Type-2 diabetes — for which weight gain is a causative factor — has become one of the most serious threats to human health. Certain cellular conditions trigger endoplasmic reticulum (ER) stress (during which unfolded or misfolded proteins accumulate in the ER). Hotamisligil and colleagues therefore proposed that obesity, by giving rise to such conditions, might stimulate ER stress in peripheral tissues, which, in turn, might be a key mechanism in triggering insulin resistance and type-2 diabetes. They report the results of their work in Science.

First, they studied the expression of several markers of ER stress in dietary and genetic mouse models of obesity. They found that obesity is associated with the induction of ER stress, mainly in the liver and adipose tissues. For example, the activity of c-Jun N-terminal kinase (JNK) — which is known to be increased by ER stress — is significantly increased in obese mice.

Next, the authors treated liver cells with agents that induce ER stress to assess whether this stress interferes with insulin function. They found that ER stress resulted in decreased insulin-stimulated Tyr phosphorylation, and increased insulin-stimulated Ser phosphorylation, of insulin-receptor substrate-1 (IRS1; Tyr phosphorylation of IRS1 propagates the insulin signal, whereas Ser phosphorylation blocks it). In addition, they found that inhibiting JNK reversed the ER-stress-induced Ser phosphorylation of IRS1. So, ER stress promotes the JNK-dependent Ser phosphorylation of IRS1, which, in turn, blocks the insulin signal.

The transcription factor X-box-binding protein-1 (XBP1) is an important regulator of ER stress, as it controls the expression of, for example, molecular chaperones. Hotamisligil and co-workers showed that the presence of XBP1 results in a suppressed ER-stress response, and vice versa, in mouse embryonic fibroblasts (MEFs). In addition, they showed that manipulating XBP1 levels alters insulin signalling — for example, overexpressing XBP1 in MEFs increased Tyr, and decreased Ser, phosphorylation of IRS1.

In the final part of this study, the authors studied Xbp1+/− mice (Xbp1−/− mice are embryonic lethal), and showed that Xbp1+/− mice that were fed a high fat diet developed continuous and progressive hyperinsulineamia, as well as high levels of blood glucose. A loss of XBP1 therefore predisposes mice to diet-induced, peripheral insulin resistance and type-2 diabetes. In addition, they showed that there was increased ER stress and disrupted insulin signalling in Xbp1+/− mice — for example, they observed an increased JNK activity and an increased Ser phosphorylation of IRS1 in these mice.

Hotamisligil and colleagues have therefore shown “...that ER stress is a central feature of peripheral insulin resistance and type 2 diabetes at the molecular, cellular and organismal levels”, although exactly how ER stress targets the insulin signalling pathway needs to be clarified. However, this work indicates that the use of therapies that regulate ER stress could be a new way to prevent and treat type-2 diabetes.