Document Detail

Evaluation of the antidiabetic activity of DPP IV resistant N-terminally modified versus mid-chain acylated analogues of glucose-dependent insulinotropic polypeptide.
MedLine Citation:
PMID:  16859646     Owner:  NLM     Status:  MEDLINE    
Glucose dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone with therapeutic potential for type 2 diabetes due to its insulin-releasing and antihyperglycaemic actions. However, development of GIP-based therapies is limited by N-terminal degradation by DPP IV resulting in a very short circulating half-life. Numerous GIP analogues have now been generated exhibiting DPP IV resistance and extended bioactivity profiles. In this study, we report a direct comparison of the long-term antidiabetic actions of three such GIP molecules, N-AcGIP, GIP(Lys(37)PAL) and N-AcGIP(Lys(37)PAL) in obese diabetic (ob/ob) mice. An extended duration of action of each GIP analogue was demonstrated prior to examining the effects of once daily injections (25nmolkg(-1) body weight) over a 14-day period. Administration of either N-AcGIP, GIP(Lys(37)PAL) or N-AcGIP(Lys(37)PAL) significantly decreased non-fasting plasma glucose and improved glucose tolerance compared to saline treated controls. All three analogues significantly enhanced glucose and nutrient-induced insulin release, and improved insulin sensitivity. The metabolic and insulin secretory responses to native GIP were also enhanced in 14-day analogue treated mice, revealing no evidence of GIP-receptor desensitization. These effects were accompanied by significantly enhanced pancreatic insulin following N-AcGIP(Lys(37)PAL) and increased islet number and islet size in all three groups. Body weight, food intake and circulating glucagon were unchanged. These data demonstrate the therapeutic potential of once daily injection of enzyme resistant GIP analogues and indicate that N-AcGIP is equally as effective as related palmitate derivatised analogues of GIP.
Nigel Irwin; Gillian C Clarke; Brian D Green; Brett Greer; Patrick Harriott; Victor A Gault; Finbarr P M O'Harte; Peter R Flatt
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-07-20
Journal Detail:
Title:  Biochemical pharmacology     Volume:  72     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2006 Sep 
Date Detail:
Created Date:  2006-08-22     Completed Date:  2006-09-26     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  719-28     Citation Subset:  IM    
School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK.
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MeSH Terms
Diabetes Mellitus, Type 2 / drug therapy*
Disease Models, Animal
Gastric Inhibitory Polypeptide / chemistry,  therapeutic use*
Glucagon-Like Peptide 1
Glucose / metabolism
Hypoglycemic Agents / chemistry,  therapeutic use*
Insulin / metabolism
Mice, Obese
Pancreas / drug effects,  metabolism
Reg. No./Substance:
0/Hypoglycemic Agents; 11061-68-0/Insulin; 50-99-7/Glucose; 59392-49-3/Gastric Inhibitory Polypeptide; 89750-14-1/Glucagon-Like Peptide 1

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