Monday, March 14, 2011

Diabetes, Venom & the Conservation of Biodiversity


In the next 15 years it is estimated that 380 million people world wide will be diagnosed with diabetes. Obesity and the accompanying resistance to insulin result in the progressive failure of b-cells to produce type 2 diabetes. The chronic complications of diabetes comprise an increased risk of death and disability from coronary heart disease, stroke and peripheral vascular disease, and microvascular disease, resulting in retinopathy, nephropathy and neuropathy. Diabetes is the major medical cause of blindness in developed countries, as well as a major cause of end-stage renal failure. Thus there is a major research effort to find new and effective therapies for diabetes. Byetta, a synthetic exenatide, was approved in 2005 as the first in class of a new molecules for treating Type 2 Diabetes. US sales peaked at $678 million in 2008. The development of Byetta resulted from two lines of investigation, these being the development of the ‘incretin concept’ and a parallel, at first unrelated, study of the venom of the American, the Gila Monster, Heloderma suspectum.The venom contained a molecule identified as exendin-4, a peptide mimicking the incretin hormone glucagon-like peptide 1 (GLP-1). The  ‘incretin concept’ hypothesis proposed that hormones from the gut contributed to the insulin secretion in response to meals, led to the identification of glucagon-like peptide 1 (GLP-1) as an important ‘incretin’ hormone. GLP-1 not only increases insulin secretion but increases b-cell proliferation and survival, while suppressing glucagon secretion, it also delays gastric emptying and suppresses appetite, all of these actions contributing to a potential anti-diabetic effect. However, GLP-1 has a very short half, it is rapidly broken down by dipeptidyl peptidase IV and ectopeptidases. A systematic investigation of the composition and activity of venom from the Gila monster,  led to the isolation of a 39-amino acid peptide, designated exendin-4, showing 53% structural homology with GLP-1. Exendin-4 mimicked GLP-1 through stimulating the GLP-1 receptor. Exendin-4 is not broken down as easily ad GLP-1 and this led to its experimental and clinical evaluation as an anti-diabetic. There is no better argument for the conservation of biodiversity when it comes to arguing with greedy corporations, than stories like this.

Citation
Furman, B.L. 2011. The development of Byetta (exenatide) from the venom of the Gila monster as an anti-diabetic agent. Toxicon, In Press, doi:10.1016/j.toxicon.2010.12.016

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