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Stress-Induced Translational Regulation Mediated by RNA Binding Proteins: Key Links to B-Cell Failure in Diabetes

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Stress-Induced Translational Regulation Mediated by RNA Binding Proteins: Key Links to B-Cell Failure in Diabetes Diabetes Volume 69, April 2020 499 Stress-Induced Translational Regulation Mediated by RNA Binding Proteins: Key Links to b-Cell Failure in Diabetes Austin L. Good and Doris A. Stoffers Diabetes 2020;69:499–507 | https://doi.org/10.2337/dbi18-0068 In type 2 diabetes, b-cells endure various forms of cel- produce and secrete greater quantities of insulin. Eventu- lular stress, including oxidative stress and endoplasmic ally, the demand for insulin surpasses the functional ca- reticulum stress, secondary to increased demand for in- pacity of b-cells, leading to hyperglycemia. Furthermore, sulin production and extracellular perturbations, includ- this discrepancy worsens as the disease advances due to ing hyperglycemia. Chronic exposure to stress causes b a decline in the number and in the functioning of -cells. PERSPECTIVES IN DIABETES impaired insulin secretion, apoptosis, and loss of cell This outcome, known as b-cell failure, leads to severe hy- identity, and a combination of these processes leads to perglycemia and diabetic complications (1–3). There are b -cell failure and severe hyperglycemia. Therefore, a bet- several proposed mechanisms to explain the development ter understanding of the molecular mechanisms under- of b-cell failure in T2D, including impaired insulin secre- lying stress responses in b-cells promises to reveal new tion, b-cell apoptosis, and loss of b-cell identity, termed therapeutic opportunities for type 2 diabetes. In this per- “dedifferentiation” (Fig. 1) (4). However, the relative con- spective, we discuss posttranscriptional control of gene tribution of these processes toward T2D pathogenesis is expression as a critical, but underappreciated, layer of regulation with broad importance during stress responses. unclear and may be dependent on the severity of the Specifically, regulation of mRNA translation occurs per- disease and the genetic makeup of the individual (3,5). vasively during stress to activate gene expression pro- In response to insulin resistance in obese individuals, b fi grams; however, the convenience of RNA sequencing -cells can augment insulin secretion as much as ve times has caused translational regulation to be overlooked com- that seen in healthy control subjects despite only a 50% pared with transcriptional controls. We highlight the role increase in b-cellmass(6,7).Thisindicatesthattheinsulin of RNA binding proteins in shaping selective translational secretory capacity of a single b-cell is dynamic and can be regulation during stress and the mechanisms underlying expanded to accommodate increased demand. Thus, the ability this level of regulation. A growing body of evidence of b-cells to compensate for insulin resistance is dependent indicates that RNA binding proteins control an array notjustonthenumberofb-cells present in the pancreas but of processes in b-cells, including the synthesis and also on the functional capacity of those cells. Indeed, it has secretion of insulin. Therefore, systematic evaluations been suggested that the initial cause of hyperglycemia in T2D of translational regulation and the upstream factors is primarily a consequence of defects in insulin secretion, not shaping this level of regulation are critical areas of a reduction in the number of b-cells (2,3). investigation to expand our understanding of b-cell On the other hand, it is clear that long-standing cases of failure in type 2 diabetes. T2D and severe hyperglycemia are associated with a sig- nificant decline in the number of b-cells (8). One cause of reduced b-cell mass in T2D is an increase in b-cell apo- ptosis (2,3). Examination of pancreatic tissue from autop- Paradigms of b-Cell Demise in Type 2 Diabetes sies indicated that individuals with T2D had reduced b-cell During the progression of type 2 diabetes (T2D), insulin mass that was associated with increased rates of b-cell resistance places a growing burden on pancreatic b-cells to apoptosis (9). It has recently come into question, however, Institute for Diabetes, Obesity, and Metabolism and Department of Medicine, © 2020 by the American Diabetes Association. Readers may use this article as Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA long as the work is properly cited, the use is educational and not for profit, and the Corresponding author: Doris A. Stoffers, [email protected] work is not altered. More information is available at https://www.diabetesjournals .org/content/license. Received 9 July 2019 and accepted 16 January 2020 500 Translational Regulation by RBPs in b-Cells Diabetes Volume 69, April 2020 Figure 1—Paradigms of pancreatic b-cell demise in T2D. Increased demand for insulin secretion and rising glucose levels lead to oxidative and ER stress in b-cells. Prolonged stress leads to dysfunction, apoptosis, and/or dedifferentiation of b-cells. Collectively, these processes contribute to b-cell failure that underlies T2D. Depicted are endocrine cells of the pancreas including b-cells (green), a-cells (blue), and d-cells (red). Dysfunction, apoptosis, and loss of identity are depicted as labeled in the figure. whether cell death can fully explain the decrease in b-cell forms of ROS include hydrogen peroxide, superoxide, and number in T2D. An alternative explanation has been pro- hydroxyl radical (16,17). When generated at low levels, ROS posed in which b-cells lose their cell identity during the can function as critical signaling molecules. For example, development of T2D, which entails the acquisition of features treatment of islets with low levels of hydrogen peroxide has normally restricted to progenitor cells or other endocrine cell been found to increase insulin secretion (18). When present types (10,11). This model has been considered plausible at high levels, however, ROS can be very detrimental to the partly because there is known to be a high degree of cellular cell by damaging lipids, proteins, and DNA, and the onset of plasticity among endocrine cells of the pancreas (12). Evi- ROS-mediated injury is referred to as oxidative stress (19). dence to support this concept includes the acquisition of Oxidative stress is proposed to be a central contributor to progenitor markers in islets seen in several mouse models of b-cell failure in T2D. Islets from patients with T2D show diabetes, reductions in key b-cell transcription factors in increased levels of 8-hydroxy-29-deoxyguanosine, a marker islets from organ donors with diabetes, and reexpression of of oxidative damage to DNA (20). Animal models of T2D, the progenitor marker ALDH1A3 in islets from individuals such as chronic high-fat diet feeding in mice, also display with T2D (13–15). While the precise definition of b-cell signs of oxidative damage in b-cells (21). dedifferentiation in T2D will require further refinement The development and resolution of oxidative stress and experimental validation, the idea that reduced b-cell depends on the balance between the generation of ROS and mass in T2D is not solely caused by apoptosis raises the the levels of antioxidant enzymes that detoxify these mol- exciting possibility that this loss may be reversible (7). ecules. Antioxidant genes are broadly expressed across tissues due to their essential role in preventing oxidative stress, but b-Cell Stress in T2D their relative expression levels can vary to meet the needs of In order to develop new treatment strategies to prevent or a particular cell type. In fact, b-cells are thought to be reverse b-cell failure in T2D, the molecular mechanisms particularly sensitive to oxidative stress due to low ex- underlying these deleterious processes need to be eluci- pression levels of antioxidant genes (22). The effect of ROS dated. For example, identification of signaling pathways or production on b-cell homeostasis is complex because it is regulatory factors that govern b-cell identity and apoptosis dependent on both the type and subcellular location of the under disease conditions could provide new targets for oxidant (23–25). Thus, a more precise understanding of the therapeutic intervention. A common theme underlying molecular mechanisms underlying oxidative stress in b-cells these processes is that b-cells endure various forms of during conditions associated with T2D, including the per- cellular stress in the pathogenesis of T2D. In this context, tinent factors promoting and ameliorating ROS levels, may the term “stress” refers to a significant deviation from provide new therapeutic opportunities for T2D (17). a homeostatic set point that causes cellular dysfunction and/or damage. In particular, an imbalance in redox ho- ER Stress meostasis, or oxidative stress, and an imbalance in protein Another instance of homeostasis that is critical for cell folding homeostasis, or endoplasmic reticulum (ER) stress, viability is the balance between the abundance of nascent have been implicated in b-cell demise in diabetes. peptides and the protein folding capacity of the ER. If protein synthesis exceeds the folding capacity of the ER, Oxidative Stress there will be an accumulation of unfolded proteins, termed Reactive oxygen species (ROS) are normal byproducts of ER stress. Prolonged ER stress can lead to protein aggre- cellular respiration, and the major endogenously produced gation, cellular dysfunction, and apoptosis (26). Since a diabetes.diabetesjournals.org Good and Stoffers 501 critical function of b-cells is to synthesize and process profiling, translating ribosome affinity purification (TRAP), proinsulin polypeptides, the balance between protein syn-
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