Inflammation as a Sensor of Metabolic Stress in Obesity and Type 2 Diabetes

Extract

It is broadly accepted that the main cause of type 2 diabetes is overfeeding. Unclear is how this metabolic stress is translated into signals leading to defective insulin secretion and action. Increasing evidence points to a role of the innate immune system in sensing changes in nutrient levels. This results in an inflammatory process that has been proposed to contribute to the pathogenesis of type 2 diabetes (1). At the origin of this process, activation of the IL-1 pathway seems to play a central role. Processing of pro-IL-1β to IL-1β is controlled by the inflammasome (see below) as a response to sensing danger signals. In this issue of Endocrinology, Youm and colleagues (2) demonstrates that the inflammasome mediates islet inflammation induced by high-fat feeding.

Activation of the innate immune system is the first response to tissue injury or aggression. It is characterized by release of cytokines and chemokines and immune cell invasion and is accompanied by functional or structural damage followed by tissue repair or fibrosis. This inflammatory process was originally thought to be caused by microbes or physical damages. However, in some cases, the innate immune system may attack the body's own tissues in the absence of an exogenous aggressor, resulting in a sterile inflammatory process, i.e. an autoinflammatory disease. In the pancreatic islet, metabolic stress may also elicit such a response. Indeed, glucose, free fatty acids, and human islet amyloid polypeptide may induce IL-1β, launching a proinflammatory response impairing insulin production and secretion (3–6). Accordingly, blocking IL-1β improves insulin release and glycemia in prediabetic and diabetic patients (7, 8).