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Combination of the insulin sensitizer, pioglitazone, and the long‐acting GLP‐1 human analog, liraglutide, exerts potent synergistic glucose‐lowering efficacy in severely diabetic ZDF rats
Author(s) -
Larsen P. J.,
Wulff E. M.,
Gotfredsen C. F.,
Brand C. L.,
Sturis J.,
Vrang N.,
Knudsen L. B.,
Lykkegaard K.
Publication year - 2008
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/j.1463-1326.2008.00865.x
Subject(s) - pioglitazone , liraglutide , medicine , endocrinology , diabetes mellitus , type 2 diabetes , insulin , glucagon like peptide 1 , insulin resistance
Objective: Severe insulin resistance and impaired pancreatic β‐cell function are pathophysiological contributors to type 2 diabetes, and ideally, antihyperglycaemic strategies should address both. Research Design and Methods: Therapeutic benefits of combining the long‐acting human glucagon‐like peptide‐1 (GLP‐1) analog, liraglutide (0.4 mg/kg/day), with insulin sensitizer, pioglitazone (10 mg/kg/day), were assessed in severely diabetic Zucker diabetic fatty rats for 42 days. Impact on glycaemic control was assessed by glycated haemoglobin (HbA 1C ) at day 28 and by oral glucose tolerance test at day 42. Results: Liraglutide and pioglitazone synergistically improved glycaemic control as reflected by a marked decrease in HbA 1C (liraglutide + pioglitazone: 4.8 ± 0.3%; liraglutide: 8.8 ± 0.6%; pioglitazone: 7.9 ± 0.4%; vehicle: 9.7 ± 0.3%) and improved oral glucose tolerance at day 42 (area under the curve; liraglutide + pioglitazone: 4244 ± 445 mmol/l × min; liraglutide: 7164 ± 187 mmol/l × min; pioglitazone: 7430 ± 446 mmol/l × min; vehicle: 8093 ± 139 mmol/l × min). A 24‐h plasma glucose profile at day 38 was significantly decreased only in the liraglutide + pioglitazone group. In addition, 24‐h insulin profile was significantly elevated only in the liraglutide + pioglitazone group. Liraglutide significantly decreased food intake alone and in combination with pioglitazone, while pioglitazone alone increased cumulated food intake. As a result, rats on liraglutide alone gained significantly less weight than vehicle‐treated rats, whereas rats on pioglitazone alone gained significantly more body weight than vehicle‐treated rats. However, combination therapy with liraglutide and pioglitazone caused the largest weight gain, probably reflecting marked improvement of energy balance because of reduction of glucosuria. Conclusions: Combination therapy with insulinotropic GLP‐1 agonist liraglutide and insulin sensitizer, pioglitazone, improves glycaemic control above and beyond what would be expected from additive effects of the two antidiabetic agents.