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Protecting the Fetus from Diabetes-associated Central Nervous System Damage with Melatonin

Review of “Melatonin Enhances Proliferation and Modulates Differentiation of Neural Stem Cells Via Autophagy in Hyperglycemia” from STEM CELLS by Stuart P. Atkinson 

Researchers from the laboratory of Shilei Ni (Qilu Hospital of Shandong University, Jinan, Shandong, PR China) recently sought to blend three scientific stories into one line of research with a new STEM CELLS study that investigated how melanin affects autophagy in neural stem cells exposed to hyperglycemia [1]. The development of this research line derived from previous studies demonstrating how gestational diabetes mellitus negatively impacts fetal central nervous system development [2], how autophagy plays a crucial role in neural development [3, 4], and how melatonin, a naturally occurring hormone with central nervous system protective roles, prevented neural tube defects in the fetus from a diabetic mother by inhibiting apoptosis [5]. 

Overall, the authors posited that hyperglycemia may influence autophagy in neural stem cells and that melatonin may act as a protective agent. So what did Li et al. discover?

  • Hyperglycemia increased autophagy and autophagic flux of mouse neural stem cells
    • Demonstrated by an increase in the LC3B II/I ratio, Beclin‐1 expression, and the number of autophagosomes
    • Hyperglycemia inhibited the proliferation of neural stem cells and induced premature differentiation of neural stem cells into neurons and astrocytes
  • Overall, hyperglycemia-induced increases in autophagy prevented the proper function of neural stem cells
  • However, melatonin enhanced the proliferation and self‐renewal of neural stem cells and helped to maintain a normal proliferation profile under hyperglycemic conditions thanks to a decrease in autophagy
    • Evidenced by Beclin‐1 downregulation and increased mTOR signaling 
  • Additional inhibition of autophagy (by 3-methyladenine treatment) aided the melatonin-associated effects on neural stem cells, while induction of autophagy (by rapamycin treatment) reduced melatonin-associated effects

Given these encouraging findings, the authors propose melatonin treatment as a means to protect from fetal central nervous system damage in mothers with gestational diabetes mellitus through the inhibition of autophagy and loss of normal physiological function of neural stem cells.

For more on the unwanted side-effects of diabetes on stem cells, potential protective agents for neural stem cells, and more stay tuned to the Stem Cells Portal!


  1. Li H, Zhang Y, Liu S, et al., Melatonin Enhances Proliferation and Modulates Differentiation of Neural Stem Cells Via Autophagy in Hyperglycemia. STEM CELLS 2019;37:504-515.
  2. Ornoy A, Reece EA, Pavlinkova G, et al., Effect of maternal diabetes on the embryo, fetus, and children: Congenital anomalies, genetic and epigenetic changes and developmental outcomes. Birth Defects Research Part C: Embryo Today: Reviews 2015;105:53-72.
  3. Lee DY, Roles of mTOR Signaling in Brain Development. Experimental Neurobiology 2015;24:177-85.
  4. Fimia GM, Stoykova A, Romagnoli A, et al., Ambra1 regulates autophagy and development of the nervous system. Nature 2007;447:1121-5.
  5. Liu S, Guo Y, Yuan Q, et al., Melatonin prevents neural tube defects in the offspring of diabetic pregnancy. Journal of Pineal Research 2015;59:508-517.