Metabolic Dysfunction Biomarkers as Predictors of Early Diabetes

Abstract

During the pathophysiological course of type 2 diabetes (T2D), several metabolic imbalances occur. There is increasing evidence that metabolic dysfunction far precedes clinical manifestations. Thus, knowing and understanding metabolic imbalances is crucial to unraveling new strategies and molecules (biomarkers) for the early-stage prediction of the disease's non-clinical phase. Lifestyle interventions must be made with considerable involvement of clinicians, and it should be considered that not all patients will respond in the same manner. Individuals with a high risk of diabetic progression will present compensatory metabolic mechanisms, translated into metabolic biomarkers that will therefore show potential predictive value to differentiate between progressors/non-progressors in T2D. Specific novel biomarkers are being proposed to entrap prediabetes and target progressors to achieve better outcomes. This study provides a review of the latest relevant biomarkers in prediabetes. A search for articles published between 2011 and 2021 was conducted; duplicates were removed, and inclusion criteria were applied. From the 29 studies considered, a survey of the most cited (relevant) biomarkers was conducted and further discussed in the two main identified fields: metabolomics, and miRNA studies.

Keywords: biomarkers; diabetes; early diagnosis; prediabetes.

Figure 1

Number of citations regarding biomarkers associated with (a) metabolomics studies; (b) microRNA studies. The grey areas highlight the most relevant biomarkers. Biomarkers with just one reference were not included in these results.

Figure 2

Metabolomics biomarkers’ discovery cycle: from the biological sample, to the identification of the disturbed metabolic signaling pathways, to its clinical significance. Metabolomics results facilitate the integration of the metabolic profile in the pathophysiology of prediabetes.

Figure 3

The current model for the biogenesis and post-transcriptional suppression of microRNAs: ① In the nucleus, the miRNA gene is a transcript from RNA polymerase II, which produces a primary miRNA: pri-microRNA (pri-miRNA). ② The pri-microRNA transcripts are first processed into ~70-nucleotide pre-miRNAs by Drosha inside the nucleus. ③ Pre-miRNA is quickly exported by Exportin-5 to the cytosol. ④ In the cytoplasm, the pre-miRNA is processed by Dicer, thus producing a double-ribbon miRNA. ⑤ This product is unwound and then joined with Argonaute to form the complex RISC. ⑥ The RISC complex obtains the pairing between the miRNA and the homolog target mRNA via reverse base complement. ⑦ It subsequently acts on its target through translational repression or mRNA cleavage ⑧, depending, at least in part, on the level of complementarity between the small RNA and its target.