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

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.

- INCLUSION CRITERIA:

- Adult, weight- and diet-stable men and women in good general health with no
significant underlying illnesses and normal or clinically insignificant results
(medical histories, laboratory profiles, physical examination, and
electrocardiograms),

- Women must be non-pregnant or post-menopausal, or women of childbearing potential must
be non-lactating and using an effective form of birth control during and for 30 days
after the study period (partner's use of condoms or partner's vasectomy is not an
acceptable contraception method for this study),

- Must be 30 - 65 years of age, inclusive

- Body Mass Index (BMI) > 24.9 and < 39.5 kg/m(2) with a stable (plus-minus 2.5 kg)
weight for the last 6 months by history,

- Pre-diabetes, as defined by a fasting blood glucose of greater than 100 mg/dL and less
than 126 mg/dL and/or A1C equal or greater than 5.7 and less than or equal to 6.5 %

- Subjects must be able to understand the protocol and provide written informed consent.

EXCLUSION CRITERIA:

- Women will be excluded from our study if they are pregnant, breastfeeding, or if they
plan to become pregnant prior to the end of the study,

- Cannot be on any medications including multivitamins or nutritional supplements that
in the investigator s opinion will affect insulin sensitivity

- Currently taking systemic corticosteroids, insulin, or anticoagulants, anxiolytics,
ketoconazole, erythromycin, cimetidine, enoxacin, strong CYP 3A4/1A2 inducers (e.g.,
rifampicin, phenobarbital, carbamazepine, phenytoin), birth control pills containing
gestodene and ethinyl estradiol, use food supplements that cannot be discontinued, or
any other medication that the investigators deem a contraindication.

- AST or ALT > 3 times the upper normal limit

- Hepatitis B antigen, HIV or C positive antibody tests,

- Liver disease, pulmonary disease, renal insufficiency, , (serum creatinine >
1.5mg/dl), coronary heart disease, heart failure (New York Heart Association heart
failure Class III or IV), peripheral vascular disease, coagulopathy.

- History of or current diagnosis of major depressive disorder, or history of or current
diagnosis of other psychiatric disorders that in the opinion of the investigator would
make participant unsafe for the participant.

- Currently being treated for any form of cancer or have a history of cancer, that in
the investigator s judgment would not make the participant a candidate for the study
for safety or scientific reasons.

- Claustrophobic,

- On a weight loss program with ongoing weight loss, or a history of eating disorders.
Actively using tobacco products or have used tobacco products within last year (>3
cigarettes/day), regular alcoholic beverage intake of more than two drinks per day.
Subjects with any condition that would have made them, in the opinion of the principal
investigator (PI), unsuitable for the study.

- Subjects with a contraindication for the ultrasound contrast agent.