Decade of effort yields diabetes susceptibility gene: Tomosyn-2 regulates insulin secretion

by Jill Sakai

Ten years of meticulous mouse breeding, screening, and record-keeping have finally paid off for Alan Attie and his lab members.

The University of Wisconsin–Madison researchers' efforts, published Oct. 6 in the journal PLoS Genetics, pinpointed a gene that confers susceptibility in obese mice.

They also showed that the protein coded by the gene, called tomosyn-2, acts as a brake on insulin secretion from the pancreas.

"It's too early for us to know how relevant this gene will be to human diabetes," says Attie, a UW–Madison biochemistry professor, "but the concept of negative regulation is one of the most interesting things to come out of this study and that very likely applies to humans."

In a properly tuned system, insulin secreted into the blood after eating helps maintain blood sugar at a safe level. Too little insulin (as in type 1 diabetes) or insulin resistance (as in type 2 diabetes) leads to high blood sugar and diabetic symptoms. Too much insulin can drive blood glucose dangerously low and lead to coma or even death in a matter of minutes.

"You can imagine that if you're in a fasted state, you don't want to increase your insulin, so it's very important to have a brake on insulin secretion," says Angie Oler, one of the lead authors. "It needs to be stopped when you're not eating and it needs to start again when you do eat."

The group honed in on tomosyn-2 while searching for that contribute to diabetes susceptibility in obese animals.

Why study fat mice?

"It takes more insulin to achieve the same glucose-lowering effect in an obese person than it does in a lean person. If you can produce that extra insulin – and most people do – you'll be okay. You will avoid diabetes at the expense of having to produce and maintain a higher insulin level," Attie explains. "Most of the type 2 diabetes that occurs in humans today would not exist were it not for the obesity epidemic."

But an insufficient insulin response leads to diabetes, and the same is true in mice.

Painstaking genetic analyses and comparisons of obese diabetes-resistant and diabetes-susceptible mouse strains ultimately revealed a single amino acid difference that destabilizes the tomosyn-2 protein in the diabetes-resistant mice, effectively releasing the brake on insulin secretion and allowing those animals to release enough insulin to avoid diabetes.

The researchers also confirmed that the human form of tomosyn-2 inhibits from human pancreatic beta cells.

Though diabetes is highly unlikely to be caused by a single gene, identifying important biological pathways can suggest clinically useful targets. "This study shows the power of genetics to discover new mechanisms for a complex disease like type 2 diabetes," says postdoctoral fellow Sushant Bhatnagar, a co-lead author of the paper.

"Now we know there are proteins that are negative regulators of secretion. Very likely they do the same thing in human beta cells, and it motivates us to move forward to try to figure out the mechanisms behind that negative regulation," Attie says.

More information: Bhatnagar S, Oler AT, Rabaglia ME, Stapleton DS, Schueler KL, et al. (2011) Positional Cloning of a Type 2 Diabetes Quantitative Trait Locus; Tomosyn-2, a Negative Regulator of Insulin Secretion. PLoS Genet 7(10): e1002323. doi:10.1371/journal.pgen.1002323. www.plosgenetics.org/article/i… journal.pgen.1002323

Related Stories

A body temperature sensor, TRPM2, promotes insulin secretion

Jan 04, 2011

The research group led by professor Makoto Tominaga and Dr. Kunitoshi Uchida, National institute for Physiological Sciences (NIPS), Japan, found TRPM2 ion channel in pancreatic beta-cells is important for insulin secretion ...

Fat cells send message that aids insulin secretion

Nov 06, 2007

The body's fat cells help the pancreas do its job of secreting insulin, according to research at Washington University School of Medicine in St. Louis. This previously unrecognized process ultimately could lead to new methods ...

Impaired fat-burning gene worsens diabetes

Feb 07, 2008

Researchers at the Swedish medical university Karolinska Institutet have in collaboration with researchers from Finland, China, Japan and the US discovered new cellular mechanisms that lead to in insulin resistance in people ...

How does insulin influence resistin?

Jan 16, 2008

Obesity is a worldwide health problem directly linked to several diseases such as hypertension and type 2 diabetes. Resistin is a cysteine-rich hormone mainly secreted by adipose tissues and may form a biochemical link between ...

Recommended for you

Study finds crucial step in DNA repair

Aug 18, 2014

Scientists at Washington State University have identified a crucial step in DNA repair that could lead to targeted gene therapy for hereditary diseases such as "children of the moon" and a common form of ...

User comments