Comparative effects of GLP-1 and GIP on cAMP production, insulin secretion, and in vivo antidiabetic actions following substitution of Ala8/Ala2 with 2-aminobutyric acid.
The two major incretin hormones, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP), are currently being considered as prospective drug candidates for treatment of type 2 diabetes. Interest in these gut hormones was initially spurred by their potent insulinotropic activities, but a number of other antihyperglycaemic actions are now established. One of the foremost barriers in progressing GLP-1 and GIP to the clinic concerns their rapid degradation and inactivation by the ubiquitous enzyme, dipeptidyl peptidase IV (DPP IV). Here, we compare the DPP IV resistance and biological properties of Abu8/Abu2 (2-aminobutyric acid) substituted analogues of GLP-1 and GIP engineered to impart DPP IV resistance. Whereas (Abu8)GLP-1 was completely stable to human plasma (half-life >12 h), GLP-1, GIP, and (Abu2)GIP were rapidly degraded (half-lives: 6.2, 6.0, and 7.1 h, respectively). Native GIP, GLP-1, and particularly (Abu8)GLP-1 elicited significant adenylate cyclase and insulinotropic activity, while (Abu2)GIP was less effective. Similarly, in obese diabetic (ob/ob) mice, GIP, GLP-1, and (Abu8)GLP-1 displayed substantial glucose-lowering and insulin-releasing activities, whereas (Abu2)GIP was only weakly active. These studies illustrate divergent effects of penultimate amino acid Ala8/Ala2 substitution with Abu on the biological properties of GLP-1 and GIP, suggesting that (Abu8)GLP-1 represents a potential candidate for future therapeutic development.
Green
B D
BD
School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK. b.green@ulster.ac.uk
Gault
V A
VA
Flatt
P R
PR
Harriott
P
P
Greer
B
B
O'Harte
F P M
FP
D000262:Adenylyl Cyclases / Q000378:metabolism; D000409:Alanine / Q000737:chemistry; D000613:Aminobutyrates / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D000242:Cyclic AMP / Q000378:metabolism; D003920:Diabetes Mellitus / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005749:Gastric Inhibitory Polypeptide / Q000737:chemistry / Q000494:pharmacology*; D005934:Glucagon / Q000737:chemistry / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D008956:Models, Chemical; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry; D011498:Protein Precursors / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D021241:Spectrometry, Mass, Electrospray Ionization; D013997:Time Factors
D000613:Aminobutyrates; D007328:Insulin; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D005749:Gastric Inhibitory Polypeptide; C012223:alpha-aminobutyric acid; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; D018819:Dipeptidyl Peptidase 4; D000262:Adenylyl Cyclases; D005947:Glucose; D000409:Alanine