Emerging roles of RNA-binding proteins in diabetes and their therapeutic potential in diabetic complications

Abstract

Diabetes is a debilitating health care problem affecting 422 million people around the world. Diabetic patients suffer from multisystemic complications that can cause mortality and morbidity. Recent advancements in high-throughput next-generation RNA-sequencing and computational algorithms led to the discovery of aberrant posttranscriptional gene regulatory programs in diabetes. However, very little is known about how these regulatory programs are mis-regulated in diabetes. RNA-binding proteins (RBPs) are important regulators of posttranscriptional RNA networks, which are also dysregulated in diabetes. Human genetic studies provide new evidence that polymorphisms and mutations in RBPs are linked to diabetes. Therefore, we will discuss the emerging roles of RBPs in abnormal posttranscriptional gene expression in diabetes. Questions that will be addressed are: Which posttranscriptional mechanisms are disrupted in diabetes? Which RBPs are responsible for such changes under diabetic conditions? How are RBPs altered in diabetes? How does dysregulation of RBPs contribute to diabetes? Can we target RBPs using RNA-based methods to restore gene expression profiles in diabetic patients? Studying the evolving roles of RBPs in diabetes is critical not only for a comprehensive understanding of diabetes pathogenesis but also to design RNA-based therapeutic approaches for diabetic complications. WIREs RNA 2018, 9:e1459. doi: 10.1002/wrna.1459 This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Processing > Splicing Regulation/Alternative Splicing Translation > Translation Regulation.

Figure 1. Glucose homeostasis in Type 1 and Type 2 diabetes

Pancreatic beta-islet cells secrete insulin to control glucose levels in the blood. Insulin allows glucose absorption into target tissues that include skeletal muscle, adipose tissue and liver to maintain normal glucose levels in the blood. In Type 1 diabetes, blood glucose levels increase because insulin is production is reduced due to the destruction of beta-islet cells in the pancreas. In Type 2 diabetes, insulin resistance prevents the efficient uptake of glucose into target tissues causing hyperglycemia.

Figure 2. Systemic complications of diabetes

Diabetes increases the risk for coronary artery disease, which can block blood flow and cause heart attack and/or stroke ^, . Hyperglycemia damages nerve fibers causing neuropathies that can adversely affect the digestive tract, urinary tract, heart and blood vessels ^–. Retinopathy is the leading cause of blindness in diabetic adults ^–. Almost half of diabetic patients develop diabetic nephropathy ^–. In most cases, patients develop kidney failure requiring dialysis . Under diabetic conditions, heart muscle structure and function are impaired leading to cardiomyopathy ^, . Diabetes also impacts skeletal muscle function causing muscle weakness and atrophy ^, .

Figure 3. RNA binding proteins involved in pathogenic events triggered in diabetes

Chronic hyperglycemia initiates pathogenic signals that can cause mitochondrial dysfunction, fibrosis, inflammation and epithelial mesenchymal transition (EMT). RNA binding proteins that are implicated in diabetes associated pathogenic events are summarized.