Our study showed that log HOMA-IR scores were significantly associated with the poor functional outcome of non-diabetic ischemic stroke patients. This association remained statistically significant even the age of the highest quartiles of log HOMA-IR was youngest among quartiles and the relationship was sustained after adjusting for cardiovascular risk factors and lipid profile abnormalities.
In this study, the initial stroke severity and the presence of END did not differ between the log HOMA-IR quartiles. These results indicate that the harmful effect of insulin resistance impacts the recovery phase of acute ischemic stroke and is not associated with worsening of a preexisting impairment. A study based on the Fukuoka registry in Japan also reported that HOMA-IR scores were related to poor functional outcomes. There were no associations with the recurrence of stroke or mortality, which supports our hypothesis. Another study reported that the HOMA-IR index scores were associated with increased mortality, recurrent stroke, and poor outcomes. The differences between the study results may be due to different study populations.
Some hypotheses may explain the association between insulin resistance and poor patient outcome after an ischemic stroke. One of them involves the concept of synaptic plasticity. Synaptic plasticity is the ability of a neuron to change the synapse in response to external stimuli and activity. In the brain, the insulin/IGF receptor signaling pathway maintains the balance between neuroprotective and neurotoxic effects.[11–13] Insulin resistance is defined as a loss of this function in insulin ligands. Subsequently, the balance is upset, causing changes in the survival of the neurons and synaptic plasticity. Likewise, the synaptic plasticity of the brain decreases in stroke patients with high insulin resistance, which interferes with its recovery from the primary insult. Second, insulin resistance in muscles may have contributed to the poor prognosis of these patients. Type 2 diabetes mellitus patients evolve whole-body insulin resistance and insulin resistance in skeletal muscles reduces glucose transport pathways, which results in excessive reactive oxygen species and mitochondrial dysfunction.[14, 15] This may interrupt recovery after an acute ischemic stroke. Third, endothelial damage might play a role. Endothelial function is related to vascular reactivity in the cerebral circulation. Insulin and insulin resistance affect the vascular endothelium.[16–18] Furthermore, insulin resistance is a risk factor for atherosclerosis.[19, 20] Endothelial dysfunction, decreased vascular reactivity, and enhanced atherosclerosis might cause recurrent stroke and delayed restoration.
Our study had some strengths. First, we demonstrated that the worsening effect of insulin resistance on ischemic stroke impacted the recovery phase. This finding indicates that we should treat insulin resistance itself, apart from diabetes mellitus, especially in the subacute stage of an acute ischemic stroke. Second, unlike previous studies, we thoroughly investigated the risk factors, including laboratory and clinical factors, associated with poor prognoses. Body mass index, individual lipid levels, and blood pressure levels were collected and adjusted for in the multivariate analysis and the association between insulin resistance and poor clinical outcome remained strong. There were several limitations to this study. First, the HOMA-IR scores were only determined once, within 24 hours of admission. This might not reflect the exact status of insulin resistance during the recovery period. Second, the HOMA-IR index scores for insulin resistance mainly reflect resistance in hepatic metabolism. Third, this was a single-center data review from a comprehensive stroke center in Korea. Consequently, the results cannot be generalized to other populations and races.