Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, Centre for Advanced Discovery & Experimental Therapeutics, School of Medical Sciences, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
Faculty of Science, School of Biological Sciences, University of Auckland, Auckland, New Zealand.
EBioMedicine. 2022 Dec;86:104317. doi: 10.1016/j.ebiom.2022.104317. Epub 2022 Nov 3.
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.
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.
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.
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.
In Acknowledgments, includes Endocore Research Trust; Lee Trust; Oakley Mental Health Research Foundation; Ministry of Business, Innovation & Employment; The Universities of Auckland and Manchester, and others.
2 型糖尿病（T2D）的特征是慢性高血糖和葡萄糖引起的器官损伤，并表现出全身铜过载、认知功能受损风险增加，以及与散发性阿尔茨海默病（sAD）的流行病学联系。相比之下，sAD 表现出脑葡萄糖摄取受损、脑葡萄糖水平升高而血糖水平正常，以及广泛的脑铜缺乏。我们假设 T2D 中会出现类似 sAD 的脑金属扰动。
我们在一项无痴呆的 T2D 病例对照研究中（6 例病例和 6 例对照）测量了四个脑区的 9 种必需元素，并将结果与我们对 sAD 脑金属的研究进行了比较（9 例病例和 9 例对照），采用了等效的分析方法。我们通过监督和非监督多变量统计方法评估了组间差异，以对比 T2D 病例和对照组，并将其与 sAD 中的脑金属模式进行比较。
出乎意料的是，我们发现 T2D 患者的海马铜水平明显高于对照组（在两个技术重复实验中，Welch's t 检验的 P 值分别为 0.005 和 0.007），与未经治疗的威尔逊病（WD）患者的水平相似，其中升高的脑铜会导致神经退行性变。相比之下，sAD 患者的海马铜水平明显缺乏。多变量分析确定了 T2D 和 sAD 病例的海马数据集之间的必需金属模式存在显著差异。
升高的海马铜可能导致 T2D 患者的脑神经退行性变和认知功能障碍的发病机制，类似于已知的脑铜升高对 WD 的影响。用类似于 WD 药物治疗中使用的降铜剂进行治疗，也可能适用于 T2D 和认知功能受损的患者。需要进一步研究来复制和扩展这些发现，并研究其潜在的治疗意义。
在致谢中，包括 Endocore 研究信托基金；李信托基金；奥克利心理健康研究基金会；商业、创新和就业部；奥克兰大学和曼彻斯特大学及其他机构。
