Claims
- 1. A method for identifying an agent for treating a patient having diabetes or a predisposition for diabetes, the method comprising the steps of:
(i) contacting a solution comprising an AKR1C polypeptide or fragment thereof with the agent, wherein the AKR1C polypeptide or the fragment thereof catalyzes the interconversion of 9α,11β-PGF2α from prostaglandin D2, and the AKR1C polypeptide or fragment thereof is encoded by a nucleic acid that hybridizes under stringent conditions to a nucleic acid encoding a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 7, SEQ ID NO: 17, SEQ ID NO: 23, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35; and SEQ ID NO: 36; and (ii) selecting an agent that modulates the expression or catalytic activity of the AKR1C polypeptide or fragment thereof, thereby identifying an agent for treating a patient having diabetes or a predisposition for diabetes.
- 2. The method of claim 1, wherein the predisposition for diabetes is manifested as reduced insulin sensitivity.
- 3. The method of claim 1, the method further comprising selecting an agent that modulates insulin sensitivity.
- 4. The method of claim 1, wherein the catalytic activity of the AKR1C polypeptide is determined by measuring a change in the level of a catalytic product or substrate.
- 5. The method of claim 4, wherein the catalytic product or substrate is 9α,11β-PGF2α.
- 6. The method of claim 4, wherein the catalytic product or substrate is prostaglandin D2.
- 7. The method of claim 1, wherein the contacting step is performed in vitro.
- 8. The method of claim 1, wherein the AKR1C polypeptide or fragment thereof is expressed in a cell and the cell is contacted with the agent.
- 9. The method of claim 1, wherein the agent increases the catalytic activity of the AKR1C polypeptide or fragment thereof.
- 10. The method of claim 1, wherein the agent decreases the catalytic activity of the AKR1C polypeptide or fragment thereof.
- 11. The method of claim 1, wherein the agent increases the expression of the AKR1C polypeptide or fragment thereof.
- 12. The method of claim 1, wherein the agent decreases the expression of the AKR1C polypeptide or fragment thereof.
- 13. The method of claim 1, further comprising the steps of administering the agent to an animal having diabetes and the testing the animal for changes in the diabetic state.
- 14. The method of claim 1, further comprising the steps of administering the agent to an animal exhibiting insulin resistance and testing the animal for modulated insulin resistance.
- 15. The method of claim 1, further comprising the steps of contacting a cell expressing an AKR1C polypeptide or fragment thereof with the agent and testing the cell for modulated PPAR activity.
- 16. The method of claim 1, further comprising the steps of contacting a cell expressing an AKR1C polypeptide or fragment thereof with the agent and testing the cell for modulated insulin sensitivity.
- 17. The method of claim 1, wherein the amino acid sequence comprises SEQ ID NO: 1.
- 18. The method of claim 1, wherein the amino acid sequence comprises SEQ ID NO: 7.
- 19. The method of claim 1, wherein the amino acid sequence comprises SEQ ID NO: 17.
- 20. The method of claim 1, wherein the amino acid sequence comprises SEQ ID NO: 23.
- 21. The method of claim 1, wherein the amino acid sequence comprises SEQ ID NO: 30.
- 22. The method of claim 1, wherein the amino acid sequence comprises SEQ ID NO: 31.
- 23. The method of claim 1, wherein the amino acid sequence comprises SEQ ID NO: 32.
- 24. The method of claim 1, wherein the amino acid sequence comprises SEQ ID NO: 33.
- 25. The method of claim 1, wherein the amino acid sequence comprises SEQ ID NO: 34.
- 26. The method of claim 1, wherein the amino acid sequence comprises SEQ ID NO: 35.
- 27. The method of claim 1, wherein the amino acid sequence comprises SEQ ID NO: 36.
- 28. A method of treating an animal having diabetes, the method comprising administering a therapeutically effective amount of an agent identified by the method of claim 1.
- 29. The method of claim 28, wherein the animal is a human.
- 30. A method of treating an animal having insulin resistance, the method comprising administering a therapeutically effective amount of an agent identified by the method of claim 1.
- 31. The method of claim 30, wherein the animal is a human.
- 32. A method of diagnosing Type 2 diabetes or a predisposition for Type 2 diabetes in a patient, the method comprising,
detecting in a sample from the patient the level of an AKR1C polypeptide or fragment thereof or the level of a polynucleotide encoding an AKR1C polypeptide, wherein the AKR1C polypeptide or the fragment thereof catalyzes the interconversion of 9α,11β-PGF2α from prostaglandin D2, and the AKR1C polypeptide or fragment thereof is encoded by a nucleic acid that hybridizes under stringent conditions to a nucleic acid encoding a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 7, SEQ ID NO: 17, SEQ ID NO: 23, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35; and SEQ ID NO: 36, wherein an increased level of the polypeptide or polynucleotide in the sample compared to a level of the polypeptide or polynucleotide in either a non-diabetic individual or a previous sample from the patient indicates that the patient is diabetic or is predisposed for at least some pathological aspects of diabetes.
- 33. The method of claim 32, wherein the detecting step comprises contacting the sample with an antibody that specifically binds to an AKR1C polypeptide or fragment thereof, wherein the AKR1C polypeptide or fragment thereof is encoded by a nucleic acid that hybridizes under stringent conditions to a nucleic acid encoding a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 7, SEQ ID NO: 17, SEQ ID NO: 23, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35; and SEQ ID NO: 36;
- 34. The method of claim 32, wherein the amino acid sequence comprises SEQ ID NO: 1.
- 35. The method of claim 32, wherein the amino acid sequence comprises SEQ ID NO: 7.
- 36. The method of claim 32, wherein the amino acid sequence comprises SEQ ID NO: 17.
- 37. The method of claim 32, wherein the amino acid sequence comprises SEQ ID NO: 23.
- 38. The method of claim 32, wherein the detecting step comprises quantifying mRNA encoding an AKR1C polypeptide or fragment thereof, wherein the AKR1C polypeptide or the fragment thereof catalyzes the interconversion of 9α,11β-PGF2α from prostaglandin D2, and the AKR1C polypeptide or fragment thereof is encoded by a nucleic acid that hybridizes under stringent conditions to a nucleic acid encoding a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 7, SEQ ID NO: 17, SEQ ID NO: 23, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35; and SEQ ID NO: 36.
- 39. The method of claim 38, wherein the mRNA is reverse transcribed and amplified in a polymerase chain reaction.
- 40. The method of claim 32, wherein the amino acid sequence comprises SEQ ID NO: 1.
- 41. The method of claim 32, wherein the amino acid sequence comprises SEQ ID NO: 7.
- 42. The method of claim 32, wherein the amino acid sequence comprises SEQ ID NO: 17.
- 43. The method of claim 32, wherein the amino acid sequence comprises SEQ ID NO: 23.
- 44. A method of diagnosing Type 2 diabetes or a predisposition for Type 2 diabetes in a patient, the method comprising,
detecting in a biological sample from the patient the level of an AKR1C enymatic substrate or product, wherein a modulated level of the AKR1C enymatic substrate or product in the sample compared to a level of the AKR1C enymatic substrate or product in either a non-diabetic individual or a previous sample from the patient indicates that the patient is diabetic or is predisposed for at least some pathological aspects of diabetes.
- 45. The method of claim 44, wherein the substrate or product is selected from the group consisting of prostaglandin D2 and 9α,11β-prostaglandin F2α.
- 46. The method of claim 44, wherein the detecting step comprises contacting the sample with an antibody that specifically binds to the AKR1C enymatic substrate or product.
- 47. The method of claim 44, wherein the sample is selected from the group consisting of a tissue sample, blood sample, saliva sample, and urine sample.
- 48. The method of claim 44, wherein the biological sample is treated to convert the AKR1C enymatic substrate or product into a derivative of the AKR1C enymatic substrate or product and the level of the derivative is determined.
- 49. A method of diagnosing Type 2 diabetes or a predisposition for Type 2 diabetes in a patient, the method comprising,
detecting AKR1C enzymatic activity in a biological sample from the patient, wherein an increased enzymatic activity in the sample compared to the activity in either a non-diabetic individual or a previous sample from the patient indicates that the patient is diabetic or is predisposed for at least some pathological aspects of diabetes.
- 50. A method of diagnosing Type 2 diabetes or a predisposition for Type 2 diabetes in a patient, the method comprising,
detecting in a biological sample from a patient a polynucleotide that either:
encodes an AKR1C polypeptide or; is genetically linked in the human genome to the polynucleotide encoding an AKR1C polypeptide; wherein the AKR1C polypeptide catalyzes the interconversion of 9α,11β-PGF2α from prostaglandin D2, and the AKR1C polypeptide is encoded by a nucleic acid that hybridizes under stringent conditions to a nucleic acid encoding a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 7, SEQ ID NO: 17, SEQ ID NO: 23, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35; and SEQ ID NO: 36 and wherein the polynucleotide is associated with Type 2 diabetes.
- 51. The method of claim 50, wherein the polynucleotide comprises a single nucleotide polymorphism.
- 52. A method of treating a patient having dyslipidemia, the method comprising administering a therapeutically effective amount of an agent identified by the method comprising,
(i) contacting a solution comprising an AKR1C polypeptide or fragment thereof with the agent, wherein the AKR1C polypeptide or the fragment thereof catalyzes the interconversion of 9α,11β-PGF2α from prostaglandin D2, and the AKR1C polypeptide or fragment thereof is encoded by a nucleic acid that hybridizes under stringent conditions to a nucleic acid encoding a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 7, SEQ ID NO: 17, SEQ ID NO: 23, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35; and SEQ ID NO: 36; and (ii) selecting an agent that modulates the expression or catalytic activity of the AKR1C polypeptide or fragment thereof.
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent Application No. 60/341,451, filed Dec. 17, 2001, which is incorporated in its entirety for any and all purposes.
Provisional Applications (1)
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Number |
Date |
Country |
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60341451 |
Dec 2001 |
US |