Insulin resistance is a hallmark of type 2 diabetes (T2DM) and can increase the risk of cognit- ive impairment, including Alzheimer’s disease. Nuciferine, an alkaloid derived from lotus leaves, shows neuroprotective effects. This study investigated nuciferine’s protective role in T2DM-induced cognitive impairment (T2DM-CI) and its mechanisms. Mouse models were cre- ated using high-fat diets and streptozotocin, along with high glucose-induced HT-22 cells. Nu- ciferine reduced blood glucose, improved cognitive function, and mitigated glial cell activa- tion, neuron and synapse loss in T2DM mice. It enhanced insulin signaling by increasing pro- tein levels of IR, IRS1, and IGF-1R, reversing PI3K and AKT phosphorylation, inhibiting GSK3β activity, and reducing hyperphosphorylated Tau in HT-22 cells and T2DM mice. mRNA levels of these molecules matched their protein levels. Further studies revealed that nuciferine dir- ectly interacts with IR, knocking out IR abolished its effects on the PI3K/AKT pathway. Thus, nuciferine activates the PI3K/AKT pathway via IR, improving insulin resistance and slowing T2DM-CI progression.
Declaration of competing interest
All authors disclosed no relevant relationships.
Acknowledge
The authors acknowledge the support from the Scientific Research Center, Hangzhou Medical College.
| [1] |
Mancusi C, Izzo R, Di Gioia G, et al. Insulin resistance the hinge between hypertension and type 2 diabetes. High Blood Press Cardiovasc Prev. 2020; 27(6):515-526. https://doi.org/10.1007/s40292—020—00408—8.
|
| [2] |
Jensen TS, Karlsson P, Gylfadottir SS, et al. Painful and non—painful diabetic neuropathy, diagnostic challenges and implications for future management. Brain. 2021; 144(6):1632-1645. https://doi.org/10.1093/brain/awab079.
|
| [3] |
Fung TH, Patel B, Wilmot EG, et al. Diabetic retinopathy for the non—ophthalmologist. Clin Med (Lond). 2022; 22(2):112-116. https://doi.org/10.7861/clinmed.2021—0792.
|
| [4] |
Deng L, Yang Y, Xu G. Empagliflozin ameliorates type 2 diabetes mellitus—related diabetic nephropathy via altering the gut microbiota. Biochim Biophys Acta Mol Cell Biol Lipids. 2022; 1867(12):159234. https://doi.org/10.1016/j.bbalip.2022.159234.
|
| [5] |
Karabaeva RZ, Vochshenkova TA, Mussin NM, et al. Epigenetics of hypertension as a risk factor for the development of coronary artery disease in type 2 diabetes mellitus. Front Endocrinol (Lausanne). 2024; 15:1365738. https://doi.org/10.3389/fendo.2024.1365738.
|
| [6] |
Li C, Bishop TRP, Imamura F, et al. Meat consumption and incident type 2 diabetes: an individual—participant federated meta—analysis of 1.97 million adults with 100 000 incident cases from 31 cohorts in 20 countries. Lancet Diabetes Endocrinol. 2024; 12(9):619-630. https://doi.org/10.1016/S2213—8587(24)00179—7.
|
| [7] |
Busche MA, Hyman BT. Synergy between amyloid—β and tau in Alzheimer’s disease. Nat Neurosci. 2020; 23(10):1183-1193. https://doi.org/10.1038/s41593—020—0687—6.
|
| [8] |
2023 Alzheimer’s disease facts and figures. Alzheimers Dement. 2023; 19(4):1598-1695. https://doi.org/10.1002/alz.13016.
|
| [9] |
Van Gennip ACE, Stehouwer CDA, Van Boxtel MPJ, et al. Association of type 2 diabetes, according to the number of risk factors within target range, with structural brain abnormalities, cognitive performance, and risk of dementia. Diabetes Care. 2021; 44(11):2493-2502. https://doi.org/10.2337/dc21—0149.
|
| [10] |
Rezaei MH, Madadizadeh E, Aminaei M, et al. Leptin signaling could mediate hippocampal decumulation of β—amyloid and Tau induced by high—intensity interval training in rats with type 2 diabetes. Cell Mol Neurobiol. 2023; 43(7):3465-3478. https://doi.org/10.1007/s10571—023—01357—1.
|
| [11] |
Pignalosa FC, Desiderio A, Mirra P, et al. Diabetes and cognitive impairment: a role for glucotoxicity and dopaminergic dysfunction. Int J Mol Sci. 2021;22(22):12366. https://doi.org/10.3390/ijms222212366.
|
| [12] |
Akhtar A, Sah SP. Insulin signaling pathway and related molecules: role in neurodegeneration and Alzheimer’s disease. Neurochem Int. 2020; 135:104707. https://doi.org/10.1016/j.neuint.2020.104707.
|
| [13] |
Gupta S, Singh V, Ganesh S, et al. siRNA mediated GSK3β knockdown targets insulin signaling pathway and rescues Alzheimer’s disease pathology: evidence from in vitro and in vivo studies. ACS Appl Mater Interfaces. 2022; 14(1):69-93. https://doi.org/10.1021/acsami.1c15305.
|
| [14] |
Saltiel AR. Insulin signaling in health and disease. J Clin Invest. 2021; 131(1):e142241. https://doi.org/10.1172/JCI142241.
|
| [15] |
Gabbouj S, Ryhanen S, Marttinen M, et al. Altered insulin signaling in Alzheimer’s disease brain—special emphasis on PI3K—Akt pathway. Front Neurosci. 2019; 13:629. https://doi.org/10.3389/fnins.2019.00629.
|
| [16] |
Sharma BR, Gautam LN, Adhikari D, et al. A comprehensive review on chemical profiling of nelumbo nucifera: potential for drug development. Phytother Res. 2017; 31(1):3-26. https://doi.org/10.1002/ptr.5732.
|
| [17] |
Ren X, Chen H, Wang H, et al. Advances in the pharmacological effects and mechanisms of Nelumbo nucifera Gaertn extract nuciferine. J Ethnopharmacol. 2024; 331:118262. https://doi.org/10.1016/j.jep.2024.118262.
|
| [18] |
Wan Y, Xia J, Xu JF, et al. Nuciferine, an active ingredient derived from lotus leaf, lights up the way for the potential treatment of obesity and obesity—related diseases. Pharmacol Res. 2022; 175:106002. https://doi.org/10.1016/j.phrs.2021.106002.
|
| [19] |
Wang Y, Yao W, Li B, et al. Nuciferine modulates the gut microbiota and prevents obesity in high—fat diet—fed rats. Exp Mol Med. 2020; 52(12):1959-1975. https://doi.org/10.1038/s12276—020—00534—2.
|
| [20] |
Qiu J, Le Y, Liu N, et al. Nuciferine alleviates high—fat diet— and ApoE(−/−)—induced hepatic steatosis and ferroptosis in NAFLD mice via the PPARα signaling pathway. J Agric Food Chem. 2024; 72(44):24417-24431. https://doi.org/10.1021/acs.jafc.4c04929.
|
| [21] |
Li J, Dong S, Quan S, et al. Nuciferine reduces inflammation induced by cerebral ischemia—reperfusion injury through the PI3K/Akt/NF—κB pathway. Phytomedicine. 2024; 125:155312. https://doi.org/10.1016/j.phymed.2023.155312.
|
| [22] |
Chen C, Ma Q, Jiang J, et al. Protective effects of nuciferine in middle cerebral artery occlusion rats based on transcriptomics. Brain Sci. 2022; 12(5):572. https://doi.org/10.3390/brainsci12050572.
|
| [23] |
Gao L, Wu S, Hu B, et al. Targeting the RAGE—RIPK1 binding site attenuates diabetes—associated cognitive deficits. J Neuroinflammation. 2025; 22(1):162. https://doi.org/10.1186/s12974—025—03489—1.
|
| [24] |
Deng H, Xu Q, Sang XT, et al. Study on the vasodilatory activity of lotus leaf extract and its representative substance nuciferine on thoracic aorta in rats. Front Pharmacol. 2022; 13:946445. https://doi.org/10.3389/fphar.2022.946445.
|
| [25] |
Xu X, Xu H, Shang Y, et al. Development of the general chapters of the Chinese Pharmacopoeia 2020 edition: a review. J Pharm Anal. 2021; 11(4):398-404. https://doi.org/10.1016/j.jpha.2021.05.001.
|
| [26] |
Zhao T, Zhu Y, Zhao R, et al. Structure—activity relationship, bioactivities, molecular mechanisms, and clinical application of nuciferine on inflammation—related diseases. Pharmacol Res. 2023; 193:106820. https://doi.org/10.1016/j.phrs.2023.106820.
|
| [27] |
Gu S, Zhu G, Wang Y, et al. A sensitive liquid chromatography—tandem mass spectrometry method for pharmacokinetics and tissue distribution of nuciferine in rats. J Chromatogr B Analyt Technol Biomed Life Sci. 2014; 961:20-28. https://doi.org/10.1016/j.jchromb.2014.04.038.
|
| [28] |
Wang F, Cao J, Hou X, et al. Pharmacokinetics, tissue distribution, bioavailability, and excretion of nuciferine, an alkaloid from lotus, in rats by LC/MS/MS. Drug Dev Ind Pharm. 2018; 44(9):1557-1562. https://doi.org/10.1080/03639045.2018.1483399.
|
| [29] |
Guo F, Yang X, Li X, et al. Nuciferine prevents hepatic steatosis and injury induced by a high—fat diet in hamsters. PLoS One. 2013; 8(5):e63770. https://doi.org/10.1371/journal.pone.0063770.
|
| [30] |
Zhang C, Deng J, Liu D, et al. Nuciferine ameliorates hepatic steatosis in high—fat diet/streptozocin—induced diabetic mice through a PPARα/PPARγ coactivator—1α pathway. Br J Pharmacol. 2018; 175(22):4218-4228. https://doi.org/10.1111/bph.14482.
|
| [31] |
Tang Z, Luo T, Huang P, et al. Nuciferine administration in C57BL/6J mice with gestational diabetes mellitus induced by a high—fat diet: the improvement of glycolipid disorders and intestinal dysbacteriosis. Food Funct. 2021; 12(22):11174-11189. https://doi.org/10.1039/d1fo02714j.
|
| [32] |
Zheng Y, Zhang J, Zhao Y, et al. Curcumin protects against cognitive impairments in a rat model of chronic cerebral hypoperfusion combined with diabetes mellitus by suppressing neuroinflammation, apoptosis, and pyroptosis. Int Immunopharmacol. 2021; 93:107422. https://doi.org/10.1016/j.intimp.2021.107422.
|
| [33] |
Chandrasekera PC, Pippin JJ. Of rodents and men: species—specific glucose regulation and type 2 diabetes research. ALTEX. 2014; 31(2):157-176. https://doi.org/10.14573/altex.1309231.
|
| [34] |
Attrill EH, Scharapow O, Perera S, et al. Controlled induction of type 2 diabetes in mice using high fat diet and osmotic—mini pump infused streptozotocin. Sci Rep. 2025; 15(1):8812. https://doi.org/10.1038/s41598—025—89162—2.
|
| [35] |
Rostami F, Javan M, Moghimi A, et al. Prenatal stress promotes icv—STZ—induced sporadic Alzheimer’s pathology through central insulin signaling change. Life Sci. 2020; 241:117154. https://doi.org/10.1016/j.lfs.2019.117154.
|
| [36] |
Huang J, Xu Z, Yu C, et al. The volatile oil of Acorus tatarinowii Schott ameliorates Alzheimer’s disease through improving insulin resistance via activating the PI3K/AKT pathway. Phytomedicine. 2024; 135:156168. https://doi.org/10.1016/j.phymed.2024.156168.
|
| [37] |
Herman R, Kravos NA, Jensterle M, et al. Metformin and insulin resistance: a review of the underlying mechanisms behind changes in GLUT4—mediated glucose transport. Int J Mol Sci. 2022; 23(3):1264. https://doi.org/10.3390/ijms23031264.
|
| [38] |
Taheri M, Roghani M, Sedaghat R. Metformin mitigates trimethyltin—induced cognition impairment and hippocampal neurodegeneration. Cell Mol Neurobiol. 2024; 44(1):70. https://doi.org/10.1007/s10571—024—01502—4.
|
| [39] |
Ozbey G, Nemutlu—Samur D, Parlak H, et al. Metformin protects rotenone—induced dopaminergic neurodegeneration by reducing lipid peroxidation. Pharmacol Rep. 2020; 72(5):1397-1406. https://doi.org/10.1007/s43440—020—00095—1.
|
| [40] |
Hong S, Nagayach A, Lu Y, et al. A high fat, sugar, and salt Western diet induces motor—muscular and sensory dysfunctions and neurodegeneration in mice during aging: ameliorative action of metformin. CNS Neurosci Ther. 2021; 27(12):1458-1471. https://doi.org/10.1111/cns.13726.
|
| [41] |
Oliveira SR, Counil H, Rabanel JM, et al. Donepezil—loaded nanocarriers for the treatment of Alzheimer’s disease: superior efficacy of extracellular vesicles over polymeric nanoparticles. Int J Nanomed. 2024; 19:1077-1096. https://doi.org/10.2147/IJN.S449227.
|
| [42] |
Zheng M, Wang P. Role of insulin receptor substance—1 modulating PI3K/Akt insulin signaling pathway in Alzheimer’s disease. 3 Biotech. 2021; 11(4):179. https://doi.org/10.1007/s13205—021—02738—3.
|
| [43] |
Rethelyi JM, Vincze K, Schall D, et al. The role of insulin/IGF1 signalling in neurodevelopmental and neuropsychiatric disorders: evidence from human neuronal cell models. Neurosci Biobehav Rev. 2023; 153:105330. https://doi.org/10.1016/j.neubiorev.2023.105330.
|
| [44] |
Choi E, Duan C, Bai XC. Regulation and function of insulin and insulin—like growth factor receptor signalling. Nat Rev Mol Cell Biol. 2025; 26(7):558-580. https://doi.org/10.1038/s41580—025—00826—3.
|
| [45] |
Meng Q, Qi X, Chao Y, et al. IRS1/PI3K/AKT pathway signal involved in the regulation of glycolipid metabolic abnormalities by mulberry (Morus alba L.) leaf extracts in 3T3—L1 adipocytes. Chin Med. 2020; 15:1. https://doi.org/10.1186/s13020—019—0281—6.
|
| [46] |
Xu A, Zeng Q, Tang Y, et al. Electroacupuncture protects cognition by regulating Tau phosphorylation and glucose metabolism via the AKT/GSK3β signaling pathway in Alzheimer’s disease model mice.Front Neurosci. 2020; 14:585476. https://doi.org/10.3389/fnins.2020.585476.
|
| [47] |
Liu S, Xu L, Shen Y, et al. Qingxin Kaiqiao Fang decreases Tau hyperphosphorylation in Alzheimer’s disease via the PI3K/Akt/GSK3β pathway in vitro and in vivo. J Ethnopharmacol. 2024; 318(Pt B):117031. https://doi.org/10.1016/j.jep.2023.117031.
|
| [48] |
Peng X, Guo H, Zhang X, et al. TREM2 inhibits Tau hyperphosphorylation and neuronal apoptosis via the PI3K/Akt/GSK—3β signaling pathway in vivo and in vitro. Mol Neurobiol. 2023; 60(5):2470-2485. https://doi.org/10.1007/s12035—023—03217—x.
|
| [49] |
Qiu Q, Lei X, Wang Y, et al. Naringin protects against Tau hyperphosphorylation in Aβ (25—35)—injured PC12 cells through modulation of ER, PI3K/AKT, and GSK—3β signaling pathways. Behav Neurol. 2023; 2023:1857330. https://doi.org/10.1155/2023/1857330.
|
| [50] |
Zhang W, Zhang Z, Xiang Y, et al. Aurora kinase A—mediated phosphorylation triggers structural alteration of Rab1A to enhance ER complexity during mitosis. Nat Struct Mol Biol. 2024; 31(2):219-231. https://doi.org/10.1038/s41594—023—01165—7.
|
| [51] |
Xiong R, Wang XL, Wu JM, et al. Polyphenols isolated from lychee seed inhibit Alzheimer’s disease—associated Tau through improving insulin resistance via the IRS—1/PI3K/Akt/GSK—3β pathway. J Ethnopharmacol. 2020; 251:112548. https://doi.org/10.1016/j.jep.2020.112548.
|
PDF
