Welcome to the Web page of Dr. George G. Holz.

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 Amylin Pharmaceutical's 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.

We and others have demonstrated that it is the pancreatic beta-cells located within the islets of Langerhans at which GLP-1 exerts a direct effect. GLP-1 binds to beta cell G protein-coupled receptors and stimulates cAMP production, an increase of intracellular calcium concentration, and exocytosis of insulin. Because the insulin secretagogue action of GLP-1 requires exposure of beta cells to an elevated concentration of glucose, we hypothesize that GLP-1 interacts with beta-cell glycolytic and/or mitochondrial metabolism, perhaps by facilitating the production of a metabolic coupling factor important to insulin secretion. Alternatively, GLP-1 might facilitate the action of such coupling factors, and in fact evidence exists that GLP-1 reinforces inhibitory effects of the adenine nucleotide ATP at beta-cell ATP-sensitive K+ channels (K-ATP channels). These channels are important determinants of beta-cell stimulus-secretion coupling, and they are also the receptors at which sulfonylureas such as glyburide and glipizide exert their blood glucose-lowering effects.

At the NYU School of Medicine I have worked with my associates Drs. Guoxin Kang and Oleg G. Chepurny to determine exactly how GLP-1 and glucose metabolism interact to stimulate insulin secretion. Because the secretagogue action of GLP-1 is glucose-dependent, and because GLP-1 utilizes cAMP to mobilize an intracellular source of Ca2+, we hypothesize that Ca2+ released from the endoplasmic reticulum acts as a direct stimulus for mitochondrial ATP production. This stimulatory effect of GLP-1 on beta cell glucose metabolism would complement the known ability of GLP-1 to render K-ATP channels more sensitive to ATP, thereby closing them. Our methods of analysis to test this hypothesis include patch clamp electrophysiology, confocal microscopy for the measurement of [Ca2+]i, the imaging of an ATP reporter (firefly luciferase), and primary cell culture of 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 (cAMPGEFs), and which mediates stimulatory actions of GLP-1 on Ca2+ signaling, ATP production, and insulin secretion. Ongoing studies are directed at the development of small molecules that activate Epac selectively and which might be of use as blood glucose-lowering agents.