15 Oct Controlling Insulin Release With Photoswitchable Sulfonylurea
Medical Research: What is the background for this research?
Dr. Hodson: Type 2 diabetes represents a huge socioeconomic challenge. As well as causing significant morbidity due to chronically elevated glucose levels, this disease is also a drain on healthcare budgets (~$20billion in the UK per year). While current treatments are effective, they are sometimes associated with side effects, usually due to off-target actions on organs such as the heart and brain. In addition, the ability to regulate blood glucose levels more tightly may decrease complications stemming from type diabetes (e.g. nerve, kidney and retina damage). As a proof-of-principle that the spatiotemporal precision of light can be harnessed to finely guide and control drug activity, we therefore decided to produce a light-activated anti-diabetic.
Medical Research: How would blue light improve the usefulness of sulfonylurea drugs?
Dr. Hodson: Sulfonylureas represent one of the most prescribed drugs for type 2 diabetes therapy, since they are effective, cheap (a few cents) and generally well tolerated. These drugs maintain normal glucose levels by acting on ion channels in pancreatic islets to increase insulin release. However, in some cases sulfonylureas can actually stimulate too much insulin release, leading to low glucose levels, a potentially dangerous scenario. We therefore reasoned that this drug class would provide a useful template to showcase the application of photopharmacology (i.e. the modification of drug activity with light) to pancreatic cells. Blue light per se won’t alter the activity of sulfonylureas. To make these drugs act as photoswitches, we collaborated with Prof Dirk Trauner and Dr Johannes Broichhagen (both LMU Munich, Germany) to synthesize a completely new molecule, which contains an azobenzene ring. This chemical element undergoes reversible alterations to shape following exposure to blue light, altering activity. With the resulting drug, termed an azosulfonylurea, we were able to optically control insulin release in vitro by turning the drug on and off at will. Therefore, light could in theory be used to target drug activity to the pancreas, as well as activate the drug only after a meal when insulin is required. At all other times, the drug can be kept in its inactive state by simply turning the light off.
Medical Research: What should clinicians and patients take away from your report?
Dr. Hodson: First of all, it’s important to note that sulfonylureas have helped patients to manage type 2 diabetes for over 60 years and the incidence of reported side effects is low and often not serious.
Secondly, our new photoswitchable sulfonylurea has not been tested in animals or humans, and many questions remain. For example, is the drug safe? Does it possess pharmacodynamics compatible with oral dosing? Can light be delivered through the abdomen to specifically illuminate the area around the pancreas? Answering such questions will take many years. Nonetheless, we believe that our new drug demonstrates that photopharmacology may one day be useful for the treatment of metabolic diseases such as type 2 diabetes.
Medical Research: What further research are you planning?
Dr. Hodson: We are currently developing new drug variants that can be switched on using red light, since these wavelengths are better at penetrating human tissue. We are also performing studies in rodents to better understand whether photoswitchable sulfonylureas will allow the optical control of insulin secretion in vivo.
Johannes Broichhagen,Matthias Schönberger,Simon C. Cork,James A. Frank,Piero Marchetti,Marco Bugliani,A. M. James Shapiro,Stefan Trapp,Guy A. Rutter,David J. Hodson & Dirk Trauner
Nature Communications 5, Published