The control of glucose homeostasis is a multi-component process where hormonal, sensory, and nutritional inputs and outputs cooperate to ensure proper energy balance. Diabetes mellitus results from dysfunctional integration of this regulatory network and is frequently associated with increased insulin resistance or inadequate insulin secretion. Mitochondria are central to both of these. Mitochondria, therefore, require mechanisms to 'sense' their own metabolic environment in order to respond to supply and demand. My lab has identified one such signal, mitochondrial GTP (mtGTP), as an important 'fuel-sensor' involved in glucose homeostasis. Every turn of the TCA cycle generates stoichiometric amounts of mtGTP, and as such mtGTP synthesis acts as a 'molecular tachometer' of mitochondrial metabolic flux. In tissues such as pancreatic cells and hepatocytes, the mtGTP is hydrolyzed by mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) to generate PEP. In ßcells, this creates a trans-mitochondrial PEP cycle essential for insulin secretion, while in hepatocytes it catalyzes the rate-limiting step of luconeogenesis. We are trying to identify how this mtGTP metabolic circuit in ßcells and the liver regulates glucose homeostasis.
Extensive Research Description
Dr. Kibbey is interested in the mechanisms of insulin secretion by beta-cells and the pathogenesis of beta-cell exhaustion in Type 2 Diabetes Mellitus. Recent studies have demonstrated that the production of mitochondrial GTP is an important indicator of TCA cycle flux and may represent a key regulator of insulin secretion. His lab is also developing animal models of chronic hyperglycemia in order to study the effects of glucose toxicity on insulin secretion by pancreatic islet cells.
- Jamison RA, Stark R, Dong J, Yonemitsu S, Zhang D, Shulman GI, *Kibbey RG. (2011) Hyperglucagonemia precedes beta-cell dysfunction and causes hyperglycemia in chronically glucose-infused rats. Epub ahead of print: Am J Physiology-Endocrinology
- Jurczak MJ, Lee HY, Birkenfeld AL, Jornayvaz FR, Frederick DW, Pongratz RL, Zhao X, Moeckel GW, Samuel VT, Whaley JM, Shulman GI, *Kibbey RG. (2011) SGLT2 Deletion Improves Glucose Homeostasis and Preserves Pancreatic ß-cell Function. Diabetes. 2011 Mar;6
- Stark R, Pasquel F, Turcu A, Pongratz RL, Roden M, Cline GW, Shulman GI, *Kibbey RG (2009) Mitochondiral PEPCK links anaplerosis and mitochondrial GTP with insulin secretion. J. Biol. Chem. 284(39): 26578-90 PMID: 19635791
- Kibbey, R.G., Pongratz, R.L., Romanelli, A.J., Wollheim, C.B., Cline, G.W., and Shulman, G.I. (2007). Mitochondrial GTP regulates glucose-stimulated insulin secretion. Cell Metab 5, 253-264.
- Pongratz, R.L., Kibbey, R.G., Shulman, G.I., and Cline, G.W. (2007). Cytosolic and mitochondrial malic enzyme isoforms differentially control insulin secretion. J Biol Chem 282, 200-207.
- Cline, G.W., Lepine, R.L., Papas, K.K., Kibbey, R.G., and Shulman, G.I. (2004). 13C NMR isotopomer analysis of anaplerotic pathways in INS-1 cells. J Biol Chem 279, 44370-44375.