Lab of Dr. George G. Holz
Location: Institute for Human Performance
Phone: 315 464-4860
Molecular Basis of Antidiabetogenic Hormone Action: GLP-1, Byetta, and the Incretin Mimetics
Our laboratory is performing studies of the "Incretin Mimetics", a newly recognized class of blood glucose-lowering agents that stimulate pancreatic insulin secretion, and which are likely to be the next line of defense for the treatment of type 2 diabetes mellitus. Incretin mimetics mimic the action of GLP-1 (glucagon-like peptide-1), a naturally-occurring incretin hormone secreted by L-cells of the intestine, and which when administered to type 2 diabetic subjects, lowers concentrations of blood glucose.
Why are GLP-1 and the incretin mimetics of special interest? Perhaps most remarkable is the finding that the immediate blood glucose-lowering action of these compounds in type 2 diabetic subjects is self-terminating once normoglycemia is achieved. Thus, unlike administered insulin, there exists a natural safeguard such that these agents are less likely to produce hypoglycemia when they are adminstered for therapeutic purposes. One such incretin mimetic is Byetta. It is an insulin secretagogue that is structurally-related to GLP-1, but unlike GLP-1 it exhibits an extended duration of action. Understanding how the beneficial "antidiabetogenic" actions of GLP-1 and Byetta are achieved is a primary focus of my research.
At Upstate I am working with my associates to determine exactly how GLP-1 and beta-cell glucose metabolism interact to stimulate insulin secretion. Our methods of analysis include patch clamp electrophysiology, confocal microscopy for the measurement of [Ca2+]i, the imaging of luminescence as an index of mitochondrial ATP production, and the primary cell culture of both mouse and human beta cells. We have also developed FRET and fura-2 based methodologies to measure simultaneous oscillations of intracellular cAMP and Ca2+ concentrations in single living beta cells. Using these methods, we have established the existence of a novel cAMP signaling mechanism that utilizes the Epac class of cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs), and which mediates stimulatory actions of GLP-1 on beta-cell insulin secretion. Ongoing studies are directed at the development of small molecules that target GLP-1 receptors and which might be of use as blood glucose-lowering agents.
Molecular physiology of stimulus-secretion coupling in excitable cells including insulin-secreting cells of the pancreatic islets of Langerhans.