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Empagliflozin Improves Insulin Sensitivity of the Hypothalamus in Humans With Prediabetes: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial

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posted on 29.10.2021, 19:02 authored by Stephanie Kullmann, Julia Hummel, Robert Wagner, Corinna Dannecker, Andreas Vosseler, Louise Fritsche, Ralf Veit, Konstantinos Kantartzis, Jürgen Machann, Andreas L. Birkenfeld, Norbert Stefan, Hans-Ulrich Häring, Andreas Peter, Hubert Preissl, Andreas Fritsche, Martin Heni
Objective: Insulin action in the human brain reduces food intake, improves whole-body insulin sensitivity, and modulates body fat mass and its’ distribution. Obesity and type 2 diabetes are often associated with brain insulin resistance, resulting in impaired brain-derived modulation of peripheral metabolism. So far, no pharmacological treatment for brain insulin resistance has been established. Since SGLT2 inhibitors lowers glucose levels and modulate energy metabolism, we hypothesized that SGLT2 inhibition may be a pharmacological approach to reverse brain insulin resistance.

Research Design and Methods: In this randomized, double-blind, placebo-controlled clinical trial, 40 patients (mean ± SD; age: 60 ± 9 years; BMI: 31.5 ± 3.8 kg/m²) with prediabetes were randomized to receive 25 mg empagliflozin qd or placebo. Before and after 8 weeks of treatment, brain insulin sensitivity was assessed by functional MRI combined with intranasal administration of insulin to the brain.

Results: We identified a significant interaction between time and treatment in the hypothalamic response to insulin. Post hoc analyses revealed that only empagliflozin treated patients experienced increased hypothalamic insulin responsiveness. Hypothalamic insulin action significantly mediated empagliflozin-induced decrease in fasting glucose and liver fat.

Conclusions: Our results corroborate insulin resistance of the 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 beneficial effects of SGLT2 inhibitors. Our findings position SGLT2 inhibition as the first pharmacological approach to reverse brain insulin resistance, with potential benefits for adiposity and whole-body metabolism.

Funding

This study was supported by Boehringer Ingelheim through an Independent Research Grant. Boehringer Ingelheim had no role in the study design, in the collection, analysis or interpretation of data, or in writing of the report.

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