Main Article Content
Neurological abnormalities, miR-16, Insulin resistance, Type 2 diabetes, miRNAs network, Non-enzymatic glycation
Aim: Type 2 diabetes mellites (T2DM) is a chronic metabolic disorder associated with oxidative stress, increased inflammation, altered energy metabolism and neurological abnormalities. Therefore, this study aimed to clarify some neurological ambiguities in diabetes. By considering master regulatory role of miRNAs in biological process, we evaluated some neuroactive miRNAs (miR-125a, Let-7 miRNA, miR-181c, miR-504, miR-16) and neurohormones such as Gamma-aminobutyric acid (GABA), serotonin and dopamine in T2DM patients.
Methods: This study were performed on 30 T2DM patients and 30 non-diabetic controls. The level of GABA, serotonin, dopamine and biochemical parameters were determined by specific ELISA kit in blood serum samples. Also, the relative contents of the miRNAs were evaluated by the real-time quantitative polymerase chain reaction (RT-qPCR) analysis.
Results: The obtained results show that dopamine and serotonin increased in hyperglycemia condition possibly due to upregulation of miR-181c and miR-125a and down-regulation of miR-16. The mentioned changes in miRNAs network also could be considered as a cause of insulin resistance (IR). Reduced content of miR-16 could lead to reduced glucose uptake that was observed in diabetes. Circular concentration of GABA decreased also that could be considered as a reason for IR and decreased glucose uptake. GABA is an excitatory neurotransmitter and its reduction could be a possible cause for dementia related disease.
Conclusion: This study revealed the examined miRNAs plays essential role in oxidative stress, inflammation and IR in T2DM and have therapeutic potential. Based on neuroendocrine abnormalities in diabetes, exogenous hormones could be considered as therapeutic agents to control the metabolism rate and decrease the neurological side effects in T2DM.
2. Agbu P, Carthew RW (2021). MicroRNA-mediated regulation of glucose and lipid metabolism. Nature reviews Molecular cell biology 22: 425-438.
3. Asghar M, Tayebati SK, Lokhandwala MF, Hussain T (2011). Potential dopamine-1 receptor stimulation in hypertension management. Current hypertension reports 13: 294-302.
4. Association AD (2010). Diagnosis and classification of diabetes mellitus. Diabetes care 33: S62-S69.
5. Bauduceau B, Doucet J, Bordier L, Garcia C, Dupuy O, Mayaudon H (2010). Hypoglycaemia and dementia in diabetic patients. Diabetes & metabolism 36: S106-S111.
6. Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P (2006). Risk of dementia in diabetes mellitus: a systematic review. The Lancet Neurology 5: 64-74.
7. Blázquez E, Velázquez E, Hurtado-Carneiro V, Ruiz-Albusac JM (2014). Insulin in the brain: its pathophysiological implications for States related with central insulin resistance, type 2 diabetes and Alzheimer’s disease. Frontiers in endocrinology 5: 161.
8. Das S, Ferlito M, Kent OA, Fox-Talbot K, Wang R, Liu D, Raghavachari N, Yang Y, et al. (2012). Nuclear miRNA regulates the mitochondrial genome in the heart. Circulation research 110: 1596-1603.
9. Deng J, Guo F (2019). MicroRNAs and type 2 diabetes. ExRNA 1: 1-5.
10. Derghal A, Djelloul M, Trouslard J, Mounien L (2016). An Emerging Role of micro-RNA in the Effect of the Endocrine Disruptors. Frontiers in neuroscience 10: 318.
11. Fujishiro M, Gotoh Y, Katagiri H, Sakoda H, Ogihara T, Anai M, Onishi Y, Ono H, et al. (2003). Three mitogen-activated protein kinases inhibit insulin signaling by different mechanisms in 3T3-L1 adipocytes. Molecular Endocrinology 17: 487-497.
12. Gajcy K, Lochynski S, Librowski T (2010). A role of GABA analogues in the treatment of neurological diseases. Current Medicinal Chemistry 17: 2338-2347.
13. Galer BS, Gianas A, Jensen MP (2000). Painful diabetic polyneuropathy: epidemiology, pain description, and quality of life. Diabetes research and clinical practice 47: 123-128.
14. Guay C, Regazzi R (2013). Circulating microRNAs as novel biomarkers for diabetes mellitus. Nature Reviews Endocrinology 9: 513-521.
15. Gylfe E (1978). Association between 5-hydroxytryptamine release and insulin secretion. Journal of Endocrinology 78: 239-248.
16. Huber W, Von Heydebreck A, Sültmann H, Poustka A, Vingron M (2002). Variance stabilization applied to microarray data calibration and to the quantification of differential expression. Bioinformatics 18: S96-S104.
17. Hutchison ER, Kawamoto EM, Taub DD, Lal A, Abdelmohsen K, Zhang Y, Wood Iii WH, Lehrmann E, et al. (2013). Evidence for miR‐181 involvement in neuroinflammatory responses of astrocytes. Glia 61: 1018-1028.
18. Jonik S, Marchel M, Grabowski M, Opolski G, Mazurek T (2022). Gastrointestinal Incretins—Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon-like Peptide-1 (GLP-1) beyond Pleiotropic Physiological Effects Are Involved in Pathophysiology of Atherosclerosis and Coronary Artery Disease—State of the Art. Biology 11: 288.
19. Lee DE, Brown JL, Rosa ME, Brown LA, Perry Jr RA, Wiggs MP, Nilsson MI, Crouse SF, et al. (2016). microRNA‐16 is downregulated during insulin resistance and controls skeletal muscle protein accretion. Journal of cellular biochemistry 117: 1775-1787.
20. Lim S, Deaver JW, Rosa-Caldwell ME, Lee DE, Morena Da Silva F, Cabrera AR, Schrems ER, Saling LW, et al. (2022). Muscle miR-16 deletion results in impaired insulin sensitivity and contractile function in a sex-dependent manner. American Journal of Physiology-Endocrinology and Metabolism 322: E278-E292.
21. Lin MT, Beal MF (2006). Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443: 787-795.
22. Lindholm D, Wootz H, Korhonen L (2006). ER stress and neurodegenerative diseases. Cell Death & Differentiation 13: 385-392.
23. Mcglashon JM, Gorecki MC, Kozlowski AE, Thirnbeck CK, Markan KR, Leslie KL, Kotas ME, Potthoff MJ, et al. (2015). Central serotonergic neurons activate and recruit thermogenic brown and beige fat and regulate glucose and lipid homeostasis. Cell metabolism 21: 692-705.
24. Paulmann N, Grohmann M, Voigt J-P, Bert B, Vowinckel J, Bader M, Skelin M, Jevšek M, et al. (2009). Intracellular serotonin modulates insulin secretion from pancreatic β-cells by protein serotonylation. PLoS biology 7: e1000229.
25. Pijl H (2003). Reduced dopaminergic tone in hypothalamic neural circuits: expression of a “thrifty” genotype underlying the metabolic syndrome? European Journal of Pharmacology 480: 125-131.
26. Shao Q-Y, You F, Zhang Y-H, Hu L-L, Liu W-J, Liu Y, Li J, Wang S-D, et al. (2018). CSF miR-16 expression and its association with miR-16 and serotonin transporter in the raphe of a rat model of depression. Journal of Affective Disorders 238: 609-614.
27. Solly EL, Psaltis PJ, Bursill CA, Tan JT (2021). The role of miR-181c in mechanisms of diabetes-impaired angiogenesis: an emerging therapeutic target for diabetic vascular complications. Frontiers in Pharmacology 12: 718679.
28. Soltani N, Qiu H, Aleksic M, Glinka Y, Zhao F, Liu R, Li Y, Zhang N, et al. (2011). GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes. Proceedings of the National Academy of Sciences 108: 11692-11697.
29. Sowell MO, Mukhopadhyay N, Cavazzoni P, Shankar S, Steinberg HO, Breier A, Beasley Jr CM, Dananberg J (2002). Hyperglycemic clamp assessment of insulin secretory responses in normal subjects treated with olanzapine, risperidone, or placebo. The Journal of Clinical Endocrinology & Metabolism 87: 2918-2923.
30. Sun X, Sit A, Feinberg MW (2014). Role of miR-181 family in regulating vascular inflammation and immunity. Trends in cardiovascular medicine 24: 105-112.
31. Talbot K, Wang H-Y, Kazi H, Han L-Y, Bakshi KP, Stucky A, Fuino RL, Kawaguchi KR, et al. (2012). Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. The Journal of clinical investigation 122: 1316-1338.
32. Tavares G, Martins FO, Melo BF, Matafome P, Conde SV (2021). Peripheral dopamine directly acts on insulin-sensitive tissues to regulate insulin signaling and metabolic function. Frontiers in pharmacology 12: 713418.
33. Wang L, Qing L, Liu H, Liu N, Qiao J, Cui C, He T, Zhao R, et al. (2017). Mesenchymal stromal cells ameliorate oxidative stress-induced islet endothelium apoptosis and functional impairment via Wnt4-β-catenin signaling. Stem cell research & therapy 8: 1-13.
34. Wu X, Xu F-L, Xia X, Wang B-J, Yao J (2020). MicroRNA-15a, microRNA-15b and microRNA-16 inhibit the human dopamine D1 receptor expression in four cell lines by targeting 3′ UTR–12 bp to+ 154 bp. Artificial cells, nanomedicine, and biotechnology 48: 276-287.
35. Xue Q, Guo Z-Y, Li W, Wen W-H, Meng Y-L, Jia L-T, Wang J, Yao L-B, et al. (2011). Human activated CD4+ T lymphocytes increase IL-2 expression by downregulating microRNA-181c. Molecular immunology 48: 592-599.
36. Yekta R, Sadeghi L, Dehghan G (2020). The inefficacy of donepezil on glycated-AChE inhibition: Binding affinity, complex stability and mechanism. International Journal of Biological Macromolecules 160: 35-46.
37. Yekta R, Sadeghi L, Dehghan G (2022). The role of non-enzymatic glycation on Tau-DNA interactions: Kinetic and mechanistic approaches. International Journal of Biological Macromolecules 207: 161-168.
38. Yu Z, Rong Z, Sheng J, Luo Z, Zhang J, Li T, Zhu Z, Fu Z, et al. (2021). Aberrant non-coding RNA expressed in gastric cancer and its diagnostic value. Frontiers in Oncology 11: 606764.
39. Zhang B-H, Shen C-A, Zhu B-W, An H-Y, Zheng B, Xu S-B, Sun J-C, Sun P-C, et al. (2019). Insight into miRNAs related with glucometabolic disorder. Biomedicine & Pharmacotherapy 111: 657-665.
40. Zhu H, Shyh-Chang N, Segrè AV, Shinoda G, Shah SP, Einhorn WS, Takeuchi A, Engreitz JM, et al. (2011). The Lin28/let-7 axis regulates glucose metabolism. Cell 147: 81-94.