Methods of using compositions comprising variants and fusions of FGF19 polypeptides for reducing glucose levels in a subject

1. A method of reducing glucose levels in a subject, comprising administering to the subject an effective amount of a peptide, wherein the peptide comprises:

a) an N-terminal region comprising at least seven amino acid residues, the N-terminal region having a first amino acid position and a last amino acid position, wherein the N-terminal region comprises DSSPL (SEQ ID NO:121), DASPH (SEQ ID NO:122), or DAGPH (amino acids 7 to 11 of SEQ ID NO:99 [FGF19]); and

b) a C-terminal region comprising a first amino acid position and a last amino acid position, wherein the C-terminal region comprises

(i) a first C-terminal region sequence comprising WGDPIRQRHLYTSG (SEQ ID NO:169 with a L7Q substitution), wherein the W residue corresponds to the first amino acid position of the C-terminal region; and

(ii) a second C-terminal region sequence comprising

(SEQ ID NO: 188)

PHGLSSCFLRIRADGVVDCARGQSAHSLLEIKAVALRTVAIK

GVHSVRYLCMGADGKMQGLLQYSEEDCAFEEEIRPDGYNV

YRSEKHRLPVSLSSAKQRQLYKNRGFLPLSHFLPMLPMVPEE

PEDLRGHLESDMFSSPLETDSMDPFGLVTGLEAVRSPSFEK;

 wherein the second C-terminal region sequence comprises a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74 to 78 of SEQ ID NO:188);

 and wherein the peptide

(i) binds to fibroblast growth factor receptor 4 (FGFR4) with an affinity equal to or greater than FGF19 binding affinity for FGFR4;

(ii) activates FGFR4 to an extent or amount equal to or greater than FGF19 activates FGFR4;

(iii) has at least one of reduced hepatocellular carcinoma (HCC) formation; greater glucose lowering activity, less lipid increasing activity, less triglyceride activity, less cholesterol activity, less non-HDL activity or less HDL increasing activity, as compared to FGF19, or as compared to an FGF19 variant sequence having any of GQV, GDI, WGPI (SEQ ID NO:171), WGDPV (SEQ ID NO:172), WGDI (SEQ ID NO:173), GDPI (SEQ ID NO:174), GPI, WGQPI (SEQ ID NO:175), WGAPI (SEQ ID NO:176), AGDPI (SEQ ID NO:177), WADPI (SEQ ID NO:178), WGDAI (SEQ ID NO:179), WGDPA (SEQ ID NO:180), WDPI (SEQ ID NO:181), WGDI(SEQ ID NO:182), WGDP (SEQ ID NO:183) or FGDPI (SEQ ID NO:184) substituted for the FGF19 WGDPI (SEQ ID NO:170) sequence at amino acids 16-20; and/or

(iv) has less lean mass reducing activity as compared to FGF21.

2. The method of claim 1 , wherein the second C-terminal region sequence comprises a EILPD (amino acids 103-107 of SEQ ID NO:193) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

3. The method of claim 1 , wherein the second C-terminal region sequence comprises a EIRED (amino acids 103-107 of SEQ ID NO:194) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

4. The method of claim 1 , wherein the second C-terminal region sequence comprises a), EILCD (amino acids 103-107 of SEQ ID NO:195) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

5. The method of claim 1 , wherein the second C-terminal region sequence comprises a EILED (amino acids 103-107 of SEQ ID NO:196) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

6. The method of claim 1 , wherein the second C-terminal region sequence comprises a LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

7. The method of claim 1 , wherein the second C-terminal region sequence comprises from 2 to 5 amino acid substitutions, deletions or insertions.

8. The method of claim 1 , wherein the peptide is less than about 250 amino acids in length.

9. The method of claim 1 , wherein the N-terminal region comprises amino acid residues VHYG (SEQ ID NO:101), DASPHVHYG (SEQ ID NO:102), or DSSPLVHYG (SEQ ID NO:103).

10. The method of claim 9 , wherein the G corresponds to the last position of the N-terminal region.

11. The method of claim 10 , wherein the N-terminal region further comprises:

RHPIP (SEQ ID NO:106), wherein R is the first amino acid position of the N-terminal region;

HPIP (SEQ ID NO:107), wherein H is the first amino acid position of the N-terminal region;

RPLAF (SEQ ID NO:108), wherein R is the first amino acid position of the N-terminal region;

PLAF (SEQ ID NO:109), wherein P is the first amino acid position of the N-terminal region; or

R, wherein R is the first amino acid position of the N-terminal region.

12. The method of claim 1 , wherein the N-terminal region comprises amino acid residues DSSPLLQ (SEQ ID NO:104), and wherein the Q residue is the last amino acid position of the N-terminal region.

13. The method of claim 12 , wherein the N-terminal region further comprises:

RHPIP (SEQ ID NO:106), wherein R is the first amino acid position of the N-terminal region;

HPIP (SEQ ID NO:107), wherein H is the first amino acid position of the N-terminal region;

RPLAF (SEQ ID NO:108), wherein R is the first amino acid position of the N-terminal region;

PLAF (SEQ ID NO:109), wherein P is the first amino acid position of the N-terminal region; or

R, wherein R is the first amino acid position of the N-terminal region.

14. The method of claim 1 , wherein the N-terminal region comprises amino acid residues DSSPLLQFGGQV (SEQ ID NO:105), and wherein the V residue corresponds to the last position of the N-terminal region.

15. The method of claim 1 , wherein the N-terminal region comprises amino acid residues

DAGPHVH (amino acids 7-13 of SEQ ID NO:16), wherein the last H residue corresponds to the last amino acid position of the N-terminal region;

DAGPHVG (amino acids 7-13 of SEQ ID NO:17), wherein the last G residue corresponds to the last amino acid position of the N-terminal region;

DAGPHYG (amino acids 7-13 of SEQ ID NO:18), wherein the last G residue corresponds to the last amino acid position of the N-terminal region;

DAGPHVHG (amino acids 7-14 of SEQ ID NO:22), wherein the last G residue corresponds to the last amino acid position of the N-terminal region;

DAGPHHG (amino acids 7-13 of SEQ ID NO:23),wherein the last G residue corresponds to the last amino acid position of the N-terminal region;

DAGPHHY (amino acids 7-13 of SEQ ID NO:24), wherein the Y residue corresponds to the last amino acid position of the N-terminal region;

DAGPHVY (amino acids 7-13 of SEQ ID NO:25), wherein the Y residue corresponds to the last amino acid position of the N-terminal region;

DAGPHV (amino acids 7-12 of SEQ ID NO:28), wherein the V residue corresponds to the last amino acid position of the N-terminal region;

DAGPHVHY (amino acids 7-14 of SEQ ID NO:29), wherein the Y residue corresponds to the last amino acid position of the N-terminal region;

DAGPHVHYA (amino acids 7-15 of SEQ ID NO:4), wherein the last A residue corresponds to the last amino acid position of the N-terminal region;

DAGPHLQ (amino acids 7-13 of SEQ ID NO:66), wherein the Q residue corresponds to the last amino acid position of the N-terminal region; or

DAGPHVHYG (amino acids 7-15 of SEQ ID NO:196), wherein the last G residue corresponds to the last amino acid position of the N-terminal region.

16. The method of claim 15 , wherein the N-terminal region further comprises:

RHPIP (SEQ ID NO:106), wherein R is the first amino acid position of the N-terminal region;

HPIP (SEQ ID NO:107), wherein H is the first amino acid position of the N-terminal region;

RPLAF (SEQ ID NO:108), wherein R is the first amino acid position of the N-terminal region;

PLAF (SEQ ID NO:109), wherein P is the first amino acid position of the N-terminal region; or

R, wherein R is the first amino acid position of the N-terminal region.

17. The method of claim 1 , wherein amino acid residues HPIP (SEQ ID NO:107) are the first 4 amino acid residues of the N-terminal region.

18. The method of claim 1 , wherein

the first position of the N-terminal region is a R or M residue;

the first and second positions of the N-terminal region is a MR, RM, RD, DS, MD or MS sequence;

the first through third positions of the N-terminal region is a MDS, RDS, MSD, MSS, or DSS sequence;

the first through fourth positions of the N-terminal region is a RDSS (SEQ ID NO:115) or MDSS (SEQ ID NO:116) sequence;

the first through fifth positions of the N-terminal region is an MRDSS (SEQ ID NO:117) sequence;

the first through sixth positions of the N-terminal region is an MDSSPL (SEQ ID NO:119) sequence; or

the first through seventh positions of the N-terminal region is an MSDSSPL (SEQ ID NO:120) sequence.

19. The method of claim 1 , wherein the N-terminal region has an amino acid sequence comprising or consisting of any of:

RPLAFSDASPHVHYG (M1) (amino acids 1-15 of SEQ ID NO:1);

PLAFSDASPHVHYG (M1-R) (amino acids 2-15 of SEQ ID NO:1);

RPLAFSDSSPLVHYG (M2) (amino acids 1-15 of SEQ ID NO:2);

PLAFSDSSPLVHYG (M2-R) (amino acids 2-15 of SEQ ID NO:2);

RHPIPDSSPLLQ (M8) (amino acids 1-12 of SEQ ID NO:8);

RHPIPDSSPLLQFG (M9) (amino acids 1-12 of SEQ ID NO:9);

RPLAFSDSSPLVH (M26) (amino acids 1-13 of SEQ ID NO:26);

PLAFSDSSPLVH (M26-R) (amino acids 2-13 of SEQ ID NO:26);

HPIPDSSPLLQ (M47) (amino acids 1-11 of SEQ ID NO:47);

RDSSPLLQ (M52) (amino acids 1-8 of SEQ ID NO:52);

DSSPLLQ (M52-R) (amino acids 2-8 of SEQ ID NO:52);

MDSSPLVHYG (M53) (amino acids 1-10 of SEQ ID NO:53);

RDSSPLVHYG (M69) (amino acids 1-10 of SEQ ID NO:69);

DSSPLVHYG (M69-R) (amino acids 2-10 of SEQ ID NO:69);

MRDSSPLVHYG (M70) (amino acids 1-11 of SEQ ID NO:70);

DSSPLVHYG (M9-R) (amino acids 1-9 of SEQ ID NO:141);

HPIPDSSPLLQFG (amino acids 1-13 of SEQ ID NO:163);

RPLAFSDAGPHVH (M16) (amino acids 1-13 of SEQ ID NO:16);

PLAFSDAGPHVH (M16-R) (amino acids 2-13 of SEQ ID NO:16);

RPLAFSDAGPHVG (M17) (amino acids 1-13 of SEQ ID NO:17);

PLAFSDAGPHVG (M17-R) (amino acids 2-13 of SEQ ID NO:17);

RPLAFSDAGPHYG (M18) (amino acids 1-13 of SEQ ID NO:18);

PLAFSDAGPHYG (M18-R) (amino acids 2-13 of SEQ ID NO:18);

RPLAFSDAGPHVHG (M22) (amino acids 1-14 of SEQ ID NO:22);

PLAFSDAGPHVHG (M22-R) (amino acids 2-14 of SEQ ID NO:22);

RPLAFSDAGPHHG (M23) (amino acids 1-13 of SEQ ID NO:23);

PLAFSDAGPHHG (M23-R) (amino acids 2-13 of SEQ ID NO:23);

RPLAFSDAGPHHY (M24) (amino acids 1-13 of SEQ ID NO:24);

PLAFSDAGPHHY (M24-R) (amino acids 2-13 of SEQ ID NO:24);

RPLAFSDAGPHVY (M25) (amino acids 1-13 of SEQ ID NO:25);

PLAFSDAGPHVY (M25-R) (amino acids 2-13 of SEQ ID NO:25);

RPLAFSDAGPHV (M28) (amino acids 1-12 of SEQ ID NO:28);

PLAFSDAGPHV (M28-R) (amino acids 2-12 of SEQ ID NO:28);

RPLAFSDAGPHVHY (M29) (amino acids 1-14 of SEQ ID NO:29);

PLAFSDAGPHVHY (M29-R) (amino acids 2-14 of SEQ ID NO:29);

RPLAFSDAGPHVHYA (M4) (amino acids 1-15 of SEQ ID NO:4);

PLAFSDAGPHVHYA (M4-R) (amino acids 2-15 of SEQ ID NO:4);

RPLAFSDAGPHLQ (M66) (amino acids 1-13 of SEQ ID NO:66);

PLAFSDAGPHLQ (M66-R) (amino acids 2-13 of SEQ ID NO:66);

RPLAFSDAGPHVHYG (M160) (amino acids 1-15 of SEQ ID NO:196); or

PLAFSDAGPHVHYG (M160-R) (amino acids 2-15 of SEQ ID NO:196).

20. The method of claim 1 , wherein the N-terminal region first amino acid position is a methionine (M), arginine (R), serine (S), histidine (H), proline (P), leucine (L) or aspartic acid (D) residue.

21. The method of claim 1 , wherein the N-terminal region does not have a methionine (M) or arginine (R) residue at the first amino acid position of the N-terminal region.

22. The method of claim 1 , wherein the N-terminal region comprises any one of the following amino acid sequences: MDSSPL (SEQ ID NO:119), MSDSSPL (SEQ ID NO:120), or SDSSPL (SEQ ID NO:112).

23. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of:

i. SEQ ID NO:1 (M1) with a L22Q substitution and a EILPD (amino acids 103-107of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188);

ii. SEQ ID NO:2 (M2) with a L22Q substitution and a EILPD (amino acids 103-107of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188);

iii. SEQ ID NO:8 (M8) with a L19Q substitution and a EILPD (amino acids 103-107of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188);

iv. SEQ ID NO:9 (M9) with a L21Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188);

v. SEQ ID NO:26 (M26) with a L20Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188);

vi. SEQ ID NO:47 (M47) with a L18Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188);

vii. SEQ ID NO:52 (M52) with a L15Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188);

viii. SEQ ID NO:192 (M53) with a L15Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188);

ix. SEQ ID NO:69 (M69) with a L17Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188);

x. SEQ ID NO:70 (M70) with a L18Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188);

xi. SEQ ID NO:141 with a L16Q substitution a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188);

xii. SEQ ID NO:163 with a L20Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188);

xiii. SEQ ID NO:4 (M4) with a L22Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188);

xiv. SEQ ID NO:16 (M16) with a L20Q substitution a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188);

xv. SEQ ID NO:17 (M17) with a L20Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188);

xvi. SEQ ID NO:18 (M18) with a L20Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188);

xvii. SEQ ID NO:22 (M22) with a L21Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188);

xviii. SEQ ID NO:23 (M23) with a L20Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188);

xix. SEQ ID NO:24 (M24) with a L20Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188);

xx. SEQ ID NO:25 (M25) with a L20Q substitution a EILPD (amino acids 103-107of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188);

xxi. SEQ ID NO:28 (M28) with a L19Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188);

xxii. SEQ ID NO:29 (M29) with a L21Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188);

xxiii. SEQ ID NO:66 (M66) with a L20Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188);

xxiv. SEQ ID NO:193 (M139) with a L22Q substitution;

xxv. SEQ ID NO:194 (M140) with a L22Q substitution;

xxvi. SEQ ID NO:195 (M141) with a L22Q substitution; or

xxvii. SEQ ID NO:196 (M160).

24. The method of claim 23 , wherein the arginine (R) residue at the first amino acid position of the N-terminal region of the sequence of claim 23 (i)-(v), (vii), (ix), and (xiii)-(xxvii) is deleted.

25. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:1 (M1) with a L22Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

26. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:2 (M2) with a L22Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

27. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:8 (M8) with a L19Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

28. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:9 (M9) with a L21Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

29. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:26 (M26) with a L20Q substitution a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

30. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:47 (M47) with a L18Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

31. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:52 (M52) with a L15Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

32. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:192 (M53) with a L15Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

33. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:69 (M69) with a L17Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

34. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:70 (M70) with a L18Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

35. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:141 with a L16Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

36. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:163 (M9-R) with a L20Q substitution and EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

37. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:4 (M4) with a L22Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

38. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:16 (M16) with a L20Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

39. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:17 (M17) with a L20Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

40. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:18 (M18) with a L20Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

41. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:22 (M22) with a L21Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

42. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:23 (M23) with a L20Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

43. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:24 (M24) with a L20Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

44. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:25 (M25) with a L20Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

45. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:28 (M28) with a L19Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

46. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:29 (M29) with a L21Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

47. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:66 (M66) with a L20Q substitution and a EILPD (amino acids 103-107 of SEQ ID NO:193), EIRED (amino acids 103-107 of SEQ ID NO:194), EILCD (amino acids 103-107 of SEQ ID NO:195), EILED (amino acids 103-107 of SEQ ID NO:196), or LLLED (amino acids 98-102 of SEQ ID NO:100) sequence substituted for the EIRPD sequence (amino acids 74-78 of SEQ ID NO:188).

48. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:193 (M139) with a L22Q substitution.

49. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:194 (M140) with a L22Q substitution.

50. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:195 (M141) with a L22Q substitution.

51. The method of claim 1 , wherein the peptide has an amino acid sequence comprising or consisting of SEQ ID NO:196 (M160).

52. The method of claim 1 , wherein the peptide has at least one of reduced HCC formation; greater glucose lowering activity, or less lipid increasing activity as compared to FGF19, or as compared to an FGF19 variant having any of GQV, GDI, WGPI (SEQ ID NO:171), WGDPV (SEQ ID NO:172), WGDI (SEQ ID NO:173), GDPI (SEQ ID NO:174), GPI, WGQPI (SEQ ID NO:175), WGAPI (SEQ ID NO:176), AGDPI (SEQ ID NO:177), WADPI (SEQ ID NO:178), WGDAI (SEQ ID NO:179), WGDPA (SEQ ID NO:180), WDPI (SEQ ID NO:181), WGDI (SEQ ID NO:182), WGDP (SEQ ID NO:183) or FGDPI (SEQ ID NO:184) substituted for the WGDPI (SEQ ID NO:170) sequence at amino acids 16-20 of FGF19 (SEQ ID NO:99).

53. The method of claim 52 , wherein the HCC formation, glucose lowering activity, or lipid increasing activity is ascertained in a db/db mouse.

54. The method of claim 1 , wherein the peptide has less lean mass reducing activity as compared to the lean mass reducing activity of FGF21.

55. The method of claim 54 , wherein the lean mass reducing activity is ascertained in a db/db mouse.

56. The method of claim 1 , wherein the peptide is formulated as a pharmaceutical composition, wherein the pharmaceutical formulation further comprises a pharmaceutically acceptable carrier.

57. The method of claim 1 , wherein the method further comprises administering or performing a supplemental therapy.

58. The method of claim 57 , wherein said supplemental therapy is a weight loss surgery, gastric bypass, gastrectomy, gastric banding, gastric balloon, or gastric sleeve.

59. The method of claim 58 , wherein said supplemental therapy is a glucose lowering agent, insulin, GLP1 analogue, biguanide, sulphonylurea, thiazolidinedione, a dipeptidyl peptidase-4 (DPP-4) inhibitor, a bromocriptine formulation, a bile acid sequestrant, metformin, a thiazolidinedione (TZD), a SGLT-2 inhibitor, or any combination thereof.

60. The method of claim 59 , wherein said biguanide or sulphonylurea is selected from the group consisting of tolbutamide, chlorpropamide, acetohexamide, tolazamide, glibenclamide, glipizide or any combination thereof.

61. The method of claim 59 , wherein said thiazolidinedione is rosiglitazone or pioglitazone, or combination thereof.

62. The method of claim 59 , wherein said bile acid sequestrant is colesevelam.

63. The method of claim 59 , wherein said insulin is bolus insulin, basal insulin, or an analogue thereof.

64. The method of claim 59 , wherein said metformin is metformin hydrochloride.

65. The method of claim 57 , wherein said supplemental therapy is administered or performed prior to said method.

66. The method of claim 57 , wherein said supplemental therapy is administered or performed contemporaneously with said method.

67. The method of claim 57 , wherein said supplemental therapy is administered or performed following said method.

68. The method of claim 1 , wherein the glucose levels are blood glucose levels.

69. The method of claim 1 , wherein the subject has a metabolic disorder.

70. The method of claim 1 , wherein the subject has an insulin resistance disorder.

71. The method of claim 1 , wherein the subject has hyperinsulinemia.

72. The method of claim 1 , wherein the subject has glucose intolerance.

73. The method of claim 1 , wherein the subject has a hyperglycemic disorder or is at risk of developing a hyperglycemic disorder.

74. The method of claim 1 , wherein the subject has diabetes.

75. The method of claim 1 , wherein the subject has insulin-dependent (type I) diabetes.

76. The method of claim 1 , wherein the subject has type II diabetes.

77. The method of claim 1 , wherein the subject has gestational diabetes.

78. The method of claim 1 , wherein the subject is obese.

79. The method of claim 1 , wherein the subject has nonalcoholic fatty liver disease (NAFLD).

80. The method of claim 1 , wherein the subject has nonalcoholic steatohepatitis (NASH).

81. The method of claim 1 , wherein the subject has a fasting plasma glucose (FPG) level of greater than 100 mg/dl.

82. The method of claim 1 , wherein the subject has an FPG of 126 mg/dl or above.

83. The method of claim 1 , wherein the subject has an FPG of between about 100 and 126 mg/dl.

84. The method of claim 1 , wherein the glucose levels are reduced by at least 5%.

85. The method of claim 1 , wherein the subject has a hemoglobin A1c (HbA1c) level above 6%.