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 not having diabetes but in need of an increased level of functional pancreatic beta cells; and
administering to the subject an amount of a nitroxide antioxidant effective to increase proliferation of pancreatic beta cells, increase intracellular levels of keratinocyte growth factor, or increase expression of a keratinocyte growth factor 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.
2. The method of claim 1 , wherein the intracellular levels of keratinocyte growth factor are increased.
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 effective amount of the one or more nitroxide antioxidants is within a range of 1-200 mg/kg.
6. The method of claim 1 , wherein the effective amount of the one or more nitroxide antioxidants is within a range of 2-150 mg/kg.
7. The method of claim 1 , wherein the effective amount of the one or more nitroxide antioxidants is within a range of 5-125 mg/kg.
8. The method of claim 1 , wherein the effective amount of the one or more nitroxide antioxidants is within a range of 7-100 mg/kg.
9. The method of claim 1 , wherein the effective amount of the one or more nitroxide antioxidants is within a range of 10-75 mg/kg.
10. The method of claim 1 , wherein the effective amount of the one or more nitroxide antioxidants is within a range of 15-30 mg/kg.
11. The method of claim 1 , wherein expression of the keratinocyte growth factor gene is increased.
12. The method of claim 11 , wherein expression of the keratinocyte growth factor gene in pancreatic ductal cells is increased.
13. The method of claim 1 , wherein the proliferation of pancreatic beta cells is increased.
14. The method of claim 1 , wherein the subject is deficient in functional pancreatic beta cells.
15. The method of claim 14 , wherein the subject is deficient in functional pancreatic beta cells not due to autoimmune destruction of the pancreatic beta cells.
16. The method of claim 1 , wherein the subject has depressed levels of keratinocyte growth factor.
17. The method of claim 1 , wherein the subject is predisposed or at risk for developing diabetes.
18. The method of claim 17 , wherein the subject has a family history of diabetes.
19. The method of claim 17 , wherein the subject has an eye disease.
20. The method of claim 17 , wherein the subject has a sensory and motor neuropathy.
21. The method of claim 17 , wherein the subject has a nephropathy.
22. The method of claim 17 , wherein the subject has a vascular disease.
23. The method of claim 17 , wherein the subject has a gastrointestinal dysfunction.
24. The method of claim 17 , wherein the subject has a genitourinary dysfunction.
25. 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.
26. The method of claim 1 , comprising inhibiting or delaying development of a condition associated with depressed levels of keratinocyte growth factor in the subject.
27. A method of treatment comprising:
identifying a subject not having diabetes but in need of enhanced levels of keratinocyte growth factor; and
administering to the subject an amount of nitroxide antioxidant effective to increase intracellular levels of keratinocyte growth factor or to increase expression of a keratinocyte growth factor 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.
28. The method of claim 27 , wherein the nitroxide antioxidant is 4-hydroxy-2,2,6,6,-tetramethylpiperdine-1-oxyl.
29. The method of claim 27 , wherein the subject is deficient in functional pancreatic beta cells.
30. The method of claim 29 , wherein the subject is deficient in functional pancreatic beta cells not due to autoimmune destruction of the pancreatic beta cells.
31. The method of claim 27 , wherein the subject has depressed levels of keratinocyte growth factor.
32. The method of claim 27 , comprising inhibiting or delaying development of a condition associated with depressed levels of keratinocyte growth factor in the subject.
33. A method for increasing expression of keratinocyte growth factor in a subject comprising:
identifying a subject predisposed or at risk for developing diabetes wherein the subject exhibits no symptoms of diabetes; and
administering to the subject an amount of nitroxide antioxidant effective to increase intracellular levels of keratinocyte growth factor or to increase expression of a keratinocyte growth factor 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.
34. The method of claim 33 , comprising inhibiting or delaying development of a condition associated with depressed levels of keratinocyte growth factor in the subject.