The poisonous lizard family Heloderma such as 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.

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 potential neuroprotection. Our GlpNP nanoparticle targeting strategy extends beyond glycemic control, offering broader therapeutic potential for metabolic diseases and related conditions.

We Published These!

• Shah Z, Pineda C, Kampfrath T, Maiseyeu A, Ying Z, Racoma I, Deiuliis J, Xu X, Sun Q, Moffatt-Bruce S, Villamena F, Rajagopalan S. Acute DPP-4 inhibition modulates vascular tone through GLP-1 independent pathways. Vascul Pharmacol. 2011;55:2–9. 
• Zhong J, Maiseyeu A, Rajagopalan S. Lipoprotein effects of incretin analogs and dipeptidyl peptidase 4 inhibitors. Clin Lipidol. 2015;10:103–112.
• Zhong J, Maiseyeu A, Davis SN, Rajagopalan S. DPP4 in cardiometabolic disease: recent insights from the laboratory and clinical trials of DPP4 inhibition. Circ Res. 2015;116:1491–1504. 
• Shah Z, Kampfrath T, Deiuliis JA, Zhong J, Pineda C, Ying Z, Xu X, Lu B, Moffatt-Bruce S, Durairaj R, Sun Q, Mihai G, Maiseyeu A, Rajagopalan S. Long-term dipeptidyl-peptidase 4 inhibition reduces atherosclerosis and inflammation via effects on monocyte recruitment and chemotaxis. Circulation. 2011;124:2338–2349.