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The Effect of Dipeptidyl Peptidase IV Inhibition on Growth Hormone- Mediated Vasodilation

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The Effect of Dipeptidyl Peptidase IV Inhibition on Growth Hormone- Mediated Vasodilation The Effect of Dipeptidyl Peptidase IV Inhibition on Growth Hormone- Mediated Vasodilation Jessica K. Devin, MD MSCI 9/8/16 1 Table of Contents: 1.0 Background and Previous Human Studies 2.0 Rationale and Specific Aims 3.0 Inclusion/Exclusion Criteria 4.0 Enrollment/Randomization 5.0 Study Procedures 6.0 Risks 7.0 Reporting of Adverse Events or Unanticipated Problems involving Risk to Participants or Others 8.0 Study Withdrawal/Discontinuation 9.0 Statistical Considerations 10.0 Privacy/Confidentiality Issues 11.0 Follow-up and Record Retention 9/8/16 2 1. Background and Previous Human Studies Dipeptidyl peptidase IV (DPPIV) is a ubiquitously expressed cell surface serine protease which cleaves a dipeptide from the N-terminus of its polypeptide substrates containing a proline or alanine at the second residue. Interest in this peptidase and its pharmacological inhibition has arisen due to its proteolytic inactivation of the incretin hormones and the role this plays in glucose homeostasis. Selective DPPIV inhibitors improve glycemic control in patients with type 2 diabetes mellitus by decreasing the degradation of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose- dependent insulinotropic peptide (GIP).(1;2) The DPPIV inhibitor sitagliptin was approved by the FDA in 2006 as a once daily oral medication to lower blood sugar levels in patients with type 2 diabetes mellitus. Two additional DPPIV inhibitors have since received FDA approval: saxagliptin (2009) and linagliptin (2011). The direct and indirect effects of these inhibitors on cardiovascular function remain an active area of investigation. GLP-1 also promotes endothelium-dependent vasodilation in the human vasculature in subjects with type 2 diabetes and stable coronary artery disease. In addition to preventing the degradation of the incretin hormones, DPPIV inhibitors prevent the degradation of other peptides with a penultimate proline or alanine including but not limited to the vasodilators substance P as well as BNP and the neurotransmitter neuropeptide Y.(3;4) Our group has previously demonstrated that five day treatment with sitagliptin significantly decreased mean arterial pressure in subjects with metabolic syndrome.(5) Others have reported that acute sitagliptin treatment reduces 24 hour ambulatory blood pressure in non-diabetic patients with mild to moderate hypertension.(6) It has recently been demonstrated in an animal model and in vitro that acute DPPIV inhibition leads to vascular relaxation via a GLP-1 independent mechanism involving nitric oxide release mediated by Akt dependent phosphorylation of endothelial nitric oxide synthase.(7) DPPIV inhibitors could affect blood pressure and vascular function in part by their effect on the somatotropic axis. Pituitary growth hormone releasing hormone (GHRH), also known as growth hormone-releasing factor (GRF) is a substrate of DPPIV, which 2 rapidly cleaves GRF(1-44)-NH2 to the biologically inactive GRF (3-44)-NH2 at Ala - 3 Asp .(1;2) Conversion to GRF (3-44)-NH2 is blocked in vitro by diprotin A, a DPPIV competitive inhibitor.(8) Human GRF is produced in the hypothalamus and stimulates the release of the growth hormone (GH) from somatotrope cells within the anterior pituitary gland; the active portion of the molecule resides in the first 29 amino acid residues. Opposing the actions of GRF, the hypothalamic hormone somatostatin inhibits the release of GRF.(9) Growth hormone circulates throughout the body exerting its 9/8/16 3 numerous effects both directly and indirectly via the hepatic production of insulin-like growth factor-1 (IGF-1). DPPIV proteolysis plays a major role in the degradation and inactivation of human GRF in vivo.(2) Thus, we hypothesize that inhibition of DPPIV will result in decreased GRF degradation and augmentation of the somatotropic axis in vivo in humans. The direct vascular effects of GH and its downstream mediator IGF-1 are well- established. Systemic and arterial GH infusion increases forearm blood flow in healthy subjects independent of systemic and local IGF-1 production.(10;11) This vasodilation is reversed by infusion of the nitric oxide inhibitor, L-N-monomethylarginine (L- NMMA).(10) Furthermore, growth hormone receptors are present in abundance on human endothelial cells. Incubation of endothelial cells with GH in vitro increases the phosphorylation and activity of endothelial nitric oxide synthase (eNOS) resulting in increased formation of nitric oxide (NO). NO is formed by endothelial nitric oxide synthase (eNOS) within the endothelial cells of the vasculature and then diffuses to underlying smooth muscle cells where it increases vasodilation via cGMP production and decreases inflammation and platelet aggregation.(12-14) Growth hormone treatment also contributes to vascular integrity by enhancing NO-mediated mobilization of endothelial progenitor cells in healthy individuals.(15;16) The exact mechanism(s) through which GH regulates eNOS remain unclear. Evidence exists for both an IGF-1 mediated activation of eNOS involving the serine/threonine Akt phosphorylation- dependent kinase as well as a direct GH-mediated activation of both Akt and JAK-STAT (Janus kinase-signal transducer and activator of transcription) pathways.(17) Interestingly, individuals with hypopituitarism experience increased cardiovascular and cerebrovascular morbidity and mortality as well as an increased prevalence of cardiovascular risk factors, despite adequate steroid and thyroid hormone replacement though lacking in growth hormone replacement.(18-20) The PI has demonstrated that adults with growth hormone deficiency also demonstrate alterations in plasma fibrinolytic balance, as compared to gender, age, and body mass index-matched controls.(21) Several prospective studies in adults with hypopituitarism have demonstrated that GH replacement improves cardiac function, intima-media thickness, endothelial function, and vascular reactivity as well as various biochemical markers of cardiovascular and metabolic disease including fat distribution and inflammatory cytokines.(22-27) Furthermore, GH deficient adults exhibit low levels of metabolites of systemic NO production; and GH replacement therapy normalizes biomarkers of NO.(16;28;29) Many of the adverse cardiovascular factors observed in GH deficient individuals are accordingly attributed to inadequate vascular NO bioavailability which can be reversed with GH treatment. 9/8/16 4 Patients with the cardiovascular risk factors of hypertension, hyperlipidemia, diabetes mellitus or tobacco use demonstrate endothelial dysfunction characterized by the inability of the endothelium to generate adequate amounts of NO.(14) Basal NO- mediated dilatation in the forearm arterial bed of patients with insulin-dependent diabetes is impaired as assessed by venous occlusion plethysmography.(30) The impairment in endothelial function in experimental animals and humans with diabetes mellitus is attributed to reduced NOS activity and/or NO availability as well as the accompanying increased production of reactive oxygen species. This characteristic endothelial dysfunction has been implicated in the pathogenesis of diabetic vascular disease.(31) This aim promises to provide important new data regarding how DPPIV inhibition affects the somatotropic axis in healthy adults. Given the known effects that growth hormone and IGF-1 have on endothelial function as well as cardiovascular and metabolic markers, an augmentation of this axis may positively impact vascular function in the diabetic population. None of our currently available anti-glycemic agents offer this benefit. Data from the Framingham Heart Study demonstrates a negative correlation between circulating IGF-1 and insulin resistance in a community based sample.(32) GRF-induced GH secretion is blunted in premenopausal women with hyperlipidemia and insulin resistance.(33) Thus derangements in the somatotropic axis have previously been described in individuals at risk for the development of diabetes. Adults with diabetes demonstrate heart disease death rates two to four times higher than adults without diabetes (“Diabetes Statistics” American Diabetes Association; www.diabetes.org); thus DPPIV inhibitors may potentially represent a novel therapy that is simultaneously able to confer both a glycemic and vascular benefit in this at-risk population. We therefore expect that findings from this study will lead to further investigations regarding currently unrecognized but significant vascular effects of this relatively new class of medications increasingly used in the diabetic population. 2. Rationale and Specific Aims This study tests the hypothesis that DPPIV inhibition will favorably augment the somatotropic axis in healthy individuals by decreasing the degradation of GRF by DPPIV. This study specifically establishes the effect of acute DPP4 inhibition on arginine-stimulated GH secretion and GH-mediated blood flow in healthy humans. Arginine decreases inhibitory hypothalamic somatostatin secretion, allowing the primary stimulus of GH secretion to be GHRH. We will study healthy adults to obtain maximal GH signal in this proof-of-concept initial aim, given that obesity diminishes the GH response to pharmacologic stimuli. 9/8/16 5 -Aim 1A tests the hypothesis that acute DPP4 inhibition will increase stimulated GH secretion in healthy lean adults by decreasing the degradation of GHRH. -Aim 1B tests the hypothesis that decreased degradation of GHRH during acute DPP4 inhibition will result in an increase in endothelium-dependent
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