Crosstalk Between the Unfolded Protein Response, MicroRNAs, and Insulin Signaling Pathways: In Search of Biomarkers for the Diagnosis and Treatment of Type 2 Diabetes

Abstract

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that is characterized by functional defects in glucose metabolism and insulin secretion. Its complex etiology and multifaceted nature have made it difficult to design effective therapies for early diagnosis and treatment. Several lines of evidence indicate that aberrant activation of the unfolded protein response (UPR) in response to endoplasmic reticulum (ER) stress impairs the β cell's ability to respond to glucose and promotes apoptosis. Elucidating the molecular mechanisms that govern β cell dysfunction and cell death can help investigators design therapies to halt or prevent the development of T2DM. Early diagnosis of T2DM, however, warrants additionally the identification of potential biomarkers. MicroRNAs (miRNAs) are key regulators of transcriptional processes that modulate various features of insulin signaling, such as insulin sensitivity, glucose tolerance, and insulin secretion. A deeper understanding of how changes in patterns of expression of miRNAs correlate with altered glucose metabolism can enable investigators to develop methods for the early diagnosis and treatment of T2DM. The first part of this review examines how altered expression of specific UPR pathway proteins disrupts ER function and causes β cell dysfunction, while the second part discusses the potential role of miRNAs in the diagnostic and treatment of T2DM.

Keywords: biomarkers; endoplasmic reticulum stress; microRNAs; type 2 diabetes; unfolded protein response.

Figure 1

Adaptive unfolded protein response (UPR) signaling under acute endoplasmic reticulum (ER) stress. Accumulation of unfolded protein triggers UPR by activation of (A) inositol-requiring 1, (B) PERK, and (C) activating transcription factor 6. This leads to upregulation of ER-associated degradation protein and folding chaperons to mitigate ER stress and maintain homeostasis.

Figure 2

Pro-apoptotic unfolded protein response (UPR) response under chronic endoplasmic reticulum (ER) stress. When UPR is dysfunctional, cell undergoes apoptosis by (A) PERK mediated production of CHOP and (B) inositol-requiring 1 α-induced activation of ASK1. This leads to cytochrome c (cyt c) release and eventual apoptosis.

Figure 3

Inflammatory unfolded protein response (UPR) response under chronic endoplasmic reticulum (ER) stress. ER stress triggers apoptosis through activation of inflammation. This can be achieved (A) inositol-requiring 1 α-mediated stimulation of IKK complex or XBP1s and (B) PERK-mediated activating transcription factor 4 activation. These induce release of pro-inflammatory factors which enhances cell death.

Figure 4

Crosstalk between miRNA and inositol-requiring 1 α signalling. (A) The endoribonuclease activity of IRE1α cleaves set of pre-miRNAs (miR-17, miR-34a, miR-96, and miR0125b) leading to decreased expression of mature miRNAs, thereby resulting in caspase-2 upregulation and eventual cell death. (B) miR-214 binds to 3′-UTR (untranslated region) of XBP-1, leading to mRNA downregulation, and inhibition of IRE1α mediated adaptive unfolded protein response (UPR) response.