With prediabetes and diabetes reaching epidemic proportions, there is an urgent need to identify more effective therapeutics. Diabetes is characterized by elevated levels of the peptide hormone glucagon,, and inappropriate suppression of glucagon during an oral glucose tolerance test. Glucagon plays a major role in up-regulating glucose release from the liver during hypoglycemic conditions, and serves as a key counter-regulatory hormone to insulin. Consequently, glucagon pathways are an attractive target for therapeutic intervention. However, tissue-specific processing of the proglucagon precursor results in the production of several other peptide hormones, such as oxyntomodulin, GLP-1 and GLP- 2, that also affect glucose levels but by different direct or indirect modes of action. The presence of several alternatively cleaved products that also harbor the glucagon sequence along with the low levels (< 50pM) of glucagon in the circulation has hampered efforts to develop a suitable assay for accurate determination of glucagon levels when analyzing potential therapeutic targets. The goal of this proposal is to use AvantGen's novel yeast display system and rabbit monoclonal antibody discovery technology to isolate pM affinity, highly specific anti-glucagon antibody clones to be used to develop a highly specific and sensitive assay reagents.
The peptide hormone, glucagon, plays a key counter-regulatory role to insulin in regulating glucose levels in the circulation. It is produced from a larger precursor in the pancreas in response to low glucose levels. However, tissue specific cleavage of the glucagon precursor results in many different peptides, each exerting different effects on the regulation of glucose blood levels. Consequently, targeting this system has therapeutic value for diabetes. However, a thorough understanding of the biology of glucagon has been limited by the availability of assays that can accurately monitor glucagon hormone levels. In this proposal we plan to address this need by using AvantGen's novel antibody discovery technology to isolate high affinity, highly specific antibodies for glucagon and use them to develop a suitable assay for accurate determination of glucagon in the circulation.
