Normally, the beta cells of the pancreas respond to high levels of glucose in the blood by producing the precursor of insulin -- proinsulin -- in the endoplasmic reticulum. Inside this and other organelles, the proinsulin is assembled and modified into insulin. Then the hormone is exported from the cell to stimulate other tissues to take up glucose and generate energy.
PERK-deficient mice differ significantly from normal mice. At birth, PERK-deficient mice have only about one-half the mass of beta cells that normal mice have. During the first few weeks after birth, PERK-deficient mice have fewer and fewer beta cells compared to normal mice and the remaining cells do not function normally in producing insulin. By three weeks after birth, the PERK-deficient mice are fully diabetic and have only one-tenth the mass of beta cells as normal mice.
Until now, the dominant hypothesis of the cause of diabetes in mice and humans deficient in PERK was developed by Heather Harding and David Ron, of New York University Medical Center, in 2001. They suggested that too much proinsulin in the endoplasmic reticulum triggers a stress response and causes many beta cells to die. The shortage of beta cells in PERK-deficient mice was thought to be caused by a high death rate of those cells.
Data collected by the Cavener team casts doubt on this hypothesis. First, they found that mice deficient in PERK made new beta cells at a much lower rate than normal mice. The mass of beta cells in deficient mice only doubled during the first few weeks of life, while that in normal mice increased twenty-fold. Second, the Penn State group found the rate of beta-cell death in PERK-deficient mice was not significantly different from that in normal mice. Finally, the team did not detect molecular markers of endoplasmic reticulum stress in the beta cells of their PERK-deficient mice.
The alternative hypothesis of the P
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Contact: Barbara K. Kennedy
science@psu.edu
814-863-4682
Penn State
5-Dec-2006