Effects of Roflumilast on Insulin and Blood Sugar Levels in Prediabetic Overweight and Obese Individuals

Phase 1

Completed

Conditions: Obesity

Interventions: Drug: Roflumilast

Registration Number: NCT01862029

Lead Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Brief Summary: Background:

- Roflumilast is a drug used to treat chronic obstructive pulmonary disease (COPD). It is designed to help reduce lung inflammation. However, during testing, roflumilast also appeared to reduce high blood sugar levels in people with COPD and type 2 diabetes. Other tests showed that roflumilast also improved blood sugar levels in people who only had type 2 diabetes. Researchers want to see how roflumilast affects insulin and blood sugar levels in overweight or obese people who are not diabetic, but who have high blood sugar levels.

Objectives:

- To see how well roflumilast improves blood sugar and insulin levels in prediabetic overweight or obese individuals.

Eligibility:

- Individuals between 30 to 65 years old who are overweight or obese (body mass index of 24.9 to 39.9 kg/m2) and have elevated blood sugar levels.

Design:

* This study will last approximately 8 weeks. Participants will have approximately five study visits over about 7 weeks. Two of these visits will be overnight inpatient stays.

* Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. They will also have a 3-day diet and exercise assessment with a dietitian.

* In Week 1, participants will have a special diet for 2 days to keep their regular weight. They will then have a 2-day inpatient stay. During their stay, they will have multiple tests, including blood sugar tests and full body scans. They may provide a fat and muscle tissue biopsy sample. They will then receive the study drug to take during the study.

* In Week 2, participants will repeat the diet study from the screening visit. They will receive a different dose of the study drug.

* In Week 3, participants will review their diet results and have blood and urine tests.

* In Week 5, participants will repeat the diet and exercise study from the screening visit.

* In Week 6, participants will repeat the inpatient studies and tests from Week 1.

In the last week, participants will have a final follow-up visit.

Detailed Description: Resveratrol, a polyphenol most notably found in red wine has anti-aging properties in mice fed a high-fat diet; resveratrol protects against obesity and type 2 diabetes. Several clinical trials have been conducted to study the metabolic effects of resveratrol. Although these trials have used different subject groups (e.g. obese healthy, type 2 diabetics or older adults with glucose intolerance), they suggest that resveratrol may improve insulin sensitivity. However, the therapeutic potential of resveratrol is diminished by the fact that it has a very promiscuous target profile. In order to translate resveratrol biology into clinical application, it is helpful to identify the cellular target(s) of resveratrol that mediate the desired effects and to develop therapies specific for that target(s). Recently, we discovered that the metabolic effects of resveratrol appear to result from competitive inhibition of cAMP-degrading phosphodiesterases (PDEs), which increases cAMP levels. The cAMP-dependent pathways activate AMP-activated protein kinase (AMPK), which is essential for the metabolic effects of resveratrol. Inhibiting PDE4 with rolipram reproduces all of the metabolic benefits of resveratrol, including protection against diet-induced obesity and an increase in mitochondrial content, fat oxidation, physical stamina and glucose tolerance in mice. Based on results from cellular and preclinical studies, we hypothesize that PDE4 inhibition will ameliorate insulin resistance in pre-diabetic individuals. To test these hypotheses, we will conduct an exploratory study on the potential beneficial effects of roflumilast (Daxas (Registered Trademark)), a PDE4 inhibitor, on insulin sensitivity in pre-diabetic individuals.Each study participant will receive oral roflumilast (250 (micro)g, once a day for 2 weeks, followed by 500 (micro)g once a day for 4 weeks). At baseline and after the 6-week treatment period, we will assess insulin sensitivity (hyperinsulinemiceuglycemic glucose clamp technique, glucose clamp ). In addition, Beta-cell function, skeletal muscle mitochondrial function, body composition, and circulating adipocytokine profile will be measured at baseline and after treatment to evaluate potential changes that may be related to improvements in metabolic function. Vascular function is not only an indicator of insulin sensitivity, but is also important for glucose delivery and metabolism. If possible, vascular function will be assessed along with the other parameters at baseline and after treatment with roflumilast. Regarding vascular function, we may measure basal and insulin-stimulated brachial artery blood flow (large conduit artery assessed by Doppler ultrasound) as well as capillary recruitment in forearm skeletal muscle (small nutritive arterioles assessed by ultrasound with microbubble contrast). This study will explore whether roflumilast is effective at improving insulin sensitivity in pre-diabetic individuals. Results from this study may have important implications for the potential use of roflumilast in treating type 2 diabetes.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 24

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Roflumilast	Roflumilast	-

Primary Outcome Measures

Name	Time	Method
Change in Insulin Sensitivity- Pre-roflumilast	Baseline	Our primary outcome measure is the change in peripheral insulin sensitivity. The hyperinsulinemic euglycemic clamp procedure's M value, which was obtained before the subjects began roflumilast, was used to assess the primary outcome.
Change in Insulin Sensitivity - Post-roflumilast	6 weeks	Our primary outcome measure is the change in peripheral insulin sensitivity. The hyperinsulinemic euglycemic clamp procedure's M value, which was obtained post-roflumilast, was used for this primary outcome assessment.

Secondary Outcome Measures