GLP-1 Biology

The poisonous lizard family Heloderma such as Gila Monster <link to https://en.wikipedia.org/wiki/Gila_monster> feeds infrequently, thus, naturally exhibits long periods of fasting, during which its GI tract adapts to conserve energy. The venom of Gila monsters contains a unique peptide that activates metabolic and digestive responses to its rare prey.

Researchers found that this peptide can be modified into a therapy, which they called exendin-4, is a synthetic peptide mimicking the human gut hormone GLP-1, later approved to treat type-2 diabetes and obesity. While GLP-1 mimetics show effects beyond blood sugar control (gut, brain, heart, and other organs), inhibiting the enzyme DPP-4 (which breaks down GLP-1) also has therapeutic value. Our work revealed significant impacts of DPP-4 inhibition and GLP-1 delivery on immune and cardiovascular systems.

A key challenge was understanding GLP-1's anti-inflammatory effects on immune cells like macrophages, as detecting the GLP-1 receptor (GLP-1R) proved difficult. We pioneered research linking GLP-1 to cardiovascular actions via monocytes/macrophages in atherosclerosis. Crucially, our landmark study using advanced techniques (lineage tracing, transcript analysis, human tissue) overturned the long-held belief that macrophages express high GLP-1R levels. Instead, we found high GLP-1R expression in transformed smooth muscle cells undergoing myeloid transition, not macrophages.

We leveraged this discovery to develop a novel targeting strategy: “activatable nanoparticles” delivering GLP-1R agonists specifically to these smooth muscle cells. Such nanoparticles, which we called GlpNP, activate in atherosclerotic plaque “on demand” releasing GLP-1 drug payload and also imaging agent, allowing for both imaging with MRI and therapy directly in the plaque. This breakthrough allows precise in vivo study of biological mechanisms of GLP-1 where genetic knockouts are impossible.

In summary, our research clarifies the critical roles of GLP-1 and DPP-4 in cardiovascular health, metabolism and smooth muscle biology. Our GlpNP nanoparticle targeting strategy extends beyond glycemic control, offering broader therapeutic potential for metabolic diseases and related conditions.

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