In a report published online March 1 in Cell Metabolism, the researchers say the work solves a longtime mystery and may lead to better treatments for type 2 diabetes, the most common form of the disease.
"Before our discovery, the mechanism behind how exactly the insulin-producing beta cells in the islet of Langerhans of the pancreas fail in type 2 diabetes was incompletely understood, making it difficult to design new and better therapies, says Mehboob Hussain, M.D., associate professor of pediatrics, medicine and biological chemistry. "Our research cracks open a decades-long mystery."
After a meal, the pancreas produces insulin to move glucose from the blood into cells for fuel. People with type 2 diabetes either don't secrete enough insulin or their cells are resistant to its effects.
In a study designed to figure out more precisely how the pancreas releases insulin, Hussain's group looked at how other cells in the body release chemicals. One particular protein, Snapin, found in nerve cells, caught their eye because it's used by nerve cells to release chemicals necessary for cell communication. Snapin also is found in the insulin-secreting pancreatic beta cells.
To test the role of Snapin, researchers engineered a change to the Snapin gene in mice to keep Snapin permanently "on" in the pancreas. Researchers removed the pancreas cells and grew them in a dish for a day, then added glucose to the cells and took samples to measure how much insulin was released.
When the scientists compared that measurement to what was released by pancreas cells in normal mice, they found that normal mice released about 2.8 billionths of a gram of insulin per cell, whereas the cells from "Snapin-on" mice released 7.3 billionths of a gram of insulin per cell — about three times the normal amount.
"We were surprised to find that the Snapin-on mice didn't have more or bigger pancreas cells, they just made more insulin naturally," says Hussain. "This means all our insulin-secreting cells have this amazing reserve of insulin that we didn't really know existed and a switch that controls it."
To see if permanently turning off Snapin would reduce insulin release and further demonstrate that Snapin controls the process, the researchers first grew normal mouse pancreas cells in a dish, and treated them with a chemical that stopped them from making the Snapin protein. They again bathed the cells in glucose and measured how much insulin was released by the cells. Normal cells released 5.8 billionths of a gram of insulin, whereas cells with no Snapin only released 1.1 billionths of a gram of insulin — about 80 percent less.
"These results convinced us that Snapin is indeed the switch that releases insulin from the pancreas," says Hussain.
Normally, according to Hussain, when we ingest glucose, the pancreatic beta cells release an initial burst of insulin almost immediately, then gradually release more insulin about 15 minutes later. However, people with type 2 diabetes and mice engineered to react metabolically like people with type 2 diabetes don't release this initial spurt of insulin when fed glucose, but still have the later gradual insulin release.
"We knew how important the first burst of insulin is for controlling our blood sugar, but we did not know what really went wrong in our beta cells in people with type 2 diabetes," says Hussain. "We have drugs that restore the first burst of insulin and yet we did not completely understand how they work."
Hussain then questioned whether Snapin could be used to fix the defects in cells from a diabetic animal.
Since the cells with Snapin on made too much insulin, researchers wanted to see if they could use this to restore these mice's ability to secrete the initial burst of insulin. After growing pancreatic beta cells from type 2 diabetes mice in a dish and engineering them to make the Snapin-on protein, the researchers fed the cells glucose and found that they did indeed regain the ability to release that initial insulin burst.
"While keeping Snapin on in these mouse cells corrects the problem in this animal model of type 2 diabetes, we're still a long way from knowing if the same mechanism will work in people, but this gives us an encouraging start," says Hussain.
This study was funded by the National Institutes of Health.
Other authors on the paper are Woo-Jin Song, Madhav Seshadri, Uzair Ashraf, Thembi Mdluli and Prosenjit Mondal of the Johns Hopkins University School of Medicine; Meg Keil and Monalisa Azevedo and Constantine Stratakis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH; and Lawrence Kirschner of Ohio State University.
On the web: Cell Metabolism http://www.cell.com/cell-metabolism/
Mehboob Hussain http://www.hopkinschildrens.org/Mehboob-Ali-Hussain-MD.aspx
Biological Chemistry http://biolchem.bs.jhmi.edu/pages/index.html
Vanessa McMains | EurekAlert!
Scientists spin artificial silk from whey protein
24.01.2017 | Deutsches Elektronen-Synchrotron DESY
Choreographing the microRNA-target dance
24.01.2017 | UT Southwestern Medical Center
A Swedish-German team of researchers has cleared up a key process for the artificial production of silk. With the help of the intense X-rays from DESY's...
For the first time ever, a cloud of ultra-cold atoms has been successfully created in space on board of a sounding rocket. The MAIUS mission demonstrates that quantum optical sensors can be operated even in harsh environments like space – a prerequi-site for finding answers to the most challenging questions of fundamental physics and an important innovation driver for everyday applications.
According to Albert Einstein's Equivalence Principle, all bodies are accelerated at the same rate by the Earth's gravity, regardless of their properties. This...
An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...
Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...
Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.
While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...
19.01.2017 | Event News
10.01.2017 | Event News
09.01.2017 | Event News
24.01.2017 | Physics and Astronomy
24.01.2017 | Life Sciences
24.01.2017 | Health and Medicine