Diabetes and brain: omics approaches to study diabetic encephalopathy

Abstract

Diabetes mellitus (DM) is a complex metabolic disorder associated with many complications, including diabetic encephalopathy (DE). DE is a severe neurological condition characterized by a progressive decline in cognitive and motor functions, significantly impacting patients' quality of life. Despite advancements in understanding DM, the intricate pathogenetic mechanisms underlying DE remain incompletely elucidated. This review comprehensively analyzes the application of omics technologies to decipher the molecular basis of DE and identify potential diagnostic biomarkers and therapeutic targets. Several studies on animal models of DE have revealed specific metabolic signatures and changes in gene expression in key memory brain regions, like the hippocampus, highlighting potential therapeutic targets. We explore how these "omics" approaches have provided novel insights into the complex interplay of factors contributing to DE. Recurrent alterations were identified upon evaluation of analysis from human tissues and in vitro models of DE. Findings indicate that this pathological condition is characterized by impaired energy metabolism, oxidative stress, neuroinflammation, neuroendocrine dysfunction and the influence of the gut microbiota. A multi-omics approach, integrating data from various models and limited human studies, enhances translational understanding of DE pathogenesis, with new implications for diagnosis and treatment.

Keywords: diabetic encephalopathy; energy metabolism; neuroinflammation; omics approaches; oxidative stress.

Figure 1

Schematic representation of the workflow of omics approaches for the study of DE. The DE models used are primarily murine, but also include human tissues and cell lines. Extraction of molecules of interest is performed depending on the approach used: nucleic acids for genomics and transcriptomics, proteins for proteomics, lipids for lipidomics, and metabolites for metabolomics. Only some of the techniques used, such as PCR, RNAseq, MALDI, and HPLC-MS, are illustrated, followed by an illustration of data analysis. Figure generated using app.biorender.com.

Figure 2

Main alterations found in DE through omics approaches.

Figure 3

Representation of principal alterations observed in the hippocampus under hyperglycemic conditions through omics analyses. The most significant observed alterations involve a series of factors: Somatostatin Receptor 2 (SSTR2), circ-Nbea/miR-128-3p, insulin-like growth factor binding protein-2 (IGFBP2), dopamine β-hydroxylase (DBH), DRAXIN, Allopregnanolone (ALLO), Synaptotagmin 1 (SYT1), calcium/calmodulin dependent protein kinase I delta (CaMK1D), 2B subunit of N-methyl-D-aspartate glutamate receptor (GRIN2B), 2B subunit of N-methyl-D-aspartate glutamate receptor (GRIN2B) and Neuro-oncological ventral antigen 1 (NOVA1), ALKBH5, arginine vasopressin receptor 1A (AVPR1A), CAT, PRKAA2, tricarboxylic acid cycle (TCA), NAA and dihydroxyacetone phosphate (DHAP); ↑,upregulation; ↓, downregulation. These alterations are involved in cognitive impairment (pink), modulation of learning and memory (light blue), neuroinflammation (orange), oxidative stress (gray), and dysregulation of energy metabolism (green). All these conditions are characteristics of DE. Oligodendrocyte precursor cells (OPCs).

Figure 4

Under hyperglycemic conditions, there is a permeability increase of the blood-brain barrier and an activation of microglia. A series of altered pathways and molecules are observed: miR-384-5p/Beclin-1, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), c-Jun N-terminal Kinase (JNK), PI3K/Akt/GSK-3β signaling, Fatty aldehydes (FALs), glucose-6-phosphate (G6P), glutamine, human islet amyloid polypeptide (hIAPP) reduced CD147, Ndufs3, phospholipids, plasmalogens, cholesterol, glutamate (Glut), adenosine, inosine, aspartate (Asp), N-acetyl aspartate (NAA), L-carnitine and myosin light chain kinase (MLCK). ↑,upregulation; ↓, downregulation. These alterations are involved in cognitive impairment (pink), modulation of learning and memory (light blue), neuroinflammation (orange), oxidative stress (gray), and dysregulation of energy metabolism (green). All these conditions are characteristics of DE.