Brain insulin action has an impact on eating behavior, metabolism and body fat distribution – in particular, it increases whole-body insulin sensitivity. However, all of these findings were obtained predominantly in studies involving men. In the journal Nature Metabolism, researchers report that although insulin action in the brain also improves whole-body insulin sensitivity in women, this only occurs during the follicular phase of the menstrual cycle.

Over the last ten years it has been demonstrated that the brain is an insulin-sensitive organ, but also that a substantial number of individuals do not respond to insulin in the brain. This is termed brain insulin resistance. While it is observed especially frequently in people with obesity, genetic factors, elevated blood lipids and impaired insulin transport across the blood-brain barrier also play a role. Preclinical studies also indicate differences between men and women.

Researchers at Ulm University and DZD partners at the Institute for Diabetes Research and Metabolic Diseases (IDM) of Helmholtz Munich at the University of Tübingen and the German Diabetes Center in Dusseldorf studied brain insulin action in 11 women at various stages of the menstrual cycle. The participants were all lean, healthy women with a regular, natural cycle.

Nasal Spray Allows Insulin to Primarily Enter the Brain

Insulin action in the brain was measured using the hyperinsulinemic-euglycemic clamp test after the women had received a nasal spray containing insulin or a placebo. Administered via the nose, substantial amounts of the insulin are delivered into the brain, while only a tiny fraction reaches the bloodstream. Therefore the nasal application allows stimulation of brain insulin action without causing peripheral side effects.

In the follicular phase of the menstrual cycle, the stimulation of the insulin effect in the brain led to an improvement in whole-body insulin sensitivity. In the luteal phase, however, the nasally-administered insulin and the brain insulin action did not have this effect.

Insulin Sensitivity Differs in Follicular and Luteal Phases
The DZD researchers thus found that during the follicular phase of the menstrual cycle there is an increased insulin sensitivity in the brain, which is not seen during the luteal phase.

A study of 15 other women, who underwent functional MRT scans on their brains, confirmed these findings. A functional MRT measures insulin sensitivity in the hypothalamus. The change in blood circulation in this brain region is used as a measure of central insulin sensitivity after a nasal administration of insulin. The responsiveness of the hypothalamus was influenced during the follicular phase but not the luteal phase.

The researchers conclude that brain insulin action also improves peripheral insulin sensitivity in women, but only during the follicular phase. They hypothesize that the insulin resistance of the brain in the luteal phase of the menstrual cycle could contribute to whole-body insulin resistance during this time.

Original publication:
Julia Hummel, Charlotte Benkendorff, Louise Fritsche, Katsiaryna Prystupa, Andreas Vosseler, Sofiya Gancheva, Sandra Trenkamp, Andreas L. Birkenfeld, Hubert Preissl, Michael Roden, Hans-Ulrich Häring, Andreas Fritsche, Andreas Peter, Robert Wagner, Stephanie Kullmann, Martin Heni. Brain insulin action on peripheral insulin sensitivity in women depends on menstrual cycle phase. Nat Metab 2023;5:1475–1482; doi:10.1038/s42255-023-00869-w