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DPP‐4 Resistant Glucagon‐Like Peptide‐1 Analog LY548806: A Novel Agent for Control of Acute Hyperglycemia
Author(s) -
Saha Joy K,
Xia Jinqi,
Millican Rohn,
Grondin Janet M,
Glaesner Wolfgang,
Jakubowski Joseph A
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a435-a
Subject(s) - medicine , endocrinology , insulin , glucagon , hypoglycemia , hormone , ed50 , endogeny , agonist , chemistry , receptor
The present studies identified a novel DPP‐4 resistant GLP‐1 analogue LY548806 and characterized its pharmacological activity in a rat model of acute hyperglycemia. LY548806 was more than 20‐fold less susceptible to DPP‐4 cleavage and exhibited a 50‐fold greater physical stability over native GLP‐1, and was a full agonist with an EC 50 of 10.6 ± 1.6 pM in vitro . In an acute hyperglycemia model, continuous infusion of LY548806 (0.1–10 μg/kg/hr) or insulin (0.01 U–0.1U/kg/hr) via the right jugular vein resulted in dose‐dependent reduction of glucose levels with estimated ED 50 values of 0.32 ± 0.11 ug and 0.08 ± 0.00 U respectively. In contrast to insulin, LY548806 did not produce hypoglycemia at higher dose levels. Continuous infusion of LY548806 (10 μg/kg/hr) or insulin (0.1 U/kg/hr) did not affect the plasma levels of the endogenous glucoregulatory hormones corticosterone, growth hormone, catecholamines, or insulin, indicating an insulin‐independent effect of LY548806 in this model. LY548806 significantly lowered the plasma levels of free fatty acids (FFA) and glucagon, whereas insulin only reduced FFA levels. In conclusion, we have identified a stable GLP‐1 analogue with improved solubility which effectively ameliorates acute hyperglycemia without the risk of hypoglycemia and may represent a novel therapeutic strategy for acute critical illness associated with acute hyperglycemia.