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 inhibiting development of diabetes, comprising:
identifying a subject in need of enhanced levels of adiponectin, wherein the subject does not have diabetes; and
administering to the subject an amount of nitroxide antioxidant effective to increase proliferation of pancreatic beta cells, ameliorate insulin resistance, increase intracellular levels of adiponectin or to increase expression of an adiponectin gene in the subject, thereby inhibiting development of diabetes, 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 nitroxide antioxidant is 4-hydroxy-2,2,6,6,-tetramethylpiperdine-1-oxyl.
3. The method of claim 1 , wherein the subject is deficient in differentiated adipocytes.
4. The method of claim 1 , wherein the subject is deficient in differentiated adipocytes due to obesity.
5. The method of claim 1 , wherein the subject has depressed levels of adiponectin.
6. The method of claim 1 , comprising treating, inhibiting or delaying development of a condition associated with existing levels of adiponectin in the subject.
7. The method of claim 1 , wherein expression of adiponectin (C1Q and collagen domain containing) gene (ADIPOQ) is increased.
8. The method of Claim 1 , wherein the method reduces TNFα levels in the patient.
9. A method for increasing expression of adiponectin in a subject comprising:
identifying a subject predisposed or at risk for developing diabetes wherein the subject exhibits no symptoms of diabetes;
administering to the subject an amount of nitroxide antioxidant effective to increase intracellular levels of adiponectin or to increase expression of a adiponectin gene 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 ; and
treating, inhibiting or delaying development of a condition associated with existing levels of adiponectin in the subject.
10. The method of claim 9 , wherein the nitroxide antioxidant is 4-hydroxy-2,2,6,6,-tetramethylpiperdine-1-oxyl.
11. The method of claim 9 , wherein expression of adiponectin (C1Q and collagen domain containing) gene (ADIPOQ) is increased.
12. The method of claim 9 , wherein the method reduces TNFα levels in the patient.