- Title: Title: Serum Ceramide Species and Meteorin-Like Protein as a Novel Combined Biomarker Panel for the Diagnosis of Early-Stage Type 2 Diabetes Mellitus

Novel Combined Biomarker Panel for the Diagnosis of Early-Stage Type 2 Diabetes Mellitus

  • Xiaoyu Zhao School of Medicine, Xuchang University, Xuchang,Henan , 461000, China
  • Muhriddin Pulatov 2. Department of Medicine, Termez University of Economics and Service, Termez, Uzbekistan,
  • Shakhlokhon Kurbanova 3. Department of Psychology and medicine, Mamun University. Khiva, Uzbekistan.
Keywords: Type 2 Diabetes Mellitus; Biomarkers; Ceramides; Sphingolipids; Meteorin-like protein; Insulin Resistance; Lipotoxicity.

Abstract


Background: The identification of biomarkers reflecting early pathophysiological changes in Type 2 Diabetes Mellitus (T2DM) is crucial for timely intervention. Ceramides, lipotoxic sphingolipids, and Meteorin-like protein (Metrnl), an insulin-sensitizing adipomyokine, are mechanistically linked to T2DM development.
Aims: To compare serum levels of specific ceramides (Cer-16, Cer-18, Cer-24, Cer-24:1) and Metrnl between T2DM patients and controls, and to evaluate their individual and combined diagnostic accuracy.
Methods: This case-control study included 80 newly diagnosed T2DM patients and 80 age- and BMI-matched normoglycemic controls. Fasting serum was analysed for standard biochemical parameters. Ceramide species were quantified by LC-MS/MS. Serum Metrnl was measured via ELISA.
Results: The T2DM group exhibited significantly elevated levels of Cer-16 (p<0.001) and Cer-18 (p<0.01), and reduced levels of Cer-24 and Metrnl (both p<0.001). The Cer-16/Cer-24 ratio was significantly higher in T2DM. Strong correlations were found between these biomarkers and HOMA-IR/HbA1c. A multivariate logistic regression model combining Cer-16, Cer-24, and Metrnl yielded an AUC of 0.93 for T2DM discrimination, superior to any single marker.
Conclusions: A distinct ceramide profile (high Cer-16, low Cer-24) coupled with low Metrnl characterizes early T2DM. Their combination forms a synergistic biomarker panel with high diagnostic potential, mirroring the dual pathology of lipotoxicity and impaired metabolic protection.

References

1. American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2023. Diabetes Care 2023;46(Suppl 1):S19-S40.
2. Srikanthan K, Shapiro JI, Sodhi K. The role of ceramides in diabetes and cardiovascular disease regulation of ceramides by adipokines. Front Endocrinol (Lausanne) 2020;11:569250.
3. Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiol Rev 2018;98(4):2133-223.
4. Raichur S, Wang ST, Chan PW, et al. CerS2 haploinsufficiency inhibits β-oxidation and confers susceptibility to diet-induced steatohepatitis and insulin resistance. Cell Metab 2014;20(4):687-95.
5. Turpin-Nolan SM, Brüning JC. The role of ceramides in metabolic disorders: when size and localization matters. Nat Rev Endocrinol 2020;16(4):224-33.
6. Park JW, Park WJ, Kuperman Y, et al. Ceramide synthase 2 deficiency aggravates AOM-DSS-induced colitis in mice: role of colon barrier integrity. Cell Mol Gastroenterol Hepatol 2017;4(1):63-81.
7. Lemaitre RN, Yu C, Hoofnagle A, et al. Circulating sphingolipids, insulin, HOMA-IR, and HOMA-B: The Strong Heart Family Study. Diabetes 2018;67(8):1663-72.
8. Scheja L, Heeren J. The endocrine function of adipose tissues in health and cardiometabolic disease. Nat Rev Endocrinol 2019;15(9):507-24.
9. Rao RR, Long JZ, White JP, et al. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 2014;157(6):1279-91.
10. Jung TW, Lee SH, Kim HC, et al. METRNL attenuates lipid-induced inflammation and insulin resistance via AMPK or PPARδ-dependent pathways in skeletal muscle of mice. Exp Mol Med 2018;50(9):1-11.
11. Wang K, Li F, Wang C, et al. Serum levels of Meteorin-like protein (Metrnl) are associated with the presence and severity of coronary artery disease. Tohoku J Exp Med 2019;247(3):173-81.
12. Li Z, Wang G, Zhu YJ, et al. The relationship between circulating Metrnl levels and type 2 diabetes mellitus: A systematic review and meta-analysis. Diabetes Res Clin Pract 2021;173:108687.
13. El-Ashmawy HM, Selim FO, Hosny TA, et al. Association of low serum Metrnl concentrations with hyperglycemia and dyslipidemia in type 2 diabetic patients. Diabetes Metab Syndr 2021;15(1):17-22.
14. International Expert Committee. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 2009;32(7):1327-34.
15. Kasumov T, Li L, Li M, et al. Ceramide as a mediator of non-alcoholic fatty liver disease and associated atherosclerosis. PLoS One 2015;10(5):e0126910.
16. Stratford S, Hoehn KL, Liu F, et al. 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.
17. Holland WL, Brozinick JT, Wang LP, et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab 2007;5(3):167-79.
18. Grosch S, Schiffmann S, Geisslinger G. Chain length-specific properties of ceramides. Prog Lipid Res 2012;51(1):50-62.
19. Laaksonen R, Ekroos K, Sysi-Aho M, et al. Plasma ceramides predict cardiovascular death in patients with stable coronary artery disease and acute coronary syndromes beyond LDL-cholesterol. Eur Heart J 2016;37(25):1967-76.
20. Lee JH, Kang YE, Chang JY, et al. An engineered Meteorin-like molecule with increased receptor binding affinity improves glucose metabolism in obese mice. J Biol Chem 2020;295(25):8569-81.
21. Lee JO, Byun WS, Kang MJ, et al. The myokine meteorin-like (Metrnl) improves glucose tolerance in both skeletal muscle cells and mice by targeting AMPKα2. FEBS J 2020;287(10):2087-104.
22. Al-Kuraishy HM, Al-Gareeb AI, Alexiou A, et al. Metrnl and irisin: new adipokines as therapeutic targets in metabolic dysregulation. Endocr Metab Immune Disord Drug Targets 2022;22(13):1277-87.
23. Meikle PJ, Summers SA. Sphingolipids and phospholipids in insulin resistance and related metabolic disorders. Nat Rev Endocrinol 2017;13(2):79-91.
24. Sokolowska E, Blachnio-Zabielska. The role of ceramides in insulin resistance. Front Endocrinol (Lausanne) 2019;10:577.
25. Guasch-Ferré M, Hruby A, Toledo E, et al. Metabolomics in prediabetes and diabetes: a systematic review and meta-analysis. Diabetes Care 2016;39(5):833-46.
26. Ottosson F, Smith E, Melander O, et al. Altered asparagine and glutamate homeostasis precede coronary artery disease and type 2 diabetes. J Clin Endocrinol Metab 2018;103(8):3060-9.
27. Wigger L, Cruciani-Guglielmacci C, Nicolas A, et al. Plasma Dihydroceramides Are Diabetes Susceptibility Biomarker Candidates in Mice and Humans. Cell Rep 2017;18(9):2269-79.
28. Bluher M. Metabolically healthy obesity. Endocr Rev 2020;41(3):bnaa004.
29. Chew WS, Torta F, Ji S, et al. Large-scale lipidomics identifies associations between plasma sphingolipids and T2DM incidence. JCI Insight 2019;5(13):e126925.
Published
2026/05/11
Section
Original paper