Boosting proteins normally triggered by inflammation may be a new treatment approach for Type 2 diabetes.
Low-grade inflammation caused by obesity is widely believed to contribute to insulin resistance and type 2 diabetes. But, as it turns out, inflammation activates two proteins that appear critical for maintaining good blood sugar levels. Reporting in Nature Medicine, endocrinology researcher Umut Ozcan demonstrates that activating either of these proteins artificially can normalize blood sugar in severely obese and diabetic mice.
That’s a completely new way of looking at diabetes, and suggests a very different way of treating it.
“This finding is completely contrary to the general dogma in the diabetes field,” says Ozcan. “For 20 years, inflammation has been seen as detrimental, whereas it is actually beneficial.”
It’s an interesting twist in a long-running line of research by Ozcan’s team. In 2004, the team helped explain the link between obesity and type 2 diabetes, demonstrating that obesity places stress on the endoplasmic reticulum (ER), a part of the cell where proteins are assembled, folded and dispatched to do their work. This cellular “ER stress” makes cells less able to respond to insulin in maintaining appropriate blood glucose levels.
Next came the demonstration that a protein that helps relieve ER stress, called XBP1s, can’t function in obese mice, getting stranded outside the cell nucleus. And then the finding that activating XBP1s artificially in the liver could normalize high blood sugar — in both obese, insulin-resistant type 2 diabetic mice and lean, insulin-deficient type 1 diabetic mice.
The new study reveals another player: XBP1s’s activity is naturally enhanced by a second protein, p38 MAPK, that’s triggered by inflammation. Without the chemical alterations induced by p38 MAPK, XBP1s can’t maintain normal glucose levels.
As with XBP1s, obese mice have reduced p38 MAPK activity. But re-activating p38 MAPK in their livers reduced their ER stress, increased insulin sensitivity and glucose tolerance, and significantly reduced their blood glucose levels.
The upshot is that either increasing p38 MAPK activity — despite its being part of an inflammatory pathway — or increasing XBP-1 activity by other means could represent new therapeutic options for diabetes.
Ozcan thinks type 2 diabetes may result from a failure of people’s cells to respond to positive inflammatory signals in the presence of obesity, so that ER stress isn’t relieved and blood sugar levels soar. “It may be that inflammatory pathways are not working optimally and there could be a resistance to the cytokines that mediate the inflammation,” he says. “This could be a paradigm shift for the field.”
Lee J, Sun C, Zhou Y, Lee J, Gokalp D, Herrema H, Park SW, Davis RJ, & Ozcan U (2011). p38 MAPK-mediated regulation of Xbp1s is crucial for glucose homeostasis. Nature Medicine PMID: 21892182
