Adults with obesity are at increased risk for cardiovascular events. While increased inflammation and lipolysis, impaired fibrinolysis, and insulin resistance may contribute to increased cardiovascular risk, perturbation of the growth hormone (GH) axis may also play a role.(7) Abdominal obesity is a strong negative determinant of endogenous GH secretion and, conversely, adults with acquired GH deficiency develop increased visceral adiposity.(1;8-10) During fellowship, I demonstrated that adults with untreated GH deficiency have an unfavorable fibrinolytic profile and impaired vascular reactivity, and that exogenous GH augments endothelial progenitor cells in healthy adults.(11;12) GH administration improves endothelial and cardiac function, body composition, and markers of cardiovascular risk, though therapy is limited by side effects including hyperglycemia.(13-19) An alternative strategy to increase GH levels is to enhance its endogenous secretion by preventing the degradation of its primary stimulus, growth hormone releasing hormone (GHRH), by dipeptidyl peptidase 4 (DPP4). (20-22) DPP4 inhibitors decrease the degradation of the incretin hormones and thereby improve post-prandial hyperglycemia in patients with type 2 diabetes mellitus. (23;24) Inhibition of the ubiquitous DPP4 affects off-target substrates with a penultimate alanine or proline. [Over the last two years, I have investigated the effect of acute DPP4 inhibition on the degradation of vasoactive DPP4 substrates, including the peptide hormones glucagon like peptide -1 (GLP-1), brain natriuretic peptide (BNP), bradykinin and substance P.(25) This experience has enriched my understanding of vascular biology and DPP4 physiology while allowing me to gather the skills and preliminary data needed to] test the hypothesis that acute DPP4 inhibition will increase stimulated GH secretion and GH-dependent vasodilation by decreasing the degradation of GHRH. I further plan to test the hypothesis that one month of DPP4 inhibitor therapy will enhance GH secretion, vascular function and glucose tolerance in a patient population with impaired GH secretion and high cardio-metabolic risk. The use of DPP4 inhibitor therapies to restore physiologic GH secretion is a potentially cost-effective, high impact approach by which we can improve cardio-metabolic risk in specific target populations. [I am committed to a career as a clinician- investigator and have demonstrated a consistent interest in the GH axis and its cardiovascular effects.] I am fortunate to benefit from protected time and an impressive research infrastructure at Vanderbilt. I am mentored by a successful physician-scientist who conducts hypothesis-driven, patient-oriented, research in vascular biology and who has previously demonstrated her dedication to shepherding physician-scientists to independence. [The proposed career development plan and studies will enhance my knowledge of GH physiology and vascular biology, and will allow me to develop a research program which contributes to our understanding of the complex pathophysiology underlying obesity and vascular risk.]
Adults with abdominal obesity are at high risk for cardiovascular disease and also exhibit diminished growth hormone (GH) secretion; the latter further contributes to the development of visceral adiposity, impaired fibrinolysis and inflammation.(1;2;7;10;26) Growth hormone releasing hormone (GHRH), the primary stimulus for endogenous GH secretion, is a substrate of dipeptidyl peptidase 4 (DPP4); inhibition of DPP4 with the currently available anti-diabetic therapy, sitagliptin, may therefore increase GH secretion by decreasing the degradation of GHRH.(22;27) The proposed research will test the novel hypotheses that acute DPP4 inhibition will enhance stimulated GH secretion and thereby improve forearm blood flow in healthy adults through GH receptor activation of nitric oxide production and secondly, that chronic DPP4 inhibition will enhance GH secretion and endothelium-dependent vasodilation while improving glucose tolerance in patients with impaired GH secretion who are at risk for the development of diabetes mellitus and cardiovascular disease, specifically obese women with polycystic ovary syndrome.
