Insulin action in the human brain modulates whole-body metabolism by increasing peripheral insulin sensitivity and suppressing endogenous glucose production. In brain insulin resistance, this modulatory function of the brain is impaired. Experimental evidence from rodents and first observations in humans suggest major differences in brain insulin action between women and men. We therefore investigated effects of brain insulin delivery on peripheral metabolism in the follicular and luteal phase of the menstrual cycle.

Eleven natural cycling women (age: 19-29 years, BMI: 17.8 - 23.8 kg/m²) underwent four hyperinsulinemic-euglycemic clamps. On two days during both the follicular and the luteal cycle phase, participants received intranasal insulin spray and placebo 90 min after initiation of the 210 min clamp in randomized, blinded order. Insulin spillover into the blood was mimicked by an appropriate iv insulin bolus on placebo days.

The phase of the menstrual cycle interacted with the type of spray on the subsequent change of glucose infusion rates (GIR) (p=0.01). During the follicular phase, more glucose had to be infused after insulin delivery to the brain as nasal spray compared to placebo administration (p<0.0001; β=0.40±0.06). This difference remained significant after adjustment for plasma glucose and insulin concentrations (p<0.0001). During the luteal phase, GIR were only transiently higher after nasal insulin (p=0.005; β=0.16±0.06), but this depended on the circulating glucose and insulin levels as the difference was no longer present after respective adjustments (p=0.1).

In the follicular phase of the menstrual cycle, insulin delivery to the brain improves peripheral insulin sensitivity in lean women, comparable to what has previously been described in lean men. However, this response was not detected in the luteal phase, suggesting brain insulin resistance. Brain insulin resistance could therefore contribute to the long known peripheral insulin resistance in the luteal phase of the menstrual cycle.


C.F.C. Benkendorff: None. J. Hummel: None. A. Vosseler: None. S. Kullmann: None. L. Fritsche: None. A.L. Birkenfeld: None. H. Preissl: None. H. Haering: None. A. Fritsche: None. A. Peter: None. R. Wagner: Advisory Panel; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Eli Lilly and Company. M. Heni: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker’s Bureau; Self; Novo Nordisk A/S.


German Federal Ministry of Education and Research (01GI0925)

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