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 pray.
This peptide, called exendin-4, shares all of the effects of native human gut hormone – glucagon-like peptide-1 (GLP-1) and can be used in its synthetic form to treat type-2 diabetes. GLP-1 is now widely used as an injectable medication for diabetes and obesity, however, research has shown that mimetics (synthetic analogues) of GLP-1 have prominent effects in gut, vasculature, adipose, brain, heart, and other organs/tissues.
GLP-1 is a hormone responsible for insulin secretion and is produced in the intestine in response to food intake. We recently discovered that besides regulation of glucose metabolism, GLP-1 might have several effects on cardiovascular parameters. Mechanisms behind cardiovascular effects are yet to be understood. However, the initial evidence, including investigations in mice from our group, demonstrated that it is possible to improve a multitude of cardiovascular, risk-associated metrics via GLP-1 regulation.
Currently prescribed GLP-1 therapies do not rely on native GLP-1 molecules because the latter are rapidly inactivated by dipeptidyl peptidase-4 (DPP4),an enzyme ubiquitous throughout the body. Another therapeutic approach uses small molecule drugs that increase circulating levels of endogenous GLP-1 by inhibiting the activity of DPP4 (DPP4 inhibitors).
We have demonstrated that, following administration of DPP4 inhibitor, atherosclerotic-diabetic mice exhibited less atherosclerosis, higher insulin sensitivity (lowered blood glucose), and lower blood pressure (figure below).
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.