Prabha Kumar, Arathi

BACKGROUND. Dementia is a rapidly expanding public health problem with major socio-economic burden. Insulin resistance (IR) is a prevalent but modifiable risk factor for dementia, yet its effects on brain structure, functional connectivity, and metabolism remain incompletely understood. METHODS. Regional brain glucose uptake (PET), volumes (MRI), functional connectivity (fMRI), and cognition (NIH Toolbox) was measured in 72 adults with or without markers of IR. To evaluate reversibility of IR-associated brain deficits, forty older adults with IR were randomized to forty weeks of metformin or placebo, and brain measures were repeated. As a proof-of-concept experiment, we developed a conditional brain-specific insulin receptor knockout mouse and assessed brain mitochondrial function and cognition. RESULTS. In older adults with markers of IR is associated with diminished total and regional brain volumes in areas critical for neuronal connectivity, memory, and learning, including cerebral white matter and the hippocampus. Reduced functional connectivity between brain regions detrimental for cognition was also noted. Further, we demonstrated that ATP production, essential for neuronal connectivity, was diminished in neuron-specific insulin receptor knockout mice accompanied by deficits in hippocampal- and prefrontal-dependent tasks. Forty weeks of metformin improved systemic insulin sensitivity concurrent to preserved brain glucose uptake, volume, and functional connectivity within specific regions central to decision-making and learning. Metformin was also associated with an improved composite measure of processing speed and working memory. CONCLUSION. These findings highlight IR as a key regulator of brain metabolism and support the concept that insulin sensitization can prevent neurobiological deficits in older people with IR.