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• Clinical Article •
Investigation of the value of olfactory neural circuit remodeling in T2DM patients treated with three anti-diabetic drugs
WU Min  LI Xin  ZHANG Wen  LI Weiping  ZHANG Yi  LI Qian  SHEN Xinyi  ZHANG Xin  JI Cheng  BI Yan  ZHANG Bing 

Cite this article as: WU M, LI X, ZHANG W, et al. Investigation of the value of olfactory neural circuit remodeling in T2DM patients treated with three anti-diabetic drugs[J]. Chin J Magn Reson Imaging, 2025, 16(6): 10-20, 26. DOI:10.12015/issn.1674-8034.2025.06.002.


[Abstract] Objective To investigate the effects of three commonly used anti-diabetic drugs-Liraglutide, Dapagliflozin, and Acarbose-on functional connectivity (FC) between olfactory vulnerable regions and the whole brain in patients with type 2 diabetes mellitus (T2DM).Materials and Methods The study consists of two phases: baseline and drug treatment. In the baseline phase, 51 normal controls and 191 T2DM patients were recruited to assess differences in FC, cognitive function, olfactory behavior, and clinical indicators between the two groups. In the drug treatment follow-up phase, 36 T2DM patients with inadequate glycemic control despite metformin treatment were randomly assigned to three treatment groups: Liraglutide (n = 12), Dapagliflozin (n = 12), and Acarbose (n = 12), for a 16-week period. A randomized controlled trial (RCT) was conducted to evaluate the effects of three drugs on FC, cognitive function, and olfactory behavior.Results After 16 weeks of Liraglutide treatment, significant improvements in glycemic control and a notable reduction in body weight were observed in patients with T2DM. Delayed memory improved (t = -6.148, P < 0.001) and olfactory thresholds increased (t = -2.321, P = 0.040). The compensatory increase in FC between the left thalamus and left inferior occipital gyrus, as well as the right thalamus and left fusiform gyrus, was restored (Gaussian random field correction, voxel level P < 0.005, cluster level P < 0.05). No statistically significant differences were observed before and after treatment in the Acarbose and Dapagliflozin groups (P > 0.05).Conclusions This study demonstrates that Liraglutide significantly improves brain FC between the bilateral thalamus and left occipital lobe, cognitive function, and olfactory thresholds, suggesting neuroprotective effects beyond its metabolic benefits. In contrast, Dapagliflozin and Acarbose did not exhibit significant effects on olfactory, cognitive, or brain function protection.
[Keywords] type 2 diabetes mellitus；anti-diabetic drugs；glucagon-like peptide-1 receptor agonists；functional connectivity；olfactory neural circuitry；magnetic resonance imaging

WU Min1   LI Xin2   ZHANG Wen2   LI Weiping1   ZHANG Yi2   LI Qian2   SHEN Xinyi2   ZHANG Xin1, 2   JI Cheng3   BI Yan4   ZHANG Bing1, 2*  

1 Department of Radiology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, China

2 Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing 210008, China

3 Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing 210008, China

4 Department of Endocrinology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing 210008, China

Corresponding author: ZHANG B, E-mail: zhangbing_nanjing@nju.edu.cn

Conflicts of interest   None.

Received  2025-01-26
Accepted  2025-05-07
DOI: 10.12015/issn.1674-8034.2025.06.002
Cite this article as: WU M, LI X, ZHANG W, et al. Investigation of the value of olfactory neural circuit remodeling in T2DM patients treated with three anti-diabetic drugs[J]. Chin J Magn Reson Imaging, 2025, 16(6): 10-20, 26. DOI:10.12015/issn.1674-8034.2025.06.002.

[1]
GBD 2021 DISEASES AND INJURIES COLLABORATORS. Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021[J]. Lancet, 2024, 403(10440): 2133-2161. DOI: 10.1016/s0140-6736(24)00757-8.
[2]
ARANGO C, DRAGIOTI E, SOLMI M, et al. Risk and protective factors for mental disorders beyond genetics: an evidence‐based atlas[J]. World Psychiatry, 2021, 20(3): 417-436. DOI: 10.1002/wps.20894.
[3]
LIVINGSTON G, SOMMERLAD A, ORGETA V, et al. Dementia prevention, intervention, and care[J]. Lancet, 2017, 390(10113): 2673-2734. DOI: 10.1016/s0140-6736(17)31363-6.
[4]
AHMAD F, KARAN A, SHARMA R, et al. Evolving therapeutic interventions for the management and treatment of Alzheimer's disease[J/OL]. Ageing Res Rev, 2024, 95: 102229 [2025-01-26]. https://doi.org/10.1016/j.arr.2024.102229. DOI: 10.1016/j.arr.2024.102229.
[5]
NAGAYACH A, BHASKAR R, GHOSH S, et al. Advancing the understanding of diabetic encephalopathy through unravelling pathogenesis and exploring future treatment perspectives[J/OL]. Ageing Res Rev, 2024, 100: 102450 [2025-01-26]. https://doi.org/10.1016/j.arr.2024.102450. DOI: 10.1016/j.arr.2024.102450.
[6]
RIZZO M R, DI MEO I, POLITO R, et al. Cognitive impairment and type 2 diabetes mellitus: Focus of SGLT2 inhibitors treatment[J/OL]. Pharmacol Res, 2022, 176: 106062 [2025-01-26]. https://doi.org/10.1016/j.phrs.2022.106062. DOI: 10.1016/j.phrs.2022.106062.
[7]
PELLE M C, ZAFFINA I, GIOFRÈ F, et al. Potential Role of Glucagon-like Peptide-1 Receptor Agonists in the Treatment of Cognitive Decline and Dementia in Diabetes Mellitus[J/OL]. Int J Mol Sci, 2023, 24(14): 11301 [2025-01-26]. https://pmc.ncbi.nlm.nih.gov/articles/PMC10379573. DOI: 10.3390/ijms241411301.
[8]
BOCCARDI V, MURASECCO I, MECOCCI P. Diabetes drugs in the fight against Alzheimer's disease[J/OL]. Ageing Res Rev, 2019, 54: 100936 [2025-01-26]. https://doi.org/10.1016/j.arr.2019.100936. DOI: 10.1016/j.arr.2019.100936.
[9]
LUO A, XIE Z, WANG Y, et al. Type 2 diabetes mellitus-associated cognitive dysfunction: Advances in potential mechanisms and therapies[J/OL]. Neurosci Biobehav Rev, 2022, 137: 104642 [2025-01-26]. https://doi.org/10.1016/j.neubiorev.2022.104642. DOI: 10.1016/j.neubiorev.2022.104642.
[10]
MüLLER T D, FINAN B, BLOOM S R, et al. Glucagon-like peptide 1 (GLP-1)[J]. Mol Metab, 2019, 30: 72-130. DOI: 10.1016/j.molmet.2019.09.010.
[11]
CUKIERMAN-YAFFE T, GERSTEIN H C, COLHOUN H M, et al. Effect of dulaglutide on cognitive impairment in type 2 diabetes: an exploratory analysis of the REWIND trial[J]. Lancet Neurol, 2020, 19(7): 582-590. DOI: 10.1016/s1474-4422(20)30173-3.
[12]
KYU SIK K, JOON SEOK P, EUNSANG H, et al. GLP-1 increases preingestive satiation via hypothalamic circuits in mice and humans[J]. Science, 2024, 385(6707): 438-446. DOI: 10.1126/science.adj2537.
[13]
HöLSCHER C. The incretin hormones glucagonlike peptide 1 and glucose‐dependent insulinotropic polypeptide are neuroprotective in mouse models of Alzheimer's disease[J]. Alzheimers Dement, 2014, 10(1Suppl): S47-S54.. DOI: 10.1016/j.jalz.2013.12.009.
[14]
AU H C T, ZHENG Y J, LE G H, et al. A systematic review in effects of glucagon-like peptide-1 (GLP-1) mono-agonists on functional connectivity: Target engagement and rationale for the development in mental disorders[J]. J Affect Disord, 2025, 370: 321-327. DOI: 10.1016/j.jad.2024.11.019.
[15]
ZHAO H, SHAO H, NIU Y M, et al. Research progress on the role of antidiabetic drugs in treatment of cognitive deficitsin patients with Alzheimer's disease[J]. The Chinese Journal of Clinical Pharmacology, 2017, 33(23): 2493-2496. DOI: 10.13699/j.cnki.1001-6821.2017.23.049.
[16]
NEUEN B L, HEERSPINK H J L, VART P, et al. Estimated Lifetime Cardiovascular, Kidney, and Mortality Benefits of Combination Treatment With SGLT2 Inhibitors, GLP-1 Receptor Agonists, and Nonsteroidal MRA Compared With Conventional Care in Patients With Type 2 Diabetes and Albuminuria[J]. Circulation, 2024, 149(6): 450-462. DOI: 10.1161/circulationaha.123.067584.
[17]
BROWN E, HEERSPINK H J L, CUTHBERTSON D J, et al. SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications[J]. Lancet, 2021, 398(10296): 262-276. DOI: 10.1016/s0140-6736(21)00536-5.
[18]
PAWLOS A, BRONCEL M, WOŹNIAK E, et al. Neuroprotective Effect of SGLT2 Inhibitors[J/OL]. Molecules, 2021, 26(23): 7213 [2025-01-26]. https://pmc.ncbi.nlm.nih.gov/articles/PMC8659196. DOI: 10.3390/molecules26237213.
[19]
GALLO M, CANDIDO R, DE MICHELI A, et al. Acarbose vs metformin for new-onset type 2 diabetes[J/OL]. Lancet Diabetes Endocrinol, 2014, 2(2): 104 [2025-01-26]. https://www.thelancet.com/journals/landia/article/PIIS2213-8587(13)70217-1/fulltext. DOI: 10.1016/s2213-8587(13)70217-1.
[20]
ZACCARDI F, DHALWANI N N, DALES J, et al. Comparison of glucose-lowering agents after dual therapy failure in type 2 diabetes: A systematic review and network meta-analysis of randomized controlled trials[J]. Diabetes Obes Metab, 2018, 20(4): 985-997. DOI: 10.1111/dom.13185.
[21]
TSAPAS A, AVGERINOS I, KARAGIANNIS T, et al. Comparative Effectiveness of Glucose-Lowering Drugs for Type 2 Diabetes: A Systematic Review and Network Meta-analysis[J]. Ann Intern Med, 2020, 173(4): 278-286. DOI: 10.7326/m20-0864.
[22]
ZHANG Z, ZHANG B, WANG X, et al. Olfactory Dysfunction Mediates Adiposity in Cognitive Impairment of Type 2 Diabetes: Insights From Clinical and Functional Neuroimaging Studies[J]. Diabetes Care, 2019, 42(7): 1274-1283. DOI: 10.2337/dc18-2584.
[23]
ZHANG Z, ZHANG B, WANG X, et al. Altered Odor-Induced Brain Activity as an Early Manifestation of Cognitive Decline in Patients With Type 2 Diabetes[J]. Diabetes, 2018, 67(5): 994-1006. DOI: 10.2337/db17-1274.
[24]
CHENG H, ZHANG Z, ZHANG B, et al. Enhancement of Impaired Olfactory Neural Activation and Cognitive Capacity by Liraglutide, but Not Dapagliflozin or Acarbose, in Patients With Type 2 Diabetes: A 16-Week Randomized Parallel Comparative Study[J]. Diabetes Care, 2022, 45(5): 1201-1210. DOI: 10.2337/dc21-2064.
[25]
XIN H, FU Y, WEN H, et al. Cognition and motion dysfunction-associated brain functional network disruption in diabetic peripheral neuropathy[J/OL]. Hum Brain Mapp, 2024, 45(1): e26563 [2025-01-26]. https://pmc.ncbi.nlm.nih.gov/articles/PMC10785193. DOI: 10.1002/hbm.26563.
[26]
ZHANG D, HUANG Y, LIU S, et al. Structural and functional connectivity alteration patterns of the cingulate gyrus in Type 2 diabetes[J]. Ann Clin Transl Neurol, 2023, 10(12): 2305-2315. DOI: 10.1002/acn3.51918.
[27]
JING J, LIU C, ZHU W, et al. Increased Resting-State Functional Connectivity as a Compensatory Mechanism for Reduced Brain Volume in Prediabetes and Type 2 Diabetes[J]. Diabetes Care, 2023, 46(4): 819-827. DOI: 10.2337/dc22-1998.
[28]
LU J M. Study on olfactory functional magnetic resonance imaging in early diagnosis of Alzheimer's disease[D]. Nanjing University, 2019. DOI: 10.27235/d.cnki.gnjiu.2019.001315.
[29]
Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2019[J]. Diabetes Care, 2019, 42(Suppl 1): S13-S28. DOI: 10.2337/dc19-S002.
[30]
BIESSELS G J, DESPA F. Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications[J]. Nat Rev Endocrinol, 2018, 14(10): 591-604. DOI: 10.1038/s41574-018-0048-7.
[31]
KAHN S E, HULL R L, UTZSCHNEIDER K M. Mechanisms linking obesity to insulin resistance and type 2 diabetes[J]. Nature, 2006, 444(7121): 840-846. DOI: 10.1038/nature05482.
[32]
DRUCKER D J. Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1[J]. Cell Metab, 2018, 27(4): 740-756. DOI: 10.1016/j.cmet.2018.03.001.
[33]
MASELLI D B, CAMILLERI M. Effects of GLP-1 and Its Analogs on Gastric Physiology in Diabetes Mellitus and Obesity[J]. Adv Exp Med Biol, 2021, 1307: 171-192. DOI: 10.1007/5584_2020_496.
[34]
MENG L, LI X Y, SHEN L, et al. Type 2 Diabetes Mellitus Drugs for Alzheimer's Disease: Current Evidence and Therapeutic Opportunities[J]. Trends Mol Med, 2020, 26(6): 597-614. DOI: 10.1016/j.molmed.2020.02.002.
[35]
MONNEY M, JORNAYVAZ F R, GARIANI K. GLP-1 receptor agonists effect on cognitive function in patients with and without type 2 diabetes[J/OL]. Diabetes Metab, 2023, 49(5): 101470 [2025-01-26]. https://doi.org/10.1016/j.diabet.2023.101470. DOI: 10.1016/j.diabet.2023.101470.
[36]
GAUTIER J F, CHOUKEM S P, GIRARD J. Physiology of incretins (GIP and GLP-1) and abnormalities in type 2 diabetes[J]. Diabetes Metab, 2008, 34 (Suppl 2): S65-S72. DOI: 10.1016/s1262-3636(08)73397-4.
[37]
DU H, MENG X, YAO Y, et al. The mechanism and efficacy of GLP-1 receptor agonists in the treatment of Alzheimer's disease[J/OL]. Front Endocrinol (Lausanne), 2022, 13: 1033479 [2025-01-26]. https://pmc.ncbi.nlm.nih.gov/articles/PMC9714676. DOI: 10.3389/fendo.2022.1033479.
[38]
MONTANER M, DENOM J, SIMON V, et al. A neuronal circuit driven by GLP-1 in the olfactory bulb regulates insulin secretion[J/OL]. Nat Commun, 2024, 15(1): 6941 [2025-01-26]. https://www.nature.com/articles/s41467-024-51076-4. DOI: 10.1038/s41467-024-51076-4.
[39]
MONTANER M, DENOM J, JIANG W, et al. The local GLP-1 system in the olfactory bulb is required for odor-evoked cephalic phase of insulin release in mice[J/OL]. Mol Metab, 2023, 73: 101738 [2025-01-26]. https://pmc.ncbi.nlm.nih.gov/articles/PMC10212752. DOI: 10.1016/j.molmet.2023.101738.
[40]
FAOUR M, MAGNAN C, GURDEN H, et al. Olfaction in the context of obesity and diabetes: Insights from animal models to humans[J/OL]. Neuropharmacology, 2022, 206: 108923 [2025-01-26]. https://doi.org/10.1016/j.neuropharm.2021.108923. DOI: 10.1016/j.neuropharm.2021.108923.
[41]
LISMAN J, BUZSÁKI G, EICHENBAUM H, et al. Viewpoints: how the hippocampus contributes to memory, navigation and cognition[J]. Nat Neurosci, 2017, 20(11): 1434-1447. DOI: 10.1038/nn.4661.
[42]
ZHANG S, LI C S R. Functional Connectivity Parcellation of the Human Thalamus by Independent Component Analysis[J]. Brain Connect, 2017, 7(9): 602-616. DOI: 10.1089/brain.2017.0500.
[43]
SHINE J M, LEWIS L D, GARRETT D D, et al. The impact of the human thalamus on brain-wide information processing[J]. Nat Rev Neurosci, 2023, 24(7): 416-430. DOI: 10.1038/s41583-023-00701-0.
[44]
VARELA C. Thalamic neuromodulation and its implications for executive networks[J/OL]. Front Neural Circuits, 2014, 8: 69 [2025-01-26]. https://pmc.ncbi.nlm.nih.gov/articles/PMC4068295. DOI: 10.3389/fncir.2014.00069.
[45]
HWANG K, SHINE J M, COLE M W, et al. Thalamocortical contributions to cognitive task activity[J/OL]. Elife, 2022, 11: e81282 [2025-01-26]. https://pmc.ncbi.nlm.nih.gov/articles/PMC9799971/. DOI: 10.7554/eLife.81282.
[46]
HWANG K, SHINE J M, BRUSS J, et al. Neuropsychological evidence of multi-domain network hubs in the human thalamus[J/OL]. Elife, 2021, 10: e69480 [2025-01-26]. https://pmc.ncbi.nlm.nih.gov/articles/PMC8526062. DOI: 10.7554/eLife.69480.
[47]
KIM J Y, KU Y S, KIM H J, et al. Oral diabetes medication and risk of dementia in elderly patients with type 2 diabetes[J]. Diabetes Res Clin Pract, 2019, 154: 116-123. DOI: 10.1016/j.diabres.2019.07.004.
[48]
Society of Diabetes, Chinese Medical Association. Guideline for the prevention and treatment of type 2 diabetes mellitus in China (2020 edition)[J]. Chinese Journal of Diabetes, 2021, 13(4): 315-409. DOI: 10.3760/cma.j.cn115791-20210221-00095.
[49]
SHAEFER C F, Jr., KUSHNER P, AGUILAR R. User's guide to mechanism of action and clinical use of GLP-1 receptor agonists[J]. Postgrad Med, 2015, 127(8): 818-826. DOI: 10.1080/00325481.2015.1090295.
[50]
PELLEGRINO R, FARRUGGIA M C, SMALL D M, et al. Post-traumatic olfactory loss and brain response beyond olfactory cortex[J/OL]. Sci Rep, 2021, 11(1): 4043 [2025-01-26]. https://pmc.ncbi.nlm.nih.gov/articles/PMC7889874. DOI: 10.1038/s41598-021-83621-2.

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