Drugs that prevent diabetes in obese people on horizon

By Mike Nagle

- Last updated on GMT

Related tags Obesity Diabetes mellitus type 2 Diabetes

Although obesity dramatically increases the risk of developing Type
II diabetes, nobody knew why until researchers found a protein that
links the two diseases, opening up the possibility of developing
drugs that prevent diabetes.

A team of scientists at the Sahlgrenska Academy, Sweden, found that a protein called SNAP23 helps store fat, but also independently increases insulin sensitivity. The more fat it has to store, the less is available for the protein's other role and the patient could become insensitive to insulin - a key characteristic in some Type II diabetes patients. "The faulty storage of fat in the muscle cells interferes with the signal from the insulin that should stimulate increased absorption of sugar by the cells,"​ said Professor Sven Olof Olofsson, director of the Wallenberg Laboratory at the Sahlgrenska Academy. The fat is stored in the form of lipid droplets in the internal liquid (cytosol) of muscle and liver cells. "We have studied in detail how these are formed and how they grow. This has enabled us to show how the insulin signal is disrupted,"​ Prof. Olofsson added. In order to do this, the team isolated lipid droplets and then used various antibodies to discover which proteins were present. Since the droplets increase in size when they merge together (fuse), it was no surprise that they found proteins associated with this process, including: N​-ethylmaleimide-sensitivefactor (NSF); soluble NSF attachment protein (alpha-SNAP); and synaptosomal-associated protein of 23 kDa (SNAP23). Their presence was then confirmed using immunoelectron microscopy. When the team knocked out the gene for SNAP23, the rate of fusion and the size of the droplets decreased. However, this protein has another, independent, function - that of passing the insulin signal onwards into the cell. Indeed, when the team used oleic acid to decrease the insulin sensitivity of the heart muscle, this sensitivity was completely restored by transfection with SNAP23. "It appears that the SNAP23 is being 'stolen' from the insulin signalling process when the cell starts to pack fat, and this causes the defect that subsequently leads to diabetes,"​ said Pontus Boström, a PhD student at the Academy who is lead author of the research paper that will be published in the next edition of Nature Cell Biology. "If we can find out more about how this works in detail, we may be able to influence the process and protect patients from developing diabetes,"​ he added. This research could provide a starting point for drug developers to design a compound that could prevent the onset of diabetes by restoring an obese person's sensitivity to insulin. Lilly acquires late-stage Type I diabetes drug ​ Eli-Lilly has penned an alliance deal with MacroGenics over teplizumab (MGA031), a humanized anti-CD3 monoclonal antibody, as well as other potential next generation anti-CD3 molecules for use in the treatment of autoimmune diseases. Teplizumab binds to an epitope of the CD3-epsilon chain expressed on mature T cells. This could enable the drug to inhibit unwanted effector T cells and enhance beneficial regulatory T cell functions and, in doing so, promote immune tolerance. As part of the deal, MacroGenics will receive an initial payment of $41m (€28.7), $3m in other committed funds, and a potential $10m equity investment by the pharma heavyweight. Milestone payments could top $600m if the MAb is successfully commercialised in this and other indications.

Related topics Preclinical Research

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