Scientists discover intergenerational ‘memory’ mechanism of diabetes

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Symptomatic treatment was commonly used for chronic diseases in the past. For example, diabetes was often treated by controlling the rise in glucose and relieving various diabetes-induced complications with insulin. However, how to prevent diabetes has remained elusive in the scientific and medical community, and it has become a global research hotspot to uncover the origin of the disease for early intervention.

Recently, the team led by Professor HUANG Hefeng from Women’s Hospital of Zhejiang University School of Medicine and the team led by Professor XU Guoliang from Center of Excellence in Molecular Cell Science of Zhejiang University Chinese Academy of Sciences have discovered a new mechanism of intergenerational transmission of diabetes. Their research indicated an environmentally sensitive window in oocyte development that confers a predisposition to glucose intolerance in the next generation. These research results were published in the May 18 issue of Nature.

Teacher. HUANG Hefeng (second from left in second row) and co-first authors CHEN Bin (first from left in first row) and ZHU Hong (center in first row)

Professor HUANG Hefeng, a renowned obstetrician and gynecologist, was intrigued by the potential impact of a mother on her offspring. To this end, she led her team to conduct research on diseases of adult offspring caused by adverse maternal environmental factors. The team found that high glucose/androgen exposure could trigger intergenerational or transgenerational transmission of chronic diseases by altering the DNA methylation profile of embryos/fetuses in utero or by affecting epigenetic changes in sperm/egg. Professor Huang concluded from clinical investigations and animal models that chronic diseases such as diabetes and hypertension could be of developmental origin and was therefore the first to report the hypothesis of “epigenetic inheritance through gametes. However, this hypothesis remained untested.

To confirm this hypothesis, Professor Huang’s team began to focus on the following questions: Do pre-gestational maternal environmental factors affect offspring health? Does maternal hyperglycemia increase the risk of chronic diseases via oocytes?

To answer these questions, the team built a hyperglycemic female mouse model. To rule out continued effects of hyperglycemia on embryological and fetal development, they ingeniously removed affected oocytes for in vitro fertilization and embryo transfer to healthy adoptive mice to produce offspring. Metabolic measurements showed that their offspring exhibited impaired glucose tolerance, indicating that oocytes, where affected by the unfavorable hyperglycemic environment, increased susceptibility to chronic disease. This discovery was therefore an appropriate testimony to Professor Huang’s hypothesis.

Faced with this important finding, the team began to wonder about the very “culprit” that increases susceptibility to diabetes in offspring. After a series of complex experiments, they found the key – TET methylcytosine dioxygenase 3 (TET3) – and proposed the pathways regulating chronic disease in offspring by TET3 deficiency.

Decreased expression of TET3 in oocytes and altered demethylation

The joint research of Prof. HUANG Hefeng and Prof. XU Guoliang confirmed that the high glucose environment in hyperglycemic female mice leads to an insufficient dose of TET3 protein in oocytes, thus contributing to the low reprogramming capacity of TET3 in the zygote. and possibly “insufficient demethylation”. or “hypermethylation”.

How does TET3 increase susceptibility to diabetes in offspring? The glucokinase (GCK) gene is one of the most important proteins regulating insulin secretion. During the process of replication and division of a fertilized egg, hypermethylation of relevant genes related to insulin secretion, including GCK, triggers the mistapped potential of TET3. This TET3 deficiency lasts until adulthood in offspring. Hypermethylation and low expression of genes such as GCK lead to inadequate insulin secretion, decreased blood sugar decline, and increased susceptibility to diabetes as they age.

This study was also confirmed in clinically diabetic pregnant women. Immature oocytes and rejected balstocysts from clinically diabetic patients received at several hospitals in Hangzhou and Shanghai also showed reduced expression of TET3 and hypermethylation in the GCK promoter region, respectively. This further suggested the clinical significance of this study.

Diagram of maternal epigenetic mechanism of glucose intolerance caused by TET3 dysfunction

“These research results offer groundbreaking insights into the prevention and control of chronic diseases at their root, which will help reduce birth defects and improve the health of our population,” said Professor Huang. “Now that diabetes and hypertension are most often inherited, special attention must be paid to the transgenerational inheritance caused by the reproductive environment. While taking care of our own health, we must also protect our next generation.

Photo credit: the research team led by Prof. HUANG Hefeng

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