How Menstrual Cycle Impacts Brain Insulin Action-Results from Young Women

The human brain is an insulin-sensitive organ that modulates whole-body glucose metabolism and adiposity. In case of brain insulin resistance, this regulation is disturbed. In the periphery, insulin sensitivity varies along the menstrual cycle, while the effects on brain insulin action are still unknown. We here investigated the impact of menstrual cycle on brain insulin sensitivity of the human hypothalamus and on brain-derived modulation of peripheral metabolism. In 26 naturally cycling women (age 19-29 years, BMI 18-24 kg/m2), brain insulin action was assessed in both the follicular and the luteal phase using nasal application of 160 U insulin. In fifteen women, we assessed hypothalamic insulin responsiveness by functional MRI combined with nasal insulin. In eleven women, brain-derived modulation of peripheral insulin sensitivity was studied by hyperinsulinemic euglycemic clamps combined with insulin vs placebo spray. Only in the follicular phase, nasal insulin significantly decreased hypothalamic blood flow (p=0.02), indicating proper brain insulin action. In the luteal phase, insulin induced no such effect (p=0.6). During hyperinsulinemic euglycemic clamps in the follicular phase, more glucose had to be infused after insulin compared to placebo spray. This difference remained significant after adjustment for circulating glucose and insulin (p<0.0001), which was not the case in the luteal phase (p=0.1). High estradiol/progesterone ratio, as present during the follicular phase, was linked to a stronger effect of insulin spray on glucose infusion rates than placebo. Brain insulin sensitivity is a regulated process that can rapidly adapt to changing physiologic requirements, as through the menstrual cycle. In the luteal phase, we detected hypothalamic insulin resistance, which likely contributed to the lacking modulation of peripheral insulin sensitivity through brain insulin delivery. Thus, brain insulin resistance could contribute to whole-body insulin resistance in the luteal phase. Disclosure J.Hummel: None. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. H.Häring: None. A.Fritsche: Advisory Panel; Novo Nordisk, Lilly, Sanofi, Boehringer-Ingelheim, Speaker's Bureau; AstraZeneca, SYNLAB Holding Deutschland GmbH. A.Peter: None. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. S.Kullmann: None. M.Heni: Advisory Panel; Boehringer-Ingelheim, Sanofi, Research Support; Boehringer Ingelheim Inc., Speaker's Bureau; Lilly, Bayer Inc., Sanofi, Boehringer-Ingelheim, Novo Nordisk, Amryt Pharma Plc. C.Benkendorff: None. L.Fritsche: None. K.Prystupa: Other Relationship; Berlin-Chemie AG. A.Vosseler: None. S.Gancheva: Consultant; Novo Nordisk, Bayer Inc. S.Trenkamp: None. A.L.Birkenfeld: None. H.Preissl: None. Funding German Federal Ministry of Education and Research