Nair K Sreekumaran, Pataky Mark, Ruegsegger Gregory, Jo Hang Joon, Klaus Katherine, Sevits Kyle, Leija Robert, Kumar Arathi, Lim Seokbeen, Sinhawansa Sumaiya, Dreconga Martina, Cobelli Claudio, Carter Rickey, Stricker Nikki, Lowe Val, Port John
Res Sq. 2025 Sep 9:rs.3.rs-7462946. doi: 10.21203/rs.3.rs-7462946/v1.
Insulin resistance (IR) is a modifiable risk factor for dementia, yet its effects on brain metabolism and function remain unclear. In older adults, greater IR was associated with reduced cerebral glucose uptake (indicating impaired mitochondrial metabolism), atrophy, and weakened connectivity between brain regions critical for cognition. In neuron-specific insulin receptor knockout mice, brain IR produced deficits in hippocampal- and prefrontal-dependent tasks accompanied by reduced brain mitochondrial ATP and elevated reactive oxygen species. To evaluate reversibility of IR-induced brain deficits, forty older adults with IR were randomized to 40-weeks of metformin or placebo. Metformin improved insulin sensitivity, increased brain glucose uptake, strengthened cognitive network connectivity, and preserved whole-brain and regional volumes implicated in decision-making and learning. Metformin also improved processing speed and working memory. Collectively, these findings highlight IR as a driver of brain metabolism and support the concept that insulin sensitization can prevent neurobiological deficits in older people with IR.
胰岛素抵抗（IR）是痴呆的一个可改变的风险因素，但其对脑代谢和功能的影响仍不清楚。在老年人中，更高的IR与脑葡萄糖摄取减少（表明线粒体代谢受损）、萎缩以及对认知至关重要的脑区之间的连接减弱有关。在神经元特异性胰岛素受体敲除小鼠中，脑IR在海马体和前额叶依赖的任务中产生缺陷，同时伴有脑线粒体ATP减少和活性氧增加。为了评估IR诱导的脑缺陷的可逆性，40名患有IR的老年人被随机分为接受40周二甲双胍或安慰剂治疗。二甲双胍改善了胰岛素敏感性，增加了脑葡萄糖摄取，增强了认知网络连接，并保留了与决策和学习相关的全脑和区域体积。二甲双胍还改善了处理速度和工作记忆。总的来说，这些发现突出了IR作为脑代谢驱动因素的作用，并支持胰岛素增敏可以预防患有IR的老年人神经生物学缺陷这一概念。
