Treatment of steroid-induced hyperglycemia with fibroblast growth factor (FGF) 1 analogs
Methods of using FGF1 analogs, such as FGF1 mutant proteins having an N-terminal deletion, point mutation(s), or combinations thereof, to reduce blood glucose levels in subjects with steroid-induced diabetes, hypercortisolemia, or diabetes due to treatment with an antipsychotic agent, are provided. Such mutant FGF1 proteins can be part of a chimeric protein that includes a β-Klotho-binding protein, an FGFR1-binding protein, a β-Klotho-binding protein and a FGFR1-binding protein, a C-terminal region from FGF19 or FGF21.
1. A composition comprising:
(1) a mutant mature FGF1 protein, comprising:
at least 95% sequence identity to SEQ ID NO: 217; and
amino acid substitutions K12V, H21Y, L44F, N95V, H102Y, F108Y, and C117V, wherein numbering refers to SEQ ID NO: 5, and
(2) a pharmaceutically acceptable carrier.
2. The composition of claim 1 , further comprising
a chemotherapy, a biologic, or combinations thereof; or
an antipsychotic agent.
3. The composition of claim 2 , wherein the composition comprises an antipsychotic agent.
4. The composition of claim 3 , wherein the antipsychotic agent is quetiapine, an olanzapine-fluoxetine combination, a phenothiazine or clozapine.
5. The composition of claim 2 , wherein the composition comprises a biologic.
6. The composition of claim 5 , wherein the biologic is a monoclonal antibody.
7. The composition of claim 1 , further comprising a glucocorticoid.
8. The composition of claim 7 , wherein the glucocorticoid is one or more of dexamethasone, prednisolone, hydrocortisone, cortisone, methylprednisolone, betamethasone, triamcinolone, and beclometasone.
9. The composition of claim 1 , wherein the mutant mature FGF1 protein comprises at least 96% sequence identity to SEQ ID NO: 217 and comprises amino acid substitutions K12V, H21Y, L44F, N95V, H102Y, F108Y, and C117V, wherein numbering refers to SEQ ID NO: 5.
10. The composition of claim 1 , wherein the mutant mature FGF1 protein comprises at least 97% sequence identity to SEQ ID NO: 217 and comprises amino acid substitutions K12V, H21Y, L44F, N95V, H102Y, F108Y, and C117V, wherein numbering refers to SEQ ID NO: 5.
11. The composition of claim 1 , wherein the mutant mature FGF1 protein comprises at least 98% sequence identity to SEQ ID NO: 217 and comprises amino acid substitutions K12V, H21Y, L44F, N95V, H102Y, F108Y, and C117V, wherein numbering refers to SEQ ID NO: 5.
12. The composition of claim 1 , wherein the mutant mature FGF1 protein comprises at least 99% sequence identity to SEQ ID NO: 217 and comprises amino acid substitutions K12V, H21Y, L44F, N95V, H102Y, F108Y, and C117V, wherein numbering refers to SEQ ID NO: 5.
13. The composition of claim 1 , wherein the mutant mature FGF1 protein comprises of SEQ ID NO: 217.
14. The composition of claim 1 , wherein the mutant mature FGF1 protein consists of SEQ ID NO: 217.
15. A composition comprising:
(1) a mutant mature FGF1 protein, comprising:
at least 95% sequence identity to SEQ ID NO: 218; and
amino acid substitutions K12V, H21Y, L44F, N95V, H102Y, F108Y, and C117V, wherein numbering refers to SEQ ID NO: 5, and
(2) a pharmaceutically acceptable carrier.
16. The composition of claim 15 , further comprising
a chemotherapy, a biologic, or combinations thereof; or
an antipsychotic agent.
17. The composition of claim 16 , wherein the composition comprises an antipsychotic agent.
18. The composition of claim 17 , wherein the antipsychotic agent is quetiapine, an olanzapine-fluoxetine combination, a phenothiazine or clozapine.
19. The composition of claim 16 , wherein the composition comprises a biologic.
20. The composition of claim 19 , wherein the biologic is a monoclonal antibody.
21. The composition of claim 15 , further comprising a glucocorticoid.
22. The composition of claim 21 , wherein the glucocorticoid is one or more of dexamethasone, prednisolone, hydrocortisone, cortisone, methylprednisolone, betamethasone, triamcinolone, and beclometasone.
23. The composition of claim 15 , wherein the mutant mature FGF1 protein comprises at least 96% sequence identity to SEQ ID NO: 218 and comprises amino acid substitutions K12V, H21Y, L44F, N95V, H102Y, F108Y, and C117V, wherein numbering refers to SEQ ID NO: 5.
24. The composition of claim 15 , wherein the mutant mature FGF1 protein comprises at least 97% sequence identity to SEQ ID NO: 218 and comprises amino acid substitutions K12V, H21Y, L44F, N95V, H102Y, F108Y, and C117V, wherein numbering refers to SEQ ID NO: 5.
25. The composition of claim 15 , wherein the mutant mature FGF1 protein comprises at least 98% sequence identity to SEQ ID NO: 218 and comprises amino acid substitutions K12V, H21Y, L44F, N95V, H102Y, F108Y, and C117V, wherein numbering refers to SEQ ID NO: 5.
26. The composition of claim 15 , wherein the mutant mature FGF1 protein comprises at least 99% sequence identity to SEQ ID NO: 218 and comprises amino acid substitutions K12V, H21Y, L44F, N95V, H102Y, F108Y, and C117V, wherein numbering refers to SEQ ID NO: 5.
27. The composition of claim 15 , wherein the mutant mature FGF1 protein comprises of SEQ ID NO: 218.
28. The composition of claim 15 , wherein the mutant mature FGF1 protein consists of SEQ ID NO: 218.