Beside the current pandemic, there are non infectious pandemics that started much earlier. Diabetes is declared by WHO as a pandemic of alarming proportions which concerns the global public health. Recent research on the prevalence of Type 2 diabetes has shown gender-related differences, especially a reduced incidence of the disease in premenopausal women. Conversely, clinical trials of estrogen replacement therapy in postmenopausal women have demonstrated a lowered insulin resistance as well as reductions in plasma glucose level. Clinical and animal studies have shown a strong correlation between estrogen deficiency and metabolic dysfunction. In general, glucose homeostasis is maintained by glucose uptake in muscle and adipose tissue in addition to glucose production in the liver. However, other researches have shown the reduction of estrogens in postmenopausal women accelerates the development of insulin resistance and Type 2 diabetes.
From previous data, researchers already knew that estrogen deficiency or impaired estrogen signaling is associated with insulin resistance and faulty regulation of metabolic homeostasis, 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 estrogen to metabolic changes and underlying mechanisms have not yet been elucidated. Premenopausal women exhibit enhanced insulin sensitivity and reduced incidence of type 2 diabetes compared with age-equivalent men. But this advantage disappears after menopause, in part due to a reduction in circulating estrogen. There is also a potential risk of breast cancer as a side effect of estrogen 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 estrogen and its molecular metabolic regulation.
The results of a recent Texas A&M University-led study provide insights into the mechanism by which estrogen can decrease insulin resistance and the production of glucose, reducing incidences of Type 2 diabetes mellitus. In this study, scientists investigated the role of estrogen in control of glucose homeostasis, which has profound impact on the understanding of obesity and diabetes as well as potential dietary interventions. 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. In their study, the team investigated the action of estrogen on glucose homeostasis in male and ovariectomized female control and liver-specific Foxo1 knockout mice. The team wanted to understand the mechanism by which estrogen regulates gluconeogenesis by means of interaction with Foxo1, an hepatic transcription factor.
Foxo1 has an important role in the regulation of glucose production through insulin signaling. It is an important component of insulin-signaling regulating cellular growth, differentiation and metabolism. In both male and ovariectomized female control mice, a subcutaneous estrogen implant improved insulin sensitivity and suppressed gluconeogenesis. However, the estrogen had no effect on the liver-specific Foxo1 knockout mice of both sexes. This suggests Foxo1 is required for estrogen to be effective in suppressing gluconeogenesis. Delving into further molecular mechanisms, scientists further demonstrated that estrogen suppresses hepatic glucose production through activation of estrogen receptor signaling, which can be independent of IRS-1 and IRS-2, two major insulin receptor substrates. This reveals an important mechanism for estrogen in the regulation of glucose homeostasis.
These data have sharp practical meaning since they may help explain why premenopausal women have lower incidence of type 2 diabetes than age-equivalent men. This suggest that targeting the estrogen receptor ER-alpha can be a potorential approach to modulate glucose metabolism for diabetes prevention. 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 cancer. Long-term studies indicate that menopausal replacement hormone therapy (MHT) reduces insulin resistance and a clinical trial published last April has brought confirmation. This placebo-controlled study recruited 80 healthy postmenopausal women. Women were randomized to treatment with estradiol 1 mg continuously combined with drospirenone 2 mg (a progestin hormone) or placebo for 6-8 weeks.
The insulin peak serum level was lower in the MHT group at the end of the study period relative to baseline. The protocol did non influenced, however, insulin resistance and C-peptide (a marker for new insulin production). This implicates that identifying a selective estrogen modulator devoided of sex-related effects is prerogative for a metabolic specificity. In vitro and in vivo approaches have demonstrated that selective activation of ERα induces adipose tissue beiging through induction of AMP-activated protein kinase (AMPK) and adipose triglyceride lipase-mediated lipolysis. This effect may be also mediated by brain. More specifically, ERα signalling induces AMPK inhibition in the ventromedial nucleus, leading to enhanced thermogenesis in brown adipose tissue through the sympathetic nervous system. Therefore, liver apart, estrogens may affect fat tussue formation from adipose cells and brain networks as well.
The observation that women are less prone to insulin resistance than men is rather unexpected considering their increased fat mass, circulating NEFA levels and lipid content in myocytes, as well as a lower skeletal muscle mass. As a plausible explanation, experimental data indicate that women are protected from free fatty acids-induced insulin resistance. Specific estrogens modulators (SERMs) are already been developed to treat breast cancer and selective erasers of ERα (SERDegrons) are investigated currently for this tumor. It twill take more knowledge and efforts to develop selective ER-activators to target glucose metabolism in menopause without affecting other comportments.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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