SIRT1 and miR-34a-5p: Valuable Biomarkers for the Early Detection of Cognitive Impairment in Type 2 Diabetes Mellitus Free

Alzheimer disease (AD) and type 2 diabetes mellitus (T2DM) are two highly prevalent conditions, particularly among the older population (1, 2). T2DM is a progressive and heterogeneous disease characterized by insulin resistance and a decline in pancreatic β-cell function. Complications that traditionally have been associated with this disorder include cardiovascular diseases, kidney disease, retinopathy, and cognitive alterations, particularly AD. AD is the leading cause of dementia among older people, and it is characterized by progressive degeneration and irreversibility, involving neuronal loss, the formation of senile plaques containing β-amyloid deposits, and the development of neurofibrillary tangles in neuronal microtubules.

Although T2DM is primarily a peripheral disease and AD is a disorder of the central nervous system, the two share some common features. Indeed, accumulating evidence highlights a higher occurrence of AD in patients with T2DM compared to those without T2DM (3). This epidemiological connection has given rise to several hypotheses concerning the pathophysiological links between the two diseases, such as disruptions in insulin signaling (which can lead to β-amyloid accumulation), abnormalities in glucose transporters, and glutamate-induced excitotoxicity in neuronal cells, as well as the formation of advanced glycation end products and the appearance of oxidative stress, tau phosphorylation, apoptosis, and mitochondrial dysfunctions within the brain (3, 4). Unfortunately, a definitive explanation for the apparent association between AD and T2DM remains elusive, and no diagnostic biomarkers are yet available for the early identification of T2DM patients with cognitive impairment (T2DM-CI).

In a recent issue of The Journal of Clinical Endocrinology & Metabolism, Xiaofeng and colleagues (5) have thrown light on the underlying mechanisms of these intricate disorders by studying the role of miR-34a-5p, a senescence-associated microRNA (miRNA) that suppresses the activity of the silent information regulator 1 (SIRT1), which acts as a key molecular regulator of mitochondrial biogenesis and longevity. Specifically, the authors determined SIRT1 and miR-34a-5p to be valuable biomarkers for the early detection of CI in T2DM, thus improving diagnosis of the disease and encouraging therapeutic trials. Using peripheral blood mononuclear cells (PBMCs) from 374 recruited individuals, including AD patients, T2DM-CI patients, T2DM patients with noncognitive impairment (T2DM-nCI), and age- and sex- matched healthy controls, the authors made substantial discoveries regarding mitochondrial dysfunction and SIRT1 expression. First, they reported a notable reduction in mitochondrial function (activity of complex I, III, and IV and adenosine triphosphate levels) and decreased expression of SIRT1in the PBMCs of AD patients vs healthy controls. Second, they investigated the expression of different miRNAs. miRNAs are small, noncoding nucleic acids widely found within the nervous system where they are critical regulators of functions such as synaptic plasticity, neuronal differentiation, dendritic spine morphology, and neurite outgrowth. This is why they have been proposed as noninvasive biomarkers for diagnosing AD. Xiaofeng et al observed that miR-34a-5p, miR-9-5p, and miR-132-3p were upregulated in the PBMCs of AD patients (6); however, only miR-34a-5p showed a marked upregulation in the PBMCs of T2DM-CI patients. In this regard, receiver operating characteristic analysis revealed that the area under the receiver operating characteristic curve (AUC) for SIRT1 messenger RNA (mRNA) in distinguishing between T2DM-CI patients and healthy controls was 0.776, with a sensitivity of 69.23% and a specificity of 84.62%. In the case of miR-34a-5p, the AUC in discriminating T2DM-CI individuals from healthy controls was 0.754, with a sensitivity of 60.01% and specificity of 86.15%. More important, the combination of SIRT1 mRNA and miR-34a-5p in PBMCs of T2DM-CI patients was more accurate than SIRT1 mRNA or miR-34a-5p individually. The combined biomarkers achieved an AUC of 0.846, with a sensitivity of 82.54% and specificity of 81.55%. These findings are noteworthy and in line with existing data. In fact, multiple studies have established the involvement of miR-34a-5p in obesity and insulin resistance. For instance, Garcia-Jacobo et al (7) identified elevated levels of serum miR-34a-5p in overweight and obese individuals, while Kong et al (8) reported a significant upregulation of serum miR-34a-5p in patients diagnosed with T2DM.

Overall, the results provided by Xiaofeng and colleagues (5) support the role of SIRT1 and miR-34a-5p as key players in the mechanisms underlying the connection between T2DM and CI and underscore the potential of a combined approach in effectively discriminating T2DM-CI from T2DM-nCI. These findings are very promising considering the great potential of miRNAs for noninvasive diagnostics in clinical practice. In fact, miRNAs play an important role in metabolic homeostasis and T2DM through regulation of multiple genes and can be quantified in body fluids such as saliva, blood, and urine, among others, making them convenient for follow-up visits. Over the last few years, considerable efforts have been made to improve miRNA detection in body fluids, leading to the development of new or improved approaches for early diagnosis and effective therapeutic interventions as well as monitoring disease evolution. However, as the authors note, their research has some limitations: 1) Other pathways involving miR-34a-5p need to be explored to comprehensively understand its role in the development of CI in T2DM; 2) a relatively small study population was included; and 3) the study was cross-sectional, so a longitudinal and prospective cohort study would be necessary to bolster its conclusions. These extra steps might provide a more robust validation of the aforementioned findings, allowing for a clearer understanding of the mechanisms at play in the context of T2DM-related CI.

Acknowledgments

The authors thank Brian Normanly (University of Valencia/CIBERehd; [email protected]) for his editorial assistance.

Funding

This work was supported by the European Regional Development Fund (ERDF “A way to build Europe”); Generalitat Valenciana (grant PROMETEO CIPROM/2022/32), Spanish Ministry of Science and Innovation (grants CIBERehd CB06/04/0071 and PI22/00424 from the Carlos III Health Institute). T.V. is a recipient of a Miguel Servet contract (No. CP22/00153) from the Carlos III Health Institute.

Disclosures

The authors have nothing to disclose.

Data Availability

Data sharing is not applicable to this article because no data sets were generated or analyzed during the present study.

References

Abbreviations

 
• AD

  Alzheimer disease

 
• AUC

  area under the curve

 
• miRNAs

  microRNAs

 
• mRNA

  messenger RNA

 
• PBMCs

  peripheral blood mononuclear cells

 
• SIRT1

  silent information regulator 1

 
• T2DM

  type 2 diabetes mellitus

 
• T2DM-CI

  type 2 diabetes mellitus patients with cognitive impairment

 
• T2DM-nCI

  T2DM patients with noncognitive impairment