Molecular Mechanism of Rare Form of Diabetes Revealed

Researchers have uncovered the molecular mechanism underlying a rare and severe form of diabetes, i.e., permanent neonatal diabetes mellitus. Children with this genetic form of diabetes have symptoms by age six months and have a lifelong dependence on insulin to maintain proper glucose levels. To investigate the disease mechanism, researchers used animal and cellular models to focus on a mutation of the KATP gene that is known to be linked to the disease. The KATP gene codes for an ATP-sensitive potassium ion channel. "The KATP channel essentially functions as a gatekeeper for insulin secretion by pancreatic beta cells,” said Dr. Faith Kline, the lead author of the study. “Without proper regulation by this gatekeeper, the pancreatic beta cells are unable to efficiently regulate insulin secretion." The researchers showed that the chaperone molecule ankyrin is present in pancreatic beta cells and that the KATP mutation prevents most KATP channels from binding with ankyrin. This failure prevents the KATP channels from reaching their normal destination in the cell membrane. "Ankyrin proteins are like cellular taxi cabs that carry passenger channels to the cell membrane. In the case of this KATP gene mutation, the ankyrin and channels cannot interact properly, and so the channels basically 'miss their ride' and do not get to the desired location," said Dr. Peter Mohler, the article’s senior author. The team also found that the few mutant KATP channels that do reach the pancreatic cell membrane do not respond to alterations in cellular metabolism. As a result, the pancreatic beta cells do not release insulin appropriately. This work was reported in the September 8 week’s early online edition of PNAS. The findings may help identify new molecular targets for treating both rare and common forms of diabetes and hyperinsulinemia.