Inflammation Inhibition in Prediabetic Humans
Inflammation Inhibition in Prediabetic Humans
Prediabetes, characterized by elevated fasting blood sugar or exaggerated blood sugar
 response to sugar ingestion, effects over 79 million adult Americans and is a precursor to
 the development of Type 2 diabetes. Importantly, approximately 42% of Iowans (950,000) have
 diabetes and 32% (670,000) have prediabetes with the majority of those with prediabetes going
 undiagnosed. Adults with prediabetes demonstrate early signs of cardiovascular and nervous
 system abnormalities and are at high risk for developing overt diabetes unless aggressive
 lifestyle (weight loss, exercise) or pharmacological interventions are employed.
 Interestingly, data in recent years has linked obesity and diabetes to chronic inflammation
 of the blood vessels and brain areas that regulate blood pressure. Therefore, the current
 study will test whether a commonly used aspirin-like anti-inflammatory drug called salsalate,
 will improve blood vessel health and nervous system dysfunction in adults with prediabetes.
 Eligible subjects will have measurements of blood pressure, blood vessel function in the arms
 and eyes, assessments of nerve activity, and blood samples taken before and after 4 weeks of
 ingesting an FDA approved aspirin-like drug called salsalate. The study is important because
 it will identify a potentially new pharmacological strategy to treat vascular and nervous
 system abnormalities in overweight and obese adults with early stage type 2 diabetes using an
 inexpensive, generically available drug with an excellent safety record that has been used
 for decades to treat chronic inflammatory conditions such as rheumatoid arthritis. If proven
 effective, this will provide preliminary support for the concept of targeting inflammation as
 a new clinical approach to treating early diabetes related complications. Furthermore, the
 current pilot study will provide support for developing a larger clinical trial using
 salsalate that could potentially then be extended to patients with type 2 diabetes and
 cardiovascular disease, as well as lead to the development of new anti-inflammatory agents
 with greater specificity for selective inflammatory pathways.
A total of 30 healthy men and women ages 18-79 years who are obese defined as body mass index
 (BMI) of 30 kg/m2 or greater and with prediabetes (defined as fasting blood glucose between
 100-126 mg/dl, a fasting blood glucose of 140-199 mg/dl at 120 min during an oral glucose
 tolerance test; or HbA1C of 6-6.5%) will be enrolled and randomized to 4-5 weeks of salsalate
 or placebo in the study. CONTROL GROUP: Another n=10 healthy obese men and women age 18-49
 WITHOUT prediabetes will be enrolled for baseline testing but will not undergo randomization
 to the salsalate/placebo intervention. Therefore, total enrollment will be n=40.

 All subjects will have no history of cardiovascular, metabolic or pulmonary disease as
 determined from medical history and physical exam, and a resting 12-lead ECG. Subjects may be
 on anti-hypertensive medications but will be asked to hold the medication on the morning of
 testing. Subjects on medications for Type I or II diabetes mellitus or for hyperlipidemia
 will be excluded (see complete list below). Subjects will be non-smokers or quit smoking at
 least one year ago. Women will have regular menses and will be tested during the early
 follicular phase of their menstrual cycle (within 8 days of onset of menses) to control for
 differences in circulating estradiol concentrations. Aim 1 will measure microvascular
 function and aortic wall stiffness in obese prediabetic adults before and after 1 month of
 salsalate or placebo. Hypothesis 1 is that chronic inflammation inhibition will improve
 microvascular and large elastic artery function in obese adults with prediabetes. Aim 2 will
 measure muscle sympathetic nervous system activity (MSNA) and baroreflex sensitivity in obese
 prediabetic adults before and after 1 month of salsalate or placebo. Hypothesis 2 is that
 chronic inflammation inhibition will decrease MSNA and improve baroreflex sensitivity in
 obese adults with prediabetes.
Inclusion Criteria:

 -  Willing and able to provide written, signed informed consent after the nature of the
 study has been explained, and prior to any research-related procedures.

 -  Age is > or = 18 and < or = 49 years (older)

 -  Obese defined as body mass index > or = 30 kg/m2

 -  Prediabetic defined as fasting blood glucose 100-126 mg/dl, blood glucose between
 140-199 mg/dl at 120 min of oral glucose tolerance test

 -  healthy, as determined by health history questionnaire, medical history and
 physical examination by physician or nurse practitioner, blood chemistries,
 resting blood pressure and exercise 12-lead ECG

 -  blood chemistries indicative of normal renal function (creatinine <2.2 mg/dl),
 liver (<3 times upper limit for ALT, AST), and thyroid function (TSH between 0.4
 - 5.0 mU/L)

 -  If currently receiving treatment with or taking any of the following supplements,
 be willing and able to discontinue taking them for 2 weeks prior and throughout
 the treatment period: Vitamin C, E or other multivitamins containing vitamin C or
 E; nutraceuticals containing vitamin C or E

 -  No history of cardiovascular disease (e.g., heart attack, stroke, heart failure,
 valvular heart disease, cardiomyopathy), Type 1 or 2 diabetes mellitus, or
 peripheral arterial disease

 -  Sedentary or recreationally active defined as performs regular aerobic exercise
 (30 min or more of vigorous walking, jogging, swimming, cycling, etc) less than 2
 days/week or less than 12 days/month over the last year

 -  Non-smokers, defined as no history of smoking, no smoking for at least the past 1
 year

 -  Normal resting 12-lead ECG.

 Exclusion Criteria:

 -  History of cardiovascular disease such as myocardial infarction, stroke, heart failure
 with or without LV ejection fraction <40%, cardiomyopathy, valvular heart disease,
 cardiomyopathy, heart transplantation, Type 2 diabetes and Type 1 diabetes

 -  Smoking or history of smoking within past one year

 -  History of gastric ulcers, bleeding disorders, dyspepsia, severe gastroesophageal
 reflux disease (GERD), or metabolic acidosis

 -  History of asthma or lung disease (chronic obstructive pulomonary disease, COPD)

 -  Abnormal resting 12-lead ECG (e.g., evidence of myocardial infarction, left
 ventricular hypertrophy, left-bundle branch block, 2nd or 3rd degree AV block,
 atrial fibrillation/flutter)

 -  Serious neurologic disorders including seizures

 -  History of renal failure, dialysis or kidney transplant

 -  Serum creatinine > 2.2 mg/dL, or hepatic enzyme concentrations > 3 times the
 upper limit of normal

 -  History of HIV infection, hepatic cirrhosis, other preexisting liver disease, or
 positive HIV, Hepatitis B or C test at screening.

 -  Use of any investigational product or investigational medical device within 30
 days prior to screening, or requirement for any investigational agent prior to
 completion of all scheduled study assessments.

 -  History of recent chicken pox, shingles or influenza (ie., risk of Reye's
 syndrome) Recent flu-like symptoms within the past 2 weeks

 -  Pregnant or breastfeeding at screening, or planning to become pregnant (self or
 partner) at any time during the study. A urinary pregnancy test will be done on
 all females. If test is positive, the subject will be excluded.

 -  Women with history of hormone replacement therapy within the past 6 months

 -  History of rheumatoid arthritis, Grave's disease, systemic lupus erythamatosis,
 and Wegener's granulomatosis;

 -  Taking medications for diabetes mellitus, kidney disease, liver disease, asthma,
 sepsis or seizure disorders;

 -  Taking lipid lowering (e.g., statins, niacin), glycemic control (e.g. metformin,
 insulin), anticoagulation, anti-seizure, anti-depression or antipsychotic agents

 -  History of co-morbid condition that would limit life expectancy to < 6 months.

 -  It is unknown if Salsalate is transferred in seminal fluid of men. However, it is
 recommended that proper protection such as a condom be used during intercourse
 during the study.

 -  Concomitant treatment with: aspirin, baby aspirin, indomethacin, naproxen
 (Aleve), acetaminophen (Tylenol), ibuprofen (Advil, Motrin), any other
 non-steroidal anti-inflammatory drugs; cox-2 inhibitors (Celebrex, Vioxx, etc);
 allopurinol (Zyloprim, Lopurin, Alopurin; coumadin (Wafarin), enoxaparin
 (Lovenox); clopidogrel (Plavix); dypyridamole (Persantine); heparin; diabetic
 medications (Metformin, glyburide, insulin, etc), TZDs (Avandia, Rezulin, Actos);
 corticosteroids (prednisone); methotrexate, infliximib (Remicade), etaneracept
 (Enbrel); levothyroxine (Levoxyl, Synthroid, Levoxyl, Unithroid); Levodopa;
 Phosphodiesterase (PDE) 5 inhibitors (e.g., Viagra®, Cialis®, Levitra®, or
 Revatio®); PDE 3 inhibitors (e.g., cilostazol, milrinone, or vesnarinone);
 lithium

 -  May participate if use of the following medications are discontinued 2 weeks
 prior to participation: salicylate medications, aspirin, antioxidants, herbal
 supplements, vitamins, omega-3 fatty acids; cox-2 inhibitors (Celebrex, Vioxx,
 etc)

 -  May participate if no use of the following medications in the 48 hours prior to
 experimental visits: naproxen (Aleve), acetaminophen (Tylenol), ibuprofen (Advil,
 Motrin), other any non-steroidal anti-inflammatory drugs

 -  Vulnerable populations (prisoners, etc.) are not included in this study because
 we are studying healthy middle-aged/older adults.

 -  Any condition that, in the view of the PI, places the subject at high risk of
 poor treatment compliance or of not completing the study.

 -  Hemoglobin <12 mg/dl for men; < 10 mg/dl for women

 -  History of alcohol abuse or >10 alcoholic units per week (1 unit= 1 beer, 1 glass
 of wine, 1 mixed cocktail containing 1 oz alcohol)

 -  Low platelets (<100,000 cu mm)

 -  On weight loss drugs (e.g., Xenical (orilistat), Meridia (sibutramine), Acutrim
 (phenylpropanol-amine), or similar over-the-counter medications) within 3 months
 of screening

 -  Any surgery within 30 days of screening