Meal-time insulin analogues of enhanced stability
A method treating a patient includes administering a physiologically effective amount of a fibrillation-resistant insulin analogue or a physiologically acceptable salt thereof to the patient. The fibrillation-resistant insulin analogue or a physiologically acceptable salt thereof, contains an insulin A-chain sequence modified at position A8 and an insulin B-chain sequence or an analogue thereof. The fibrillation-resistant insulin analogue may exhibit thermodynamic stability similar to or exceeding that of wild-type human insulin and displays a susceptibility to fibrillation similar to or exceeding that of wild-type human insulin. An insulin analogue may display greater in vitro insulin receptor binding than normal insulin while displaying binding to IGFR less than twice that of normal insulin and less than that of fast-acting insulin analogs. The fibrillation-resistant insulin may be used to treat a patient by subcutaneous injection or by using an implantable or external insulin pump, due to its fibrillation resistance.
1. A composition comprising a vertebrate insulin analogue or a physiologically acceptable salt thereof, containing a first substitution at position A8, wherein the first substitution is a tryptophan substitution or a methionine substitution, and also containing at least one second substitution that provides a decreased lag time for activity compared to a corresponding wild-type vertebrate insulin, wherein the at least one second substitution comprises an aspartic acid substitution at position B28 or a combination of a lysine substitution at position B28 and a proline substitution at position B29, to provide an insulin analogue having an affinity for insulin analogue at least as high as the corresponding vertebrate wild type insulin.
2. The composition of claim 1 , wherein the first substitution at position A8 is a methionine substitution.
3. The composition of claim 1 , wherein the vertebrate insulin analogue or a physiologically acceptable salt thereof comprises the sequence of SEQ. ID. NO. 7, and Xaa is methionine or tryptophan.
4. The composition of claim 1 , wherein the vertebrate insulin analogue or a physiologically acceptable salt thereof comprises the sequence of SEQ.ID. NO. 10.
5. The composition of claim 1 , wherein the vertebrate insulin analogue or a physiologically acceptable salt thereof comprises the sequence of SEQ ID NO: 7, and Xaa is methionine or tryptophan.
6. The composition of claim 1 , wherein the vertebrate insulin analogue or a physiologically acceptable salt thereof comprises the sequence of SEQ ID NO: 10.
7. The composition of claim 1 , wherein the vertebrate insulin analogue or a physiologically acceptable salt thereof comprises the sequences of SEQ ID NOS: 4 and 10.
8. The composition of claim 1 , wherein the vertebrate insulin analogue or a physiologically acceptable salt thereof comprises the sequences of SEQ ID NOS: 5 and 10.
9. The composition of claim 1 , wherein the vertebrate insulin analogue or a physiologically acceptable salt thereof comprises the sequence of SEQ ID NO: 12.
10. The composition of claim 1 , wherein the vertebrate insulin analogue or a physiologically acceptable salt thereof comprises the sequences of SEQ ID NOS: 4 and 12.
11. The composition of claim 1 , wherein the vertebrate insulin analogue or a physiologically acceptable salt thereof comprises the sequences of SEQ ID NOS: 5 and 12.