The finding is important because it provides evidence that the same gene in humans could provide clinicians with a powerful tool to determine the likelihood that some individuals will acquire the condition. Moreover, the finding that the gene works through a pathway not generally studied in the context of diabetes, suggests new avenues to explore in the search for new drugs to treat or prevent the disease, says Alan Attie, a UW-Madison professor of biochemistry and the senior author of the study published this week (May 7) in the journal Nature Genetics.
Type 2 diabetes is the most common form of the condition in the United States, with an estimated 16 million Americans afflicted with the disease. It is caused by an inability of the pancreas to produce enough insulin, or by the body’s reduced ability to respond to insulin, or both. Insulin is necessary for the body to properly utilize sugar.
Often, the development of type 2 diabetes is caused by obesity. Obese individuals tend to have insulin resistance; that is, it takes more insulin for the body to respond normally. Type 2 diabetes occurs when the pancreas is unable to manufacture enough insulin to compensate for the body’s increased demand for the hormone, which it does by growing more insulin-producing beta cells or by ramping up insulin secretion.
The Wisconsin study, comparing two strains of obese mice differing in susceptibility to diabetes, helps explain why this is so.
"Most people who are obese don’t have diabetes, but people who are obese are insulin resistant," says Attie. "If there is a fall-off in insulin production, that’s when you go from prediabetes to diabetes."
The gene found by Attie’s group likely influences the ability of the pancreas to recruit a type of cell essential for constructing the walls of blood vessels. The beta cells of the pancreas, which are the critical insulin producing cells of the organ, are found clustered together in structures called islets and are nourished by a complex network of small blood vessels. If there are changes in this gene, the Wisconsin scientists believe, the blood vessels within islets may not form properly.
The consequences of this, says Attie, may be that not all beta cells receive the proper nutrition critical for their survival, that they may not receive the proper signals to secrete insulin, or that the blood vessels are insufficient to receive all the insulin they secrete.
The findings, says Attie, provide new insight into a process that might be impaired in individuals who fail to increase or maintain beta cell mass in the pancreas and sufficient insulin secretion to compensate for resistance. What’s more, because the Wisconsin group believes the gene plays a role in regulating the tiny blood vessels that nourish the insulin-producing islet cells of the pancreas, it implicates features beyond defective beta cells in the onset of the disease.
"The hope is this will open up scientists’ thinking to realize that there are other cells of importance (in diabetes) beyond beta cells," says Susanne Clee, the lead author of the new Nature Genetics study.
Genetic factors are believed to account for roughly half of an individual’s risk of developing type 2 diabetes. Knowing which genes might contribute to the onset of the disease can help clinicians develop profiles of obese individuals at the greatest risk. Importantly, the new Wisconsin study looks beyond genetic influences exerted directly on insulin resistance and secretion to genes that govern structures of the pancreas that may help the organ compensate for diminished insulin production and insulin resistance. In humans, the search for such genes has yielded little success so far.
The new findings, according to Attie, will give scientists searching for those genes in people a roadmap to help locate a new "genetic bottleneck" that contributes to the onset of type 2 diabetes in humans.
"We hope this is replicating what happens in humans," Attie says. "Our work covered a lot of genetic real estate, and it should help others drill down to something similar in people. Time will tell, but I think we’ll have answers to the question about how general this is pretty quickly."
In addition to Attie and Clee, authors of the new study include Brian S. Yandell, Kathryn M. Schueler, Mary E. Rabaglia, Oliver C. Richards, Summer M. Raines, Edward A. Kabara, Daniel M. Klass, Eric T.-K. Mui, Donald S. Stapleton, Mark P. Gray-Keller, Matthew B. Young, Jonathan P. Stoehr, Hong Lan, Igor Boronenkov, Phillip W. Raess, and Matthew T. Flowers.
Alan D. Attie | EurekAlert!
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