Higher Serum Soluble TREM2 as a Potential Indicative Biomarker for Cognitive Impairment in Inadequately Controlled Type 2 Diabetes Without Obesity: The DOR-KyotoJ-1

Abstract

ObjectiveType 2 diabetes is a risk factor for dementia. We investigated whether serum levels of soluble triggering receptor expressed on myeloid cell 2 (sTREM2), a soluble form of the cell surface receptor TREM2, were predictive of cognitive impairment in type 2 diabetes without obesity.MethodsA total of 166 Japanese patients with type 2 diabetes without obesity were followed-up for 2 years. We measured clinical parameters, assessed cognitive function using the mini-mental state examination (MMSE), quantified and divided serum sTREM2 levels into quartiles, and examined the longitudinal associations.ResultsDuring the follow-up, HbA1c levels were elevated in 98 patients and decreased in 68 patients. In the HbA1c-elevated group, higher sTREM2 levels at baseline showed a significant association with a greater tendency for reduction in MMSE scores (P for trend = 0.015), whereas they were not significantly associated with other examined parameters. In the HbA1c-decreased group, there was no significant association between sTREM2 levels at baseline and changes in MMSE scores, but higher sTREM2 levels at baseline were significantly associated with a greater tendency for reduction in waist circumference (P for trend = 0.027), homeostasis model assessment of insulin resistance (P for trend = 0.039), and sTREM2 levels (P for trend = 0.023).ConclusionsGlycemic control is suggested to be important in preventing cognitive impairment in patients with type 2 diabetes without obesity. Higher serum sTREM2 levels would be a predictive marker for cognitive impairment in inadequately controlled type 2 diabetes without obesity.

Taxifolin Suppresses Inflammatory Responses of High-Glucose-Stimulated Mouse Microglia by Attenuating the TXNIP–NLRP3 Axis

“…Diabetes deleteriously affects microglial function and results in cognitive impairment in both mouse models [ 11 , 42 , 43 ] and patients with T2DM [ 12 , 13 , 14 ]. Moreover, an HG environment elevated the intracellular ROS levels and triggered inflammatory responses in the microglia, which were implicated in several pathways including NF-κB signaling [ 17 , 18 ], p38 and SAPK/JNK MAPK pathways [ 19 ], and NLRP3 inflammasome activation [ 20 ].…”

“…These results suggest that GLP-1 receptor agonists have neuroprotective effects under diabetic conditions [ 10 , 11 ]. Diabetes-related microglial dysfunction is reportedly implicated in the cognitive impairment of patients with T2DM [ 12 , 13 , 14 ]. Although certain anti-diabetic medications, such as GLP-1 receptor agonists, may have beneficial effects on cognitive impairment, the therapeutic efficacy of these agents has not yet been established in humans [ 15 ].…”

Decoding sTREM2: its impact on Alzheimer’s disease – a comprehensive review of mechanisms and implications

“…Recent findings also revealed increased sTREM2 levels in the serum of long-COVID patients with cognitive impairment when compared to healthy controls ( Besteher et al, 2024 ), suggesting a corresponding shift in microglial reactivity in response to neuronal degeneration. In patients whose diabetes control deteriorated, those with higher baseline levels of sTREM2 experienced a more pronounced decline in Mini-Mental State Examination (MMSE) scores over a 2-year period, which suggests a potential link between higher sTREM2 levels and the acceleration of cognitive impairment under conditions of poor glycemic control ( Tanaka et al, 2022 ). This aligns with previous studies demonstrating an association between sTREM2 levels and neuronal injury markers in the early stages of AD.…”

Soluble TREM2 and Alzheimer-related biomarker trajectories in the blood of diabetic patients based on their cognitive status

“…In the general elderly Japanese population of the Hisayama study, higher levels of serum sTREM2 at baseline were found to be associated with an increased subsequent risk of both AD and VaD [20]. Furthermore, we recently demonstrated that higher levels of serum sTREM2 are cross-sectionally [21] and longitudinally [22] associated with an increased risk of diabetes-related cognitive impairment. In contrast, a recent longitudinal study of participants of the Dominantly Inherited Alzheimer Network (DIAN) found that higher CSF sTREM2 levels reduced the risk of AD pathologies [23].…”

“…Second, not all cell types capable of releasing sTREM2 into the peripheral blood have been identified. Serum sTREM2 levels appear to reflect microglial activation [20] and it has been hypothesized that adipose tissue also produces sTREM2 [22]. The comprehensive identification of sTREM2-releasing cells and further cohort studies with larger sample sizes are needed to address these issues.…”