Turning Off a Viral/Lipid Sensor Improves Type 2 Diabetes

Abstract

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 …