Emerging roles of microRNAs as diagnostics and potential therapeutic interest in type 2 diabetes mellitus

Abstract

Background: Type 2 diabetes mellitus (T2DM) is a metabolic disease of impaired glucose utilization. Uncontrolled high sugar levels lead to advanced glycation end products (AGEs), which affects several metabolic pathways by its receptor of advanced glycation end products (RAGE) and causes diabetic complication. MiRNAs are small RNA molecules which regulate genes linked to diabetes and affect AGEs pathogenesis, and target tissues, influencing health and disease processes.

Aim: To explore miRNA roles in T2DM's metabolic pathways for potential therapeutic and diagnostic advancements in diabetes complications.

Methods: We systematically searched the electronic database PubMed using keywords. We included free, full-length research articles that evaluate the role of miRNAs in T2DM and its complications, focusing on genetic and molecular disease mechanisms. After assessing the full-length papers of the shortlisted articles, we included 12 research articles.

Results: Several types of miRNAs are linked in metabolic pathways which are affected by AGE/RAGE axis in T2DM and its complications. miR-96-5p, miR-7-5p, miR-132, has_circ_0071106, miR-143, miR-21, miR-145-5p, and more are associated with various aspects of T2DM, including disease risk, diagnostic markers, complications, and gene regulation.

Conclusion: Targeting the AGE/RAGE axis, with a focus on miRNA regulation, holds promise for managing T2DM and its complications. MiRNAs have therapeutic potential as they can influence the metabolic pathways affected by AGEs and RAGE, potentially reducing inflammation, oxidative stress, and vascular complications. Additionally, miRNAs may serve as early diagnostic biomarkers for T2DM. Further research in this area may lead to innovative therapeutic strategies for diabetes and its associated complications.

Keywords: Advanced glycation end products; MicroRNAs; Receptor for advanced glycation end products; Type 2 diabetes mellitus.

Figure 1

Advanced glycation end products formation. Reaction between the carbonyl group of reducing sugar and the amino group of proteins and lipids via a Schiff base reaction cascade, followed by amadori rearrangement and oxidative modification.

Figure 2

PRISMA flow diagram of study selection process for preclinical and clinical evidence.

Figure 3

MiRNA regulation in the advanced glycation end product/receptor of advanced glycation end products activated nuclear factor pathway. Advanced glycation end product - receptor of advanced glycation end product interaction activates the nuclear factor pathway, which is inhibited by miR-200b, miR-200c, and miR-471-3p and upregulated by miR-124 and miR-146a. AGE: Advanced glycation end product; RAGE: Receptor of advanced glycation end product; MAPK: Mitogen-activated protein kinases; NF-κB: Nuclear factor kappa beta; TNF-α: Tumor necrosis factor.

Figure 4

Interaction of advanced glycation end product and receptor of advanced glycation end product activates the protein kinase C pathway: The interaction of advanced glycation end product and advanced glycation end product activates the nuclear factor pathway and damages DNA, causing PARP-1 to be released and GAPDH to be inhibited. The inhibition of GAPDH affects the glycolysis pathway and increases fatty acid synthesis. This increased synthesis of fatty acids activates diacyl glycerol in the cell membrane, which is a potent activator of protein kinase C (PKC). Increased PKC promotes synthesis of NADPH oxidase, super oxide and oxidative stress and ultimately decreases cellular nitric oxide. In this pathway, miRNA 210, miR-25, and miR-21-3p inhibit NADPH oxidase and oxidative stress. Apart from that, miR 92a promotes the expression of the antioxidant HO-1. AGE: Advanced glycation end product; RAGE: Receptor of advanced glycation end product; NF-κB: Nuclear factor kappa beta.

Figure 5

Regulation of miRNA in the nitric oxide pathway: The interaction of advanced glycation end product and receptor of advanced glycation end product affects the availability of Nitric Oxide via inhibition of eNOS. miR-195, miR-582, and miR-182 all inhibit AGE/RAGE-mediated eNOS alterations and nitric oxide production. AGE: Advanced glycation end product; RAGE: Receptor of advanced glycation end product; NF-κB: Nuclear factor kappa beta; NO: Nitric oxide.

Figure 6

Functional role of miRNA in the advanced glycation end product/receptor of advanced glycation end products activated phosphoinositide 3-kinase pathway. The advanced glycation end product/receptor of advanced glycation end products -activated nuclear factor (NF) pathway inhibits GLUT-4 release from the cellular membrane. miR-129-5p, miR-29b-3p upregulate the pathway. However, miR-191, miR-146b-3p and miR-191 show an inhibitory effect. Furthermore, miR 214 increases GLUT-4 expression by simultaneously upregulating the PI3k/AKT pathway and inhibiting the NF- pathway. AGE: Advanced glycation end product; RAGE: Receptor of advanced glycation end product; NF-κB: Nuclear factor kappa beta.