Liraglutide improves cognitive impairment via the AMPK and PI3K/Akt signaling pathways in type 2 diabetic rats

Yang,Ying; Fang,Hui; Xu,Gang; Zhen,Yanfeng; Zhang,Yazhong; Tian,Jinli; Zhang,Dandan; Zhang,Guyue; Xu,Jing

doi:10.3892/mmr.2018.9180

Liraglutide improves cognitive impairment via the AMPK and PI3K/Akt signaling pathways in type 2 diabetic rats

Authors:
- Ying Yang
- Hui Fang
- Gang Xu
- Yanfeng Zhen
- Yazhong Zhang
- Jinli Tian
- Dandan Zhang
- Guyue Zhang
- Jing Xu
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Affiliations: Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China, Department of Burns and Orthopedics, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China, Second Department of Endocrinology, Tangshan Gongren Hospital, Tangshan, Hebei 063000, P.R. China
Published online on: June 18, 2018 https://doi.org/10.3892/mmr.2018.9180
Pages: 2449-2457

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Abstract

Liraglutide is a type of glucagon‑like‑peptide 1 receptor agonist, which has been reported as a novel type of antidiabetic agent with numerous benefits, including cardiovascular and neuroprotective effects. To the best of our knowledge, few studies to date have reported the potential mechanism underlying the neuroprotective effects of liraglutide on rats with type 2 diabetes mellitus (T2DM). The present study aimed to investigate the neuroprotective actions of liraglutide in diabetic rats and to determine the mechanisms underlying these effects. A total of 30 male T2DM Goto‑Kakizaki (GK) rats (age, 32 weeks; weight, 300‑350 g) and 10 male Wistar rats (age, 32 weeks; weight, 300‑350 g) were used in the present study. Wistar rats received vehicle treatment, and GK rats randomly received treatment with vehicle, low dose of liraglutide (75 µg/kg) or high dose of liraglutide (200 µg/kg) for 28 days. Cognitive deficits were evaluated using the Morris water maze test. The expression levels of phosphoinositide 3‑kinase (PI3K), protein kinase B (Akt), phosphorylated (p)‑Akt, AMP‑activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), Beclin‑1, microtubule‑associated protein light chain 3 (LC)‑3 II, caspase‑3, B‑cell lymphoma 2 (Bcl‑2)‑associated X protein and Bcl‑2 were assessed by western blot analysis. The results demonstrated that diabetic GK rats exhibited cognitive dysfunction, whereas treatment with liraglutide alleviated the learning and memory deficits, particularly in the high‑dose liraglutide group. The expression levels of Beclin‑1 and LC‑3 II were decreased in GK rats; however, this decrease was alleviated in the presence of liraglutide. Liraglutide also reversed T2DM model‑induced increases in mTOR, and decreases in p‑AMPK, PI3K and p‑Akt expression, and modulated the expression of apoptosis‑associated proteins. Furthermore, the administration of liraglutide inhibited apoptosis and exerted a protective effect against cognitive deficits via the activation of autophagy. In conclusion, the protective effects of liraglutide may be associated with increased mTOR expression via activation of the AMPK and PI3K/Akt signaling pathways.

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1	Dobretsov M, Romanovsky D and Stimers JR: Early diabetic neuropathy: Triggers and mechanisms. World J Gastroenterol. 13:175–191. 2007. View Article : Google Scholar : PubMed/NCBI
2	McCrimmon RJ, Ryan CM and Frier BM: Diabetes and cognitive dysfunction. Lancet. 379:2291–2299. 2012. View Article : Google Scholar : PubMed/NCBI
3	Mijnhout GS, Scheltens P, Diamant M, Biessels GJ, Wessels AM, Simsek S, Snoek FJ and Heine RJ: Diabetic encephalopathy: A concept in need of a definition. Diabetologia. 49:1447–1448. 2006. View Article : Google Scholar : PubMed/NCBI
4	Carvalho C, Santos MS, Oliveira CR and Moreira PI: Alzheimer's disease and type 2 diabetes-related alterations in brain mitochondria, autophagy and synaptic markers. Biochim Biophys Acta. 1852:1665–1675. 2015. View Article : Google Scholar : PubMed/NCBI
5	Feinkohl I, Price JF, Strachan MW and Frier BM: The impact of diabetes on cognitive decline: Potential vascular, metabolic and psychosocial risk factors. Alzheimers Res Ther. 7:462015. View Article : Google Scholar : PubMed/NCBI
6	Vagelatos NT and Eslick GD: Type 2 diabetes as a risk factor for Alzheimer's disease: The confounders, interactions and neuropathology associated with this relationship. Epidemiol Rev. 35:152–160. 2013. View Article : Google Scholar : PubMed/NCBI
7	Muriach M, Flores-Bellver M, Romero FJ and Barcia JM: Diabetes and the brain: Oxidative stress, inflammation and autophagy. Oxid Med Cell Longev. 2014:1021582014. View Article : Google Scholar : PubMed/NCBI
8	Guan ZF, Tao YH, Zhang XM, Guo QL, Liu YC, Zhang Y, Wang YM, Ji G, Wu GF, Wang NN, et al: G-CSF and cognitive dysfunction in elderly diabetic mice with cerebral small vessel disease: Preventive intervention effects and underlying mechanisms. CNS Neurosci Ther. 23:462–474. 2017. View Article : Google Scholar : PubMed/NCBI
9	Kong FJ, Ma LL, Guo JJ, Xu LH, Li Y and Qu S: Endoplasmic reticulum stress/autophagy pathway is involved in diabetes-induced neuronal apoptosis and cognitive decline in mice. Clin Sci. 132:111–125. 2018. View Article : Google Scholar : PubMed/NCBI
10	Qian M, Fang X and Wang X: Autophagy and inflammation. Clin Transl Med. 6:242017. View Article : Google Scholar : PubMed/NCBI
11	Guan ZF, Zhou XL, Zhang XM, Zhang Y, Wang YM, Guo QL, Ji G, Wu GF, Wang NN, Yang H, et al: Beclin-1-mediated autophagy may be involved in the elderly cognitive and affective disorders in streptozotocin-induced diabetic mice. Transl Neurodegener. 5:222016. View Article : Google Scholar : PubMed/NCBI
12	Palleria C, Leporini C, Maida F, Succurro E, De Sarro G, Arturi F and Russo E: Potential effects of current drug therapies on cognitive impairment in patients with type 2 diabetes. Front Neuroendocrinol. 42:76–92. 2016. View Article : Google Scholar : PubMed/NCBI
13	Goto H, Nomiyama T, Mita T, Yasunari E, Azuma K, Komiya K, Arakawa M, Jin WL, Kanazawa A, Kawamori R, et al: Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces intimal thickening after vascular injury. Biochem Biophys Res Commun. 405:79–84. 2011. View Article : Google Scholar : PubMed/NCBI
14	Chen S, Liu AR, An FM, Yao WB and Gao XD: Amelioration of neurodegenerative changes in cellular and rat models of diabetes-related Alzheimer's disease by exendin-4. Age. 34:1211–1224. 2012. View Article : Google Scholar : PubMed/NCBI
15	Solmaz V, Çınar BP, Yiğittürk G, Çavuşoğlu T, Taşkıran D and Erbaş O: Exenatide reduces TNF-α expression and improves hippocampal neuron numbers and memory in streptozotocin treated rats. Eur J Pharmacol. 765:482–487. 2015. View Article : Google Scholar : PubMed/NCBI
16	Zheng T, Qin L, Chen B, Hu X, Zhang X, Liu Y, Liu H, Qin S, Li G and Li Q: Association of plasma DPP4 activity with mild cognitive impairment in elderly patients with type 2 diabetes: Results from the GDMD study in China. Diabetes Care. 39:1594–1601. 2016. View Article : Google Scholar : PubMed/NCBI
17	Chen B, Zheng T, Qin L, Hu X, Zhang X, Liu Y, Liu H, Qin S, Li G and Li Q: Strong association between plasma dipeptidyl peptidase-4 activity and impaired cognitive function in elderly population with normal glucose tolerance. Fron Aging Neurosci. 9:2472017. View Article : Google Scholar
18	Zheng T, Liu H, Qin L, Chen B, Zhang X, Hu X, Xiao L and Qin S: Oxidative stress-mediated influence of plasma DPP4 activity to BDNF ratio on mild cognitive impairment in elderly type 2 diabetic patients: Results from the GDMD study in China. Metabolism. March 21–2018.(Epub ahead of print). View Article : Google Scholar :
19	Jacobsen LV, Hindsberger C, Robson R and Zdravkovic M: Effect of renal impairment on the pharmacokinetics of the GLP-1 analogue liraglutide. Br J Clin Pharmacol. 68:898–905. 2009. View Article : Google Scholar : PubMed/NCBI
20	McClean PL and Hölscher C: Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer's disease. Neuropharmacology. 76:57–67. 2014. View Article : Google Scholar : PubMed/NCBI
21	Hansen HH, Fabricius K, Barkholt P, Niehoff ML, Morley JE, Jelsing J, Pyke C, Knudsen LB, Farr SA and Vrang N: The GLP-1 receptor agonist liraglutide improves memory function and increases hippocampal CA1 neuronal numbers in a senescence-accelerated mouse model of Alzheimer's disease. J Alzheimers Dis. 46:877–888. 2015. View Article : Google Scholar : PubMed/NCBI
22	Miao X, Gu Z, Liu Y, Jin M, Lu Y, Gong Y, Li L and Li C: The glucagon-like peptide-1 analogue liraglutide promotes autophagy through the modulation of 5′-AMP-activated protein kinase in INS-1 β-cells under high glucose conditions. Peptides. 100:127–139. 2018. View Article : Google Scholar : PubMed/NCBI
23	Candeias E, Sebastião I, Cardoso S, Carvalho C, Santos MS, Oliveira CR, Moreira PI and Duarte AI: Brain GLP-1/IGF-1 signaling and autophagy mediate exendin-4 protection against apoptosis in type 2 diabetic rats. Mol Neurobiol. 55:4030–4050. 2018.PubMed/NCBI
24	National Research Council (US), . Institute for Laboratory Animal Research: Guide for the care and use of laboratory animals. The National Academies Press; Washington, DC: 1996
25	Ryan CM, van Duinkerken E and Rosano C: Neurocognitive consequences of diabetes. Am Psychol. 71:563–576. 2016. View Article : Google Scholar : PubMed/NCBI
26	Stranahan AM: Models and mechanisms for hippocampal dysfunction in obesity and diabetes. Neuroscience. 309:125–139. 2015. View Article : Google Scholar : PubMed/NCBI
27	Yates KF, Sweat V, Yau PL, Turchiano MM and Convit A: Impact of metabolic syndrome on cognition and brain: A selected review of the literature. Arterioscler Thromb Vasc Biol. 32:2060–2067. 2012. View Article : Google Scholar : PubMed/NCBI
28	de Faria JM, Duarte DA, Montemurro C, Papadimitriou A, Consonni SR and de Faria Lopes JB: Defective autophagy in diabetic retinopathy defective autophagy. Invest Ophthalmol Vis Sci. 57:4356–4366. 2016. View Article : Google Scholar : PubMed/NCBI
29	Ma LY, Lv YL, Huo K, Liu J, Shang SH, Fei YL, Li YB, Zhao BY, Wei M, Deng YN and Qu QM: Autophagy-lysosome dysfunction is involved in Aβ deposition in STZ-induced diabetic rats. Behav Brain Res. 320:484–493. 2017. View Article : Google Scholar : PubMed/NCBI
30	Guan ZF, Zhou XL, Zhang XM, Zhang Y, Wang YM, Guo QL, Ji G, Wu GF, Wang NN, Yang H, et al: Beclin-1-mediated autophagy may be involved in the elderly cognitive and affective disorders in streptozotocin-induced diabetic mice. Transl Neurodegener. 5:222016. View Article : Google Scholar : PubMed/NCBI
31	Li XH, Xin X, Wang Y, Wu JZ, Jin ZD, Ma LN, Nie CJ, Xiao X, Hu Y and Jin MW: Pentamethylquercetin protects against diabetes-related cognitive deficits in diabetic Goto-Kakizaki rats. J Alzheimers Dis. 34:755–767. 2013. View Article : Google Scholar : PubMed/NCBI
32	Xue H, Ji Y, Wei S, Yu Y, Yan X, Liu S, Zhang M, Yao F, Lan X and Chen L: HGSD attenuates neuronal apoptosis through enhancing neuronal autophagy in the brain of diabetic mice: The role of AMP-activated protein kinase. Life Sci. 153:23–34. 2016. View Article : Google Scholar : PubMed/NCBI
33	Qin L, Wang Z, Tao L and Wang Y: ER stress negatively regulates AKT/TSC/mTOR pathway to enhance autophagy. Autophagy. 6:239–247. 2010. View Article : Google Scholar : PubMed/NCBI
34	Yan J, Feng Z and Liu J, Shen W, Wang Y, Wertz K, Weber P, Long J and Liu J: Enhanced autophagy plays a cardinal role in mitochondrial dysfunction in type 2 diabetic Goto-Kakizaki (GK) rats: Ameliorating effects of (−)-epigallocatechin-3-gallate. J Nutr Biochem. 23:716–724. 2012. View Article : Google Scholar : PubMed/NCBI
35	Holz GG IV, Kiihtreiber WM and Habener JF: Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7–37). Nature. 36:362–365. 1993. View Article : Google Scholar
36	Palleria C, Leo A, Andreozzi F, Citaro R, Lannone M, Spiga R, Sesti G, Constanti A, De Sarri G, Arturi F and Russo E: Liraglutide prevents cognitive decline in a rat model of streptozotocin-induced diabetes independently from its peripheral metabolic effects. Behav Brain Res. 321:157–169. 2017. View Article : Google Scholar : PubMed/NCBI
37	Porter WD, Flatt PR, Hölscher C and Gault VA: Liraglutide improves hippocampal synaptic plasticity associated with increased expression of Mash1 in ob/ob mice. Int J Obes (Lond). 37:678–684. 2013. View Article : Google Scholar : PubMed/NCBI
38	Wu XM, Ou QY, Zhao W, Liu J and Zhang H: The GLP-1 analogue liraglutide protects cardiomyocytes from high glucose-induced apoptosis by activating the Epac-1/Akt pathway. Exp Clin Endocrinol Diabetes. 122:608–614. 2014. View Article : Google Scholar : PubMed/NCBI
39	Badawi GA, Abd El Fattah MA, Zaki HF and Sayed EI MI: Sitagliptin and liraglutide reversed nigrostriatal degeneration of rodent brain in rotenone-induced Parkinson's disease. Inflammopharmacology. 25:369–382. 2017. View Article : Google Scholar : PubMed/NCBI
40	Abbas NAT and Kabil SL: Liraglutide ameliorates cardiotoxicity induced by doxorubicin in rats through the Akt/GSK-3β signaling pathway (J). Archiv Für Exp Pathol Und Pharmakol. 1–9. 2017.
41	Zhu H, Zhang Y, Shi Z, Lu D, Li T, Ding Y, Ruan Y and Xu A: The neuroprotection of liraglutide against ischaemia-induced apoptosis through the activation of the PI3K/AKT and MAPK Pathways. Sci Rep. 6:268592016. View Article : Google Scholar : PubMed/NCBI