Welcome to the Kibbey Lab
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 β-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 α-cells.
The Kibbey Lab 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. The lab focuses mostly on 13C mass spectrometry, insulin resistance and secretion, bioenergetics, and applications to cellular, cancer and animal preclinical models.
The Kibbey Laboratory is a part of the Department of Internal Medicine/Endocrinology, the Department of Cellular and Molecular Physiology, the Diabetes Research Center (DRC) and the Yale Cancer Center.