Carriers of the risk variant have stressed insulin producing cells which greatly reduces their ability to secrete insulin. Further, making the finding even more interesting, there are already known substances that completely restore the capacity of the insulin cells.
"Our work opens new avenues to more exact diabetes diagnosis as well as treatments that directly target the disease mechanism, in contrast to the current therapies that are directed towards the symptoms", says Erik Renström, professor of experimental endocrinology at Lund University Diabetes Centre (LUDC) in Malmö and the responsible author of the article in Science.
The work behind the finding is based on collaboration between LUDC scientists with different specialities: geneticists, experts on animal models of diabetes and cell biologists who focus on finding out what fails on the level of the individual insulin cells.
The new risk variant of the adrenalin receptor gene claims a place high on the list of known risk genes for type 2 diabetes. It is common, approximately one third of the population are carriers, and it increases the risk of developing diabetes by 30 to 42 percent depending on whether the carrier has one or two copies.
Further, the research group has described in detail by what mechanism the risk of disease is increased.
"Yes, and it is the first time anyone has been able to explain, in detail, what fails in type 2 diabetes", says Anders Rosengren, researcher at LUDC and main author of the article.
The work process that led to the finding started with the GK-rat. A rat strain that spontaneously develops a disease that resembles human type 2 diabetes and that is commonly used in diabetes research (see below).
"We knew that the rat develops diabetes due to insulin deficiency but we did not know what causes the deficiency", says Erik Renström and continues by telling how they used systematic breeding, in collaboration with Holger Luthman, professor of medical genetics, to map a gene variant that causes an 80% increase in expression of the receptor for the stress hormone adrenalin on the surface of the insulin cells.
"This makes the cells more sensitive to stress, which impairs insulin secretion and raises the blood sugar", says Anders Rosengren and explains that in a functional perspective it is logical that the stress hormone adrenalin lowers the insulin levels in the blood.
"In an emergency situation, when the fight or flight response is activated, a low blood glucose level is a disadvantage while a high level gives you a safety margin. But the modern day stress is normally not the type that you can fight or run from, which is why this type of stress increases the risk of diabetes."
Experiments confirmed that the overexpression of the adrenalin receptor caused a 35 percent decrease of insulin secretion.
"We have also shown that a substance that blocks the receptors can normalize the secretion", says Erik Renström.
This substance, Yohimbine, was previously used to treat erectile dysfunction but was deregistered in 2007.
Since the position of the human gene that corresponds to the rat adrenalin receptor gene is known, the research group continues by investigating genetic variants in this region in several studies of individuals that were known to have decreased insulin secretion capacity. One of the variants gave a strong signal. Carriers of this risk variant had impaired insulin secretion. This was confirmed in a follow up study where the frequency of the variant was compared between thousands of diabetes patients and healthy controls. Carriers that have two copies of the variant, one from each parent, have a 42 percent increased risk of developing type 2 diabetes. A single copy increases the risk by 30 percent.
"This makes this risk gene as important as the strongest known risk variants so far", says Erik Renström.
Studies on donated beta cells from deceased carriers of the risk variant confirmed the increased risk. At high glucose levels insulin secretion was 40 percent lower in carriers.
"And the cells regained their full capacity when we added Yohimbine", says Anders Rosengren.
Yohimbine has an unspecific effect and many side effects. A substance that blocks the receptor on the beta cells more specifically could be a possible future treatment for type 2 diabetes.
"Yes, and then we could target the therapy directly at the disease causative mechanism", says Erik Renström.
The GK rat is named after the two Japanese scientists Goto and Kakizaki who created the strain by breeding more than 30 years ago. The starting point was 211 normal rats. By systematically breeding the 10 percent with the highest blood sugar levels for 35 generations they generated a strain that develops diabetes spontaneously due to insulin deficiency.
For more information:
Erik Renström, 040 39 11 57, Erik [dot] Renstrom [at] med [dot] lu [dot] se
Anders Rosengren, 040 39 11 55, 070 531 67 04, Anders [dot] Rosengren [at] med [dot] lu
Link to the abstract in Science