de Klerk E, Xiao Y, Emfinger C, Keller MP,Berrios DI, Loconte V, Ekman A, White KL, Cardone RL, Kibbey RG, Attie A, Hebrok M, Loss of ZNF148 enhances insulin secretion in human pancreatic ß cells. JCI Insights, 2023 (in press)
- UCP2-dependent redox sensing in POMC neurons regulates feedingYoon N, Jin S, Kim J, Liu Z, Sun Q, Cardone R, Kibbey R, Diano S. UCP2-dependent redox sensing in POMC neurons regulates feeding. Cell Reports 2022, 41: 111894. PMID: 36577374, PMCID: PMC9885759, DOI: 10.1016/j.celrep.2022.111894.
- 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.
- 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. PMID: 36389721, PMCID: PMC9647083, DOI: 10.3389/fimmu.2022.1028130.
- Ketones: the double-edged sword of SGLT2 inhibitors?Lupsa BC, Kibbey RG, Inzucchi SE. Ketones: the double-edged sword of SGLT2 inhibitors? Diabetologia 2022, 66: 23-32. PMID: 36255460, DOI: 10.1007/s00125-022-05815-1.
- Overexpression of UCP3 decreases mitochondrial efficiency in mouse skeletal muscle in vivoCodella R, Alves TC, Befroy DE, Choi CS, Luzi L, Rothman DL, Kibbey RG, Shulman GI. Overexpression of UCP3 decreases mitochondrial efficiency in mouse skeletal muscle in vivo. FEBS Letters 2022, 597: 309-319. PMID: 36114012, DOI: 10.1002/1873-3468.14494.
- β-cell deletion of the PKm1 and PKm2 isoforms of pyruvate kinase in mice reveals their essential role as nutrient sensors for the KATP channelFoster HR, Ho T, Potapenko E, Sdao SM, Huang SM, Lewandowski SL, VanDeusen HR, Davidson SM, Cardone RL, Prentki M, Kibbey RG, Merrins MJ. β-cell deletion of the PKm1 and PKm2 isoforms of pyruvate kinase in mice reveals their essential role as nutrient sensors for the KATP channel. ELife 2022, 11: e79422. PMID: 35997256, PMCID: PMC9444242, DOI: 10.7554/elife.79422.
- 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.
- Metabolic cycles and signals for insulin secretionMerrins MJ, Corkey BE, Kibbey RG, Prentki M. Metabolic cycles and signals for insulin secretion. Cell Metabolism 2022, 34: 947-968. PMID: 35728586, PMCID: PMC9262871, DOI: 10.1016/j.cmet.2022.06.003.
- 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.
- β Cell–specific deletion of Zfp148 improves nutrient-stimulated β cell Ca2+ responsesEmfinger 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: e154198. PMID: 35603790, PMCID: PMC9220824, DOI: 10.1172/jci.insight.154198.
- Citrullination of glucokinase is linked to autoimmune diabetesYang 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.
- 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.
- 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.
- Dyrk1b promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in miceBhat 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. Journal Of Clinical Investigation 2022, 132: e153724. PMID: 34855620, PMCID: PMC8803348, DOI: 10.1172/jci153724.
- 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.
- Mitochondrial Fission Governed by Drp1 Regulates Exogenous Fatty Acid Usage and Storage in Hela CellsSong 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: 322. PMID: 34069800, PMCID: PMC8157282, DOI: 10.3390/metabo11050322.
- A Single Virtual Consult Reduces Severe Hyperglycemia in Patients Admitted with COVID19 InfectionAthonvarangkul D, Gunawan F, Nagel K, Bak L, Herold K, Hwang J, Jastreboff A, Kibbey R, Shulman G, Vatner D, Alausa J, 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.
- Development of a Bioartificial Vascular PancreasHan 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.
- NLRX1 Deletion Increases Ischemia-Reperfusion Damage and Activates Glucose Metabolism in Mouse HeartZhang 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.
- Pyruvate Kinase Controls Signal Strength in the Insulin Secretory PathwayLewandowski 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 HealthAbulizi 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.
- 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.
- Glucose Response by Stem Cell-Derived β Cells In Vitro Is Inhibited by a Bottleneck in GlycolysisDavis 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.
- Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal AdenocarcinomaChung 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.
- Distinct Hepatic PKA and CDK Signaling Pathways Control Activity-Independent Pyruvate Kinase Phosphorylation and Hepatic Glucose ProductionGassaway 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.
- Mitochondrial Proton Leak Regulated by Cyclophilin D Elevates Insulin Secretion in Islets at Nonstimulatory Glucose LevelsTaddeo 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 2019, 69: 131-145. PMID: 31740442, PMCID: PMC6971491, DOI: 10.2337/db19-0379.
- N-acyl taurines are endogenous lipid messengers that improve glucose homeostasisGrevengoed 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.
- Childhood Pancreatitis and Risk for Incident Diabetes in AdulthoodBendor 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 2019, 43: 145-151. PMID: 31694859, PMCID: PMC7011197, DOI: 10.2337/dc19-1562.
- 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.
- Pathogenesis of hypothyroidism-induced NAFLD is driven by intra- and extrahepatic mechanismsFerrandino G, Kaspari RR, Spadaro O, Reyna-Neyra A, Perry RJ, Cardone R, Kibbey RG, Shulman GI, Dixit VD, Carrasco N. Pathogenesis of hypothyroidism-induced NAFLD is driven by intra- and extrahepatic mechanisms. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: e9172-e9180. PMID: 29073114, PMCID: PMC5664516, DOI: 10.1073/pnas.1707797114.
- PEPCK-MKibbey RG, PEPCK-M, Encyclopedia of Signaling Molecules, 2nd Edition, Sangdun Choi (Ed), 2017, Springer ISBN 978-3-319-67200-7
- 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.
- Association of SGLT-2 Inhibitors and Euglycemic Diabetic KetoacidosisKibbey RG. Association of SGLT-2 Inhibitors and Euglycemic Diabetic Ketoacidosis. PracticeUpdate website. Available at: http://www.practiceupdate.com/c/26536/48/8. Accessed June 30, 2015.