An experimental oral drug has lowered blood sugar levels and inflammation in mice with Type 2 diabetes, suggesting that the medication could someday be added to the arsenal of drugs used by millions of Americans with this disease, according to new research.
The drug consists of a synthetic molecule that stops the biological activity of a protein called macrophage migration inhibitory factor, or MIF. This protein is implicated in a number of diseases because it is associated with the production of inflammation in the body.
The researchers first determined that mice that have been genetically engineered not to carry the MIF protein are less likely to develop symptoms of Type 2 diabetes. This finding suggested that MIF indeed has a role in at least two hallmarks of diabetes: impaired blood sugar control and the presence of other inflammatory proteins.
The scientists then treated diabetic mice with the investigational drug and found that most animals showed lower blood sugar levels and reduced inflammatory proteins in their blood when compared to untreated mice with Type 2 diabetes.
"We also found that if we stopped administering the drug, then the blood sugar level would go up," said Abhay Satoskar, associate professor of pathology at Ohio State University and senior author of the study. "This does not present a cure for diabetes, but we think, if it is approved in humans, that it has potential to become an oral drug taken for the long term to control a very common symptom of the disease."
The researchers supported their animal findings by measuring proteins and hormones in blood samples from a small group of people with Type 2 diabetes and healthy human participants for comparison. The patients with diabetes had significantly higher levels of MIF in their blood than did the healthy patients, as well as higher levels of two compounds that contribute to inflammation and insulin resistance.
"All of this evidence combined suggests strongly that MIF is a viable therapeutic target in Type 2 diabetes," Satoskar said.
The study appears online and is scheduled for later print publication in the Journal of the Federation of American Societies for Experimental Biology.
This research applies only to non-insulin-dependent diabetes mellitus and not Type 1 diabetes, which occurs when the pancreas does not produce enough insulin. Not all people with Type 2 diabetes have a shortage of insulin, but their bodies do not respond correctly to the hormone.
Insulin is responsible for transferring sugar, or glucose, from the blood into the cells to be used for energy. When people become insulin resistant, the main characteristic of Type 2 diabetes, that process does not function properly, which tends to drive up blood sugar levels and starve cells of energy.
Many current diabetes drugs stimulate the body to release more insulin or otherwise act in a way that affects sensitivity to insulin. A drug targeting MIF could offer different benefits by lowering blood sugar and inflammation without the need to generate more insulin, Satoskar noted.
Satoskar and colleagues induced Type 2 diabetes in two groups of mice: normal mice and those lacking MIF. They induced the disease by injecting them one time with a naturally occurring toxin, streptozotocin, which acts on cells in the pancreas.
Researchers collected blood samples from the mice multiple times over 10 weeks, conducted oral glucose tolerance tests, and monitored their weight and urine output.
All animals with induced disease showed a spike in blood sugar levels shortly after the injection of the toxin, but the blood sugar levels continued to rise in the normal diabetic mice. These mice also took in more food, lost weight and produced excessive amounts of urine - all symptoms associated with insulin resistance.
Mice lacking the MIF protein, on the other hand, showed a drop in their blood sugar levels by week seven and experienced minimal weight loss. Additionally, after glucose tolerance tests, the blood sugar levels in mice lacking MIF decreased more rapidly than did levels in normal diabetic mice.
Finally, the mice lacking MIF produced significantly lower amounts than the normal mice of two proinflammatory cytokines: interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). These are chemical messengers that cause inflammation, most often to fight infection or repair injury. When these proteins circulate without an infection to fight, the body experiences excess inflammation, which is associated with a variety of diseases depending on which cells are producing the proteins.
All of these observations led researchers to believe that MIF has one or more roles in the development and maintenance of Type 2 diabetes, Satoskar said.