Liraglutide Enhances Autophagy and Promotes Pancreatic β Cell Proliferation to Ameliorate Type 2 Diabetes in High-Fat-Fed and Streptozotocin-Treated Mice

Abstract

BackgroundClinical and experimental studies have revealed that liraglutide has multiple anti-diabetes biological effects. However, little is known about its role in autophagy and pancreatic β cell proliferation. This study aimed to assessed the effects of liraglutide on pancreatic β cell proliferation and autophagy in a mouse model of type 2 diabetes.Material/MethodsThe effect of liraglutide on autophagy and proliferation in pancreatic β cells was investigated using a high-fat-fed and streptozotocin-induced mouse model of type 2 diabetes.ResultsLiraglutide significantly improved the symptoms of high-fat-fed (HFD) and streptozotocin (STZ)-induced type 2 diabetic mice, as indicated by body weight gain, reduction of blood glucose and plasma insulin, and enhanced sensitivity to insulin. The results of quantitative real-time polymerase chain reaction and Western blot analysis showed that liraglutide upregulated AGT5 expression and promoted the conversion of LC3-I to LC3-II, thus improving the defective autophagy. In addition, we observed that both mRNA and protein expressions of PCNA and Ki-67 were upregulated by liraglutide treatment. Immunocytochemical staining results showed that the number of PCNA- or Ki-67-positive cells in pancreatic islet tissues in the HFD + STZ + liraglutide group were increased compared with the HFD + STZ group.ConclusionsThese results strongly suggest that liraglutide is able to enhance autophagy and promote pancreatic β cell proliferation. This study improves our insights into the mechanism by which liraglutide treatment relieves diabetes, and provides experimental evidence for clinical utilization of liraglutide in type 2 diabetes treatment.

Liraglutide protects palmitate-induced INS-1 cell injury by enhancing autophagy mediated via FoxO1

“…Liraglutide, a GLP-1 analog, serves a pivotal role in pancreatic β-cell proliferation, anti-apoptotic function and autophagy ( 1 , 3 , 4 , 21 ). Liraglutide protects islet β-cells from FFA and affects glucolipid metabolism by activating autophagy ( 3 ).…”

“…Therefore, the regulation of pancreatic β-cells mass and its function serve a critical role in the pathogenesis of T2DM. Currently, there are a limited number of drugs, such as liraglutide and metformin, approved for the prevention of islet β-cells from injury (1,(3)(4)(5).…”

“…Liraglutide prevents high glucose or free fatty acids (FFA)-induced INS-1 cell apoptosis by targeting autophagy ( 1 , 3 ). Fan et al ( 4 ) reported that liraglutide can enhance autophagy and promote islet β-cells proliferation in a high-fat-fed and streptozotocin-induced mouse model of T2DM. Moreover, liraglutide markedly improves islet β-cells function under lipid stress and blocks the inhibitory effect of palmitate (PA) on FoxO1 ( 21 ).…”

Glucagon-Like Peptide-1 Receptor Agonist Attenuates Autophagy to Ameliorate Pulmonary Arterial Hypertension through Drp1/NOX- and Atg-5/Atg-7/Beclin-1/LC3β Pathways

“…The autophagy protein ATG5 plays an essential role in the formation of the autophagosome via promoting the lipidation of microtubule-associated protein LC3, which is involved in the expansion and completion of the autophagosome [45]. In an animal study, the expression of Atg-5 and conversion of LC3-II to LC3-I were significantly enhanced by liraglutide, indicating that liraglutide enhanced autophagy in a high-fat diet and streptomycin-induced type 2 diabetic mice [46].…”

Role of FoxO1 in regulating autophagy in type 2 diabetes mellitus (Review)

“…Inhibition of the excessive apoptosis of islet β-cells is essential for the treatment of diabetes (3). Increasing evidence suggest that islet β-cell apoptosis, cell viability and insulin secretion play essential roles in the pathogenesis of T2DM (2)(3)(4)(5)(6). In addition, insulin resistance plays a key role in T2DM and is associated with metabolic syndrome (7).…”