Effect of DPP4 Inhibition on Vasoconstriction
Condition: Type 2 Diabetes Mellitus
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: Sitagliptin; Placebo; Neuropeptide Y; Enalaprilat; Valsartan 160mg
Intervention description: Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.; Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.; During the study days, neuropeptide Y will be infused through an intra-arterial line. There will be four doses of neuropeptide Y used (0.1, 0.3, 1.0, and 3.0 nmol/min) and each dose will be infused for 10 minutes.; Ninety minutes after the last dose of neuropeptide Y, enalaprilat will be infused through the intra-arterial line at 0.33 µg/min/100mL of forearm volume. After 30 minutes, a second infusion of neuropeptide Y will begin. Similar to the previous neuropeptide infusion, four doses of neuropeptide Y will be used (0.1, 0.3, 1.0, and 3.0 nmol/min) and each dose will be infused for 10 minutes.; Valsartan 160 mg/d for 7 days prior to one of the study days.
Intervention MeSH terms: Sitagliptin Phosphate; Valsartan; Enalaprilat; Enalapril
Phase: Phase 4
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Crossover Arms 1 and 2, Crossover Arms 3 and 4
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 18.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: No
Keywords: Type 2 Diabetes Mellitus; Sitagliptin; Dipeptidyl Peptidase IV Inhibitors; Angiotensin Converting Enzyme Inhibitors; Enalaprilat; Neuropeptide Y

Summary:

      The purpose of this study is to understand how dipeptidyl peptidase IV (DPP4) inhibition in
      diabetics affects hemodynamic parameters and sympathetic activation in the setting of
      increasing concentrations of neuropeptide Y, an endogenous peptide. The central hypothesis is
      that DPP4 inhibition decreases degradation of neuropeptide Y, resulting in increased
      vasoconstriction and sympathetic activation.
    

Eligibility criteria:

        Inclusion Criteria:

        Type 2 Diabetes Mellitus, as defined by one or more of the following,

          -  Hgb A1C ≥6.5%, or

          -  Fasting plasma glucose ≥126mg/dL, or

          -  Two hour plasma glucose ≥200 mg/dL following 75gr oral glucose load

        For female subjects the following conditions must be met:

          -  Postmenopausal status for at least 1 year, or

          -  Status post-surgical sterilization, or

          -  If of childbearing potential, utilization of some form of birth control and
             willingness to undergo β-HCG testing prior to drug treatment and on every study day

        Exclusion Criteria:

          -  Type 1 diabetes.

          -  Poorly controlled T2DM, defined as Hgb A1C>8.7%.

          -  Use of anti-diabetic medications other than metformin.

          -  Hypertension.

          -  Subjects who have participated in a weight-reduction program during the last 6 months
             and whose weight has increased or decreased more than 5 kg over the preceding 6
             months.

          -  Pregnancy. Breast-feeding.

          -  Treatment with any of the following drugs: cisapride, pimozide, terfenadine, astemizol

          -  Clinically significant gastrointestinal impairment that could interfere with drug
             absorption

          -  Cardiovascular disease that would pose risk for the subject to participate in the
             study, such as: myocardial infarction within 6 months prior to enrollment, presence of
             angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy
             acceptable), deep vein thrombosis, pulmonary embolism, second- or third-degree AV
             block, mitral valve stenosis, or hypertrophic cardiomyopathy.

          -  Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino
             transaminase [ALT] >2 x upper limit of normal range)

          -  Impaired renal function (eGFR< 60mL/min/1.73m2 as determined by the MDRD equation).

          -  History or presence of immunological or hematological disorders.

          -  History of pancreatitis or known pancreatic lesions.

          -  History of angioedema or cough while taking an ACE inhibitor.

          -  Hematocrit <35%.

          -  Treatment with anticoagulants.

          -  Growth hormone deficiency.

          -  Diagnosis of asthma requiring use of an inhaled β-2 agonist more than 1 time per week.

          -  Any underlying or acute disease requiring regular medication which could possibly pose
             a threat to the subject or make implementation of the protocol or interpretation of
             the study results difficult

          -  Treatment with systemic glucocorticoids within the last 6 months.

          -  Treatment with lithium salts

          -  Ongoing tobacco use or recreational drug use.

          -  Treatment with any investigational drug in the 1 month preceding the study

          -  Mental conditions rendering the subject unable to understand the nature, scope, or
             possible consequences of the study

          -  Inability to comply with the protocol, e.g., uncooperative attitude, inability to
             return for follow-up visits, and unlikelihood of completing the study