Stimulating Munc1-13 as a means of increasing insulin release

According to WHO, there are some 130 million diagnosed diabetics in the world, a figure that is predicted to increase to 300 million by 2025. The market for diabetes therapeutics is also rising with global sales reportedly topping $8.1 billion for the 12 months to September 2000, a 19% increase over the previous 12 months (for a full analysis of diabetes therapeutics and market opportunities click here). Oral antidiabetic drugs, the leading class of drugs used to treat the disease, accounted for almost 63% of sales during this period, while sales of insulin, to which many diabetics must resort as a treatment option with time, stand at around 30%. Further increases are inevitable and the market for diabetes medications could exceed $20 billion by 2006.

Oral antidiabetic drugs have traditionally focussed on metformin and sulphonylurea. Until 1995, the sulfonylurea class of drugs which act by increasing insulin secretion was the only choice in the United States other than insulin for treating type 2 diabetes. The explosion of drugs available for controlling blood glucose began when Glucophage (metformin) became available in 1995, quickly followed by the approval of the insulinotropic agent Repaglinide in 1997 and the thiazolidinedione insulin sensitizers such as Avandia and Actos, which were both launched in 1999. The largest unmet need in the diabetes market is improved delivery of insulin. Currently, the predominant mode of insulin administration is subcutaneous injection, which is extremely unpopular among patients and consequently much effort is be placed on identify new insulin delivery technologies. In addition the development of improved insulinotropics would be of use.

Repaglinide stimulates the release of insulin from the pancreatic beta cells by closure of ATP-dependent potassium channels. Other means of stimulating insulin release include the regulation of the vesicular transport of insulin out of the beta cell. This process involves the mobilization, priming and secretion of insulin granules. Not all granules that are docked with the plasma membrane are primed for insulin release explaining why insulin release is quite a slow process. Of interest insulin release, and in particular first phase release in response to glucose is defective in diabetes and identifying the defective step(s) in the mobilization, priming and secretion mechanism may lead to the development of new therapeutics that target the etiology of diabetes.

As in neurons, secretion from pancreatic islet beta cells is regulated by the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins VAMP, SNAP-25, and syntaxin-1A. These proteins form a ternary complex that is thought to drive the vesicular fusion reaction. SNARE protein function in mammals is regulated by Munc13s. Overexpression of Munc13-1 in chromaffin cells has been previously shown to provoke a dramatic increase in secretory vesicle priming by unfolding or “activating” syntaxin. In a recently published study a collaboration of Canadian and German researchers report that Munc13-1 is expressed in human and rat pancreatic islet beta cells. Importantly, in an insulinoma cell line Munc13-1 expression stimulates the release of insulin, but only in the presence of glucose suggesting a preferential role in hyperglycemic states rather than under basal conditions. Perhaps even more importantly, expression levels are reduced in the diabetic state suggesting that not only is Munc13-1 responsible for insulin release in response to glucose but that reduced expression of this protein may contribute to the etiology of diabetes. This important publication suggests that the therapeutic up-regulation of Munc13-1 either by gene therapy or by pharmacological intervention may stimulate glucose stimulated insulin release through a mechanism that differs from currently used insulinotropic agents and which is directly related to the etiology of diabetes.

Entry date Monday, November 10, 2003

Adapted from Sheu et al, J Biol Chem. 2003 Jul 25;278(30):27556-63