Insulins with polar recombinant extensions

1. An oligomer extended insulin or insulin analogue, wherein said insulin or insulin analogue is a two-chain insulin molecule comprising an A- and a B-chain, and is extended at the N-terminal end of the B-chain, and/or from the C-terminal end of the A-chain, with an extension consisting only of amino acid residues selected from the group consisting of His (H), Gln (Q), Ala (A), Asp (D), Glu (E), Gly (G), Pro (P), Ser (S) and Thr (T); wherein the extension comprises from about 100 to about 800 contiguous amino acids and wherein

I) a first subset of amino acid residues in the extension are selected from the group consisting of His (H) and Gln (Q); and

II) a second subset of amino acid residues in the extension are selected from the group consisting of Ala (A), Asp (D), Glu (E), Gly (G), Pro (P), Ser (S) and Thr (T);

wherein the number of amino acid residues in the second subset is equal to or greater than the number of amino acid residues in the first subset,

wherein the number of amino acid residues in the second subset is no more than three times the number of amino acid residues in the first subset,

and wherein said insulin or insulin analogue is extended with motifs A, B, C, D and/or any combination of A, B, C and D:

A) contiguous amino acid residues comprising amino acid residues selected from the group of [A, G, and H or Q]; or from the group of [E, G, and H or Q]; or from the group of [G, P, and H or Q]; (Group A); or

B) contiguous amino acid residues comprising amino acid residues selected from the group of [A, G, P, and H or Q]; or from the group of [E, G, P, and H or Q]; or from the group of [G, K, P, and H or Q]; or from the group of [E, G, H, and Q]; (Group B); or

C) contiguous amino acid residues comprising amino acid residues selected from the group of [A, G, P, H, and Q]; from the group of [E, G, P, H, and Q]; (Group C); or

D) contiguous amino acid residues comprising amino acid residues selected from the group of [A, E, G, P, H, and Q]; or from the group of [E, G, K, P, H, and Q]; (Group D);

wherein the motif, or combination of motifs, may be repeated as needed in order to obtain an extension of the desired length and size.

2. A pharmaceutical composition comprising a therapeutically effective amount of an oligomer extended insulin or insulin analogue according to claim 1 , or a pharmaceutically acceptable salt thereof, together with one of more adjuvants, excipients, carriers and/or diluents.

3. A method of treatment or alleviation of a metabolic disease or disorder or condition of a human, comprising the step of administering to such a human in need thereof, a therapeutically effective amount of the oligomer extended insulin or insulin analogue according to claim 1 , wherein said disease, disorder or condition is selected from the group consisting of diabetes, impaired glucose tolerance, hyperglycemia, dyslipidemia, obesity, metabolic syndrome X, and insulin resistance syndrome.

4. The method according to claim 3 , wherein said disease, disorder or condition is Type 1 diabetes or Type 2 diabetes.

5. An oligomer extended insulin or insulin analogue wherein said insulin or insulin analogue is a two-chain insulin molecule comprising an A- and a B-chain, and is extended at the N-terminal end of the B-chain, and/or from the C-terminal end of the A-chain, with an extension consisting only of amino acid residues selected from the group consisting of His (H), Gln (Q), Ala (A), Asp (D), Glu (E), Gly (G), Pro (P), Ser (S) and Thr (T); wherein the extension comprises from about 100 to about 800 contiguous amino acids and wherein

I) a first subset of amino acid residues in the extension are selected from the group consisting of His (H) and Gln (Q); and

II) a second subset of amino acid residues in the extension are selected from the group consisting of Ala (A), Asp (D), Glu (E), Gly (G), Pro (P), Ser (S) and Thr (T);

wherein the number of amino acid residues in the second subset is equal to or greater than the number of amino acid residues in the first subset,

wherein the number of amino acid residues in the second subset is no more than three times the number of amino acid residues in the first subset,

and wherein the insulin or insulin analogue is extended with

a motif of Group A selected from [GAQ]; [GEH]; [GEQ]; [GQA]; [GQE]; and [GQP]; and/or any combination hereof; and/or

a motif of Group B selected from [GAPH]; [GAPQ]; [GAQP]; [GEHP]; [GEPH]; [GEPQ]; [GEQH]; [GEQP]; [GHEP]; [GHEQ]; [GHPE]; [GHQE]; [GPAQ]; [GPEH]; [GPEQ]; [GPHE]; [GPQA]; [GPQE]; [GQAP]; [GQEH]; [GQEP]; [GQHE]; [GQPA]; and[GQPE]; and/or any combination hereof; and/or

a motif of Group C selected from [GHEPGQHP]; [GQEPGQHP]; [GQAPGQAPGQAPGAPH]; and [GQAPGQAPGAPHGAPH]; and/or any combination hereof; and/or

a motif of Group D selected from [GEHPGAPHGQEPGQAP]; [GQEPGQEPGQEPGAPH]; [GQEPGQEPGAPHGAPH]; and [A,E,G,P,H,Q]; and/or any combination hereof.

6. An oligomer extended insulin or insulin analogue, wherein said insulin or insulin analogue is a two-chain insulin molecule comprising an A- and a B-chain, and is extended at the N-terminal end of the B-chain, and/or from the C-terminal end of the A-chain, which is a compound of the general Formula I

Ins-Ext (I)

wherein:

“Ins” represents an analogue of human insulin selected from the group consisting of

A14E,A21G*,B25H,desB30;

A21G*,desB30;

A21G,B1F*,desB30;

A21G,A22A,A23P,A24Q*,desB30;

A21G,A22A,A23Q,A24P*,desB30;

A21G,A22P,A23A,A24Q*,desB30;

A21G,A22P,A23Q,A24A*,desB30;

A21G,A22Q,A23A,A24P*,desB30;

A21G,A22Q,A23P,A24A*,desB30;

A21G,A22Q,A23P*,desB30; and

A21Q*,desB30; and

“Ext” indicates an extension composed of a motif selected from the group consisting of

[GAQ]; [GEH]; [GEQ]; [GQA]; [GQE]; [GQP]; [GAPH]; [GAPQ]; [GAQP]; [GEHP]; [GEPH]; [GEPQ]; [GEQH]; [GEQP]; [GHEP]; [GHEQ]; [GHPE]; [GHQE]; [GPAQ]; [GPEH]; [GPEQ]; [GPHE]; [GPQA]; [GPQE]; [GQAP]; [GQEH]; [GQEP]; [GQHE]; [GQPA]; [GQPE]; [GHEPGQHP]; [GQEPGQHP]; [GQAPGQAPGQAPGAPH]; [GQAPGQAPGAPHGAPH]; [GEHPGAPHGQEPGQAP]; [GQEPGQEPGQEPGAPH]; [GQEPGQEPGAPHGAPH]; and [A,E,G,P,H,Q] (in random);

repeated or extended to render an oligomer extended insulin or insulin analogue with an extension comprising of from about 100 to about 800 contiguous amino acid residues.

7. An oligomer extended insulin or insulin analogue selected from the group consisting of

A21Q(GQEP) 50 , desB30 human insulin;

A21Q(GAPQ) 50 , desB30 human insulin;

A21Q(GQAP) 50 , desB30 human insulin;

A21Q(GEPH) 50 , desB30 human insulin;

A21Q(GEHP) 50 , desB30 human insulin;

A14E, A21G(GQEP) 50 , B25H, desB30 human insulin;

A14E, A21G(GAPQ) 50 , B25H, desB30 human insulin;

A14E, A21G(GEPH) 50 , B25H, desB30 human insulin;

A14E, A21G(GEHP) 50 , B25H, desB30 human insulin;

A14E, A21G(GAPH) 50 , B25H, desB30 human insulin;

A21G(GEHPGAPHGQEPGQAP) 13 , desB30 human insulin;

A21G(GEH) 67 , desB30 human insulin;

A21G(GQA) 67 , desB30 human insulin;

A21G(GQE) 67 , desB30 human insulin;

A21G(GEQH) 50 , desB30 human insulin;

A21G(GQEPGQEPGQEPGAPH) 12 GQEPGQEP, desB30 human insulin;

A21G(GQEPGQEPGAPHGAPH) 12 GQEPGQEP, desB30 human insulin;

A21G(GQAPGQAPGQAPGAPH) 12 GQAPGQAP, desB30 human insulin;

A21G(GQAPGQAPGAPHGAPH) 12 GQAPGQAP, desB30 human insulin;

A21G[A,E,G,H,P,Q] (random 200 amino acids), desB30 human insulin;

A21G(GHEPGQHP) 25 , desB30 human insulin;

A21G(GQEPGQHP) 25 , desB30 human insulin;

A21G(GQPE) 50 , desB30 human insulin;

A21G(GEQP) 50 , desB30 human insulin;

A21G(GEPQ) 50 , desB30 human insulin;

A21G(GPEQ) 50 , desB30 human insulin;

A21G(GPQE) 50 , desB30 human insulin;

A21G(GQPA) 50 , desB30 human insulin;

A21G(GAQP) 50 , desB30 human insulin;

A21G(GPAQ) 50 , desB30 human insulin;

A21G(GPQA) 50 , desB30 human insulin;

A21G(GHEP) 50 , desB30 human insulin;

A21G(GHPE) 50 , desB30 human insulin;

A21G(GPEH) 50 , desB30 human insulin;

A21G(GPHE) 50 , desB30 human insulin;

A21G(GQEH) 50 , desB30 human insulin;

A21G(GQHE) 50 , desB30 human insulin;

A21G(GHEQ) 50 , desB30 human insulin;

A21G(GHQE) 50 , desB30 human insulin;

A21G(GEQ) 67 , desB30 human insulin;

A21G(GAQ) 67 , desB30 human insulin;

A21G(GQAP) 62 , desB30 human insulin;

A21G(GQAP) 75 , desB30 human insulin;

A21G(GQAP) 100 , desB30 human insulin;

A21G(GQAP) 50 , desB30 human insulin;

A21G(GQAP) 125 , desB30 human insulin;

A21G(GQAP) 150 , desB30 human insulin;

A14E, A21G(GQAP) 50 , B25H, desB30 human insulin;

A14E, A21G(GQAP) 75 , B25H, desB30 human insulin;

A14E, A21G(GQAP) 150 , B25H, desB30 human insulin;

A21G, B1F(GQAP) 50 , desB30 human insulin;

A21G, B1F(GQAP) 100 , desB30 human insulin;

A21G, A22A, A23P, A24Q(GAPQ) 49 , desB30 human insulin;

A21G, A22A, A23Q, A24P(GAQP) 49 , desB30 human insulin;

A21G, A22Q, A23A, A24P(GQAP) 49 , desB30 human insulin;

A21G, A22Q, A23P, A24A(GQPA) 49 , desB30 human insulin;

A21G, A22P, A23A, A24Q(GPAQ) 49 , desB30 human insulin;

A21G, A22P, A23Q, A24A(GPQA) 49 , desB30 human insulin;

A21G(GQAP) 56 , desB30 human insulin;

A21G(GQAP) 69 , desB30 human insulin;

A21G(GQAP) 31 , desB30 human insulin;

A21G(GQAP) 37 , desB30 human insulin;

A21G(GQAP) 44 , desB30 human insulin;

A21G, A22Q, A23P(GQP) 66 , desB30 human insulin;

A21G, A22A, A23Q, A24P(GAQP) 37 , desB30 human insulin; and

A21G, A22A, A23Q, A24P(GAQP) 62 , desB30 human insulin.