Associations between plasma kynurenines and cognitive function in individuals with normal glucose metabolism, prediabetes and type 2 diabetes: the Maastricht Study,Diabetologia

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Associations between plasma kynurenines and cognitive function in individuals with normal glucose metabolism, prediabetes and type 2 diabetes: the Maastricht Study
Diabetologia ( IF 8.4 ) Pub Date : 2021-08-19 , DOI: 10.1007/s00125-021-05521-4
Lieke Bakker _{1,

2} , Inez H G B Ramakers _{1,

2} , Martin P J van Boxtel _{1,

2} , Miranda T Schram _{1,

3,

4,

5} , Coen D A Stehouwer _{3,

4} , Carla J H van der Kallen _{3,

4} , Pieter C Dagnelie _{3,

4} , Marleen M J van Greevenbroek _{3,

4} , Anke Wesselius _{3,

6,

7} , Øivind Midttun ₈ , Per M Ueland _{9,

10} , Frans R J Verhey _{1,

2} , Simone J P M Eussen _{3,

11} , Sebastian Köhler _{1,

2}

Affiliation

MHeNs School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, Maastricht University, Maastricht, the Netherlands.
CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands.
Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, the Netherlands.
Heart and Vascular Center, Maastricht University Medical Center+, Maastricht, the Netherlands.
CAPHRI School for Public Health and Primary Care, Maastricht University, Maastricht, the Netherlands.
Department of Complex Genetics and Epidemiology, Maastricht University, Maastricht, the Netherlands.
Bevital AS, Bergen, Norway.
University of Bergen, Bergen, Norway.
Haukeland University Hospital, Bergen, Norway.
Department of Epidemiology, Maastricht University, Maastricht, the Netherlands.

Aims/hypothesis

Studies investigating associations between kynurenines and cognitive function have generally been small, restricted to clinical samples or have found inconsistent results, and associations in the general adult population, and in individuals with type 2 diabetes in particular, are not clear. Therefore, the aim of the present study was to investigate cross-sectional associations between plasma kynurenines and cognitive function in a cohort of middle-aged participants with normal glucose metabolism, prediabetes (defined as impaired fasting glucose and/or impaired glucose tolerance) and type 2 diabetes.

Methods

Plasma kynurenines were quantified in 2358 participants aged 61 ± 8 years. Cross-sectional associations of kynurenines with cognitive impairment and cognitive domain scores were investigated using logistic, multiple linear and restricted cubic spline regression analyses adjusted for several confounders.

Results

Effect modification by glucose metabolism status was found for several associations with cognitive impairment, hence analyses were stratified. In individuals with prediabetes, 3-hydroxykynurenine (OR per SD 0.59 [95% CI 0.37, 0.94]) and 3-hydroxyanthranilic acid (0.67 [0.47, 0.96]) were associated with lower odds of cognitive impairment after full adjustment. In individuals with type 2 diabetes, kynurenine (0.80 [0.66, 0.98]), 3-hydroxykynurenine (0.82 [0.68, 0.99]), kynurenic acid (0.81 [0.68, 0.96]), xanthurenic acid (0.73 [0.61, 0.87]) and 3-hydroxyanthranilic acid (0.73 [0.60, 0.87]) were all associated with lower odds of cognitive impairment. Kynurenic acid (β per SD 0.07 [95% CI 0.02, 0.13]) and xanthurenic acid (0.06 [0.01, 0.11]) were also associated with better executive function/attention. No associations were observed in individuals with normal glucose metabolism.

Conclusions/interpretation

Several kynurenines were cross-sectionally associated with lower odds of cognitive impairment and better cognitive functioning in type 2 diabetes, while less widespread associations were seen in prediabetes. Low levels of kynurenines might be involved in the pathway of type 2 diabetes and cognitive decline but this needs further studies.

Graphical abstract

中文翻译：

葡萄糖代谢正常、糖尿病前期和 2 型糖尿病患者血浆犬尿氨酸与认知功能之间的关联：马斯特里赫特研究

目标/假设

犬尿氨酸与认知功能之间关联的研究通常很少，仅限于临床样本或发现不一致的结果，并且在一般成年人群中，特别是在 2 型糖尿病患者中的关联尚不清楚。因此，本研究的目的是在一组糖代谢正常、糖尿病前期（定义为空腹血糖受损和/或糖耐量受损）和糖尿病类型的中年参与者中调查血浆犬尿氨酸与认知功能之间的横断面关联。 2糖尿病。

方法

在 2358 名 61 ± 8 岁的参与者中对血浆犬尿氨酸进行了量化。犬尿氨酸与认知障碍和认知领域评分的横断面关联使用逻辑、多重线性和限制三次样条回归分析进行了研究，该分析针对几个混杂因素进行了调整。

结果

发现葡萄糖代谢状态的影响与认知障碍的几种关联有关，因此对分析进行了分层。在糖尿病前期患者中，3-羟基犬尿氨酸（OR per SD 0.59 [95% CI 0.37, 0.94]）和 3-羟基邻氨基苯甲酸（0.67 [0.47, 0.96]）与完全调整后认知障碍的几率降低相关。在 2 型糖尿病患者中，犬尿氨酸 (0.80 [0.66, 0.98])、3-羟基犬尿氨酸 (0.82 [0.68, 0.99])、犬尿酸 (0.81 [0.68, 0.96])、黄尿酸 (0.73 [0.61, 0.87])和 3-羟基邻氨基苯甲酸 (0.73 [0.60, 0.87]) 都与较低的认知障碍发生率相关。犬尿酸（β per SD 0.07 [95% CI 0.02, 0.13]）和黄尿酸（0.06 [0.01, 0.11]）也与更好的执行功能/注意力相关。