Comparative effects of selective and non-selective sodium–glucose cotransporter inhibition on cognitive dysfunction in a rat model of type 2 diabetes

Year 2026, Volume: 30 Issue: 2, 660 - 670, 15.03.2026

Ayşe Nur Hazar-Yavuz , Büşra Ertaş , Rumeysa Macide Keleş Kaya , Fadime Topal , Levent Kabasakal

https://doi.org/10.12991/jrespharm.1873927

https://izlik.org/JA66ZM63FE

Abstract

Type 2 diabetes mellitus (T2DM) is increasingly recognized as a major risk factor for cognitive decline and Alzheimer’s disease (AD), yet the therapeutic potential of antidiabetic agents on diabetes-associated neurodegeneration remains incompletely understood. In this study, we investigated the effects of the non-selective sodium–glucose cotransporter (SGLT) inhibitor phlorizin and the selective SGLT2 inhibitor dapagliflozin on metabolic parameters and cognitive performance in a rat model of T2DM-related cognitive dysfunction (T2DM-CD). Male Sprague–Dawley rats were fed a high-fat diet and administered low-dose streptozotocin to induce a diabetic phenotype accompanied by cognitive impairment. Animals were treated for four weeks with dapagliflozin, phlorizin, metformin, or rivastigmine. Blood glucose levels, body weight, locomotor activity, and recognition memory were assessed using standardized metabolic and behavioural tests. The T2DM-CD model exhibited sustained hyperglycaemia and significant impairment in recognition memory without alterations in locomotor activity. Treatment with dapagliflozin and phlorizin significantly reduced blood glucose levels and markedly improved recognition memory compared with untreated animals. Rivastigmine also improved cognitive performance without affecting glycaemic control, whereas metformin produced only modest cognitive benefits. None of the treatments significantly altered body weight. These findings demonstrate that SGLT inhibition ameliorates cognitive deficits in a T2DM-CD model, suggesting that SGLT inhibitors may exert beneficial effects on diabetes-associated cognitive dysfunction through combined metabolic and central mechanisms.

Keywords

Type 2 diabetes mellitus , SGLT inhibitors , cognitive impairment , high-fat-diet , streptozotocin

Ethical Statement

Marmara University Animal Experiments Local Ethics Committee (Approval no: 86.2017.mar)

Supporting Institution

Scientific Research Projects Unit of Marmara University (Project No: SAG-C-DRP-110718-0445)

Project Number

SAG-C-DRP-110718-0445

References

• [1] Goyal R, Singhal M, Jialal I. Type 2 Diabetes. In StatPearls. StatPearls Publishing. 2023.
• [2] Zheng Y, Ley S. Hu F. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol. 2018; 14: 88–98. https://doi.org/10.1038/nrendo.2017.151
• [3] Nanda M, Sharma R, Mubarik S, Aashima A, Zhang K. Type-2 Diabetes Mellitus (T2DM): spatial-temporal patterns of incidence, mortality and attributable risk factors from 1990 to 2019 among 21 world regions. Endocrine, 2022; 77(3): 444–454. https://doi.org/10.1007/s12020-022-03125-5
• [4] Cao F, Yang F, Li J, Guo W, Zhang C, Gao F, Sun X, Zhou Y, Zhang W. The relationship between diabetes and the dementia risk: a meta-analysis. Diabetol Metab Syndr 2024; 16: 101. https://doi.org/10.1186/s13098-024-01346-4
• [5] Li Z, Lin C, Cai X, Lv F, Yang W, Ji L Anti-diabetic agents and the risks of dementia in patients with type 2 diabetes: a systematic review and network meta-analysis of observational studies and randomized controlled trials. Alz Res Therapy. 2024; 16: 272. https://doi.org/10.1186/s13195-024-01645-y
• [6] Ezkurdia A, Ramírez MJ, Solas M. Metabolic syndrome as a risk factor for Alzheimer's disease: a focus on insulin resistance. Int J Mol Sci. 2023; 24(5): 4354. https://doi.org/10.3390/ijms24054354
• [7] You Y, Liu Z, Chen Y, Xu Y, Qin J, Guo S, Huang J, Tao J. The prevalence of mild cognitive impairment in type 2 diabetes mellitus patients: a systematic review and meta-analysis. Acta Diabetol. 2021; 58(6): 671–685. https://doi.org/10.1007/s00592-020-01648-9
• [8] Zhao Y, Wang H, Tang G, Wang L, Tian X, Li R. Risk factors for mild cognitive impairment in type 2 diabetes: a systematic review and meta-analysis. Front Endocrinol. 2025; 16: 1617248. https://doi.org/10.3389/fendo.2025.1617248
• [9] Kim J, Han KD, Lee JY, Yang YS, Cheon DY, Lee JJ, Lee M. Diabetes status, duration, and risk of dementia among ischemic stroke patients. Alz Res Therapy. 2025; 17: 58. https://doi.org/10.1186/s13195-025-01708-8
• [10] Seo DH, Kim M, Cho Y, Ahn SH, Hong S, Kim SH. Association between age at diagnosis of type 2 diabetes and subsequent risk of dementia and its major subtypes. J Clin Med. 2024; 13(15): 4386. https://doi.org/10.3390/jcm13154386
• [11] Alzheimer’s Disease International. World Alzheimer Report 2024, https://www.alzint.org/resource/world-alzheimer-report-2024/ (accessed on 14 January 2026).
• [12] World Health Organization. Dementia. https://www.who.int/news-room/fact-sheets/detail/dementia (accessed on 14 January 2026).
• [13] Tao M, Guo HY, Ji X, Wang W, Yuan H, Peng H. Long-term trends in Alzheimer’s disease and other dementias deaths with high body mass index in China from 1990 to 2019, and projections up to 2042. Arch Public Health. 2024; 82: 42. https://doi.org/10.1186/s13690-024-01273-w
• [14] Bello-Chavolla OY, Antonio-Villa NE, Vargas-Vázquez A, Ávila-Funes JA, Aguilar-Salinas CA. Pathophysiological mechanisms linking type 2 diabetes and dementia: review of evidence from clinical, translational and epidemiological research. Curr Diabetes Rev. 2019; 15(6): 456–470. https://doi.org/10.2174/1573399815666190129155654
• [15] DeFronzo RA, Eldor R, Abdul-Ghani M. Pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes. Diabetes care. 2013; 36(2): 127–138. https://doi.org/10.2337/dcS13-2011
• [16] Tian L, Ai S, Zheng H, Yang H, Zhou M, Tang J, Liu W, Zhao W, Wang Y. Cardiovascular and renal outcomes with sodium glucose co-transporter 2 inhibitors in patients with type 2 diabetes mellitus: a system review and network meta-analysis. Front Pharmacol. 2022; 13: 986186. https://doi.org/10.3389/fphar.2022.986186
• [17] Gunawan PY, Gunawan PA, Hariyanto TI. Risk of dementia in patients with diabetes using sodium-glucose transporter 2 inhibitors (SGLT2i): a systematic review, meta-analysis, and meta-regression. Diabetes Ther. 2024; 15(3): 663–675. https://doi.org/10.1007/s13300-024-01538-1
• [18] Pan J, Yang H, Lu J, Chen L, Wen T, Zhao S, Shi L. The impact of SGLT2 inhibitors on dementia onset in patients with type 2 diabetes: a meta-analysis of cohort studies. Neuroendocrinology. 2025; 115(3-4): 351–359. https://doi.org/10.1159/000543533
• [19] Sa-Nguanmoo P, Tanajak P, Kerdphoo S, Jaiwongkam T, Pratchayasakul W, Chattipakorn N, Chattipakorn SC. SGLT2-inhibitor and DPP-4 inhibitor improve brain function via attenuating mitochondrial dysfunction, insulin resistance, inflammation, and apoptosis in HFD-induced obese rats. Toxicol Appl Pharmacol. 2017; 333: 43–50. https://doi.org/10.1016/j.taap.2017.08.005
• [20] Lin B, Koibuchi N, Hasegawa Y, Sueta D, Toyama K, Uekawa K, Ma M, Nakagawa T, Kusaka H, Kim-Mitsuyama S. Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovasc Diabetol. 2014; 13: 148. https://doi.org/10.1186/s12933-014-0148-1
• [21] Arafa NMS, Ali EHA, Hassan MK. Canagliflozin prevents scopolamine-induced memory impairment in rats: comparison with galantamine hydrobromide action. Chem Biol Interact. 2017; 277: 195–203. https://doi.org/10.1016/j.cbi.2017.08.013
• [22] Srinivasan K, Viswanad B, Asrat L, Kaul CL, Ramarao P. Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacol Res. 2005; 52(4): 313–320. https://doi.org/10.1016/j.phrs.2005.05.004
• [23] Ertas B, Hazar-Yavuz AN, Topal F, Keles-Kaya R, Karakus Ö, Ozcan GS, Taskin T, Cam ME. Rosa canina L. improves learning and memory-associated cognitive impairment by regulating glucose levels and reducing hippocampal insulin resistance in high-fat diet/streptozotocin-induced diabetic rats. J Ethnopharmacol. 2023; 313: 116541. https://doi.org/10.1016/j.jep.2023.116541
• [24] Cam ME, Hazar-Yavuz AN, Yildiz S, Keles R, Ertas B, Kabasakal L. Dapagliflozin attenuates depressive-like behavior of male rats in the forced swim test. Eur Neuropsychopharmacol. 2019; 29: 262-263.
• [25] Keles R, Hazar-Yavuz AN, Yildiz S, Cam ME, Sener G. Dapagliflozin attenuates anxiolytic-like behavior of rats in open field test. Eur Neuropsychopharmacol. 2019; 29: 201-202.
• [26] Hazar-Yavuz AN, Yıldız S, Keles Kaya R, Cam ME, Kabasakal L. Sodium-glucose co-transporter inhibitor dapagliflozin attenuates cognitive deficits in sporadic Alzheimer’s rat model. J Res Pharm. 2025; 26(2): 298-310.
• [27] Wongchitrat P, Lansubsakul N, Kamsrijai U, Sae-Ung K, Mukda S, Govitrapong P. Melatonin attenuates the high-fat diet and streptozotocin-induced reduction in rat hippocampal neurogenesis. Neurochem Int. 2016; 100: 97–109. https://doi.org/10.1016/j.neuint.2016.09.006
• [28] Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation. 2016; 134(10): 752–772. https://doi.org/10.1161/CIRCULATIONAHA.116.021887
• [29] Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia, 2017; 60(9): 1577–1585. https://doi.org/10.1007/s00125-017-4342-z
• [30] Isik AT, Bozoglu E, Eker D. aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease. J Nutr Health Aging. 2012; 16(2): 139–141. https://doi.org/10.1007/s12603-011-0095-4
• [31] Stranahan AM, Arumugam TV, Cutler RG, Lee K, Egan JM, Mattson MP. Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons. Nat Neurosci, 2008; 11(3): 309–317. https://doi.org/10.1038/nn2055
• [32] Birks J, Grimley Evans J, Iakovidou V, Tsolaki M, Holt FE. Rivastigmine for Alzheimer's disease. Cochrane Database Syst Rev. 2009; 2: CD001191. https://doi.org/10.1002/14651858.CD001191.pub2
• [33] Zhang QQ, Li WS, Liu Z, Zhang HL, Ba YG, Zhang RX. Metformin therapy and cognitive dysfunction in patients with type 2 diabetes: A meta-analysis and systematic review. Medicine. 2020; 99(10): e19378. https://doi.org/10.1097/MD.0000000000019378
• [34] Zhang W, Chen S, Fu H, Shu G, Tang H, Zhao X, Chen Y, Huang X, Zhao L, Yin L, Lv C, Lin J. Hypoglycemic and hypolipidemic activities of phlorizin from Lithocarpus polystachyus Rehd in diabetes rats. Food Sci Nutr. 2021; 9(4): 1989–1996. https://doi.org/10.1002/fsn3.2165
• [35] Cam ME, Hazar-Yavuz AN, Yildiz S, Ertas B, Ayaz Adakul B, Taskin T, Alan S, Kabasakal L. The methanolic extract of Thymus praecox subsp. skorpilii var. skorpilii restores glucose homeostasis, ameliorates insulin resistance and improves pancreatic β-cell function on streptozotocin/nicotinamide-induced type 2 diabetic rats. J Ethnopharmacol. 2019; 231: 29–38. https://doi.org/10.1016/j.jep.2018.10.028
• [36] Gothwal A, Singh H, Jain SK, Dutta A, Borah A, Gupta U. Behavioral and biochemical implications of dendrimeric rivastigmine in memory-deficit and Alzheimer's induced rodents. ACS Chem Neurosci, 2019; 10(8): 3789–3795. https://doi.org/10.1021/acschemneuro.9b00286
• [37] Kraeuter AK, Guest PC, Sarnyai Z. The open field test for measuring locomotor activity and anxiety-like behavior. Methods Mol Biol. 2019; 1916: 99–103. https://doi.org/10.1007/978-1-4939-8994-2_9
• [38] Bevins RA, Besheer J. Object recognition in rats and mice: a one-trial non-matching-to-sample learning task to study 'recognition memory'. Nat Protoc. 2006; 1(3): 1306–1311. https://doi.org/10.1038/nprot.2006.205