Abstract
Exploitation of glucose-dependent insulinotropic polypeptide (GIP) is hindered by its short biological half-life and rapid renal clearance. To circumvent these problems, two novel acylated N-terminally modified GIP analogues, N-pGluGIP(LysPAL(16)) and N-pGluGIP(LysPAL(37)), were evaluated. In contrast to native GIP, both analogues were completely resistant to dipeptidyl peptidase IV degradation. In GIP-receptor transfected fibroblasts, N-pGluGIP(LysPAL(16)) and N-pGluGIP(LysPAL(37)) exhibited enhanced stimulation of cAMP production. Insulinotropic responses in clonal beta-cells were similar to native GIP. When administered together with glucose to ob/ob mice, the glycemic excursions were significantly less for both analogues and insulin responses were greater than native GIP. Extended insulinotropic and antihyperglycemic actions were also evident. These data indicate that palmitate-derivitized analogues of N-terminal pyroglutamyl GIP represent a novel class of stable, long-acting, and effective GIP analogues for potential type 2 diabetes therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blood Glucose / drug effects
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Cell Line
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Cricetinae
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Cricetulus
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Cyclic AMP / biosynthesis
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Diabetes Mellitus, Type 2 / metabolism
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Diabetes Mellitus, Type 2 / physiopathology
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Dipeptidyl Peptidase 4 / chemistry
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Dose-Response Relationship, Drug
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Gastric Inhibitory Polypeptide / analogs & derivatives*
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Gastric Inhibitory Polypeptide / chemical synthesis*
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Gastric Inhibitory Polypeptide / chemistry*
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Gastric Inhibitory Polypeptide / pharmacology
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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / chemistry
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Hypoglycemic Agents / pharmacology
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Insulin / metabolism*
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Insulin Secretion
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Mice
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Mice, Obese
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Palmitates / chemistry*
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Pyrrolidonecarboxylic Acid / chemistry*
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Structure-Activity Relationship
Substances
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Blood Glucose
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Hypoglycemic Agents
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Insulin
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Palmitates
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glucose-dependent insulinotropic polypeptide, N-pyroglutamyl-epsilon-palmitoyllysyl(16)-
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glucose-dependent insulinotropic polypeptide, N-pyroglutamyl-epsilon-palmitoyllysyl(37)-
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Gastric Inhibitory Polypeptide
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Cyclic AMP
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Dipeptidyl Peptidase 4
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Pyrrolidonecarboxylic Acid