title: Liraglutide ameliorates glycometabolism and insulin resistance through the upregulation of GLUT4 in diabetic KKAy mice.
abstract: Liraglutide, a long-lasting glucagon‑like peptide‑1 analogue, has been used for the treatment of patients with type 2 diabetes mellitus since 2009. In this study, we investigated the anti-diabetic effects and mechanisms of action of liraglutide in a spontaneous diabetic animal model, using KK/Upj-Ay/J (KKAy) mice. The KKAy mice were divided into 2 groups, the liraglutide group (mice were treated with 250 µg/kg/day liraglutide) and the model group (treated with an equivalent amount of normal saline). C57BL/6J mice were used as the controls (treated with an equivalent amount of normal saline). The treatment period lasted 6 weeks. During this treatment period, fasting blood glucose (FBG) levels and the body weight of the mice were measured on a weekly basis. Our results revealed that liraglutide significantly decreased FBG levels, the area under the curve following a oral glucose tolerance test and insulin tolerance test, increased serum insulin levels, reduced homeostasis model assessment of insulin resistance and increased the insulin sensitivity index. Furthermore, liraglutide ameliorated glycometabolism dysfunction by increasing glycolysis via hexokinase and glycogenesis via pyruvate kinase activation. An ultrastructural examination of the pancreas revealed that liraglutide improved the damaged state of islet β cells and increased the number of insulin secretory granules. The real-time PCR results revealed that the gene expression of glucose transporter 4 (GLUT4) increased following treatment with liraglutide. Liraglutide also upregulated the protein expression of GLUT4 in liver tissue and skeletal muscle. Our results suggest that liraglutide ameliorates glycometabolism and insulin resistance in diabetic KKAy mice by stimulating insulin secretion, increasing glycogenesis and glycolysis and upregulating the expression of GLUT4.
authors.affiliation: Department of Pharmacology, College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Chen
authors.forename: Juan
authors.initials: J
authors.lastname: Lyu
authors.forename: Xue-Fei
authors.initials: XF
authors.lastname: Yang
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Ji
authors.forename: Bing-Xiang
authors.initials: BX
authors.lastname: Yuan
authors.forename: Ming-Xia
authors.initials: MX
authors.lastname: Chen
authors.forename: Xin
authors.initials: X
authors.lastname: Ma
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4 / Q000235:genetics* / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D000069450:Liraglutide; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; C495693:Slc2a4 protein, mouse; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1