Insulin action in the human brain reduces food intake, improves whole-body insulin sensitivity, and modulates adiposity. In most cases of obesity and diabetes, the brain becomes insulin resistant with impaired brain-derived modulation of peripheral metabolism. As treatment with the SGLT2-inhibitor empagliflozin not only improves glucose metabolism but also reduces body weight and cardiovascular risk, we hypothesized that improved brain insulin sensitivity could be involved.
Methods: In this double blind study, 40 participants with prediabetes (according to ADA’s OGTT criteria) were 1:1 randomized to receive 25 mg empagliflozin qd or placebo (mean ± SD: age: 60 ± 9 years; BMI: 31.5 ± 3.8 kg/m²). Before and after 8 weeks of treatment, brain insulin sensitivity was assessed by functional MRI combined with the intranasal administration of insulin to the brain.
Results: In healthy persons, intranasal insulin administration significantly decreases cerebral blood flow in the hypothalamus. In the current study, volunteers with prediabetes were unresponsive to this, as insulin could not induce hypothalamic inhibition prior treatment. We identified a significant interaction between treatment and the hypothalamic response to insulin (p<0.05, corrected for multiple comparisons). Post-hoc analyses showed that only participants on empagliflozin showed a significant insulin-induced decrease in hypothalamic blood flow after treatment. The group receiving placebo showed no such improvement.
Conclusion: Our current results corroborate insulin resistance of the human hypothalamus in humans with prediabetes. Treatment with empagliflozin for 8 weeks was able to restore hypothalamic insulin sensitivity; a favorable response that could contribute to the positive effects of SGLT2 inhibitors. These findings reveal that brain insulin resistance is treatable by pharmacological interventions with potential benefits for cognition, adiposity, and whole-body metabolism.
M. Heni: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker’s Bureau; Self; Novo Nordisk A/S. S. Kullmann: 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. J. Hummel: None. C. Dannecker: None. A. Vosseler: None. L. Fritsche: None. K. Kantartzis: None. J. Machann: None. H. Haering: None. A. Fritsche: None. H. Preissl: None.