Depiction of Branched-Chain Amino Acids (BCAAs) in Diabetes with a Focus on Diabetic Microvascular Complications

Abstract

Type 2 diabetes mellitus (T2DM) still holds the title as one of the most debilitating chronic diseases with rising prevalence and incidence, including its complications such as retinal, renal, and peripheral nerve disease. In order to develop novel molecules for diagnosis and treatment, a deep understanding of the complex molecular pathways is imperative. Currently, the existing agents for T2DM treatment target only blood glucose levels. Over the past decades, specific building blocks of proteins-branched-chain amino acids (BCAAs) including leucine, isoleucine, and valine-have gained attention because they are linked with insulin resistance, pre-diabetes, and diabetes development. In this review, we discuss the hypothetical link between BCAA metabolism, insulin resistance, T2DM, and its microvascular complications including diabetic retinopathy and diabetic nephropathy. Further research on these amino acids and their derivates may eventually pave the way to novel biomarkers or therapeutic concepts for the treatment of diabetes and its accompanied complications.

Keywords: BCAAs; T2DM; branched chain amino acids; diabetes mellitus; diabetic nephropathy; diabetic retinopathy.

Figure 1

The BCAA catabolic and metabolic complex pathway regulates energy metabolism. Increased levels of BCAAs and fatty acids can interfere with normal insulin signaling through various mechanisms and ultimately lead to IR. In glycolysis and the Krebs cycle, NAD+ is reduced to form the NADH molecule. If NAD+ is not present, glycolysis will not be able to continue. IRS-1 (insulin receptor substrate-1); GLUT4 (glucose transporter type 4); SREBP (Sterol regulatory element binding proteins); Ras homolog enriched in brain (RHEB).

Figure 2

Dysregulated BCAA catabolism is highly associated with chronic inflammation and tissue damage in T2DM. Additionally, in the early stages of T2DM development, hyperglycemia and insulin resistance contribute to elevations in BCAA levels, which further promotes the activation of inflammatory pathways, oxidative stress with endothelial impairment, and vascular damage, leading to microvascular complication advancement. c-Jun N-terminal kinase (JNK); matrix metalloproteinase-9 (MMP-9).