Dipeptidyl peptidase IV-resistant [D-Ala(2)]glucose-dependent insulinotropic polypeptide (GIP) improves glucose tolerance in normal and obese diabetic rats.
The therapeutic potential of glucose-dependent insulinotropic polypeptide (GIP) for improving glycemic control has largely gone unstudied. A series of synthetic GIP peptides modified at the NH(2)-terminus were screened in vitro for resistance to dipeptidyl peptidase IV (DP IV) degradation and potency to stimulate cyclic AMP and affinity for the transfected rat GIP receptor. In vitro experiments indicated that [D-Ala(2)]GIP possessed the greatest resistance to enzymatic degradation, combined with minimal effects on efficacy at the receptor. Thus, [D-Ala(2)]GIP(1--42) was selected for further testing in the perfused rat pancreas and bioassay in conscious Wistar and Zucker rats. When injected subcutaneously in normal Wistar, Fa/?, or fa/fa Vancouver Diabetic Fatty (VDF) Zucker rats, both GIP and [D-Ala(2)]GIP significantly reduced glycemic excursions during a concurrent oral glucose tolerance test via stimulation of insulin release. The latter peptide displayed greater in vivo effectiveness, likely because of resistance to enzymatic degradation. Hence, despite reduced bioactivity in diabetic models at physiological concentrations, GIP and analogs with improved plasma stability still improve glucose tolerance when given in supraphysiological doses, and thus may prove useful in the treatment of diabetic states.
Hinke
Simon A
SA
Department of Physiology, University of British Columbia, Vancouver, Canada.
Gelling
Richard W
RW
Pederson
Raymond A
RA
Manhart
Susanne
S
Nian
Cuilan
C
Demuth
Hans-Ulrich
HU
McIntosh
Christopher H S
CH
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism*; D000242:Cyclic AMP / Q000096:biosynthesis; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004789:Enzyme Activation; D005749:Gastric Inhibitory Polypeptide / Q000097:blood / Q000737:chemistry / Q000627:therapeutic use*; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood; D007700:Kinetics; D008297:Male; D009765:Obesity; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
D001786:Blood Glucose; D007328:Insulin; D011964:Receptors, Gastrointestinal Hormone; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor; D000242:Cyclic AMP; D018819:Dipeptidyl Peptidase 4; D000262:Adenylyl Cyclases