Effect of DPP4 Inhibition on Vasoconstriction

• Sponsor: Vanderbilt University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02639637
• Collaborator: (none)
• Enrollment: 18
• Location: 1
• Arms: 4
• Duration (Months): 21
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus	Drug: Sitagliptin; Drug: Placebo; Drug: Neuropeptide Y; Drug: Enalaprilat; Drug: Valsartan 160mg	Phase 4

Detailed Description

Dipeptidyl peptidase IV (DPP4) inhibitors are routinely used for the treatment of type II diabetes mellitus (T2DM). Since the prevalence of hypertension is 1.5-3 times greater in diabetics compared to sex-aged matched controls, the use of antihypertensives such as ACE inhibitors is also common in diabetics. DPP4 is involved in the degradation of multiple vasoactive peptides, one of which is neuropeptide Y. This peptide is thought to play a role in blood pressure regulation and sympathetic nervous system activation. The aim of this study is to investigate how DPP4 inhibition affects vasoconstriction in response to increasing neuropeptide Y concentrations. Additionally, the investigators want to understand how the combination of DPP4 inhibition and ACE inhibition affects vasoconstriction and sympathetic activation. Understanding the hemodynamic and neurohumoral changes associated with DPP4 and ACE inhibitors has important implications for the millions of patients with T2DM who take these drugs concurrently.

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: Crossover Arms 1 and 2, Crossover Arms 3 and 4Crossover Arms 1 and 2, Crossover Arms 3 and 4
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Contribution of Neuropeptide Y (NPY) to Vasoconstriction and Sympathetic Activation in the Setting of Dipeptidyl Peptidase IV (DPP4) Inhibition
• Study Start Date: Dec 1, 2015
• Actual Primary Completion Date: Jun 1, 2017
• Actual Study Completion Date: Sep 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Other: Sitagliptin then Placebo Subjects in this arm will receive sitagliptin 100 mg daily. After one week of treatment, subjects will report for study day #1. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. A four week washout of medications will occur after the study day. Subjects will then receive placebo for one week followed by study day #2.	Drug: Sitagliptin; Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.; Other Names: Januvia ; Drug: Placebo; Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.; Other Names: Microcrystalline cellulose ; Drug: Neuropeptide Y; 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.; Other Names: NPY ; Drug: Enalaprilat; 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.; Other Names: Vasotec I.V.
Other: Placebo then Sitagliptin Subjects in this arm will receive placebo for one week. After this, subjects will report for study day #1. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. A four week washout of medications will occur after the study day. Subjects will then receive 100 mg of sitagliptin daily for one week followed by study day #2.	Drug: Sitagliptin; Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.; Other Names: Januvia ; Drug: Placebo; Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.; Other Names: Microcrystalline cellulose ; Drug: Neuropeptide Y; 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.; Other Names: NPY ; Drug: Enalaprilat; 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.; Other Names: Vasotec I.V.
Placebo Comparator: Sitagliptin then Placebo: Valsartan Subjects in this arm will receive sitagliptin 100 mg/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for study day #1. During the study day, subjects will be given intra-arterial neuropeptide Y. A four week washout of medication will occur after the study day. Subjects will then receive placebo/d and valsartan 160 mg/d for one week followed by study day #2.	Drug: Sitagliptin; Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.; Other Names: Januvia ; Drug: Placebo; Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.; Other Names: Microcrystalline cellulose ; Drug: Valsartan 160mg; Valsartan 160 mg/d for 7 days prior to one of the study days.; Other Names: valsartan p.o.
Placebo Comparator: Placebo then Sitagliptin: Valsartan Subjects in this arm will receive placebo/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for study day #1. During the study day, subjects will be given intra-arterial neuropeptide Y. A four week washout of medication will occur after the study day. Subjects will then receive sitagliptin 100mg/d and valsartan 160 mg/d for one week followed by study day #2.	Drug: Sitagliptin; Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.; Other Names: Januvia ; Drug: Placebo; Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.; Other Names: Microcrystalline cellulose ; Drug: Valsartan 160mg; Valsartan 160 mg/d for 7 days prior to one of the study days.; Other Names: valsartan p.o.

Outcome Measures

Primary Outcome Measures

1. Forearm Blood Flow [FBF measured after 5 min of the 1 nmol/min dose of neuropeptide Y on study days 1 and 2. Study days 1 and two were separated by five weeks.]

   Forearm blood flow measured by strain gauge plethysmography in response to 1.0 nmol/min neuropeptide Y, the highest dose that all received.

Secondary Outcome Measures

1. Arterial Norepinephrine [Measured at baseline (time 0) prior to the infusion of neuropeptide Y on each study day. Study days 1 and 2 were separated by five weeks.]

   Arterial norepinephrine concentration measured by high-performance liquid chromatography.

2. Venous Norepinephrine [Measured at baseline (time 0) prior to the infusion of neuropeptide Y on each study day. Study days 1 and 2 were separated by five weeks.]

   Venous norepinephrine concentration measured by high-performance liquid chromatography

3. NPY Metabolites [Measured after 5 min infusion of the 1.0 nmol/min dose of neuropeptide Y on study days 1 and 2. Study days 1 and 2 were separated by five weeks.]

   NPY (3-36) concentration measured by micro ultra-hgih pressure liquid chromatography tandem mass spectrometry. NPY (3-36) is the degradation product of NPY by dipeptidyl peptidase 4. It was measured only in the diabetics studied.

4. Insulin [Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days 1 and 2 were separated by five weeks, a four-week washout and one-week treatment period.]

   Plasma insulin measured by radioimmunoassay.

5. GLP-1 [Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.]

   GLP--1 was not analyzed as subjects were studied in the fasting state.

6. Glucose [Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.]

   Glucose was measured by the glucose oxidase method using a YSI glucose analyzer

7. ACE Activity [Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.]

   ACE activity was measured using a commercially available assay (Olympus AU400/AU600, Alpco Diagnotics, Salem, NH.) The lower level of detection was 15 U/L and values below the level of detection were reported at half the level of detection.

8. DPP4 Activity [Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.]

   DPP4 activity was measured by detection of cleavage of a colorimetric substrate.

9. Low Frequency Variability of Blood Pressure Activity [Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.]

   Measured using the VITAL-GARD 450c monitor Ivy Biomedical Systems, Branford, CT, USA)

10. Arterial tPA [Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.]

    Measured using an ELISA.

11. Venous tPA [Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.]

    Measured using an ELISA. This was measured in a few subjects. After it was determined that there was no change in net t-PA release it was not measured in the remainder.

12. Mean Arterial Pressure [Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.]

13. Heart Rate [Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232

Sponsors and Collaborators

• Vanderbilt University

Investigators

• Principal Investigator: Nancy J Brown, MD, Vanderbilt University Medical Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 5, 2017

More Information

Publications

None provided.

• Responsible Party: Nancy J. Brown, MD, Professor, Vanderbilt University
• ClinicalTrials.gov Identifier: NCT02639637
• Other Study ID Numbers: 151133
• First Posted: Dec 24, 2015
• Last Update Posted: Aug 27, 2018
• Last Verified: Jul 1, 2018

• Keywords provided by Nancy J. Brown, MD, Professor, Vanderbilt University: Type 2 Diabetes Mellitus; Sitagliptin; Dipeptidyl Peptidase IV Inhibitors; Angiotensin Converting Enzyme Inhibitors; Enalaprilat; Neuropeptide Y
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Sitagliptin Phosphate; Valsartan; Enalaprilat; Enalapril

Study Results

Participant Flow

Arm/Group Title	Sitagliptin Then Placebo (Diabetics and Controls)	Placebo Then Sitagliptin (Diabetics and Controls)	Sitagliptin Then Placebo: Valsartan (Controls Only)	Placebo Then Sitagliptin: Valsartan (Controls Only)
Arm/Group Description	Subjects in this arm will receive sitagliptin 100 mg daily. After one week of treatment, subjects will report for study day #1. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. A four week washout of medications will occur after the study day. Subjects will then receive placebo for one week followed by study day #2. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects in this arm will receive placebo for one week. After this, subjects will report for study day #1. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. A four week washout of medications will occur after the study day. Subjects will then receive 100 mg of sitagliptin daily for one week followed by study day #2. Neuropeptide Y: 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. Enalaprilat: 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 NPY at graded doses was started ten minutes after that.	Subjects in this arm will receive sitagliptin 100 mg/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for study day #1. During the study day, subjects will be given intra-arterial neuropeptide Y. A four week washout of medication will occur after the study day. Subjects will then receive placebo/d and valsartan 160 mg/d for one week followed by study day #2. Sitagliptin: Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days. Placebo: Subjects will receive a placebo capsule daily for 7 days prior to one of the study days. Valsartan 160mg: Valsartan 160 mg/d for 7 days prior to one of the study days.	Subjects in this arm will receive placebo/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for study day #1. During the study day, subjects will be given intra-arterial neuropeptide Y. A four week washout of medication will occur after the study day. Subjects will then receive sitagliptin 100mg/d and valsartan 160 mg/d for one week followed by study day #2. Sitagliptin: Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days. Placebo: Subjects will receive a placebo capsule daily for 7 days prior to one of the study days. Valsartan 160mg: Valsartan 160 mg/d for 7 days prior to one of the study days.
Period Title: Overall Study
STARTED	7	6	2	3
COMPLETED	7	6	2	3
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Controls Who Completed Crossover Arm 1 or 2	Patients With Diabetes Who Completed Crossover Arm 1 or 2	Controls Who Completed Crossover Arm 3 or 4	Total
Arm/Group Description	Healthy non-smokers Crossover arm 1 is sitagliptin then placebo Crossover arm 2 is placebo then sitagliptin	Non-smokers with diabetes who were taking no medication or metformin only Crossover arm 1 is sitagliptin then placebo Crossover arm 2 is placebo then sitagliptin	Healthy non-smokers Crossover arm 3 is sitagliptin and valsartan, then placebo and valsartan Crossover arm 4 is placebo and valsartan, then sitagliptin and valsartan	Total of all reporting groups
Overall Participants	7	6	5	18
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33.2 (10.0)	43.6 (6.0)	31.4 (9.0)	36.2 (9.7)
Sex: Female, Male (Count of Participants)
Female	4 57.1%	3 50%	2 40%	9 50%
Male	3 42.9%	3 50%	3 60%	9 50%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	1 16.7%	0 0%	1 5.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	1 14.3%	1 16.7%	0 0%	2 11.1%
White	6 85.7%	4 66.7%	5 100%	15 83.3%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	7 100%	6 100%	5 100%	18 100%
Body mass index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	25.9 (2.7)	33.6 (8.7)	25.7 (2.0)	28.4 (6.3)
Hemoglobin A1c (percentage of hemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of hemoglobin]	5.2 (0.6)	6.6 (0.2)	5.0 (0.2)	5.6 (0.8)
Fasting glucose (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	78.3 (12.7)	105.7 (12.7)	80.4 (4.4)	88.0 (15.3)

Outcome Measures

1. Primary Outcome

Title	Forearm Blood Flow
Description	Forearm blood flow measured by strain gauge plethysmography in response to 1.0 nmol/min neuropeptide Y, the highest dose that all received.
Time Frame	FBF measured after 5 min of the 1 nmol/min dose of neuropeptide Y on study days 1 and 2. Study days 1 and two were separated by five weeks.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sitagliptin and Enalaprilat (Diabetics and Controls)	Placebo and Enalaprilat (Diabetics and Controls)	Sitagliptin and Valsartan (Controls Only)	Placebo and Valsartan (Controls Only)
Arm/Group Description	Subjects will receive sitagliptin 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects will receive placebo 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects in this arm will receive sitagliptin 100 mg/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.	Subjects in this arm will receive a placebo for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.
Measure Participants	13	13	5	5
Mean (Standard Deviation) [mL/min/100 mL]	1.72 (0.93)	2.29 (0.93)	1.17 (0.21)	1.63 (0.85)

2. Secondary Outcome

Title	Arterial Norepinephrine
Description	Arterial norepinephrine concentration measured by high-performance liquid chromatography.
Time Frame	Measured at baseline (time 0) prior to the infusion of neuropeptide Y on each study day. Study days 1 and 2 were separated by five weeks.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sitagliptin + Enalaprilat (Diabetics and Controls)	Placebo + Enalaprilat (Diabetics and Controls)	Sitagliptin and Valsartan (Controls Only)	Placebo and Valsartan (Controls Only)
Arm/Group Description	Subjects will receive sitagliptin 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects will receive placebo 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects in this arm will receive sitagliptin 100 mg/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.	Subjects in this arm will receive a placebo for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.
Measure Participants	13	13	5	5
Mean (Standard Deviation) [pg/mL]	211.8 (81.8)	174.7 (80.2)	151.8 (31.3)	125.5 (35.1)

3. Secondary Outcome

Title	Venous Norepinephrine
Description	Venous norepinephrine concentration measured by high-performance liquid chromatography
Time Frame	Measured at baseline (time 0) prior to the infusion of neuropeptide Y on each study day. Study days 1 and 2 were separated by five weeks.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sitagliptin + Enalaprilat (Diabetics and Controls)	Placebo + Enalaprilat (Diabetics and Controls)	Sitagliptin and Valsartan (Controls Only)	Placebo and Valsartan (Controls Only)
Arm/Group Description	Subjects will receive sitagliptin 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects will receive placebo 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects in this arm will receive sitagliptin 100 mg/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.	Subjects in this arm will receive a placebo for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.
Measure Participants	13	13	5	5
Mean (Standard Deviation) [pg/mL]	250.6 (192.9)	178.3 (85.1)	192.6 (88.6)	173.1 (65.5)

4. Secondary Outcome

Title	NPY Metabolites
Description	NPY (3-36) concentration measured by micro ultra-hgih pressure liquid chromatography tandem mass spectrometry. NPY (3-36) is the degradation product of NPY by dipeptidyl peptidase 4. It was measured only in the diabetics studied.
Time Frame	Measured after 5 min infusion of the 1.0 nmol/min dose of neuropeptide Y on study days 1 and 2. Study days 1 and 2 were separated by five weeks.

Outcome Measure Data

Analysis Population Description

Because the purpose of measuring NPY metabolites was to assess whether sitagliptin blocks the formation of the metabolites, and because the analysis is laborious and costly, measurements were only completed in the diabetics studied.

Arm/Group Title	Sitagliptin (Diabetics)	Placebo (Diabetics)	Sitagliptin and Valsartan (Controls Only)	Placebo and Valsartan (Controls Only)
Arm/Group Description	Subjects will receive sitagliptin 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects will receive placebo 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects in this arm will receive sitagliptin 100 mg/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.	Subjects in this arm will receive a placebo for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.
Measure Participants	6	6	0	0
Mean (Standard Deviation) [pmol/L]	749 (562)	1206 (1559)

5. Secondary Outcome

Title	Insulin
Description	Plasma insulin measured by radioimmunoassay.
Time Frame	Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days 1 and 2 were separated by five weeks, a four-week washout and one-week treatment period.

Outcome Measure Data

Analysis Population Description

The comparison of sitagliptin and placebo were original to the study. Because the purpose of the sitagliptin and valsartan versus placebo and valsartan comparison was to further understand the mechanism for forearm blood flow effects it was not necessary to measure insulin in that added part of the study.

Arm/Group Title	Sitagliptin (Diabetics and Controls)	Placebo (Diabetics and Controls)	Sitagliptin and Valsartan (Controls Only)	Placebo and Valsartan (Controls Only)
Arm/Group Description	Subjects will receive sitagliptin 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects will receive placebo 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects in this arm will receive sitagliptin 100 mg/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.	Subjects in this arm will receive a placebo for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.
Measure Participants	12	11	0	0
Mean (Standard Deviation) [microU/mL]	16.2 (10.6)	19.6 (14.1)

6. Secondary Outcome

Title	GLP-1
Description	GLP--1 was not analyzed as subjects were studied in the fasting state.
Time Frame	Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.

Outcome Measure Data

Analysis Population Description

GLP--1 was not analyzed as subjects were studied in the fasting state.

Arm/Group Title	Sitagliptin (Diabetics and Controls)	Placebo (Diabetics and Controls)	Sitagliptin and Valsartan (Controls Only)	Placebo and Valsartan (Controls Only)
Arm/Group Description	Subjects will receive sitagliptin 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects will receive placebo 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects in this arm will receive sitagliptin 100 mg/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.	Subjects in this arm will receive a placebo for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.
Measure Participants	0	0	0	0

7. Secondary Outcome

Title	Glucose
Description	Glucose was measured by the glucose oxidase method using a YSI glucose analyzer
Time Frame	Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sitagliptin (Diabetics and Controls)	Placebo (Diabetics and Controls)	Sitagliptin and Valsartan (Controls Only)	Placebo and Valsartan (Controls Only)
Arm/Group Description	Subjects will receive sitagliptin 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects will receive placebo 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects in this arm will receive sitagliptin 100 mg/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.	Subjects in this arm will receive a placebo for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.
Measure Participants	13	13	5	5
Mean (Standard Deviation) [mg/dL]	94.3 (16.1)	100.3 (19.6)	85.7 (3.4)	88.3 (1.9)

8. Secondary Outcome

Title	ACE Activity
Description	ACE activity was measured using a commercially available assay (Olympus AU400/AU600, Alpco Diagnotics, Salem, NH.) The lower level of detection was 15 U/L and values below the level of detection were reported at half the level of detection.
Time Frame	Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.

Outcome Measure Data

Analysis Population Description

Was not measured during the valsartan study days.

Arm/Group Title	Sitagliptin + Enalaprilat (Diabetics and Controls)	Placebo + Enalaprilat (Diabetics and Controls)	Sitagliptin and Valsartan (Controls Only)	Placebo and Valsartan (Controls Only)
Arm/Group Description	Subjects will receive sitagliptin 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects will receive placebo 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects in this arm will receive sitagliptin 100 mg/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.	Subjects in this arm will receive a placebo for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.
Measure Participants	13	13	0	0
Mean (Standard Deviation) [U/L]	7.5 (0)	7.5 (0)

9. Secondary Outcome

Title	DPP4 Activity
Description	DPP4 activity was measured by detection of cleavage of a colorimetric substrate.
Time Frame	Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sitagliptin (Diabetics and Controls)	Placebo (Diabetics and Controls)	Sitagliptin and Valsartan (Controls Only)	Placebo and Valsartan (Controls Only)
Arm/Group Description	Subjects will receive sitagliptin 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects will receive placebo 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects in this arm will receive sitagliptin 100 mg/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.	Subjects in this arm will receive a placebo for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.
Measure Participants	13	13	5	5
Mean (Standard Deviation) [nmol/ml/min]	10.97 (4.47)	21.22 (5.36)	17.46 (7.35)	32.55 (5.58)

10. Secondary Outcome

Title	Low Frequency Variability of Blood Pressure Activity
Description	Measured using the VITAL-GARD 450c monitor Ivy Biomedical Systems, Branford, CT, USA)
Time Frame	Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sitagliptin (Diabetics and Controls)	Placebo (Diabetics and Controls)	Sitagliptin and Valsartan (Controls Only)	Placebo and Valsartan (Controls Only)
Arm/Group Description	Subjects will receive sitagliptin 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects will receive placebo 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects in this arm will receive sitagliptin 100 mg/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.	Subjects in this arm will receive a placebo for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.
Measure Participants	13	13	5	5
Mean (Standard Deviation) [mm Hg2]	5.16 (2.54)	5.60 (2.45)	6.05 (4.30)	4.27 (2.21)

11. Secondary Outcome

Title	Arterial tPA
Description	Measured using an ELISA.
Time Frame	Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.

Outcome Measure Data

Analysis Population Description

This was measured in a few subjects. After it was determined that there was no change in net t-PA release it was not measured in the remainder.

Arm/Group Title	Sitagliptin (Diabetics and Controls)	Placebo (Diabetics and Controls)	Sitagliptin and Valsartan (Controls Only)	Placebo and Valsartan (Controls Only)
Arm/Group Description	Subjects will receive sitagliptin 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects will receive placebo 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects in this arm will receive sitagliptin 100 mg/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.	Subjects in this arm will receive a placebo for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.
Measure Participants	3	2	0	0
Mean (Standard Deviation) [ng/mL]	0.047 (0.057)	0.115 (0.070)

12. Secondary Outcome

Title	Venous tPA
Description	Measured using an ELISA. This was measured in a few subjects. After it was determined that there was no change in net t-PA release it was not measured in the remainder.
Time Frame	Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.

Outcome Measure Data

Analysis Population Description

This was measured in a few subjects. After it was determined that there was no change in net t-PA release it was not measured in the remainder.

Arm/Group Title	Sitagliptin (Diabetics and Controls)	Placebo (Diabetics and Controls)	Sitagliptin and Valsartan (Controls Only)	Placebo and Valsartan (Controls Only)
Arm/Group Description	Subjects will receive sitagliptin 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects will receive placebo 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects in this arm will receive sitagliptin 100 mg/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.	Subjects in this arm will receive a placebo for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.
Measure Participants	3	2	0	0
Mean (Standard Deviation) [ng/mL]	0.030 (0.060)	0.110 (0.096)

13. Secondary Outcome

Title	Mean Arterial Pressure
Time Frame	Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sitagliptin (Diabetics and Controls)	Placebo (Diabetics and Controls)	Sitagliptin and Valsartan (Controls Only)	Placebo and Valsartan (Controls Only)
Arm/Group Description	Subjects will receive sitagliptin 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects will receive placebo 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects in this arm will receive sitagliptin 100 mg/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.	Subjects in this arm will receive a placebo for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.
Measure Participants	13	13	5	5
Mean (Standard Deviation) [mm Hg]	79.3 (8.0)	81.4 (6.5)	75.4 (4.2)	74.0 (5.7)

14. Secondary Outcome

Title	Heart Rate
Time Frame	Measured at baseline (time 0) of each study day prior to the infusion of neuropeptide Y. Study days were separated by five weeks, a four-week washout and one-week treatment period.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sitagliptin (Diabetics and Controls)	Placebo (Diabetics and Controls)	Sitagliptin and Valsartan (Controls Only)	Placebo and Valsartan (Controls Only)
Arm/Group Description	Subjects will receive sitagliptin 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects will receive placebo 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.	Subjects in this arm will receive sitagliptin 100 mg/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.	Subjects in this arm will receive a placebo for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y.
Measure Participants	13	13	5	5
Mean (Standard Deviation) [beats per minute]	67.4 (11.7)	66.0 (9.4)	59.8 (14.3)	60.2 (14.2)

Adverse Events

Time Frame	Adverse events were assessed at each study day from consent until completion of the last study day. The total duration of the study from consent to the last study day was completed ranged from six to ten weeks.
Arm/Group Title	Sitagliptin (Diabetics and Controls)		Placebo (Diabetics and Controls)		Sitagliptin and Valsartan (Controls Only)		Placebo and Valsartan (Controls Only)
Arm/Group Description	Subjects will receive sitagliptin 100 mg daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.		Subjects will receive placebo daily. After one week of treatment, subjects will report for a study day. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. Neuropeptide Y: 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. Enalaprilat: 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 After 30 minutes, a second NPY at graded doses was started ten minutes after that.		Subjects in this arm will receive sitagliptin 100 mg/d for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y		Subjects in this arm will receive splacebo for one week as well as valsartan 160 mg/d for one week. After this subjects will report for a study day. During the study day, subjects will be given intra-arterial neuropeptide Y
All Cause Mortality
	Sitagliptin (Diabetics and Controls)		Placebo (Diabetics and Controls)		Sitagliptin and Valsartan (Controls Only)		Placebo and Valsartan (Controls Only)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)		0/5 (0%)		0/5 (0%)
Serious Adverse Events
	Sitagliptin (Diabetics and Controls)		Placebo (Diabetics and Controls)		Sitagliptin and Valsartan (Controls Only)		Placebo and Valsartan (Controls Only)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)		0/5 (0%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Sitagliptin (Diabetics and Controls)		Placebo (Diabetics and Controls)		Sitagliptin and Valsartan (Controls Only)		Placebo and Valsartan (Controls Only)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/13 (15.4%)		2/13 (15.4%)		0/5 (0%)		1/5 (20%)
Gastrointestinal disorders
Nausea	0/13 (0%)	0	1/13 (7.7%)	1	0/5 (0%)	0	0/5 (0%)	0
General disorders
Light-headedness	1/13 (7.7%)	1	1/13 (7.7%)	1	0/5 (0%)	0	1/5 (20%)	1
Nervous system disorders
paresthesias	1/13 (7.7%)	1	0/13 (0%)	0	0/5 (0%)	0	0/5 (0%)	0
Skin and subcutaneous tissue disorders
Rash	0/13 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	1/5 (20%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.