Effects of Roflumilast on Insulin and Blood Sugar Levels in Prediabetic Overweight and Obese Individuals
Condition: Obesity
MeSH terms: Overweight
Study type: Interventional
Phase: Phase 1/Phase 2

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.
    

Intervention name(s): Roflumilast
Intervention type(s): Drug
Intervention description(s): Selective phosphodiesterase 4 (PDE4) inhibitor
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Mitochondria in Diabetes; Obesity; Roflumilast; Phosphodiesterase-4; Pre-Diabetes