Could Hormonal Therapy Prevent Diabetes in Post-Menopausal Women?

Sandra Handgraaf, PhD, MA

A new study has clarified the mechanism by which hormonal replacement therapy (HRT) decreases the risk of type 2 diabetes (T2D) in postmenopausal women.

The researchers, led by Sandra Handgraaf, PhD, MA, a postdoctoral researcher at the University of Geneva Medical School, hope the insight will lead to more targeted hormonal replacement therapies.

It has long been known that before menopause, women have a lower risk of T2D than men, but after menopause, women end up with a higher risk than their male counterparts. For some time, HRT was commonly used for postmenopausal women but fell out of favor due to adverse effects and potentially dangerous thrombolytic action.

More recently, researchers have regained interest in the therapy after recognizing that these adverse effects depended strongly on the timing of the therapy. If the therapy is given early in menopause, thrombolytic risks are minimal. Researchers at the University of Geneva Medical School believe that a better understanding of the relationship between hormones and the regulation of blood sugar might allow scientists to better design these types of treatments.

"A number of scientists are working on the effect of [estrogens] on pancreatic insulin-producing cells," Handgraaf said in a statement. "But its effect on glucagon-producing cells, another hormone regulating blood sugar, had never been explored before.”

First, the team ovariectomized adult female mice and observed its effect on glucose metabolism. As expected, the loss of sex hormones led the mice to develop glucose intolerance, the first step before the onset of diabetes. Again, as expected, treating these mice with an estrogen, estradiol, restored glucose tolerance.

Next, the team went a step further to investigate the methods through which estrogen exerted this protective effect. They took measurements from the mice, and they cultured pancreatic alpha cells and enteroendocrine L cells from female human donors in vitro.

They were able to show that estrogen can act directly on pancreatic alpha cells and enteroendocrine L cells, which are proglucagons. Proglucagons are the precursors to several proteins, including glucagon-like protein 1 (GLP-1,) which is known to increase insulin secretion, and therefore, prevent diabetes.

They tested the effects of several selective estrogen receptor agonists. While agonists of all 3 increased the production of GLP-1 from the pancreatic alpha cells, the team identified a single receptor, ERβ, which seems to be responsible for the increase in GLP-1 production by the enteroendocrine cells. Targeting just this receptor was sufficient to improve glucose metabolism in both the ovariectomized mice and the human cell samples.

Hormonal replacement that targets this receptor is likely to be effective in helping prevent the onset of T2D in postmenopausal women. It may also decrease the likelihood of the undesirable adverse effects of current hormonal replacement strategies.

“These data reveal that estrogen directly regulates glucose homeostasis by promoting GLP-1 secretion in the pancreas and intestine and pave the way to potential new therapeutic approach by selectively modulating ERs, to treat or prevent type 2 diabetes in at least [post-]menopause women,” Handgraaf told MD Magazine.

The study, “17-β Estradiol regulates proglucagon-derived peptide secretion in mouse and human α- and L cells,” was published in the Journal of Clinical Insight.