Chemosensory receptor ligand-based therapies
Provided herein are methods of modulating hormone concentrations in a subject comprising the administration of a composition comprising a chemosensory receptor ligand, wherein the composition is adapted to deliver the ligand to one or more regions of the intestine of said subject. Also provided are methods directed to the modulation of circulating concentrations of one or more of GLP-1 (total), GLP-1 (active), GLP-2, oxyntomodulin, PYY (total), PYY 3-36, CCK, GIP, insulin, C-peptide, glycentin, uroguanylin amylin, and ghrelin (total), ghrelin (active) and glucagon.
1. A method of increasing the circulating concentration of one or more of GLP-1 (total), GLP-1 (active), PYY (total), PYY 3-36, GIP, and insulin, by about 2.5% to about 50% compared to placebo-controlled circulating concentrations, in a subject comprising orally delivering an enterically coated composition comprising a sweet receptor agonist, an unami receptor agonist, and a bitter receptor agonist to one or more regions of the intestine of said subject.
2. The method of claim 1 , wherein the circulating concentration of one or more of GLP-1 (total), GLP-1 (active), PYY (total), PYY 3-36, GIP, and insulin, is increased by about 2.5% compared to placebo-controlled circulating concentrations.
3. The method of claim 1 , wherein the circulating concentrations of two or more of GLP-1 (total), GLP-1 (active), PYY (total), PYY 3-36 , GIP, and insulin, are increased by about 2.5% compared to placebo-controlled circulating concentrations.
4. The method of claim 1 , wherein the circulating concentrations of two or more of GLP-1 (total), GLP-1 (active), PYY (total), PYY 3-36 , GIP, and insulin are increased by about 2.5% to about 50% compared to placebo-controlled circulating concentrations.
5. The method of claim 1 , wherein circulating concentrations of GLP-1 (active) and PYY (total) are increased by about 5% compared to placebo-controlled circulating concentrations.
6. The method of claim 1 , wherein circulating concentrations of GLP-1 (active) and PYY (total) are increased by about 10% compared to placebo-controlled circulating concentrations.
7. The method of claim 1 , wherein the circulating concentration of three or more of GLP-1 (total), GLP-1 (active), PYY (total), PYY 3-36 , GIP, and insulin are increased by about 2.5% to about 50% compared to baseline circulating concentration.
8. The method of claim 1 , wherein the circulating concentration of GLP-1 (active) is increased by about 25% compared to baseline circulating concentration.
9. The method of claim 1 , wherein the circulating concentration of PYY (total) is increased by about 25% compared to baseline circulating concentration.
10. The method of claim 1 , wherein the circulating concentrations of GLP-1 (active) and PYY (total) are increased by about 25% compared to baseline circulating concentrations.
11. The method of claim 1 , wherein the circulating hormone concentrations are determined by C max values, AUC last values, AUC (0−∞) values, and/or repeated measures values.
12. A method of decreasing the T max of the circulating concentration of GLP-1active by about 10% to about 200% compared to the placebo-controlled T max of the GLP-1 active concentration in a subject comprising orally delivering a composition comprising a sweet receptor agonist, an unami receptor agonist, and a bitter receptor agonist to one or more regions of the intestine of said subject.
13. The method of claim 1 , wherein the sweet receptor agonist is selected from the group consisting of sucralose, aspartame, Stevioside, Rebaudioside A, Rebaudioside B, Rebaudioside C, Rebaudioside D, Rebaudioside E, Rebaudioside F, Neotame, acesulfame-K and saccharin.
14. The method of claim 1 , wherein one or more regions of the intestine are the duodenum, jejunum, ileum, caecum, colon, and/or rectum.
15. The method of claim 1 , wherein one or more regions of the intestine are the jejunum, ileum caecum, colon, and/or rectum.
16. The method of claim 1 , wherein the composition further releases at least some of the chemosensory receptor ligand in the stomach.
17. The method of claim 1 , wherein the subject has a disorder or condition associated with a chemosensory receptor.
18. The method of claim 17 , wherein the disorder or condition associated with a chemosensory receptor is selected from metabolic syndrome, diabetes type I, diabetes type II, obesity, binge eating, undesired food cravings, food addiction, a desire to reduce food intake or to lose weight or maintain weight loss, desire to maintain healthy weight, desire to maintain normal blood glucose metabolism, anorexia, pre-diabetes, glucose intolerance, gestational diabetes mellitus (GDM), impaired fasting glycemia (IFG), post-prandial hyperglycemia, accelerated gastric emptying, dumping syndrome, delayed gastric emptying, dyslipidemia, post-prandial dyslipidemia, hyperlipidemia, post-prandial hypertriglyceridemia, post hypertriglyceridemia, insulin resistance, bone loss disorders, osteopenia, osteoporosis, muscle wasting disease, muscle degenerative disorders, polycystic ovary syndrome (PCOS), non-alcoholic fatty liver disease (NAFL), non- alcoholic steatohepatitis (NASH), immune disorders of the gut, celiac disease), bowel irregularity, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), ulcerative colitis, Crohn's disease, short bowel syndrome and peripheral neuropathy and diabetic neuropathy.
19. The method of claim 17 , wherein the disorder or condition associated with a chemosensory receptor is selected from sadness, stress, grief, anxiety, anxiety disorder (e.g., generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder or social anxiety disorder or a mood disorder (e.g., depression, bipolar disorder, dysthymic disorder and cyclothymic disorder).
20. The method of claim 1 , further comprising the administration of a second composition used in the treatment of a disorder or condition associated with a chemosensory receptor.
21. The method of claim 19 , wherein the second composition comprises an agent used in the treatment of diabetes or obesity.
22. The method of claim 20 , wherein the second composition comprises a DPP-IV inhibitor.
23. The method of claim 20 , wherein the second composition comprises metformin or metformin hydrochloride.
24. The method of claim 21 wherein the subject has a body mass index (BMI) of less than about 40.
25. The method of claim 21 wherein the subject has a body mass index (BMI) between about 30 and about 35.
26. The method of claim 21 wherein the subject has a body mass index (BMI) between about 27 and about 30.
27. The method of claim 21 wherein the subject has a body mass index (BMI) between about 25 and about 27.
28. The method of claim 1 , wherein the circulating concentration of GLP-1 is over 1.5-fold basal concentration.
29. The method of claim 1 , wherein the circulating concentration of PYY is over 1.5-fold basal concentration.
30. The method of claim 1 , wherein the circulating concentration of GLP-1 is over 3-fold basal concentration.
31. The method of claim 1 , wherein the circulating concentration of PYY is over 3-fold basal concentration.
32. The method of claim 1 , wherein said sweet receptor agonist is Rebaudioside A.
33. The method of claim 12 , wherein said sweet receptor agonist having no caloric value is Rebaudioside A.