Treatment of post-prandial hyperinsulinemia and hypoglycemia after bariatric surgery
The present disclosure relates, in general, to methods of treating or preventing post-prandial hypoglycemia after gastric bypass surgery using a negative modulator antibody that binds to the insulin receptor and modulates the action of insulin at the insulin receptor.
1. A method of treating post-prandial hypoglycemia following bariatric surgery, comprising administering to a subject in need thereof an antibody that is a negative modulator of insulin binding to the insulin receptor and/or insulin action at the insulin receptor in an amount effective to ameliorate post-prandial hypoglycemia, wherein the antibody comprises three heavy chain CDRs set out in SEQ ID NO: 11-13 and three light chain CDRs set out in SEQ ID NO: 26-28.
2. The method of claim 1 , wherein the antibody binds to (i) insulin receptor or (ii) a complex comprising insulin and insulin receptor, or both (i) and (ii), with an equilibrium dissociation constant KD of 10 −5 M or less that is capable of weakening the binding affinity between insulin and insulin receptor by at least about 3-fold.
3. The method of claim l wherein the antibody is capable of weakening the binding affinity between said insulin and insulin receptor by about 3-fold to 500-fold.
4. The method of claim 3 , wherein the antibody increases the EC 50 of insulin signaling activity by about 2-fold to 1000-fold, as measured in a pAKT assay.
5. The method of claim 1 , wherein the variable heavy chain is set out in SEQ ID NO: 1 and the variable light chain is set out in SEQ ID NO: 6.
6. The method of claim 1 , wherein said antibody is a monoclonal antibody.
7. The method of claim 1 , wherein said antibody is a human antibody.
8. The method of claim 1 , wherein the antibody is conjugated to a hydrophobic moiety.
9. The method of claim 1 , wherein the antibody is in a pharmaceutical composition.
10. The method of claim 1 , wherein the antibody reduces hyperinsulinemia or excess insulin signaling.
11. The method of claim 1 , wherein the subject has a blood glucose level of less than 70 mg/dL prior to administration.
12. The method of claim 1 , wherein the antibody is administered at a dose of from 0.1 to 25 mg/kg.
13. The method of claim 1 , wherein the antibody is administered at a dose of from 0.3. to 9.0 mg/kg.
14. The method of claim 1 , wherein the antibody is administered once per week, once every two weeks, or once a month.
15. The method of claim 1 , wherein the half-life of the antibody is approximately 14 to 25 days.
16. The method of claim 1 , wherein the antibody is administered intravenously, intraarterially, intraperitoneally, intramuscularly, intradermally, subcutaneously, orally or by continuous infusion.
17. The method of claim 1 , wherein administration increases post-prandial blood glucose in the subject by 1.5 to 10 fold or by 10 to 40%.
18. The method of claim 1 , wherein administration increases post-prandial blood glucose in the subject by at least 10 mg/dL.
19. The method of claim 1 , wherein the administration induces insulin resistance.
20. The method of claim 19 , wherein insulin resistance is measured by meal tolerance test, insulin tolerance test or fasting HOMA-IR assay.
21. The method of claim 1 , wherein the patient is also on a restricted diet regimen.
22. The method of claim 1 , further comprising administering a second agent.
23. The method of claim 1 , wherein the administration ameliorates one or more symptoms of post-prandial hypoglycemia selected from the group consisting of pancreatic nesidioblastosis, islet cell enlargement, islet cell hyperplasia, α cell budding, tachycardia, diaphoresis, and flushing.
24. The method of claim 1 , wherein the administration takes place during a fasting regimen.