New research findings relating to low-grade inflammation are sure to cause controversy, as they seem to contradict current mainstream views of diabetes. While increases in low-grade inflammation are commonly believed to be a contributing factor in the development of Type 2 diabetes, a team of researchers at Children’s Hospital in Boston have reported that two proteins activated by inflammation are actually vital in regulating blood sugar levels; not only that, but increasing the activity of these proteins leads to better blood glucose stability in obese and diabetic mice.
The findings were reported in the October issue of Nature Medicine. The research team was headed by Umut Ozcan, M.D., with the Division of Endocrinology at Children’s Hospital.
“This finding is completely contrary to the general dogma in the diabetes field that low-grade inflammation in obesity causes insulin resistance and type 2 diabetes,” said Ozcan. “For 20 years, this inflammation has been seen as detrimental, whereas it is actually beneficial.”
The team headed by Ozcan has shown in the past that obese individuals experience increased stress on the endoplasmic reticulum, or ER. This cellular structure is involved in the assembling, folding, and releasing of proteins to conduct the operations of the cell. “ER stress,” as it’s called, reduces the body’s efficiency in responding to insulin and regulating blood sugar levels; this deficiency is one of the primary links between Type 2 diabetes and obesity.
Ozcan’s team previously found that proteins called XBP1s, which play a role in mitigating ER stress, are unable to function in overweight mice. Then, they showed that inducing XBP1s to activate in the liver resulted in normalization of the blood sugar levels of obese, Type 2 diabetic mice as well as in Type 1 diabetic mice.
The team’s newest study shows that yet another protein which is activated by inflammation, known as p38 MAPK, is responsible for chemically altering XBP1s to increase their activity. Without the increase in activity from p38 MAPK, XBP1s are unable to maintain normal blood sugar levels. In addition, the study showed that activity of the p38 MAPK protein is reduced in obese mice, and re-activating the protein in the liver reduced ER stress while reducing blood glucose levels and increasing glucose tolerance and insulin sensitivity.
When taken together, the findings of the two studies suggest that new therapies for diabetes could be developed by increasing the activity of the p38 MAPK protein and thereby increase XBP1 activity, or by increasing XBP1 activity directly. Since these proteins are associated with low-grade inflammation, any such therapies will likely be controversial and need further study.
The studies also provide new information about Type 2 diabetes that could help with our understanding of the disease. “It may be that inflammatory pathways are not working optimally and there could be a resistance to cytokines which mediates the inflammation,” said Ozcan. “This could be a paradigm shift for the field.” In other words, obesity could be related to diabetes by causing a disruption in the ability of the individual’s cells to respond to inflammatory signals.
Though the research team is hopeful that their findings could lead to new therapeutics, they warn that there could be downsides to using p38 MAPK inhibitors to treat inflammatory diseases, such as asthma, psoriasis and Chrohn’s disease. “These therapeutic approaches should… be evaluated within the context of our results, and in light of the possibility that inhibition of XBP1s activity also decreases the ability of the cell to cope with the inflammatory conditions,” the study states.