Turning Off a Viral/Lipid Sensor Improves Type 2 Diabetes
- Laboratory of Cell Signaling, Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil
- Corresponding author: Licio A. Velloso, .
Type 2 diabetes (T2D) results from the combination of insulin resistance and a relative deficiency of insulin secretion (1,2). Over the last 20 years, clinical and experimental studies have advanced our understanding of the cause of insulin resistance, revealing the existence of subclinical inflammation in subjects with increased adiposity (3,4). Inflammatory cytokines produced in the context of this metabolic inflammation activate serine/threonine kinases that target proteins of the insulin signaling pathway, rendering them unresponsive to the insulin signal (5,6). Unfortunately, despite great advances obtained in the characterization of the pathophysiology of T2D, no anti-inflammatory approaches have been developed as therapeutic options for this disease.
Excessive nutrient consumption, particularly fatty acids, is regarded as one of the main triggers of metabolic inflammation (7). Among the mechanisms identified as a link between dietary fats, inflammation, and insulin resistance, endoplasmic reticulum (ER) stress has received special attention; it occupies a pivotal position, as it simultaneously acts as a target and a trigger of a number of inflammatory and metabolic events that are closely related to insulin resistance (8,9). On the one hand, ER stress can be induced by either excessive nutrient load (10) or extracellular inflammatory signals (11); alternatively, the unfolded protein response generated to reestablish ER homeostasis can activate inflammatory signaling proteins, such as Jun NH2-terminal kinase (JNK) and inhibitory κB kinase (IKK), thereby inducing transcription of inflammatory genes, such as Tnfa and Il6 (10).
A recent study provided an important advance in this field when it identified the double-stranded RNA–dependent kinase (PKR) as a protein that integrates inflammation, nutrient overload, and ER stress (12). PKR was originally described as an intracellular sensor of viral infection (13), whose activation leads to the simultaneous induction of an inflammatory response against the infecting agent and a reduction of protein synthesis aimed at inhibiting viral proliferation (14). As the molecular actions of PKR intersect with pathways involved in insulin resistance, it was hypothesized that PKR could act as a sensor of not only viral infection but also of nutrient overload (12). In fact, PKR is activated in metabolically relevant tissues in obesity as well as when lipids are infused in lean mice. Once active, PKR can directly and indirectly (through JNK) target insulin receptor substrate-1, leading to its serine phosphorylation, thereby rendering it unresponsive to insulin (12). In addition, a recent study has shown that PKR is active in the liver, skeletal muscle, and white adipose tissue of obese humans, and that body mass reduction resulting from bariatric surgery is accompanied by a reduction of PKR activity (15). In at least two studies (12,16), genetic approaches aimed at reducing PKR activity resulted in considerable improvement in a number of metabolic parameters related to obesity and T2D. Thus, because of its nodal position in which it integrates infectious, inflammatory, and metabolic signals, PKR emerges as a potential target for pharmacological treatment of diabetes.
In this issue, Nakamura et al. (17) tested two small molecules that act as chemical inhibitors of PKR—imoxin and 2-aminopurine—for their efficacy to reduce the diabetes phenotype of ob/ob mice. They showed that pharmacological inhibition of PKR resulted in improved insulin signal transduction and improved glucose tolerance, which were accompanied by a reduction in obesity-associated inflammatory activity in adipose tissue.
Imoxin is an imidazolo-oxindole inhibitor of PKR that was identified during the screening of a library of compounds evaluated for their capacity to bind and inhibit the ATP-binding site of PKR (18). In a recent study, imoxin efficiently inhibited the PKR-dependent activation of inflammasome, thereby illustrating its potential use as an anti-inflammatory drug (19). Another molecule, 2-aminopurine, is an analog of guanine and adenine and a well-known inhibitor of PKR. Although not structurally related to imoxin, it also acts by inhibiting the ATP-dependent activation of PKR (20).
A number of distinct genetic and pharmacological approaches aimed at reducing inflammation have been tested in the treatment of experimental T2D, with widespread success (8,9). Targets such as tumor necrosis factor-α (TNFα), JNK, IKK and the SOCS-3 gene were all efficiently inhibited in animal models, resulting in an improved metabolic phenotype (2,8,9). However, more than 20 years after the first descriptions of the pathogenetic role of inflammation in T2D, we have yet to see an anti-inflammatory drug available as an option to treat diabetic humans. Currently, only three classes of drugs are recommended by the American Diabetes Association as pharmacological options for treating people affected by T2D: metformin, insulin, and inhibitors of glucagon-like peptide 1 (21).
Studies have been conducted to evaluate the effects of anti-TNFα and anti–interleukin-1β therapy in T2D. The results are controversial, with some describing significant improvements in glucose control and others reporting no metabolic benefits (22–24). However, the main problem here, particularly concerning anti-TNFα therapy, appears to be the complications that may arise over the course of prolonged use. These include tuberculosis and some types of malignancies (23,25). Perhaps more promising are the results obtained using salsalate, which is a modified form of salicylate that acts as an inhibitor of IKK. A recent trial reported improvements in blood glucose control without major side effects, although the actual reduction of the HbA1c level was less than 1% (26).
With the findings of these studies in mind, what would be the advantage of inhibiting PKR over the other anti-inflammatory approaches that have already been tested? At the mechanistic level, PKR lies at the interface between metabolic and inflammatory pathways. It acts as a sensor for nutrients and integrates the incoming signal with intracellular inflammatory pathways, the insulin signaling pathway, and protein/lipid synthesis in the ER (Fig. 1). The drugs currently in use for T2D, including metformin, insulin, and inhibitors of glucagon-like peptide 1 signaling, act primarily on the metabolic side of this problem, whereas the drugs tested, with limited success, for inhibiting TNFα, interleukin-1β, and IKK act primarily on the inflammatory side. Therefore, it could be anticipated that a drug that simultaneously modulates the metabolic and inflammatory aspects of T2D would represent a therapeutic advantage. Concerning safety, inhibiting some inflammatory pathways may impact general immune surveillance, raising concerns about the risk/benefits of clinical use. Compared with the impact of inhibiting inflammatory cytokines, targeting PKR has been reported to be quite safe in experimental animals, as no important immunological defects have been observed. In humans, no major clinical outcomes are related to the genetic variants of the Pkr gene. However, a few reports have linked somatic Pkr mutations to leukemia (27,28). Therefore, preclinical studies should be performed to evaluate the impact of the long-term chemical inhibition of PKR. An additional potential advantage offered by Nakamura et al. (17) is that PKR inhibition was achieved using small molecules. In a number of diseases, identification of potential therapeutic targets can fall short because of the inability to produce drugs with practical clinical use. Here, we have a case in which the identification of PKR as a potential target for T2D only two years ago was rapidly followed by experimental tests with small molecules that, at least in theory, may offer a tremendous advantage for clinical use.
As the prevalence of obesity and T2D continues to increase, identification of novel targets for therapy renews the hope for safer and more efficient therapeutic methods. The inhibition of PKR may represent the first attempt to simultaneously tackle distinct pathways that are intimately related to the development of T2D.
Funding. The Laboratory of Cell Signaling and the Obesity and Comorbidities Research Center are supported by grants from Sao Paulo Research Foundation and Conselho Nacional de Desenvolvimento Cientifico e Tecnológico.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.
- © 2014 by the American Diabetes Association.
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