Diabetes as a stress response

Abstract

The origin of adult-onset diabetes may be a counterproductive stress reaction in the endoplasmic reticulum (ER), according to Umut Ozcan, Gokhan Hotamisligil (Harvard School of Public Health, Boston, MA), and colleagues. Figure Stressed-out ER (top) may cause diabetes in overfed mice. Type II or adult-onset diabetes has remained a mystery because the body seemingly acts against its own interests. As caloric intake and obesity rise, the body does not increase insulin responses to pack away the excess energy but instead becomes resistant to insulin's energy-storing signal. This just makes the situation worse. “You develop a little bit of obesity and then everything starts going crazy,” says Hotamisligil. The Boston team now suggests that the body sees the stress of dealing with excess calories as analogous to an environmental or infectious stress, and responds appropriately. “Insulin is the most powerful signal opposing the mobilization of energy,” says Hotamisligil. “You turn it off to mobilize energy against the pathogen or other stress.” The ER appears to be the site of this regulatory action. The Boston team found that indicators of ER stress such as the unfolded protein response were elevated in liver and adipose tissue but not muscle of diabetic mice. Drugs and genetic conditions that exacerbated ER stress, both in cultured cells and diabetic mice, resulted in increased insulin resistance. In cultured cells the converse was also true: an overdose of a stress-fighting protein reduced markers of insulin resistance. ER stress may arise because extra calories have to be processed by the ER as they get turned into either extra proteins or more lipids. “Under the best conditions the [fat] cell uses all its capacity,” says Hotamisligil. The stress signaling goes from the ER to the insulin receptor complex via the immune-activating JNK kinase, which may explain why the immune response is also turned on during type II diabetes. Muscle is not a secretory cell type and thus may escape the original insult, but other studies suggest that it succumbs to a signal from fat cells that promotes insulin resistance. This signal may have been helpful during evolution but is now less useful, when the greater threat is not bugs but burgers. Reference: Ozcan, U., et al. 2004. Science. 306:457–461. [PubMed]