How can estrogen help control type 2 diabetes?

By Ana Sandoiu 

checked by Gianna D’Emilio

New research finds that estrogen improves
insulin sensitivity and details the mechanism behind this effect. The findings
have a “profound impact on our understanding of obesity and diabetes, as
well as potential dietary interventions,” say the researchers.

About 84 million people in the United States
are living with prediabetes, a condition in which blood sugar levels are very
high but not high enough to warrant a diagnosis of type 2 diabetes.
Usually, prediabetes occurs in people with
insulin resistance — a condition in which the cells in some vital organs do not
respond well to insulin and therefore do not absorb enough glucose from the
But what if there was a hormone that could
lower insulin resistance and the production of glucose?
Researchers believe that estrogen has the
potential to do so, and consequently, to reduce the prevalence of type 2
Currently, over 100 million people in the
U.S. are living with diabetes or prediabetes, and estimates show that over 30
million adults have type 2 diabetes.
Shaodong Guo, Ph.D., an associate professor
in the Department of Nutrition and Food Science at Texas A&M University in
College Station, led the new research. The study appears in Diabetes, the
journal of the American Diabetes Association.

Why study the metabolic effect of estrogen?

Guo explains the motivation for the study,
saying that previous observational research has uncovered a link between a
lower incidence of type 2 diabetes and premenopausal women.
Furthermore, clinical and animal studies
found a strong link between estrogen deficiency and metabolic disorders.
“Premenopausal women exhibit enhanced
insulin sensitivity and reduced incidence of type 2 diabetes, compared with
age-equivalent men,” Guo says. “But this advantage disappears after
menopause with disrupted glucose homeostasis, in part owing to a reduction in
circulating estrogen.”
However, researchers have not yet been able
to elucidate the mechanisms responsible for these connections.
Also, blindly using estrogen as a potential
treatment for type 2 diabetes and other prediabetes metabolic dysfunctions
could have serious side effects. For example, stroke, breast cancer, blood
clots, and heart attack are some of the health risks associated with estrogen
“This is why it is so important to
understand the tissue-specific action of estrogen and its molecular mechanism
in metabolic regulation,” Guo explains. “Once that mechanism is
understood, it will aid in the development of targeted estrogen mimics that can
provide the therapeutic benefits without unwanted side effects.”

Foxo1 mediates estrogen’s metabolic effects

In the new study, the researchers
“wanted to understand the mechanism by which estrogen regulates
gluconeogenesis by means of interaction with hepatic Foxo1,” the lead
investigator continues, referring to a gene also called forkhead box O1.
Gluconeogenesis describes the synthesis
process through which glucose is generated.
The Foxo1 gene encodes a transcription
factor, or a type of protein that helps activate or deactivate other genes.
Foxo1 “is the main target of insulin
signaling and regulates metabolic homeostasis in response to oxidative
stress,” the U.S. National Library of Medicine report.
As Guo explains, “Foxo1 has an important
role in the regulation of glucose production through insulin signaling. It is
an important component of insulin-signaling cascades regulating cellular
growth, differentiation, and metabolism.”
To investigate the gene’s role and how it
interacts with estrogen, the researchers studied male mice, female mice whose
ovaries had been removed, and both male and female mice whose Foxo1 genes had
been knocked out in the liver.
The researchers used a subcutaneous implant
that released estrogen in the mice. This implant “improved insulin
sensitivity and suppressed gluconeogenesis” in the male mice as well as in
the ovariectomized female mice.
However, the implant did not affect the
rodents whose liver-specific Foxo1 genes had been knocked out. “This
suggests Foxo1 is required for estrogen to be effective in suppressing
gluconeogenesis,” Guo explains.
The researcher reports, “We further
demonstrated that estrogen suppresses hepatic glucose production through
activation of estrogen receptor signaling, which can be independent of insulin
receptor substrates Irs1 and Irs2.”
“This reveals an important mechanism for
estrogen in the regulation of glucose homeostasis,” Guo says. The
beneficial effects of estrogen on glucose homeostasis may be controlled by
gluconeogenesis — which is, in turn, mediated by liver-specific Foxo1 — not by
promoting the uptake of glucose in the muscles.

Therapeutic and dietary implications

Guo explains the therapeutic implications of
the findings. “The identification of tissue-specific actions of estrogen
and direct targets of estrogen receptors will facilitate the development of
novel selective ligands that prevent type 2 diabetes, cardiovascular disease,
and obesity without promoting abnormal sex characteristics or breast
Finally, the researcher also comments on the
dietary implications of the study. Certain foods, such as soybeans, tofu, and
miso soup contain phytoestrogens, which may have the same beneficial effects on
metabolic health.
The study “provides a fundamental
understanding that dietary intervention can play a crucial role in controlling
obesity, diabetes, and associated chronic diseases,” says Guo.
“[W]e investigated the role of estrogen
in control of glucose homeostasis, which has profound impact on our
understanding of obesity and diabetes as well as potential dietary

Shaodong Guo, Ph.D.

Kayode Ojo
Kayode Emmanuel Ojo is the Co-Founder and Managing Director at SHEFFA Limited. He is presently studying Computer Science at the National Open University, Victoria Island, Lagos.