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A team led by scientists at the University of Oxford and the Leibniz-Forschungsinstitut für Molekulare Pharmakologie in Berlin has used fluorescent versions of next-generation diabetes and obesity drugs to reveal, for the first time, exactly which cells they target in the pancreas and brain.

daLUXendins can be visualized using fluorescence microscopy to pinpoint GLP1R and GIPR binding and activation. This is shown in the periphery (islet of Langerhans in the pancreas, left) and centrally (hypothalamus in the brain, right) where daLUXendins act to drive insulin secretion and to control appetite, respectively.
daLUXendins can be visualized using fluorescence microscopy to pinpoint GLP1R and GIPR binding and activation. This is shown in the periphery (islet of Langerhans in the pancreas, left) and centrally (hypothalamus in the brain, right) where daLUXendins act to drive insulin secretion and to control appetite, respectively.

Drugs like Ozempic and Wegovy mimic a natural hormone called GLP-1 to lower blood sugar and reduce appetite. A newer medicine, Mounjaro (tirzepatide), goes one step further, activating two hormone receptors — GLP-1 and GIP — and delivering greater benefits for both glucose control and weight loss. However, until now, scientists did not fully understand which cells and brain circuits made this possible.

The research team developed fluorescent versions of these dual-target drugs, known as daLUXendins. These probes behave like the real medicines but also light up under a microscope, allowing researchers to track them in fine detail.
In studies on mice, the team discovered that daLUXendins targeted a wider range of pancreatic cells than single-target drugs — not just insulin-producing beta cells, but also alpha and delta cells, which communicate with beta cells to regulate blood sugar. In the brain, the glowing drugs reached regions that control appetite and even lit up metabolite-sensing cells called tanycytes, which send signals about hunger.

'Dual agonists aren't just more powerful because they act on two receptors,' said Professor David Hodson, Radcliffe Department of Medicine, University of Oxford. 'They also reach a broader network of cells, which may be key to their superior effects.'

 

Read the full story on the Radcliffe Department of Medicine website.