Elevated hippocampal copper in cases of type 2 diabetes

Background Type-2 diabetes (T2D) is characterized by chronic hyperglycaemia and glucose-evoked organ damage, and displays systemic copper overload, elevated risk of impaired cognitive function, and epidemiological links to sporadic Alzheimer's disease (sAD). Contrastingly, sAD exhibits impaired cerebral-glucose uptake, elevation of cerebral glucose but not blood glucose levels, and widespread cerebral-copper deficiency. We hypothesized that sAD-like brain-metal perturbations would occur in T2D. Methods We measured nine essential elements in an observational case-control study of T2D without dementia (6 cases and 6 controls) in four brain regions and compared the results with those from our study of brain metals in sAD (9 cases and 9 controls), which employed equivalent analytical methodology. We evaluated intergroup differences by supervised and unsupervised multivariate-statistical approaches to contrast between T2D cases and controls, and to compare them with cerebral-metal patterns in sAD. Findings Unexpectedly, we found that hippocampal-copper levels in T2D were markedly elevated compared with controls (P = 0.005 and 0.007 by Welch's t-test in two technical-replicate experiments), to levels similar to those in cases of untreated Wilson's disease (WD), wherein elevated cerebral copper causes neurodegeneration. By contrast, hippocampal-copper levels in sAD were markedly deficient. Multivariate analysis identified marked differences in patterns of essential metals between hippocampal datasets from cases of T2D and of sAD. Interpretation Elevated hippocampal copper could contribute to the pathogenesis of cerebral neurodegeneration and cognitive impairment in T2D, similar to known impacts of elevated brain copper in WD. Therapeutic approaches with copper-lowering agents similar to those currently employed in pharmacotherapy of WD, may also be applicable in patients with T2D and impaired cognitive function. Further studies will be required to replicate and extend these findings and to investigate their potential therapeutic implications. Copyright (C) 2022 The Author(s). Published by Elsevier B.V.

Automated summary

The study found that hippocampal copper levels were significantly elevated in patients with T2D, similar to untreated cases of Wilson's disease (WD), while hippocampal copper levels were markedly deficient in patients with sAD. These results suggest that hippocampal copper may play a role in the neurodegeneration and cognitive impairment in T2D, and therapeutic approaches targeting copper reduction, similar to those used in WD, may be applicable to patients with T2D.