Nitroxides for use in treating predisposed or at risk patients
Inventors
Habash, Louis • Jones, Clarence
Assignees
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Publication Number
US-8563581-B2
Publication Date
2013-10-22
Expiration Date
Abstract
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).
Core Innovation
The invention relates to diabetes-treatment and diabetes prevention using a nitroxide antioxidant, specifically 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl, in a subject predisposed to or at risk for developing diabetes who exhibits no symptoms of diabetes. The method includes administering an amount of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl effective to increase proliferation of pancreatic beta cells, ameliorate insulin resistance, increase intracellular levels of adiponectin or keratinocyte growth factor, and/or increase expression of an adiponectin or keratinocyte growth factor gene in the subject.
The disclosure states that Tempol increases keratinocyte growth factor (KGF, FGF-7) expression in cardiac tissue by more than 2-fold and increases adiponectin (ADIPOQ) expression in adipose tissue by about 1.22-fold. The document also includes gene-function rationale linking KGF with beta-cell proliferation and linking adiponectin with insulin resistance.
The disclosure specifies identifying subjects with abnormally depressed levels of adiponectin due to abnormally high levels of adipose tissue, and identifying subjects with abnormally high levels of adipose tissue, each where the subject exhibits no symptoms of diabetes. In these populations, administering 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl is stated to increase intracellular levels of adiponectin and/or increase expression of an adiponectin gene.
Claims Coverage
The partial content provides three independent method-of-treatment claims. Across the independents, the inventive features are centered on selecting an asymptomatic subject at risk or with specified adiponectin/adipose-tissue abnormalities and administering 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl for specified increases in pancreatic beta-cell proliferation, insulin resistance amelioration, adiponectin and/or keratinocyte growth factor levels, and/or corresponding gene expression.
Diabetes risk identification and nitroxide administration for beta-cell proliferation, insulin resistance, adiponectin/KGF and gene expression
Identifying a subject predisposed to or at risk for developing diabetes wherein the subject exhibits no symptoms of diabetes; and administering to the subject an amount of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl effective to increase proliferation of pancreatic beta cells, ameliorate insulin resistance, increase intracellular levels of adiponectin or keratinocyte growth factor, or increase expression of an adiponectin or keratinocyte growth factor gene in the subject.
Abnormally depressed adiponectin due to high adipose tissue in an asymptomatic subject and adiponectin intracellular/gene upregulation
Identifying a subject with abnormally depressed levels of adiponectin due to abnormally high levels of adipose tissue, wherein the subject exhibits no symptoms of diabetes; and administering to the subject an amount of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl effective to increase intracellular levels of adiponectin or to increase expression of an adiponectin gene in the subject.
Abnormally high adipose tissue in an asymptomatic subject and adiponectin intracellular/gene upregulation
Identifying a subject with abnormally high levels of adipose tissue, wherein the subject exhibits no symptoms of diabetes; and administering to the subject an amount of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl effective to increase intracellular levels of adiponectin or to increase expression of an adiponectin gene in the subject.
Overall, the independent claims cover treatment methods that administer 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl to asymptomatic subjects selected based on diabetes risk and/or specified adiponectin/adipose-tissue abnormalities, to increase intracellular adiponectin and/or adiponectin gene expression, and in the broader claim also to promote pancreatic beta-cell proliferation, ameliorate insulin resistance, and increase keratinocyte growth factor and/or adiponectin/KGF gene expression.
Stated Advantages
Increases proliferation of pancreatic beta cells.
Ameliorates insulin resistance.
Increases intracellular levels of adiponectin or keratinocyte growth factor.
Increases expression of an adiponectin or keratinocyte growth factor gene.
Provides prophylaxis or treatment directed to subjects predisposed to or at risk for developing diabetes who exhibit no symptoms of diabetes.
Documented Applications
Prophylaxis or treatment of a subject predisposed to or at risk for developing diabetes with no symptoms of diabetes, including increasing beta-cell proliferation, ameliorating insulin resistance, and increasing adiponectin and/or keratinocyte growth factor levels or gene expression.
Treatment of a subject with abnormally depressed adiponectin levels due to abnormally high levels of adipose tissue, with no symptoms of diabetes, by increasing intracellular adiponectin and/or adiponectin gene expression.
Treatment of a subject with abnormally high levels of adipose tissue, with no symptoms of diabetes, by increasing intracellular adiponectin and/or adiponectin gene expression.
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