Lower functional hippocampal connectivity in healthy adults is jointly associated with higher levels of leptin and insulin resistance

BACKGROUND: Metabolic dysregulation is currently considered a major risk factor for hippocampal pathology. The aim of the present study was to characterize the influence of key metabolic drivers on functional connectivity of the hippocampus in healthy adults. METHODS: Insulin resistance was directly quantified by measuring steady-state plasma glucose (SSPG) concentration during the insulin suppression test and fasting levels of insulin, glucose, leptin, and cortisol, and measurements of body mass index and waist circumference were obtained in a sample of healthy cognitively intact adults (n = 104). Resting-state neuroimaging data were also acquired for the quantification of hippocampal functional cohesiveness and integration with the major resting-state networks (RSNs). Data-driven analysis using unsupervised machine learning (k-means clustering) was then employed to identify clusters of individuals based on their metabolic and functional connectivity profiles. RESULTS: K-means clustering identified two clusters of increasing metabolic deviance evidenced by cluster differences in the plasma levels of leptin (40.36 (29.97) vs. 27.59 (25.58) μg/L) and the degree of insulin resistance (SSPG concentration: 161.63 (65.27) vs. 125.72 (66.81) mg/dL). Individuals in the cluster with higher metabolic deviance showed lower functional cohesiveness within each hippocampus and lower integration of posterior and anterior components of the left and right hippocampus with the major RSNs. The two clusters did not differ in general intellectual ability or episodic memory. CONCLUSIONS: We identified two clusters of individuals differentiated by abnormalities in insulin resistance, leptin levels, and hippocampal connectivity, with one of the clusters showing greater deviance. These findings support the link between metabolic dysregulation and hippocampal function even in nonclinical samples.