In Type 2 Diabetes, Insight into Cell Death Leads to New Treatment Idea

By Jeffrey Norris

A new discovery about cell death in type 2 diabetes suggests a novel strategy for fighting the disease.

Feroz Papa

When insulin-secreting beta cells of the pancreas die, the resultant loss of control over blood sugar wreaks havoc if left untreated. However, why these cells die is perhaps the biggest unanswered question in the field of diabetes, according to UCSF researcher Feroz Papa, MD, PhD. Papa, winner of a New Innovator Award from the National Institutes of Health, investigates whether beta cells die when they become stressed in trying to make large amounts of insulin to meet the body’s increasing demands. This particular type of stress is called ER stress. In the August 7 issue of the journal Cell, Papa reports that a specialized form of a type of drug known as a kinase inhibitor may prolong survival among cells experiencing ER stress. It may one day become possible to use a member of this class of drugs to forestall cell death in diseases such as type 2 diabetes, he says. Papa calls the newly identified class of drugs KIRAs. No diabetes drugs to date have had a direct impact on cell survival.

New Drug Target

“This paper describes how a cellular protein called IRE1 controls a life-or-death decision in cells experiencing ER stress,” Papa says. He describes IRE1 as a switch. “IRE1 helps cells survive under ER stress, but only up to a point,” Papa says. “If the stress continues, IRE1 flips into executioner mode and polishes off the cell.” To try to stop cell death due to ER stress, it makes sense to target IRE1. “We identified a class of drugs that targets IRE1,” Papa says. “We call these drugs KIRAs, for Kinase Inhibitory RNAse Attenuators. KIRAs may protect cells by reducing death signals emanating from IRE1. We hope that it may be possible someday to develop KIRAs for use in humans in order to slow progression of ER stress-related diseases such as diabetes.” “Diabetes is a growing health problem in the U.S. and we urgently need new medicines to reverse the disease process,” said acting NIH director Raynard Kington, MD, PhD. “Dr. Papa’s discovery opens up promising new approaches for saving crucial insulin-producing cells. This is exactly the type of research that the New Innovator Program was designed to foster.”

Endoplasmic Reticulum Is a Protein-Folding Factory

The ER, or endoplasmic reticulum, acts within cells as a protein-folding factory. Like other proteins, insulin needs to fold into its proper shape within the ER. When the amount of protein that needs folding becomes excessive, protein molecules tend to fold incorrectly, causing ER stress. Beta cells are especially prone to ER stress because the normal level of insulin traffic going through the protein-folding factory is high. Becoming insulin-resistant causes even more insulin traffic, increasing the risk of ER stress and cell death. The protective side of IRE1’s response to ER stress was understood previously. IRE1 increases the capacity of the ER’s protein-folding factory by making another protein, called XBP1. By producing XBP1, the ER has a better chance to eliminate the backlog of unfolded proteins, so cells can recover and once again perform their protein-folding jobs accurately. If the cellular strategy of producing XBP1 fails to restore cells to their pre-stressed state, then IRE1 switches tactics, and instead helps the dysfunctional cells commit suicide. Working with insulin-secreting beta cells, Papa determined that IRE1 destroys the messenger RNAs that produce insulin and enzymes needed to fold insulin into its proper shape in the ER. This “kill-the-messenger” strategy, which was first discovered in fly cells by UCSF Professor Jonathan Weissman, PhD, is conserved in mammalian cells and ensures that highly stressed cells cannot recover. “IRE-mediated, messenger RNA decay appears to be strictly required for IRE1’s ability to induce cell death,” Papa says. “Mammals appear to have evolved a strategy to discard ER-stressed cells by forcing them to commit suicide. This is a very stringent, but ultimately a harsh form of quality control. It is conceivable that if the process gets out of hand, it could lead to disease.”

KIRAs Favor Protective Response to Help Cells Survive

Papa discovered that IRE1’s protective and destructive impulses were both triggered by the same enzymatic part of the protein, called an RNAse, acting in two different ways. Using KIRAs, Papa reports that he was able to force the RNAse to activate the protective response while turning off the suicidal response. Papa hopes that such an approach can eventually be used to keep insulin-secreting cells alive in individuals who are insulin-resistant, and help keep their blood sugar under control.

Scott Oakes

Papa credits the success of the research to a close collaboration among outstanding researchers in both his own lab at UCSF Mission Bay and the lab run by UCSF pathologist Scott Oakes, MD, at the UCSF Parnassus Heights campus. Oakes is a co-author on the Cell paper. Oakes is a member of the UCSF Helen Diller Family Comprehensive Cancer Center and the Multiple Myeloma Translational Initiative. Papa is a practicing endocrinologist who treats diabetic patients at San Francisco General Hospital. He also is a member of the UCSF Diabetes Center and of the California Institute for Quantitative Biosciences (QB3), where his UCSF Mission Bay lab is based. Papa’s is not the only UCSF paper on IRE1 to be published this week. Weissman, along with fellow Howard Hughes Medical Institute investigator and biochemist Peter Walter, PhD – a pioneer in the exploration of the ER’s unfolded protein response -- and postdoctoral fellow Julie Hollien, PhD, used similar techniques to also find that the protective and destructive effects of the RNAse could be controlled separately. However, unlike Papa’s lab group, Weissman’s team found that kinases were not required to take the cell down the path to suicide. According to Oakes, “There is mounting evidence that ER stress and IRE1 signaling contribute to cell loss in important human diseases. The discovery that small molecules that can be designed to fit into the kinase pocket of IRE1 to control the life and death outputs of its attached RNAse now makes this a highly attractive target for drug development. As physician-scientists, Feroz and I are very excited about ultimately translating these findings into clinical practice.” Although Weissman’s lab group did not find evidence to support the potential usefulness of kinase-blocking drugs, Weissman agrees that the discovery by both groups that the IRE’s protective and destructive functions are controlled separately bodes well for new drug development strategies.

IRE1a Kinase Activation Modes Control Alternate Endoribonuclease Outputs to Determine
Divergent Cell Fates

Dan Han, Alana G. Lerner, Lieselotte Vande Walle, John-Paul Upton, Weihong Xu, Andrew Hagen, Bradley J. Backes, Scott A. Oakes and Feroz R. Papa

Cell (Published online August 7, 2009)


Regulated Ire1-Dependent Decay of Messenger RNAs in Mammalian Cells

Julie Hollien, Jonathan H. Lin, Han Li, Nicole Stevens, Peter Walter, and Jonathan S. Weissman

Journal of Cell Biology (Published online August 3, 2009)


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