CLAIMS
1. An insulin derivative, wherein said insulin derivative comprises B5Y or B5F and a substituent comprising an acyl group, or a pharmaceutically acceptable salt, amide or ester thereof.
2. The insulin derivative according to claim 1, wherein said insulin derivative further comprises B26G or B26A.
3. The insulin derivative according to any one of claims 1 or 2, wherein said substituent comprising an acyl group is attached to B28K, B26K or B29K.
4. The insulin derivative according to any one of claims 1-3, wherein said substituent has the following formula (I):
Acy-L1-L2-L3 wherein:
• Acy is an acyl group and is represented by lithocholic acid or comprises at least one
functional group of formulae:
Chem. 1:-CO-(CH2)x-COOH; or
Chem. 2: -CO-(CH2)x-tetrazolyl; wherein x represents an integer in the range of from 12 to 20; and the tetrazolyl group is 1H-tetrazol-5-yl. or is a fatty acid of formula:
Chem. 3: -CO-(CH2)x-CH3 wherein x represents an integer in the range from 8 to 16,
• L1 is absent and represents a covalent bond or represents OEG, gGlu, DgGlu or sulfonimide C-4
• L2 is absent and represents a covalent bond or represents OEG, gGlu, DgGlu or sulfonimide C-4
• L3 is absent and represents a covalent bond or represents OEG, gGlu, DgGlu or sulfonimide C-4
wherein gGlu represents a gamma glutamic acid residue and OEG represents [2-(2-aminoethoxy)ethoxy]acetyl.
5. The insulin derivative according to any one of the preceding claims, wherein said insulin derivative further comprises A14E and/or desB30 and/or desB29-30 and/or desB27-30.
6. The insulin derivative according to any of the previous claims, wherein said substitutions are selected from the group consisting of:
i. A14E, B5Y, B26A, B28K, desB29-30 (SEQ ID NO: 3 and 4) ii. A14E, B5Y, B26G, B28K, desB29-30 (SEQ ID NO: 3 and 5)

iii. B5Y, B26A, B28K, desB29-30 (SEQ ID NO: 1 and 7)
iv. B5Y, B26G, B28K, desB29-30 (SEQ ID NO: 1 and 8)
v. B5Y, B28K, desB29-30 (SEQ ID NO: 1 and 9)
vi. A14E, B5F, B26G, B28K, desB29-30 (SEQ ID NO: 3 and 10)
vii. B5F, B28K, desB29-30 (SEQ ID NO: 1 and 11)
viii. B5Y, B26K, desB27-desB30 (SEQ ID 1 and 12)
ix. B5Y, desB30(SEQID 1 and 13)
x. B5Y, B26G, desB30 (SEQ ID 1 and 14)
xi. B5Y, B26A, desB30 (SEQ ID 1 and 15)
xii. B5F, B26A, B28K, desB29-30 (SEQ ID 1 and 6)
xiii. B5Y, B26A, B28K, desB29-30 (SEQ ID NO: 1 and 4)
xiv. B5Y, B26G, B28K, desB29-30 (SEQ ID NO: 1 and 5)
xv. B5F, B26G, B28K, desB29-30 (SEQ ID NO: 1 and 10)
xvi. A14E, B5F, B26A, B28K, desB29-30 (SEQ ID 3 and 6)
xvii. A14E, B5Y, B26A, B28K, desB29-30 (SEQ ID NO: 3 and 7)
xviii. A14E, B5Y, B26G, B28K, desB29-30 (SEQ ID NO: 3 and 8)
xix. A14E, B5Y, B28K, desB29-30 (SEQ ID NO: 3 and 9)
xx. A14E, B5F, B28K, desB29-30 (SEQ ID NO: 3 and 11)
xxi. A14E, B5Y, B26K, desB27-desB30 (SEQ ID 3 and 12)
xxii. A14E, B5Y, desB30 (SEQ ID 3 and 13)
xxiii. A14E, B5Y, B26G, desB30 (SEQ ID 3 and 14)
xxiv. A14E, B5Y, B26A, desB30 (SEQ ID 3 and 15)
7. The insulin derivative according to claim 6, wherein Acy is selected from the group consisting of: lithocholic acid, 1,16-hexadecanedioicacid, 1,18-octadecanedioic acid, 1,20-eicosanedioic acid, tetrazole-C16, tetrazole-C17, tetrazole C18 and tetradecanoic acid.
8. The insulin derivative according to claim 6, wherein -L1-L2-L3 represents a divalent linking group selected from DgGlu, gGlu, gGlu-gGlu, gGlu-OEG, gGlu-OEG-OEG, OEG, sulfonimide-C4, and sulfonimide-C4-sulfonimide-C4.
9. The insulin derivative according to any of the previous claims, wherein said insulin derivative is compound of Example 15: N{Epsilon-B28}-[2-[2-[2-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]-[GluA14,TyrB5,GlyB26,LysB28],des-(B29-B30)-lnsulin

10. An intermediate product comprising a backbone selected from the group consisting of:
i. A14E, B5Y, B26A, B28K, desB29-30 (SEQ ID NO: 3 and 4)
ii. A14E, B5Y, B26G, B28K, desB29-30 (SEQ ID NO: 3 and 5)
iii. B5Y, B26A, B28K, desB29-30 (SEQ ID NO: 1 and 7)
iv. B5Y, B26G, B28K, desB29-30 (SEQ ID NO: 1 and 8)
v. B5Y, B28K, desB29-30 (SEQ ID NO: 1 and 9)
vi. A14E, B5F, B26G, B28K, desB29-30 (SEQ ID NO: 3 and 10)
vii. B5F, B28K, desB29-30 (SEQ ID NO: 1 and 11)
viii. B5Y, B26K, desB27-desB30 (SEQ ID 1 and 12)
ix. B5Y, desB30(SEQID 1 and 13)
x. B5Y, B26G, desB30 (SEQ ID 1 and 14)
xi. B5Y, B26A, desB30 (SEQ ID 1 and 15)
xii. B5F, B26A, B28K, desB29-30 (SEQ ID 1 and 6)
xiii. B5Y, B26A, B28K, desB29-30 (SEQ ID NO: 1 and 4)
xiv. B5Y, B26G, B28K, desB29-30 (SEQ ID NO: 1 and 5)
xv. B5F, B26G, B28K, desB29-30 (SEQ ID NO: 1 and 10)
xvi. A14E, B5F, B26A, B28K, desB29-30 (SEQ ID 3 and 6)
xvii. A14E, B5Y, B26A, B28K, desB29-30 (SEQ ID NO: 3 and 7)
xviii. A14E, B5Y, B26G, B28K, desB29-30 (SEQ ID NO: 3 and 8)
xix. A14E, B5Y, B28K, desB29-30 (SEQ ID NO: 3 and 9)
xx. A14E, B5F, B28K, desB29-30 (SEQ ID NO: 3 and 11)
xxi. A14E, B5Y, B26K, desB27-desB30 (SEQ ID 3 and 12)

xxii. A14E, B5Y, desB30 (SEQ ID 3 and 13) xxiii. A14E, B5Y, B26G, desB30 (SEQ ID 3 and 14) xxiv. A14E, B5Y, B26A, desB30 (SEQ ID 3 and 15) or a pharmaceutically acceptable salt, amide or ester thereof.
11. An insulin derivative according to any one of claims 1-9, for use as a medicament.
12. An insulin derivative according to any one of claims 1-9, for use in the prevention or treatment of diabetes, cardiovascular disease, atherosclerosis, and/or endothelial dysfunction and/or for preventing or reducing liver triglyceride content and/or for preventing or reducing body weight gain.
13. Use of an insulin derivative according to any one of claims 1-9, for the manufacture of a medicament for the treatment or prevention of diabetes, diabetes of Type 1, diabetes of Type 2, impaired glucose tolerance, hyperglycemia, dyslipidemia, obesity, metabolic syndrome (metabolic syndrome X, insulin resistance syndrome), hypertension, cognitive disorders, atherosclerosis, myocardial infarction, stroke, cardiovascular disorders, coronary heart disease, stroke, inflammatory bowel syndrome, dyspepsia, hypotension or gastric ulcers.
14. A method for the treatment or prevention of diabetes, diabetes of Type 1, diabetes of Type 2, impaired glucose tolerance, hyperglycemia, dyslipidemia, obesity, metabolic syndrome (metabolic syndrome X, insulin resistance syndrome), hypertension, cognitive disorders, atherosclerosis, myocardial infarction, stroke, cardiovascular disorders, coronary heart disease, stroke, inflammatory bowel syndrome, dyspepsia, hypotension or gastric ulcers, which method comprises administration to a subject in need thereof a therapeutically effective amount of an insulin derivative according to any one of claims 1-9 or an insulin analogue of claim 10.
15. A method for determining selectivity of an insulin compound comprising the following steps:

• measuring the maximal AKT phosphorylation induced by said insulin compound relative to human insulin
• measuring the maximal ERK activation induced by said insulin compound relative to human insulin,
wherein the ERK/AKT ratio is less than 1.