EXENDIN-4 AS A TREATMENT FOR DIABETES MELLITUS

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Beta cells of the pancreas, which make insulin, do not respond normally to glucose in type 2 diabetes. In conjunction with this, and despite all treatments currently available to treat diabetes, beta cell function continues to deteriorate over time. With the data now available from the United Kingdom Prospective Diabetes Study (Sept. 1998) this point was brought home even more forcefully. Despite continual monitoring of patients enrolled in the study euglycemia could not be maintained, even with intensive therapy, because of declining beta cell function. We have been working for some time with GLP-1, a naturally occurring peptide, produced and released from the gut in response to food. It augments the insulin-releasing capacity of beta cells in response to food. Of great interest is the finding that in type 2 diabetes pharmacological doses of GLP-1 can normalize blood sugars, ie, euglycemia is achieved. However, GLP-1 has a biological half-life of only 2-4 minutes and has to be given systemically. This means that it would have to be given continuously in order to maintain euglycemia. The Gila monster is a lizard whose natural habitat is in Arizona. It produces a venom in its saliva which is a homolog of GLP-1, called Exendin-4. When it is given systemically to rodents its biological half-life is 12-16 hours. We gave Exendin-4 intraperitoneally, once daily, to db/db mice and showed that the hemoglobin A1c, a marker of long-term control of blood glucose, was 5.7% in the treated animals vs 9.1% in the non treated animals. We are expanding this project to find the minimal amount of Exendin-4 that is anti-diabetogenic and we are looking at the mechanisms whereby Exendin-4 has such beneficial long-term effects. We have obtained antibodies to exendin-4 so as to develop assays in order to measure its concentrations in plasma. An Investigational IND from the FDA has just been granted to us so that we can begin to administer Exendin-4 to diabetic subjects in order to monitor its efficacy after subcutaneous administration at various concentrations. We plan to begin the studies in the next year.