A Review of the Mechanisms of Abnormal Ceramide Metabolism in Type 2 Diabetes Mellitus, Alzheimer's Disease, and Their Co-morbidities

Overview

Journal Front Pharmacol

Date 2024 Feb 21

PMID 38379904

Authors

Yun Pan

Jieying Li

Panjie Lin

Lihua Wan

Yiqian Qu

Lingyong Cao

Lei Wang

Affiliations

Soon will be listed here.

Abstract

The global prevalence of type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) is rapidly increasing, revealing a strong association between these two diseases. Currently, there are no curative medication available for the comorbidity of T2DM and AD. Ceramides are structural components of cell membrane lipids and act as signal molecules regulating cell homeostasis. Their synthesis and degradation play crucial roles in maintaining metabolic balance , serving as important mediators in the development of neurodegenerative and metabolic disorders. Abnormal ceramide metabolism disrupts intracellular signaling, induces oxidative stress, activates inflammatory factors, and impacts glucose and lipid homeostasis in metabolism-related tissues like the liver, skeletal muscle, and adipose tissue, driving the occurrence and progression of T2DM. The connection between changes in ceramide levels in the brain, amyloid β accumulation, and tau hyper-phosphorylation is evident. Additionally, ceramide regulates cell survival and apoptosis through related signaling pathways, actively participating in the occurrence and progression of AD. Regulatory enzymes, their metabolites, and signaling pathways impact core pathological molecular mechanisms shared by T2DM and AD, such as insulin resistance and inflammatory response. Consequently, regulating ceramide metabolism may become a potential therapeutic target and intervention for the comorbidity of T2DM and AD. The paper comprehensively summarizes and discusses the role of ceramide and its metabolites in the pathogenesis of T2DM and AD, as well as the latest progress in the treatment of T2DM with AD.

Citing Articles

Environmental Temperature Variation Affects Brain Lipid Composition in Adult Zebrafish ().

Maffioli E, Nonnis S, Negri A, Fontana M, Frabetti F, Rossi A Int J Mol Sci. 2024; 25(17).

PMID: 39273578 PMC: 11394874. DOI: 10.3390/ijms25179629.

References

Kim S, Winter K, Nian C, Tsuneoka M, Koda Y, McIntosh C . Glucose-dependent insulinotropic polypeptide (GIP) stimulation of pancreatic beta-cell survival is dependent upon phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) signaling, inactivation of the forkhead transcription factor Foxo1, and.... J Biol Chem. 2005; 280(23):22297-307. DOI: 10.1074/jbc.M500540200. View

Akyol O, Akyol S, Chou M, Chen S, Liu C, Selek S . Lipids and lipoproteins may play a role in the neuropathology of Alzheimer's disease. Front Neurosci. 2023; 17:1275932. PMC: 10687420. DOI: 10.3389/fnins.2023.1275932. View

Verdile G, Keane K, Cruzat V, Medic S, Sabale M, Rowles J . Inflammation and Oxidative Stress: The Molecular Connectivity between Insulin Resistance, Obesity, and Alzheimer's Disease. Mediators Inflamm. 2015; 2015:105828. PMC: 4674598. DOI: 10.1155/2015/105828. View

Maceyka M, Spiegel S . Sphingolipid metabolites in inflammatory disease. Nature. 2014; 510(7503):58-67. PMC: 4320971. DOI: 10.1038/nature13475. View

Butterfield D, Poon H, St Clair D, Keller J, Pierce W, Klein J . Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment: insights into the development of Alzheimer's disease. Neurobiol Dis. 2006; 22(2):223-32. DOI: 10.1016/j.nbd.2005.11.002. View

Wang X, Song M, Li X, Su C, Yang Y, Wang K . CERS6-derived ceramides aggravate kidney fibrosis by inhibiting PINK1-mediated mitophagy in diabetic kidney disease. Am J Physiol Cell Physiol. 2023; 325(2):C538-C549. PMC: 10511179. DOI: 10.1152/ajpcell.00144.2023. View

Li Y, Chen X, Zhou M, Feng S, Peng X, Wang Y . Microglial TLR4/NLRP3 Inflammasome Signaling in Alzheimer's Disease. J Alzheimers Dis. 2023; 97(1):75-88. DOI: 10.3233/JAD-230273. View

Mowry F, Espejo-Porras F, Jin S, Quadri Z, Wu L, Bertolio M . Chronic nSMase inhibition suppresses neuronal exosome spreading and sex-specifically attenuates amyloid pathology in APP knock-in Alzheimer's disease mice. Neurobiol Dis. 2023; 184:106213. PMC: 10777534. DOI: 10.1016/j.nbd.2023.106213. View

Varma V, Oommen A, Varma S, Casanova R, An Y, Andrews R . Brain and blood metabolite signatures of pathology and progression in Alzheimer disease: A targeted metabolomics study. PLoS Med. 2018; 15(1):e1002482. PMC: 5784884. DOI: 10.1371/journal.pmed.1002482. View

10.

Saraya A, Tunvirachaisakul C, Sonpee C, Katasrila P, Sathaporn T, Tepmongkol S . Serum proinsulin levels as peripheral blood biomarkers in patients with cognitive impairment. Sci Rep. 2023; 13(1):22436. PMC: 10725871. DOI: 10.1038/s41598-023-49479-2. View

11.

Bae J, Wander P, Lemaitre R, Fretts A, Sitlani C, Bui H . Associations of plasma sphingolipids with measures of insulin sensitivity, β-cell function, and incident diabetes in Japanese Americans. Nutr Metab Cardiovasc Dis. 2023; 34(3):633-641. PMC: 10922320. DOI: 10.1016/j.numecd.2023.10.026. View

12.

Charytoniuk T, Sztolsztener K, Harasim-Symbor E, Berk K, Chabowski A, Konstantynowicz-Nowicka K . Cannabidiol - A phytocannabinoid that widely affects sphingolipid metabolism under conditions of brain insulin resistance. Biomed Pharmacother. 2021; 142:112057. DOI: 10.1016/j.biopha.2021.112057. View

13.

Kitatani K, Idkowiak-Baldys J, Hannun Y . The sphingolipid salvage pathway in ceramide metabolism and signaling. Cell Signal. 2008; 20(6):1010-8. PMC: 2422835. DOI: 10.1016/j.cellsig.2007.12.006. View

14.

Naeem A, Prakash R, Kumari N, Khan M, Quaiyoom Khan A, Uddin S . MCC950 reduces autophagy and improves cognitive function by inhibiting NLRP3-dependent neuroinflammation in a rat model of Alzheimer's disease. Brain Behav Immun. 2023; 116:70-84. DOI: 10.1016/j.bbi.2023.11.031. View

15.

Yang W, Jiang W, Guo S . Regulation of Macronutrients in Insulin Resistance and Glucose Homeostasis during Type 2 Diabetes Mellitus. Nutrients. 2023; 15(21). PMC: 10647592. DOI: 10.3390/nu15214671. View

16.

Makki B, Rahman S . Alzheimer's Disease in Diabetic Patients: A Lipidomic Prospect. Neuroscience. 2023; 530:79-94. DOI: 10.1016/j.neuroscience.2023.08.033. View

17.

Zheng X, Ho Q, Chua M, Stelmashenko O, Yeo X, Muralidharan S . Destabilization of β Cell FIT2 by saturated fatty acids alter lipid droplet numbers and contribute to ER stress and diabetes. Proc Natl Acad Sci U S A. 2022; 119(11):e2113074119. PMC: 8931238. DOI: 10.1073/pnas.2113074119. View

18.

Stratford S, Hoehn K, Liu F, Summers S . Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. J Biol Chem. 2004; 279(35):36608-15. DOI: 10.1074/jbc.M406499200. View

19.

Park M, Cha H, Kim J, Kim J, Yang H, Yoon S . NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases. Redox Biol. 2021; 41:101947. PMC: 8027773. DOI: 10.1016/j.redox.2021.101947. View

20.

Heppner F, Ransohoff R, Becher B . Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci. 2015; 16(6):358-72. DOI: 10.1038/nrn3880. View