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.
Highlights
Diabetes mellitus is a chronic, progressive disorder that results from the body’s inability to either produce sufficient insulin or utilize it efficiently [1]
The combination of chronic hyperglycemia and sustained endoplasmic reticulum (ER) stress in Type 2 diabetes mellitus (T2DM) skews this balance in favor of overactivation of the PERK pathway, which leads to excessive phosphorylation of eIF2α
Despite the inherent complexity of T2DM, miRNAs, and ER stress have emerged as key regulators of transcriptional and translational responses that control insulin signaling
Summary
Diabetes mellitus is a chronic, progressive disorder that results from the body’s inability to either produce sufficient insulin or utilize it efficiently [1]. According to WHO statistics, the global prevalence of diabetes among adults in 2014 was nearly double of what it was in 1980, due, in part, to Crosstalk Between the UPR and miRNAs in Type 2 Diabetes increasing obesity, sedentary lifestyles, and unhealthy diet [5]. In 2012, diabetes accounted for the death of 1.5 million people worldwide, with another 2.2 million deaths being the result of complications of high blood glucose [5]. Perhaps what is most troubling is that a large proportion of people with diabetes do not even know they have it—India alone had an estimated 70 million diabetics in 2015, of which 36 million went undiagnosed [1]
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