Posttranscriptional Regulation of Insulin Resistance: Implications for Metabolic Diseases

Abstract

Insulin resistance defines an impairment in the biologic response to insulin action in target tissues, primarily the liver, muscle, adipose tissue, and brain. Insulin resistance affects physiology in many ways, causing hyperglycemia, hypertension, dyslipidemia, visceral adiposity, hyperinsulinemia, elevated inflammatory markers, and endothelial dysfunction, and its persistence leads to the development metabolic disease, including diabetes, obesity, cardiovascular disease, or nonalcoholic fatty liver disease (NAFLD), as well as neurological disorders such as Alzheimer’s disease. In addition to classical transcriptional factors, posttranscriptional control of gene expression exerted by microRNAs and RNA-binding proteins constitutes a new level of regulation with important implications in metabolic homeostasis. In this review, we describe miRNAs and RBPs that control key genes involved in the insulin signaling pathway and related regulatory networks, and their impact on human metabolic diseases at the molecular level, as well as their potential use for diagnosis and future therapeutics.

New Insights on the Regulation of the Insulin-Degrading Enzyme: Role of microRNAs and RBPs

“…Indeed, the discovery of the crystal structure of IDE opens the door to novel pharmacological regulators of IDE functions [ 70 ]. Although miRNAs are abundantly expressed in the brain, where they are involved in the modulation of multiple physiological functions and pathological states and metabolic pathways involved in neurodegeneration [ 24 , 25 , 33 , 71 ], only a few studies have explored the potential post-transcriptional regulation of IDE [ 28 ].…”

“…However, in vitro analyses are needed to confirm this prediction of direct binding of these RBPs to the hIDE 3′UTR or, alternatively, by a competing mechanism with other post-transcriptional regulators. Indeed, several examples in the literature have demonstrated the interplay between miRNAs and RBPs [ 33 ]. Our data suggest a potential novel regulatory mechanism through miRNAs and RBPs that could be exploited as a therapeutical target in vivo.…”

“…Our data suggest a potential novel regulatory mechanism through miRNAs and RBPs that could be exploited as a therapeutical target in vivo. Future studies will help decipher the possible mechanisms underlying IDE regulation by these RBPs, which is even more important considering that little is known regarding RBPs functions in the context of insulin resistance in AD [ 33 ].…”

“…In addition to non-coding RNAs, RNA binding proteins (RBPs) are a heterogeneous group of proteins that play a major role in gene expression by controlling all stages of RNA biology, from transcription, RNA processing, alternative splicing, mRNA stability and mRNA localization to translation and RNA degradation, via specific RNA interaction motifs generally present in the 3´UTR of the target mRNA [ 31 , 32 ]. As we reviewed, several RBPs have been shown to regulate metabolism and take part in insulin resistance [ 33 ]. However, until now, there has been no evidence that RBPs can potentially bind to IDE transcript or even regulate its levels of expression.…”

Extracellular vesicles in metabolic dysfunction associated fatty liver disease: mechanisms, diagnostic and therapeutic implications

“…Moreover, the role of miRNAs in liver inflammation, fibrosis, and cirrhosis has been acknowledged [80]. miRNAs are detected in biological fluids like blood, urine, tears, saliva, and breastmilk and can be used as diagnostic biomarkers, e.g., in type 2 diabetes, HCC, and MAFLD [81,82]. miR-122 is released from damaged hepatocytes in alcoholic liver disease, viral hepatitis, and drug-induced liver injury [83][84][85].…”