Jun 9, 2022
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Discovered the mechanism of “memory” of hereditary diabetes

Discovered the mechanism of "memory" of hereditary diabetes

Symptomatic treatment has been a common approach to chronic disease in the past. For example, diabetes is treated by controlling the increase in glucose levels and alleviating the various complications caused by diabetes with the help of insulin. However, the question of how to prevent diabetes is still elusive for the scientific and medical community, so finding the causes of the disease for early intervention has become one of the priorities of global research.

Recently, a team led by Prof. Huang Hefeng of the Zhejiang University School of Medicine Women’s Hospital and a team led by Prof. Xu Guoliang of the Center of Excellence in Molecular Cell Science of the Chinese Academy of Sciences discovered a new generational transmission mechanism for diabetes. Their study showed an environmentally sensitive window in egg development that predisposes to glucose intolerance in the next generation. The results of the study were published in an issue of the journal Nature.

Professor Huang Hefeng, a respected obstetrician and gynecologist, was intrigued by the mother’s potential influence on her offspring. To this end, she, at the head of her group, conducted a study of diseases of adult offspring caused by adverse environmental factors of the mother.

The team found that high glucose/androgen exposure can induce intergenerational or transgenerational inheritance of chronic diseases by altering the DNA methylation profile of intrauterine embryos/fetuses or by influencing sperm/egg epigenetic modifications. Based on clinical studies and animal models, Professor Huang concluded that chronic diseases such as diabetes and hypertension may be developmental, and was therefore the first to hypothesize “epigenetic inheritance through gametes.” However, this hypothesis remained untested.

To confirm this hypothesis, Prof. Huang’s team focused on the following questions: Do pregestational maternal environmental factors influence offspring health? Does maternal hyperglycemia increase the risk of developing chronic diseases through oocytes?

To answer these questions, the team created a hyperglycemic female mouse model. To rule out the continued impact of hyperglycemia on embryological and fetal development, they ingeniously removed diseased oocytes for in vitro fertilization and embryo transfer to healthy foster mice for offspring. Metabolic measurements showed that the offspring had impaired glucose tolerance, indicating that oocytes that were affected by an unfavorable hyperglycemic environment increased susceptibility to chronic diseases. Thus, the results of the study confirmed Professor Huang’s hypothesis.

In the face of this significant discovery, the research team began to wonder who is the “culprit” that increases the susceptibility to diabetes in offspring. After a series of complex experiments, they found a clue – methylcytosine dioxygenase 3 (TET3) – and suggested ways to regulate chronic diseases in offspring through TET3 deficiency.

A joint study by Prof. Huang Hefeng and Prof. Xu Guoliang confirmed that a high glucose environment in hyperglycemic female mice results in an insufficient dose of TET3 protein in oocytes, contributing to poor TET3 reprogramming ability in the zygote and ultimately “insufficient demethylation” or ” hypermethylation”.

How does TET3 increase diabetes susceptibility in offspring? The glucokinase (GCK) gene is one of the most important proteins regulating insulin secretion. During the process of replication and division of the fertilized egg, hypermethylation of the relevant genes associated with insulin secretion, including GCK, triggers an underused potential of TET3. This TET3 deficiency persists in offspring until adulthood. Hypermethylation and low expression of genes such as GCK leads to insufficient insulin secretion, lower blood glucose levels and increased vulnerability to diabetes as we age.

The results of this study were also confirmed in pregnant women with clinical diabetes. Immature oocytes and discarded balstocysts from patients with clinical diabetes obtained from several hospitals in Hangzhou and Shanghai also showed reduced TET3 expression and hypermethylation in the GCK promoter region, respectively. This further confirmed the clinical relevance of this study.

“The results of these studies offer a revolutionary insight into the prevention and control of chronic diseases at their origin, which will help reduce birth defects and improve the health of our population,” said Professor Huang. “Now that diabetes and hypertension are more likely to run in families, special attention should be paid to transgenerational inheritance due to the reproductive environment. While taking care of our own health, we must also protect our next generation.”

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