Methods of treating diabetes and/or obesity using an enteroendocrine peptide secretion enhancing agent

1. A method for treating obesity or diabetes in an individual comprising non-systemically administering to the colon or the rectum of an individual in need thereof, a therapeutically effective amount of a pharmaceutical composition consisting essentially of an enteroendocrine peptide secretion enhancing agent and at least one excipient formulated for less than 10% w/w systemic absorption, wherein the enteroendocrine peptide secretion enhancing agent is a bile acid, a bile salt, a bile acid mimic, a bile salt mimic, or a combination thereof.

2. The method of claim 1 , wherein the enteroendocrine peptide secretion enhancing agent is administered rectally or orally.

3. The method of claim 1 , wherein the bile acid, the bile salt, the bile acid mimic, the bile salt mimic, or the combination thereof enhances a glucagon-like peptide secretion.

4. The method of claim 3 , wherein the bile acid, the bile salt, the bile acid mimic, the bile salt mimic, or the combination thereof enhances glucagon-like peptide-1 (GLP-1) secretion or glucagon-like peptide-2 (GLP-2) secretion.

5. The method of claim 1 , wherein the bile acid, the bile salt, the bile acid mimic, the bile salt mimic, or the combination thereof enhances a pancreatic polypeptide-fold peptide secretion.

6. The method of claim 5 , wherein the bile acid, the bile salt, the bile acid mimic, the bile salt mimic, or the combination thereof enhances peptide YY (PYY) secretion.

7. The method of claim 1 , further comprising a mucoadhesive agent.

8. The method of claim 7 , wherein the mucoadhesive agent is selected from methyl cellulose, polycarbophil, polyvinylpyrrolidone, sodium carboxymethyl cellulose, and combinations thereof.

9. The method of claim 1 , further comprising a therapeutically effective amount of a dipeptidyl peptidase-4 (DPP-IV) inhibitor.

10. The method of claim 1 , wherein the bile acid or the bile acid mimic is a compound represented by formula (I):

wherein:

each R 1 is independently H, OH, lower alkyl, or lower heteroalkyl;

L is a substituted or =substituted alkyl or substituted or =substituted heteroalkyl;

each R 2 is independently H, OH, lower alkyl, or lower heteroalkyl;

R 3 is H, OH, O-lower alkyl, lower alkyl, or lower heteroalkyl;

A is COOR 4 , S(O) n R 4 , or OR 5 ;

R 4 is H, an anion, a pharmaceutically acceptable cation, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino acid;

n is 1-3;

R 5 is lower alkyl or H.

11. The method of claim 1 , wherein the bile acid mimic is a TGR5-binding analog selected from the group consisting of 6-methyl-2-oxo-4-thiophen-2-yl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid benzyl ester and oleanolic acid.

12. The method of claim 1 , wherein the bile acid, the bile salt, the bile acid mimic, the bile salt mimic, or the combination thereof is formulated as a suppository, an enema solution, a rectal foam, a rectal gel, or an enterically coated oral dosage form.

13. The method of claim 1 , wherein the bile acid is a cholic acid, a deoxycholic acid, a glycocholic acid, a glycodeoxycholic acid, a taurocholic acid, a taurodihydrofusidate, a taurodeoxycholic acid, a cholate, a glycocholate, a deoxycholate, a taurocholate, a taurodeoxycholate, a chenodeoxycholic acid, or a salt thereof, or a combination thereof.

14. The method of claim 1 , wherein the bile acid, the bile salt, the bile acid mimic, the bile salt mimic, or the combination thereof enhances oxyntomodulin secretion.

15. A method of reducing circulating glucose levels in an individual comprising non-systemically administering to the colon or the rectum of an individual in need thereof, a therapeutically effective amount of a pharmaceutical composition consisting essentially of an enteroendocrine peptide secretion enhancing agent and at least one excipient formulated for less than 10% w/w systemic absorption, wherein the enteroendocrine peptide secretion enhancing agent is a bile acid, a bile salt, a bile acid mimic, a bile salt mimic, or a combination thereof.

16. A method of increasing insulin levels in an individual comprising non-systemically administering to the colon or the rectum of an individual in need thereof, a therapeutically effective amount of a pharmaceutical composition consisting essentially of an enteroendocrine peptide secretion enhancing agent and at least one excipient formulated for less than 10% w/w systemic absorption, wherein the enteroendocrine peptide secretion enhancing agent is a bile acid, a bile salt, a bile acid mimic, a bile salt mimic, or a combination thereof.

17. A method of reducing food intake in an individual comprising non-systemically administering to the colon or the rectum of an individual in need thereof, a therapeutically effective amount of a pharmaceutical composition consisting essentially of an enteroendocrine peptide secretion enhancing agent and at least one excipient formulated for less than 10% w/w systemic absorption, wherein the enteroendocrine peptide secretion enhancing agent is a bile acid, a bile salt, a bile acid mimic, a bile salt mimic, or a combination thereof.