Normalizing blood sugar in type 2 diabetes
It’s well known that obesity contributes to type 2 diabetes. In previous work with mice, researcher Umut Ozcan, MD, in Children’s Division of Endocrinology, discovered a key link between the two conditions, showing that obesity overloads a structure in the cell that assembles and folds proteins, known as the endoplasmic reticulum (ER). This so-called “ER stress” sparks a chain of events that reduce the body's response to insulin.
Until now, however, researchers haven't known precisely why this happens. Reporting online in Nature Medicine on March 28, Ozcan and first author Sang Won Park, PhD, of Endocrinology, identify a specific cellular pathway that fails when people become obese. That discovery also suggests an approach to treating diabetes.
Normally, when stimulated by insulin, a protein fragment called p85 attaches to a protein in the cell called XBP-1. This enables XBP-1 to travel to the cell nucleus, where it turns on genes that help relieve ER stress. But obesity impairs the insulin signaling that normally frees up p85 to interact with XBP-1. Without p85, the researchers showed, XBP-1 becomes stranded and never gets to the nucleus. The result is more ER stress and even less response to insulin, a vicious cycle.
The good news is that Ozcan’s team was able to break the destructive sequence. “When we increase levels of free p85 in the liver of obese, severely diabetic mice, we see a significant increase in XBP1 activity and, consequently, improved glucose tolerance and reduced blood glucose levels,” says Ozcan. “Our results indicate that a high-fat diet and consequent obesity weaken the ER’s capacity and reduce its normal functioning ability.”
Ozcan’s group is now looking for practical ways to activate XBP-1 artificially, which could translate into a promising treatment strategy for type 2 diabetes.
Does air pollution contribute to diabetes?
A link between air quality and diabetes may not seem intuitive, but a national population-based study from the Children’s Hospital Informatics Program finds a strong, consistent correlation—even after adjustment for variables like obesity.
Researchers led by John Pearson and John Brownstein, PhD, focused on fine particulates 0.1 to 2.5 nanometers in size (known as PM2.5), amain component of haze, smoke and car exhaust. They obtainedcounty-by-county data on PM2.5 pollution from the Environmental Protection Agency (EPA), and crunched it against health data from the Centers for Disease Control and the U.S. Census.
After adjustment for known diabetes risk factors, including obesity, exercise, geographic latitude, ethnicity and population density, the level of PM2.5 pollution was strongly predictive of diabetes prevalence.Even at concentrations below the EPA safetylimit,counties with highest PM2.5 levels had 20 percent more diabetes than counties with the lowest.
The findings jive with prior laboratory studies. Obese mice exposed to PM2.5 show an increase in insulin resistance, a precursor to diabetes. They also have increased blood markers of inflammation, which may contribute to insulin resistance.“We didn’t have data on individual exposure, so we can’t prove causality, and we can’t know exactly the mechanism of these peoples’ diabetes,” acknowledges Brownstein. “But pollution came across as a significant predictor in all our models.” (Diabetes Care, October.)
The Type 2 Diabetes Program, part of the Optimal Weight for Life (OWL) Program at Children’s Hospital Boston, is actively involved in developing novel dietary approaches and progressive clinical protocols to treat childhood obesity and type 2 diabetes. We’re also engaged in a variety of studies to improve the treatment and ongoing management of overweight children and adolescents, including those with type 2 diabetes.
Diabetes research initiatives
Because diabetes requires lifelong management, researchers at Children’s are investigating the earliest stages of the disease in order to understand how it develops and how it can be treated. Areas of research include:
- how to keep insulin-secreting beta cells alive as a method for treating and preventing type 1 diabetes
- tempering autoimmune activity in type 1 diabetes
- genetic factors for obesity, which can lead to type 2 diabetes
- predictors related to glycemic control
- the utility of using continuous glucose monitoring in non-diabetic patients in the ICU setting
- long-term follow-up of diabetic patients