Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany.
German Center for Diabetes Research, Neuherberg, Germany.
Diabetes Care. 2022 Feb 1;45(2):398-406. doi: 10.2337/dc21-1136.
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，并调节体脂肪量及其分布。肥胖症和 2 型糖尿病常与大脑胰岛素抵抗相关，导致外周代谢的脑源性调节受损。迄今为止，尚未建立针对大脑胰岛素抵抗的药物治疗方法。由于钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂可降低血糖水平并调节能量代谢，我们假设 SGLT2 抑制可能是逆转大脑胰岛素抵抗的一种药物治疗方法。
在这项随机、双盲、安慰剂对照的临床试验中，40 名（平均±标准差；年龄 60±9 岁；BMI 31.5±3.8kg/m2）患有前驱糖尿病的患者被随机分为每天接受 25mg 恩格列净或安慰剂治疗。在治疗前和 8 周后，通过功能性 MRI 结合胰岛素经鼻内给药评估大脑胰岛素敏感性。
我们发现，胰岛素对下丘脑反应的时间和治疗之间存在显著的交互作用。事后分析显示，只有恩格列净治疗的患者下丘脑对胰岛素的反应性增加。下丘脑胰岛素作用显著介导了恩格列净治疗引起的空腹血糖和肝脂肪降低。
我们的结果证实了前驱糖尿病患者的下丘脑胰岛素抵抗。恩格列净治疗 8 周能够恢复下丘脑胰岛素敏感性，这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 抑制定位为逆转大脑胰岛素抵抗的第一种药物治疗方法，可能对肥胖和全身代谢有益。
