Vol 72, No 6 (2021)
Original paper
Published online: 2021-10-06

open access

Page views 7197
Article views/downloads 740
Get Citation

Connect on Social Media

Connect on Social Media

Neu-P11 — a novel melatonin receptor agonist, could improve the features of type-2 diabetes mellitus in rats

Xiuping Li1, Juan He2, Xing Li3, Yuxian Li4, Yang Zhou5, Shichang Cai6
Pubmed: 34647606
Endokrynol Pol 2021;72(6):634-642.


Introduction: Melatonin (Mel) and its receptors are promising for glycaemic control in patients with type 2 diabetes mellitus (T2DM) and its complications, but there is significant heterogeneity among studies. This study aims to investigate the effects of Mel receptor agonist Neu-P11 on glucose metabolism, immunity, and islet function in T2DM rats.

Material and methods: In this study, SD rats were treated with a high-fat diet and streptozotocin (STZ) to establish a T2DM model. The glucose oxidase method was used to measure blood glucose levels. Glucose and insulin tolerance tests were used to assess glucose metabolism. Haematoxylin-eosin staining was used to observe pancreatic tissue injury. The apoptosis of islet β cells was analysed by TUNEL and insulin staining. Reactive oxygen species (ROS) levels and immune cell expression were analysed by flow cytometry. IF was used to analyse the activation of microglia. The immunoglobulins: IgA, IgG, IgM, tumour necrosis factor α (TNF-α), interleukins IL-10 and IL-1β, interferon γ (IFN-γ), C-peptide, and insulin levels were determined by ELISA. The expression of CD11b, CD86, cleaved caspase 3, p21, and P16 proteins were analysed by western blot.

Results: The results showed that the blood glucose level increased, insulin resistance occurred, spleen coefficient and ROS levels increased, humoral immunity in peripheral blood decreased, and inflammation increased in the model group compared to the control group. After Mel and Neu-P11 treatment, the blood glucose level decreased significantly, insulin sensitivity improved, spleen coefficient and ROS levels decreased, humoral immunity in peripheral blood was enhanced, and inflammation improved in T2DM rats. Brain functional analysis of T2DM rats showed that microglia cells were activated, TNF-α and IL-β levels were increased, and IL-10 levels were decreased. Mel and Neu-P11 treatment reversed these indexes. Functional analysis of islets in T2DM rats showed that islet structure inflammation was impaired, islet β cells were apoptotic, p21 and p16 protein expressions were increased, and blood C-peptide and insulin were decreased.
Mel and Neu-P11 treatment restored the function of pancreatic b cells and improved the damage of pancreatic tissue.

Conclusion: Melatonin and its receptor Neu-P11 can reduce the blood glucose level, enhance humoral and cellular immunity, inhibit microglia activation and inflammation, and repair islet β cell function, and this improve the characterization of T2DM-related diseases.

Article available in PDF format

View PDF Download PDF file


  1. Kaul N, Ali S. Genes, Genetics, and Environment in Type 2 Diabetes: Implication in Personalized Medicine. DNA Cell Biol. 2016; 35(1): 1–12.
  2. Artasensi A, Pedretti A, Vistoli G, et al. Type 2 Diabetes Mellitus: A Review of Multi-Target Drugs. Molecules. 2020; 25(8).
  3. American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2021. Diabetes Care. 2020; 44(Suppl 1): S15–S33.
  4. Cho NH, Shaw JE, Karuranga S, et al. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018; 138: 271–281.
  5. Saeedi P, Petersohn I, Salpea P, et al. IDF Diabetes Atlas Committee. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9 edition. Diabetes Res Clin Pract. 2019; 157: 107843.
  6. Hallakou-Bozec S, Kergoat M, Moller DE, et al. Imeglimin preserves islet β-cell mass in Type 2 diabetic ZDF rats. Endocrinol Diabetes Metab. 2021; 4(2): e00193.
  7. Saisho Y. Importance of Beta Cell Function for the Treatment of Type 2 Diabetes. J Clin Med. 2014; 3(3): 923–943.
  8. Boutin JA, Jockers R. Melatonin controversies, an update. J Pineal Res. 2021; 70(2): e12702.
  9. Calvo JR, González-Yanes C, Maldonado MD. The role of melatonin in the cells of the innate immunity: a review. J Pineal Res. 2013; 55(2): 103–120.
  10. Vishwas DK, Mukherjee A, Haldar C. Melatonin improves humoral and cell-mediated immune responses of male golden hamster following stress induced by dexamethasone. J Neuroimmunol. 2013; 259(1-2): 17–25.
  11. Wojcik M, Krawczyk M, Wojcik P, et al. Melatonin as a Pleiotropic Molecule with Therapeutic Potential for Type 2 Diabetes and Cancer. Curr Med Chem. 2017; 24(35): 3829–3850.
  12. Rahman MdM, Kwon HS, Kim MJ, et al. Melatonin supplementation plus exercise behavior ameliorate insulin resistance, hypertension and fatigue in a rat model of type 2 diabetes mellitus. Biomed Pharmacother. 2017; 92: 606–614.
  13. Karamitri A, Jockers R. Melatonin in type 2 diabetes mellitus and obesity. Nat Rev Endocrinol. 2019; 15(2): 105–125.
  14. He P, Ouyang X, Zhou S, et al. A novel melatonin agonist Neu-P11 facilitates memory performance and improves cognitive impairment in a rat model of Alzheimer' disease. Horm Behav. 2013; 64(1): 1–7.
  15. She M, Deng X, Guo Z, et al. NEU-P11, a novel melatonin agonist, inhibits weight gain and improves insulin sensitivity in high-fat/high-sucrose-fed rats. Pharmacol Res. 2009; 59(4): 248–253.
  16. Zhou J, Zhang J, Luo X, et al. Neu-P11, a novel MT1/MT2 agonist, reverses diabetes by suppressing the hypothalamic-pituitary-adrenal axis in rats. Eur J Pharmacol. 2017; 812: 225–233.
  17. Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol. 2018; 14(2): 88–98.
  18. Chen HS, Su LT, Lin SZ, et al. Increased risk of urinary tract calculi among patients with diabetes mellitus--a population-based cohort study. Urology. 2012; 79(1): 86–92.
  19. Jalil A, Barlaan PI, Fung BK, et al. Hand infection in diabetic patients. Hand Surg. 2011; 16(3): 307–312.
  20. Pal R, Bhadada SK. COVID-19 and diabetes mellitus: An unholy interaction of two pandemics. Diabetes Metab Syndr. 2020; 14(4): 513–517.
  21. Öztürk AM, Uysal S, Yıldırım Şımşır I, et al. Hand infection in patients with diabetes: a series of 17 cases and a pooled analysis of the literature. Turk J Med Sci. 2018; 48(2): 372–377.
  22. Anderson G, Reiter RJ. Melatonin: Roles in influenza, Covid-19, and other viral infections. Rev Med Virol. 2020; 30(3): e2109.
  23. Martín Giménez VM, Inserra F, Tajer CD, et al. Lungs as target of COVID-19 infection: Protective common molecular mechanisms of vitamin D and melatonin as a new potential synergistic treatment. Life Sci. 2020; 254: 117808.
  24. Heydemann A. An Overview of Murine High Fat Diet as a Model for Type 2 Diabetes Mellitus. J Diabetes Res. 2016; 2016: 2902351.
  25. Tan X, Egmond Lv, Chapman C, et al. Aiding sleep in type 2 diabetes: therapeutic considerations. Lancet Diabetes Endocrinol. 2018; 6(1): 60–68.
  26. Li X, Cai S, Yin W, et al. Role of Neu-p11/luzindole in the regulation of insulin signaling pathways and insulin resistance. Acta Biochim Biophys Sin (Shanghai). 2016; 48(5): 485–486.
  27. Oertel R, Goltz L, Kirch W. Elucidation of Neu-P11 metabolism in urine of volunteers by liquid chromatography-tandem mass spectrometry. J Chromatogr A. 2013; 1278: 69–75.
  28. Li X, Cai S, Yin W, et al. Neu-p11 reduces clock/apelin expression in insulin-resistant mouse adipocyte model. Acta Biochim Biophys Sin (Shanghai). 2013; 45(9): 798–800.
  29. Karvani M, Kapoukranidou D. Implementation of Imaging Methods in Evaluation of T2DM-Correlated Brain Alterations and Cognitive Dysfunction. Acta Inform Med. 2020; 28(2): 138.
  30. Lee JH, Choi Y, Jun C, et al. Neurocognitive changes and their neural correlates in patients with type 2 diabetes mellitus. Endocrinol Metab (Seoul). 2014; 29(2): 112–121.
  31. Hayden MR. Type 2 Diabetes Mellitus Increases The Risk of Late-Onset Alzheimer's Disease: Ultrastructural Remodeling of the Neurovascular Unit and Diabetic Gliopathy. Brain Sci. 2019; 9(10).
  32. Bare Y, Marhendra AP, Sasase T, et al. Differential Expression of IL-10 Gene and Protein in Target Tissues of Rattus Norvegicus Strain Wistar Model Type 2 Diabetes Mellitus (T2DM). Acta Inform Med. 2018; 26(2): 87–92.
  33. Tomita T. Apoptosis in pancreatic β-islet cells in Type 2 diabetes. Bosn J Basic Med Sci. 2016; 16(3): 162–179.
  34. Eizirik DL, Pasquali L, Cnop M. Pancreatic β-cells in type 1 and type 2 diabetes mellitus: different pathways to failure. Nat Rev Endocrinol. 2020; 16(7): 349–362.
  35. Rorsman P, Ashcroft FM. Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men. Physiol Rev. 2018; 98(1): 117–214.
  36. Wang J, Yang X, Zhang J. Bridges between mitochondrial oxidative stress, ER stress and mTOR signaling in pancreatic β cells. Cell Signal. 2016; 28(8): 1099–1104.
  37. Costes S, Boss M, Thomas AP, et al. Activation of Melatonin Signaling Promotes β-Cell Survival and Function. Mol Endocrinol. 2015; 29(5): 682–692.
  38. Li Y, Wu H, Liu N, et al. Melatonin exerts an inhibitory effect on insulin gene transcription via MTNR1B and the downstream Raf‑1/ERK signaling pathway. Int J Mol Med. 2018; 41(2): 955–961.
  39. Hardeland R. Melatonin and Synthetic Melatoninergic Agonists in Psychiatric and Age-associated Disorders: Successful and Unsuccessful Approaches. Curr Pharm Des. 2016; 22(8): 1086–1101.
  40. She M, Hu X, Su Z, et al. Piromelatine, a novel melatonin receptor agonist, stabilizes metabolic profiles and ameliorates insulin resistance in chronic sleep restricted rats. Eur J Pharmacol. 2014; 727: 60–65.
  41. Zhou J, Wang D, Luo X, et al. Melatonin Receptor Agonist Piromelatine Ameliorates Impaired Glucose Metabolism in Chronically Stressed Rats Fed a High-Fat Diet. J Pharmacol Exp Ther. 2018; 364(1): 55–69.