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- Title
Insulinotropic Actions of a Long Acting GIP Analog AC163794 In Vivo.
- Authors
Gedulin, Bronislava; Hargrove, Diane; Smith, Pamela; Srivastava, Ved; Ghosh, Soumitra; Young, Andrew; Baron, Alain; Parkes, David
- Abstract
Glucose-dependent insulinotropic peptide (GIP) is an incretin hormone released from intestinal K cells in response to nutrient ingestion. AC 163794 is a novel peptidic GIP analog that has similar binding potency as native GIP at the GIP receptor and is resistant to DPPIV cleavage. This study compares in vivo insulinotropic actions of GIP and AC 163794 during an intravenous glucose tolerance test (IVGTT) in normal rats (Harlan Sprague-Dawley, HSD) and in rat models of diabetes. Fed HSD rats were anesthetized and continuously infused (IV, from t=-30 through t=90 min) with vehicle (saline), GIP or AC163794 (100 pmol/kg/min). At t=0 min, glucose was administered (5.7 mmol/kg, IV bolus). Mean baseline insulin concentration at t=-30 min was 1.0 ng/mL. Prior to the glucose challenge (t=-30 to t = 0 min) plasma insulin significantly increased 3.2- to 3.8-fold in rats infused with GIP or AC163794 (P<0.05) and did not change in saline infused rats. After glucose administration, insulin peaked at 5 min to a maximum of 2.9±0.3 ng/ml in saline infused rats and 12.4±1.8 and 11.4±0.8 ng/ml in rats infused with GIP or AC 163794 respectively (P<0.001 for both groups vs saline controls). In separate studies, the duration of insulinotropic action was tested by administering the peptides as a single subcutaneous (SC) injection (3 µg per rat) at time points up to 4 hours before IV glucose. GIP administered by SC injection at t=-30 min produced no significant change in glucose-stimulated insulin compared to the saline group (peak insulin, saline: 2.8 and GIP: 3.3 ng/mL), while AC163794 injected SC at -30, -60 or -120 min before IV glucose exhibited a significant insulinotropic effect with maximal insulin levels of 10.8, 9.5 and 11.2 ng/mL (P<0.001 for all groups vs control). In summary, the GIP analog AC 163794, under the infusion conditions in this study, demonstrated insulinotropic activity similar to GIP in normal rats and when acutely delivered exhibited a significantly prolonged duration of action.
- Subjects
PEPTIDE hormones; KILLER cells; GLUCOSE tolerance tests; INSULIN; BLOOD sugar; LABORATORY rats
- Publication
Diabetes, 2007, Vol 56, pA380
- ISSN
0012-1797
- Publication type
Article