Physical Activity and Obesity

Physical Activity and Obesity: The Role of Nitric Oxide and Eicosanoids in Regulating Capillary Perfusion and Vascular Insulin Resistance

The purpose of the study is to see if a twelve-week exercise intervention in overweight or obese subjects with pre-diabetes or early disease course type 2 diabetes can lead to improved skeletal muscle capillary blood flow by improving substances that dilate blood vessels and result in improved insulin sensitivity.

Study Overview

• Status: Completed
• Conditions: Obesity; Sedentary Lifestyle; Prediabetic State
• Intervention / Treatment: Behavioral: High Activity

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Males and females ages 30-60 years of age
2. Overweight and Obese (28< BMI <45)
3. Confirmed pre-diabetic (5.7≤ HbA1c < 6.5)
4. Type 2 DM, Diagnosis 2 years or less, on no medications or metformin only, HbA1c ≤ 6.7

Exclusion Criteria:

1. Stage 3 chronic kidney disease (glomerular filtration rate [GFR] < 60)
2. Obstructive Coronary artery disease
3. Congestive heart failure (ejection fraction < 55%)
4. Peripheral vascular disease,
5. Degenerative joint disease, musculoskeletal disease, or peripheral vascular disease that limits ability to exercise
6. Know hypersensitivity to Definity® ultrasound contrast agent
7. Intra-cardiac or pulmonary shunt
8. The use of antithrombotic agents or a severe bleeding diathesis due to risk of bleeding with intravenous and arterial line placement
9. Physical activity greater than three hours per week
10. Pregnancy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High Activity Group; Subject randomized to High Activity group will have 36, one hour training sessions over 12 weeks.	Behavioral: High Activity; The high activity group will undergo a 12 week ramped exercise protocol.
No Intervention: Standard of Care Group; The standard of care group will maintain their baseline level of activity for 12 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin mediated skeletal muslce blood flow and capillary recruitment	Contrast enhanced ultrasound skeltal muscle perfusion imaging will be performed at rest and during glucose steady state infusion during an insulin clamp. The change in blood flow will be determined between the resting state and at peak steady state to determine the absolute increase in skeletal muslce blood flow (ml/min/g) as well as the absolute increase in capillary blood volume (ml/g) of tissue	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantification of endothelial derived Vasodilators	To quantify the changes in endothelial derived vasodilators. For this aim nitric oxide bioavailability as tested by flow mediated vasodilation will be performed and reported as absolute change (cm) and percent change (%) in brachial artery diameter from baseline to post ischemic occlusion of the forearm. Plasma samples for eicosanoids will be collected and assessed by liquid chormatography/mass spectroscopy to to assess changes in endothelial derived vasodilators.	3 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correalte changes in fitness to vasodilators, blood flow, and insulin sensitivity	Aim 3. To correlate changes in fitness as measured by peak VO2 and anaerobic threshold during cardiopulmonary exercise testing with changes in endothelial derived vasodilators, skeletal muscle blood flow, and insulin sensitivity.	3 months

Collaborators and Investigators

• Sponsor: Oregon Health and Science University
• Investigators: Principal Investigator: Scott M Chadderdon, MD, Oregon Health and Science University

Publications and helpful links

General Publications

• Coggins M, Lindner J, Rattigan S, Jahn L, Fasy E, Kaul S, Barrett E. Physiologic hyperinsulinemia enhances human skeletal muscle perfusion by capillary recruitment. Diabetes. 2001 Dec;50(12):2682-90. doi: 10.2337/diabetes.50.12.2682.
• Clerk LH, Vincent MA, Jahn LA, Liu Z, Lindner JR, Barrett EJ. Obesity blunts insulin-mediated microvascular recruitment in human forearm muscle. Diabetes. 2006 May;55(5):1436-42. doi: 10.2337/db05-1373.
• Chadderdon SM, Belcik JT, Smith E, Pranger L, Kievit P, Grove KL, Lindner JR. Activity restriction, impaired capillary function, and the development of insulin resistance in lean primates. Am J Physiol Endocrinol Metab. 2012 Sep 1;303(5):E607-13. doi: 10.1152/ajpendo.00231.2012. Epub 2012 Jun 26.

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (Actual): April 1, 2016
• Study Completion (Actual): April 1, 2017

Study Registration Dates

• First Submitted: February 6, 2014
• First Submitted That Met QC Criteria: February 7, 2014
• First Posted (Estimate): February 12, 2014

Study Record Updates

• Last Update Posted (Actual): August 6, 2019
• Last Update Submitted That Met QC Criteria: August 2, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Obesity; Insulin Resistance; Nitric Oxide; Endothelium; Sedentary Lifestyle; Prediabetic State; Regional Blood Flow; Eicosanoids
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity; Prediabetic State
• Other Study ID Numbers: OHSUIRB#10299; 5KL2TR000152-08 (U.S. NIH Grant/Contract)