Study reports that high insulin levels are toxic to placenta cells, potentially causing miscarriages

February 21, 2019
Zev Williams, MD, PhD
Zev Williams, MD, PhD

Zev Williams, MD, PhD, Chief of the Division of Reproductive Endocrinology and Infertility at Columbia University Irving Medical Center, recently co-authored a study published in the journal Fertility and Sterility examining the effects of insulin and metformin on placenta cells (trophoblasts) from first-trimester pregnancies. We spoke with Dr. Williams to learn more about the surprising results that offer insight into one of the reasons why some miscarriages may happen.

What did you expect to conclude from this study?

One of the great challenges in successfully treating women and couples suffering from infertility and recurrent pregnancy loss is to accurately determine the cause for the problem so that we can correct the problem and help our patients have success. We have known for a while that women with insulin resistance have much higher rates of pregnancy loss, but the reason was unknown. Knowing the cause is critical to trying to prevent the losses in the future.

Is insulin resistance a common condition?

Insulin resistance, defined as impaired metabolic response to insulin, affects 34 percent of the US population (84 million people) and is markedly increased by a risk of poor pregnancy outcomes including fetal anomalies, delayed development, perinatal morbidity and mortality, and recurrent miscarriage.

What were your experiments and what did you find?

We first cultured placental cells (trophoblasts) in media supplemented with either vehicle control or insulin at concentrations found in patients with insulin resistance. Insulin is a growth factor, and most cells, such as skin cells, muscle cells, liver cells, fibroblasts, etc, grow better in the presence of insulin.  Remarkably, we found that insulin – even at levels found in patients with insulin resistance – was directly toxic to the early placenta cells.  The insulin caused widespread DNA damage, the equivalent amount of DNA damage found when we cultured regular cells in the presence of therapeutic levels of chemotherapy drugs. However, when the cells were cultured in the presence of metformin, a commonly used medication for the treatment of insulin resistance, the placenta cells were protected from damage.

What were your results?

Elevated insulin levels are directly toxic to first trimester placenta cells (trophoblasts) and result in increased DNA damage, apoptosis, and decreased cell survival. These effects are prevented by metformin. Trophoblast cells from early pregnancy are uniquely vulnerable to elevated levels of insulin. These findings, if confirmed in vivo, suggest that there may be a role for insulin resistance screening before attempting pregnancy and for focusing on prevention of hyperinsulinemia during early pregnancy.

Due to your findings, are you implementing insulin resistance screening at Columbia University Fertility Center?

Clinical trials will be needed to validate these results in patients, however we have now changed how we screen for insulin resistance. Traditional screening tests have looked at only glucose in the blood; we now screen for both glucose and insulin.