Nitroxides for use in treating or preventing diabetes and obesity
Pharmaceutical compositions are provided that are useful in treating diabetes. The compositions comprise a pharmaceutically acceptable carrier, and an effective therapeutic or prophylactic amount of a nitroxide antioxidant that alters the expression of genes related to diabetes. Methods are also provided for the use of the pharmaceutical compositions in the treatment or prevention of diabetes. In a preferred embodiment, the nitroxide antioxidant is Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl).
1. A method of treatment comprising:
identifying a subject having elevated TNFa levels, and
administering to the subject an amount of a nitroxide antioxidant effective to reduce said levels in the subject, wherein the nitroxide antioxidant is selected from the following formulas:
wherein X is selected from O— and OH, and R is selected from COOH, CONH 2 , CN, and CH 2 NH 2 ;
wherein X is selected from O— and OH, and R 1 is CH 3 , R 2 is C 2 H 5 , or R 1 and R 2 taken together are spirocyclohexyl;
wherein X is selected from O— and OH and R is selected from CONH 2 ; and
wherein X is selected from O— and OH and R is selected from H, OH, and NH 2 , or wherein the nitroxide antioxidant is selected from the group consisting of 4-Oxo-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-(2-bromoacetamido)-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-(ethoxyfluorophosphonyloxy)-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-(2-iodoacetamido)-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-isothiocyanato-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-maleimido-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-(4-nitrobenzoyloxyl)-2,2,6,6-tetramethylpiperidine-1-oxyl, and 4-phosphonooxy-2,2,6,6-tetramethylpiperidine-1-oxyl.
2. The method of claim 1 , wherein the subject has not been diagnosed with diabetes, or wherein the subject has silent diabetes.
3. The method of claim 1 , wherein the effective amount of the one or more nitroxide antioxidants is within a range of 0.01-300 mg/kg.
4. The method of claim 1 , wherein the effective amount of the one or more nitroxide antioxidants is within a range of 0.1-250 mg/kg.
5. The method of claim 1 , wherein the subject is predisposed or at risk for developing diabetes.
6. The method of claim 1 , wherein the subject has a family history of diabetes.
7. The method of claim 1 , wherein the subject has an eye disease.
8. The method of claim 1 , wherein the subject has a nephropathy.
9. The method of claim 1 , wherein the subject has a sensory or motor neuropathy.
10. The method of claim 1 , wherein the subject has a vascular disease.
11. The method of claim 1 , wherein the subject has a gastrointestinal dysfunction.
12. The method of claim 1 , wherein the subject has a genitourinary dysfunction.
13. The method of claim 1 , wherein the subject has a diabetic risk factor and the amount of nitroxide antioxidant is effective to reduce the diabetic risk factor.
14. The method of claim 1 , wherein the level of TNF-α expression is reduced.
15. The method of claim 1 , wherein the level of adiponectin expression is increased.