Findings could lead to identification of new drugs for diabetes management 

Sept. 5, 2006  

WORCESTER, Mass. - Marking an important advancement in the study of diabetes, researchers at the University of Massachusetts Medical School have found that the regulation of a recently discovered enzyme could control the production of insulin and blood sugar levels. In "Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1," published in the September 5 issue of Cell Metabolism, Assistant Professor of Molecular Medicine Fumihiko Urano, MD, and colleagues, including Aldo A. Rossini, MD, the William and Doris Krupp Professor of Medicine and professor of medicine and molecular medicine, explain that the moderate activation of IRE1 stimulates the production of insulin in pancreatic beta cells and protects the cells from damage and death. 

Diabetes is a group of disorders defined by a state of high blood sugar caused by an absolute deficiency of insulin (type 1 diabetes) or a relative deficiency of insulin (type 2 diabetes).  Secreted from pancreatic beta cells, insulin is essential to lowering blood sugar.  While patients with type 2 diabetes need to take medications that stimulate insulin secretion from beta cells, patients with type 1 diabetes lack insulin-producing beta cells and need to inject themselves with synthetic insulin.  

Researchers therefore are seeking to develop methods for treating diabetes that can both stimulate insulin production and, importantly, to protect insulin-producing beta cells from damage and death from such factors as environmental stress, obesity and virus infection.  Previously, Dr. Urano and colleagues discovered that the enzyme IRE1 has an essential function in removing abnormal proteins (i.e. hormones) from cells.  In this current paper, the scientists demonstrate that the production of insulin and therefore blood sugar level can be controlled by regulating the activity of IRE1. They further identify some drugs, namely synthetic peptides, that have the ability to control IRE1 activity.  Interestingly, these drugs can also protect insulin-producing beta cells from cell stress, specifically stress to the endoplasmic reticulum (ER), a membranous network enclosing the nucleus. Among other functions, the ER is responsible for making proteins to be secreted outside the cell, carbohydrate metabolism, protein, fat, and steroid synthesis, and the folding of proteins. 

Ultimately, Urano aims to identify additional drugs that can ideally be taken orally for the activation of IRE1, with the goal to identify drugs with the potential to bring to clinical trials.  However, the scientists note, caution is required; although mild activation of IRE1 has a beneficial effect on pancreatic beta cells, very strong activation of IRE1 has a harmful effect on pancreatic beta cells and reduces insulin production in our body.  The ideal drug would cause only mild activation of IRE1. 

Funding for this research was provided by the Juvenile Diabetes Research Foundation (JDRF), the world's largest charitable funder of type 1 diabetes research. According to Dr. Richard Insel, JDRF's Executive Vice President of Research, "JDRF is excited by these novel insights on the effects of high blood sugar on ER stress in the beta cell because of their therapeutic potential in developing approaches to protect regenerated or transplanted beta cells from cell death." 

Dr. Urano's work was also funded by the National Institutes of Health, the American Diabetes Association, and the Iacocca Foundation 


The University of Massachusetts Medical School, one of the fastest growing academic health centers in the country, has built a reputation as a world-class research institution, consistently producing noteworthy advances in clinical and basic research.  The Medical School attracts more than $174 million in research funding annually, 80 percent of which comes from federal funding sources. UMMS is the academic partner of UMass Memorial Health Care, the largest health care provider in Central Massachusetts. 

About JDRF 
The JDRF was founded in 1970 by the parents of children with juvenile diabetes-a disease that strikes children suddenly, makes them insulin dependent for life, and carries the constant threat of devastating complications. Since inception, JDRF has provided more than $1 billion to diabetes research worldwide. More than 80 percent of JDRF's expenditures directly support research and education about research. JDRF's mission is constant: to find a cure for diabetes and its complications through the support of research.


Contact: Kelly Bishop