Richard Glenn Kibbey MD/PhD
Associate Professor of Medicine (Endocrinology) and of Cellular and Molecular Physiology
Mechanisms of insulin secretion by beta-cells; Pathogenesis of beta-cell exhaustion in Type 2 Diabetes Mellitus; Mitochondria
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.