|
|
|
| Thanks to the following for materials & support |
|
 |
|
 |
|
 |
|
 |
|
 |
|
|
|
|
|
|
|
The Mechanism of Action of a Newly Developed
Blood Glucose- Lowering Hormone (complete)
|
|
|
|
|
| PROJECT INVESTIGATOR
George G. Holz, PhD
State University of New York
Syracuse, New York
|
|
 |
|
|
|
Description:
For several years I have sought to identify and characterize novel therapeutic strategies that might be of use for the treatment of type 2 (adult-onset) diabetes mellitus. To this end, I have focused on ascertaining the blood glucose-lowering properties of an insulinotropic hormone that is currently under clinical investigation. This hormone is glucagon-like peptide-1-(7-36)-amide (GLP-1), a peptide secreted by enteroendocrine L-cells of the distal intestine, and which when administered to type 2 diabetic subjects, lowers blood glucose concentration. Earlier on it was recognized that GLP-1 stimulates beta-cell insulin gene transcription, translational biosynthesis of proinsulin, and glucose-dependent insulin secretion. What has recently become appreciated is that GLP-1 also exerts growth factor-like effects on beta cells. For example, GLP-1 stimulates neogenesis of rodent beta cells thereby increasing their number substantially. This later growth factor-like action has attracted attention because it suggests that GLP-1 might stimulate an increase of beta cell mass not only in type 2 diabetic subjects, but perhaps in type 1 (juvenile-onset) diabetic subjects as well. The purpose of the proposed research is first to develop a method for following the modulation of cell metabolism by GLP.
|
|
|
|
|
|
Illustrated is the consensus model for glucose-dependent insulin secretion in the beta-cell. Metabolism of glucose produces an increase of ATP/ADP concentration ratio. This causes closure of ATP-sensitive K+ channels (K-ATP), depolarization (DVm), and influx of Ca2+ through voltage-dependent Ca2+ channels (VDCCs).
|
| We Hypothesize that GLP-1 accelerates glycolytic and mitochondrial metabolism of glucose while also rendering K-ATP channels more sensitive to the increase of ATP/ADP concentration ratio generated as a consequence of glucose metabolism. |
|
|
|
Progress:
Using cell culture facilities and a sensitive digital imaging system developed at the BioCurrents Research Center, I am performing preliminary studies examining luciferase activity in an insulin-secreting cell line. These are rat INS-1 stably expressing luciferase within the inner mitochondrial matrix. Luciferase, in the presence of the cell permeant luciferin luminesces in the presence of ATP. Initial studies have shown the technical feasibility of the project spurring further instrument and software development.
These studies are of medical importance because they are likely to shed light on the mechanism of the glucose-lowering hormone (GLP-1). In particular, these studies may reveal a novel mechanism of peptide hormone action that serves to upregulate mitochondrial ATP production, thereby stimulating the secretion of insulin from beta cells.
For more information on the Molecular Basis of Antidiabetogenic Hormone Action click here.
|
|
|
|
| Peyot, M. Gray, J.P., Lamontagne, J., Smith, P.J.S., Holz, G.G., Madiraju, M., Prentki, M. & Heart, E. 2009. Glucagon Like Peptide-1 Induced Signaling and Insulin Secretion do not Drive Fuel and Energy Metabolism in Primary Rodent Pancreatic beta-Cells. PLoS. In Press. |
| Holz, G.G., Heart, E., Leech, C.A. 2008. Synchronizing Ca2+ and cAMP oscillations in pancreatic {beta}-cells: a role for glucose metabolism and GLP-1 receptors? Focus on "Regulation of cAMP dynamics by Ca2+ and G protein-coupled receptors in the pancreatic {beta}-cell: a computational approach. Am. J. Physiol. Cell Physiol. 294: C4-C6. |
| Kang, G., Chepurny, O.G., Malester, B., Rindler, M.J., Rehmann, H., Bos, J.L., Schwede, F., Coetzee, W.A., Holz, G.G. 2006. cAMP sensor Epac as a determinant of ATP-sensitive potassium channel activity in human pancreatic beta cells and rat INS-1 cells. Journal of Physiology. 573:595-609. |
|
Kang, G., Chepurny, O.G., Rindler, M.J., Collis, L., Chepurny, Z., Li, W.H., Harbeck, M., Roe, M.W. and Holz, G.G. 2005. A cAMP and Ca2+ coincidence detector in support of Ca2+-induced Ca2+ release in mouse pancreatic beta cells. Journal of Physiology, 556 (Pt. 1): 173- 88.
|
| Holz, G.G., Chepurny, O.G. 2005. Diabetes outfoxed by GLP-1? Science's STKE, 268: pe2. |
| Holz, G.G. 2004. Epac: A new cAMP-binding protein in support of glucagon-like peptide-1 receptor-mediated signal transduction in the pancreatic beta-cell. Diabetes, 53(1):5-13. |
|
|
|
|
|
Equipment
