Abstract
Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone with a potentially therapeutic role in type 2 diabetes. Rapid degradation by dipeptidylpeptidase IV has prompted the development of enzyme-resistant N-terminally modified analogs, but renal clearance still limits in vivo bioactivity. In this study, we report long-term antidiabetic effects of a novel, N-terminally protected, fatty acid-derivatized analog of GIP, N-AcGIP(LysPAL37), in obese diabetic (ob/ob) mice. Once-daily injections of N-AcGIP(LysPAL37) over a 14-day period significantly decreased plasma glucose, glycated hemoglobin, and improved glucose tolerance compared with ob/ob mice treated with saline or native GIP. Plasma insulin and pancreatic insulin content were significantly increased by N-AcGIP(LysPAL37). This was accompanied by a significant enhancement in the insulin response to glucose together with a notable improvement of insulin sensitivity. No evidence was found for GIP receptor desensitization and the metabolic effects of N-AcGIP(LysPAL37) were independent of any change in feeding or body weight. Similar daily injections of native GIP did not affect any of the parameters measured. These data demonstrate the ability of once-daily injections of N-terminally modified, fatty acid-derivatized analogs of GIP, such as N-AcGIP(LysPAL37), to improve diabetes control and to offer a new class of agents for the treatment of type 2 diabetes.
Footnotes
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This work was supported by University of Ulster Research Strategy Funding and by a Project Grant from Diabetes UK.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.086082.
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ABBREVIATIONS: GIP, glucose-dependent insulinotropic polypeptide; DPP IV, dipeptidylpeptidase IV; GLP-1, glucagon-like peptide-1; AUC, area under the curve.
- Received March 10, 2005.
- Accepted May 25, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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