Oestrogen and controlling Type 2 diabetes

Sunday, February 17, 2019

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The results of a recent Texas A&M University-led study provide insights into the mechanism by which oestrogen can decrease insulin resistance and the production of glucose, reducing incidence of Type 2 diabetes mellitus.

The study, 'Oestrogen Improves Insulin Sensitivity and Suppresses Gluconeogenesis via the Transcription Factor Foxo1', can be found online in the diabetes journal of the American Diabetes Association.

“In this study, we investigated the role of oestrogen in control of glucose homoeostasis, which has profound impact on our understanding of obesity and diabetes as well as potential dietary interventions,” said Dr Shaodong Guo, primary study investigator and Texas A&M AgriLife Research scientist in the department of nutrition and food science in College Station.

Guo said recent research on the prevalence of Type 2 diabetes has shown gender-related differences, especially a reduced incidence of the disease in premenopausal women. Clinical and animal studies have shown a strong correlation between oestrogen deficiency and metabolic dysfunction.

“In general, glucose homoeostasis is maintained by glucose uptake in muscle and adipose tissue in addition to glucose production in the liver,” he explained. “However, studies have shown the reduction of oestrogen in postmenopausal women accelerates the development of insulin resistance and Type 2 diabetes.

“Conversely, clinical trials of oestrogen replacement therapy in postmenopausal women have demonstrated a lowered insulin resistance as well as reductions in plasma glucose level.”

Guo said oestrogen deficiency or impaired oestrogen signalling is associated with insulin resistance and faulty regulation of metabolic homoeostasis, which contributes to the development of Type 2 diabetes and obesity in both human and animal models. But the exact contribution of the tissue-specific action of oestrogen to metabolic changes and underlying mechanisms have not yet been elucidated through research.

“Premenopausal women exhibit enhanced insulin sensitivity and reduced incidence of Type 2 diabetes compared with age-equivalent men,” he explained. “But this advantage disappears after menopause with disrupted glucose homoeostasis, in part owing to a reduction in circulating oestrogen.”

Guo noted there is also a potential risk of breast cancer or stroke as a side effect of oestrogen therapy, which is a significant roadblock to its use as a therapeutic agent.

“This is why it is so important to understand the tissue-specific action of oestrogen and its molecular mechanism in metabolic regulation,” he said. “Once that mechanism is understood, it will aid in the development of targeted oestrogen mimics that can provide the therapeutic benefits without unwanted side effects.”

In their study, Guo and other researchers investigated the action of oestrogen on glucose homoeostasis in male and ovariectomised female control and liver-specific Foxo1 knockout mice.

“We wanted to understand the mechanism by which oestrogen regulates gluconeogenesis by means of interaction with hepatic Foxo1,” he explained. “Foxo1 has an important role in the regulation of glucose production through insulin signalling. It is an important component of insulin-signalling cascades regulating cellular growth, differentiation and metabolism.”

He said in both male and ovariectomised female control mice, a subcutaneous oestrogen implant improved insulin sensitivity and suppressed gluconeogenesis. However, the oestrogen had no effect on the liver-specific Foxo1 knockout mice of both sexes.

“This suggests Foxo1 is required for oestrogen to be effective in suppressing gluconeogenesis,” he said.

“We further demonstrated that oestrogen suppresses hepatic glucose production through activation of oestrogen receptor signalling, which can be independent of insulin receptor substrates Irs1 and Irs2. This reveals an important mechanism for oestrogen in the regulation of glucose homoeostasis.”

Guo said study results support the hypothesis that improvement of glucose homoeostasis by oestrogen is regulated by hepatic Foxo1-mediated gluconeogenesis rather than by promoting muscle glucose uptake.

He said results may also help explain why premenopausal women have lower incidence of Type 2 diabetes than age-equivalent men and suggest that targeting the oestrogen receptor ERa can be a potential approach to modulate glucose metabolism and prevent diabetes.

“The identification of tissue-specific actions of oestrogen 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 cancer,” he said.

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