New research from the US reported in the journal Diabetes, shows that the loss of just one gene in mice is enough to cause fasting hyperglycemia - a major symptom of type 2 diabetes.
In their paper, researchers from the College of Medicine at the University of Illinois at Chicago (UIC) explain how malfunctions in insulin-producing pancreatic beta cells is a common feature of type 2 diabetes.
Lead author Bellur S. Prabhakar, professor and head of microbiology and immunology at UIC, says they found that when a gene called MADD is not working properly, insulin is not released into the bloodstream. Lack of insulin means the body is unable to regulate blood sugar or glucose - a major feature of diabetes.
About 8% of Americans and more than 360 million people around the world have type 2 diabetes, a disease that in turn can lead to more serious conditions like cardiovascular disease, kidney failure, blindness, and loss of limbs.
In healthy people without diabetes, the beta cells of the pancreas release insulin into the bloodstream to help regulate blood sugar levels which rise after eating.
In a mouse study, researchers found that lack of a gene called MADD caused fasting hyperglycemia - a major symptom of type 2 diabetes.
Glucose requires the presence of insulin to enter muscle, fat, and liver cells and give them energy. The balance between insulin release and glucose uptake by cells keeps blood sugar levels inside a narrow range.
But in people with type 2 diabetes, blood sugar levels become too high, either because the body does not produce enough insulin, or it becomes resistant to its effect.
In previous work, Prof. Prabhakar had already established that a mutation in the MADD gene was linked to type 2 diabetes in Europeans and Han Chinese, in that people with the mutation had problems with insulin secretion and had high blood sugar.
MADD-deficient beta cells in mice produce, but do not secrete, insulin
But that work did not reveal how the mutation led to those symptoms - did it work with other genes or was it working alone?
To clarify this point, the researchers developed a strain of lab mouse whose insulin-producing beta cells had no MADD gene.
They found all these mice had high levels of blood glucose and that this was a result of their beta cells not releasing enough insulin.
Prof. Prabhakar says it was clear the beta cells were not working properly, but when they looked inside them they found they were full of insulin. "The cells were producing plenty of insulin, they just weren't secreting it," he says.
He explains that the study shows that loss of a functioning MADD gene is a direct cause of type 2 diabetes, because:
"Without the gene, insulin can't leave the beta cells, and blood glucose levels are chronically high."
The team now wants to test a drug that allows beta cells lacking the MADD gene to secrete the insulin they produce.
They believe if the drug reverses the effect of having no MADD gene in the mouse strain they developed, then it offers a starting point for treating patients with a similar genetic defect who are unable to secrete insulin or have type 2 diabetes.
In another mouse study published in September 2013, UK researchers describe a new method for diabetic transplants that, if successful in humans, would require only one pancreas donation to make enough insulin-producing cells for transplanting into type 1 diabetic patients, who currently have to wait months for the requisite two donors.