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 sodium–glucose cotransporter 2 (SGLT2) inhibitors lower glucose levels and modulate energy metabolism, we hypothesized that SGLT2 inhibition may be a pharmacological approach to reverse brain insulin resistance.

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 every day 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.

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 the empagliflozin-induced decrease in fasting glucose and liver fat.

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.

人脑中的胰岛素作用可减少食物摄入，提高全身胰岛素敏感性，并调节身体脂肪量及其分布。肥胖和 2 型糖尿病通常与脑胰岛素抵抗有关，导致脑源性外周代谢调节受损。迄今为止，尚未建立针对脑胰岛素抵抗的药物治疗。由于钠 - 葡萄糖协同转运蛋白 2 (SGLT2) 抑制剂可降低葡萄糖水平并调节能量代谢，我们假设 SGLT2 抑制可能是逆转脑胰岛素抵抗的药理学方法。

在这项随机、双盲、安慰剂对照的临床试验中，40 名糖尿病前期患者（平均值 ± SD；年龄 60 ± 9 岁；BMI 31.5 ± 3.8 kg/m ²）被随机分配接受每天 25 mg 依格列净或安慰剂治疗。在治疗 8 周之前和之后，通过功能性 MRI 结合鼻内向大脑注射胰岛素来评估大脑胰岛素敏感性。

我们确定了下丘脑对胰岛素反应的时间和治疗之间的显着相互作用。事后分析显示，只有恩格列净治疗的患者下丘脑胰岛素反应性增加。下丘脑胰岛素作用显着介导了恩格列净诱导的空腹血糖和肝脂肪减少。

我们的结果证实了糖尿病前期患者下丘脑的胰岛素抵抗。使用 empagliflozin 治疗 8 周能够恢复下丘脑胰岛素敏感性，这是一种有利的反应，可能有助于 SGLT2 抑制剂的有益作用。我们的研究结果将 SGLT2 抑制定位为第一种逆转脑胰岛素抵抗的药理学方法，对肥胖和全身代谢具有潜在益处。