New findings open up for targeted diabetes drugs

In a new study, published in Nature Communications today, researchers from Uppsala University describe findings that offer new clues as to why insulin secretion might fail in diabetes and open the possibility of discovering novel drugs.

The cells of our body use small messenger molecules, such as insulin or adrenalin, to communicate with each other. These messenger molecules are stored in small vesicular containers that fuse on demand with the cell membrane to discharge their content into the bloodstream or onto neighboring cells.

When this fails, we get sick. For example, impaired secretion of insulin causes diabetes, and there is growing evidence that defective neurotransmitter secretion plays an important role in neurodegenerative disease. At the core of this process is a set of so called SNARE proteins whose function is to force vesicle and membrane together to cause membrane fusion. Their discovery was recognized with the 2013 Nobel prize in Physiology.

Nikhil Gandasi and Sebastian Barg, at the Department of Medical Cell Biology, Uppsala University, now show in insulin secreting beta-cells that one of the SNARE proteins, syntaxin, has an additional function: It locks the vesicular container in place at the membrane so that the fusion machinery can assemble. Using a novel fluorescence microscopy technique they were able to count syntaxin molecules at individual fusion sites from the moment a vesicle arrived until it fused and released insulin.

Strikingly, contact of a vesicle with the membrane induced accumulation of syntaxin, which in turn acted as glue to hold the vesicle in place. Only when this happened could the vesicle build the fusion machinery and eventually secrete insulin. They then repeated the experiment for a number of other proteins to generate a timetable of how the fusion machinery assembles.

The findings offer new clues as to why insulin secretion might fail in diabetes and open the possibility of discovering novel drugs directly targeted at the fusion machinery that would better prepare insulin vesicles for secretion.

Contact-induced clustering of syntaxin and munc18 docks secretory granules at the exocytosis site by Nikhil R. Gandasi and Sebastian Barg, Nature Communications (2014), doi: 10.1038/ncomms4914

For more information, please contact, Sebastian Barg, Docent at the Department of Medical Cell Biology, tel: +46-18-4714660, e-mail: sebastian.barg@mcb.uu.se, Or visit: www.mcb.uu.se/res/groups/sb/