Metabolic effects of orally administered small-molecule agonists of GPR55 and GPR119 in multiple low-dose streptozotocin-induced diabetic and incretin-receptor-knockout mice.
Abnormal cannabidiol (Abn-CBD) and AS-1269574 are potent selective agonists for GPR55 and GPR119, respectively. The present study evaluated the actions and ability of these small-molecule agonists to counteract experimental diabetes in mice.



Diabetes was induced in NIH Swiss mice by five consecutive daily intraperitoneal injections of 40 mg/(kg body weight) streptozotocin. Diabetic mice received daily oral administration of Abn-CBD or AS-1269574 (0.1 μmol/kg) or saline vehicle (0.9% wt/vol. NaCl) over 28 days. Body weight, food intake, fluid intake, plasma glucose, insulin, glucose tolerance, insulin release, lipid profile and pancreatic morphology were examined. Mechanism of action of agonists was assessed in acute studies using incretin-receptor-knockout mice.



Abn-CBD and AS-1269574 decreased plasma glucose (20-26%, p < 0.05) and increased circulating insulin (47-48%, p < 0.05) by 10-28 days, compared with saline-treated diabetic controls. Food intake and polydipsia were reduced by both agonists (21-23%, p < 0.05 and 33-35%, p < 0.01, respectively). After 28 days of treatment, plasma glucagon concentrations were reduced (p < 0.01) and glucose tolerance was enhanced by 19-44% by Abn-CBD (p < 0.05 or p < 0.001) and AS-1269574 (p < 0.05 to p < 0.001). Plasma insulin responses were improved (p < 0.01) and insulin resistance was decreased (p < 0.05 or p < 0.01) in both Abn-CBD- and AS-1269574-treated groups. Triacylglycerols were decreased by 19% with Abn-CBD (p < 0.05) and 32% with AS-1269574 (p < 0.01) while total cholesterol was reduced by 17% (p < 0.01) and 15% (p < 0.05), respectively. Both agonists enhanced beta cell proliferation (p < 0.001) although islet area was unchanged. Acute studies in Gipr- and Glp1r-knockout mice revealed an important role for the glucagon-like peptide 1 (GLP-1) receptor in the actions of both agonists, with the glucose-lowering effects of Abn-CBD also partly mediated through the glucose-dependent insulinotropic peptide (GIP) receptor.



These data highlight the potential for fatty acid G-protein-coupled receptor-based therapies as novel insulinotropic and glucose-lowering agents acting partly through the activation of incretin receptors.
School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, UK. am.mckillop@ulster.ac.uk.
Aine M
AM
McKillop
School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, UK.
Brian M
BM
Moran
School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, UK.
Yasser H A
YH
Abdel-Wahab
School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, UK.
Noella M
NM
Gormley
School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, UK.
Peter R
PR
Flatt
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004435:Eating / Q000187:drug effects / Q000235:genetics; D004983:Ethanolamines / Q000627:therapeutic use; D054795:Incretins / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D012118:Resorcinols / Q000627:therapeutic use; D013311:Streptozocin / Q000494:pharmacology*
C552740:2-(2-(4-bromophenyl)-6-methylpyrimidin-4-yl)aminoethanol; C479832:4-(3-3,4-p-menthadien-(1,8)-yl)olivetol; D004983:Ethanolamines; C519854:GPR119 protein, human; C524885:GPR55 protein, human; D054795:Incretins; D010446:Peptide Fragments; D011743:Pyrimidines; D043882:Receptors, Cannabinoid; D043562:Receptors, G-Protein-Coupled; D012118:Resorcinols; C083773:exendin (9-39); D013311:Streptozocin
Beta cell regeneration; Diabetes; Fatty acid agonists; G-protein-coupled receptors; Glucose homeostasis; Insulin secretion; Multiple low-dose streptozotocin
Acta Diabetol. 2016 Apr;53(2):279-93
26112416
Transpl Int. 2011 Nov;24(11):1124-34
21902730
J Biol Chem. 2009 Oct 23;284(43):29817-27
19723626
Diabetes. 2012 Feb;61(2):281-91
22179809
Biol Chem. 2014 Apr;395(4):453-64
24323890
Br J Pharmacol. 2013 Nov;170(5):978-90
23992544
J Pharmacol Exp Ther. 2011 Apr;337(1):50-8
21228065
Expert Opin Ther Targets. 2007 May;11(5):661-71
17465724
Physiol Rev. 2015 Apr;95(2):513-48
25834231
J Endocrinol. 2013 Sep 06;219(1):59-68
23911987
PLoS One. 2013;8(1):e53345
23382843
Curr Med Chem. 2013;20(31):3855-71
23862620
Diabetes Care. 2011 May;34 Suppl 2:S258-63
21525465
PLoS One. 2013 May 21;8(5):e63861
23704946
Pharmacol Ther. 2015 Jan;145:35-42
24972076
Endocrinology. 2011 Feb;152(2):374-83
21068156
Mol Endocrinol. 2013 Aug;27(8):1267-82
23798572
Prostaglandins Other Lipid Mediat. 2009 Sep;89(3-4):105-11
19615459
Pain. 2008 Sep 30;139(1):225-36
18502582
Bone. 2013 Oct;56(2):337-42
23851294
Neurogastroenterol Motil. 2011 Sep;23 (9):862-e342
21726355
Diabetologia. 2000 Aug;43(8):1020-30
10990080
Endocrinology. 2008 May;149(5):2038-47
18202141
Biochem Biophys Res Commun. 2010 Sep 24;400(3):437-41
20804735
Acta Diabetol. 2016 Apr;53(2):177-88
26739335
Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16511-6
19805329
J Endocrinol. 2011 Nov;211(2):177-85
21885477
Cell Metab. 2006 Mar;3(3):153-65
16517403
Mol Endocrinol. 2016 Jun;30(6):614-29
27082897
Biochem Biophys Res Commun. 2010 Oct 1;400(4):745-51
20816753
Int J Obes (Lond). 2016 Mar;40(3):417-24
26447738
Ther Adv Endocrinol Metab. 2010 Aug;1(4):165-75
23148161
Diabetes. 2009 May;58(5):1058-66
19208912
Diabetologia. 1981 May;20(5):573-7
7026332
Br J Pharmacol. 2010 Aug;160(7):1577-9
20649561