Public Release: 

Gene study points to novel pathway for diabetes treatment

CHOP/Penn researchers report potential target for protecting insulin-producing cells in type 1 diabetes

Children's Hospital of Philadelphia

New research describes details of how a diabetes-related gene functions on a biological pathway that affects the release of insulin. The study authors say that finding drugs that act on that pathway may eventually lead to a new treatment for type 1 diabetes.

"In 2007, our genomics team found the first gene in a genome-wide search to play a major role in type 1 diabetes, but we did not know its function," said co-study leader Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at The Children's Hospital of Philadelphia (CHOP). "Now we understand how this gene plays a critical role in regulating insulin metabolism."

Doris A. Stoffers, M.D., Ph.D., of the Institute for Diabetes, Obesity and Metabolism of the Perelman School of Medicine at the University of Pennsylvania, was the co-senior author with Hakonarson, and is the corresponding author of the study, which appears online today in Cell.

The current finding builds on the 2007 genome-wide association study (GWAS) by Hakonarson and colleagues at CHOP showing that variations in the KIAA0305 gene, also known as CLEC16A, correlate with higher risk of type 1 diabetes and other autoimmune diseases.

Hakonarson's group subsequently developed a strain of mice in which the Clec16a gene was deactivated. They then collaborated with Stoffers, an endocrinology expert, to breed a subset of the knockout mice in which only the pancreatic cells were affected.

The scientists show that the Clec16a gene acts upon a pathway crucial to insulin secretion. Clec16a normally helps protect mitochondria, the tiny energy-producing components of cells. When the Clec 16a gene is knocked out, damaged mitochondria are then digested, a process called mitophagy, and the resulting loss of energy output disrupts beta cells in the pancreas in their normal job of secreting insulin. "The ultimate result of the deletion of Clec16a is an accumulation of unhealthy mitochondria, leading to less insulin being secreted by the beta cells," said Stoffers.

In humans, inability to produce insulin is the hallmark of type 1 diabetes. The study team showed that humans with single-base variants in CLEC16A have reduced beta cell function, although with less extreme effects than in the knockout mice.

The researchers showed that the Clec16a biological pathway has downstream effects on a protein clled Parkin, already known to be a master regulator of mitophagy. The current study is the first to link the Clec16a pathway with regulation of Parkin-mediated mitophagy and to suggest how this process may affect diabetes by dysregulating insulin secretion.

If drugs can be developed to act on the Clec16a pathway, they could provide a new, targeted therapy for patients with type 1 diabetes who harbor risk variants in the CLEC16A gene, said Hakonarson.

Hakonarson said that GWAS research has often been criticized for not identifying gene variants with major impacts on the risk of complex diseases, but that in this case, the GWAS seven years ago identified a previously uncharacterized gene that has proved to play a crucial role, not only in type 1 diabetes, but also, as his group subsequently helped discover, in multiple sclerosis, rheumatoid arthritis, Crohn's disease and other autoimmune diseases. He added that "more work needs to be done to identify additional causal gene variants in type 1 diabetes."


The National Institutes of Health provided support for this study (grants DK089117, DK049210, and DK085708). Other funders were the Margaret Q. Landenberger Foundation, the Juvenile Diabetes Research Foundation and the Charles H. Humpton, Jr. Endowment. First author Scott A. Soleimanpour, M.D., a postdoctoral researcher in the Stoffers lab when the study was performed, is now at the Brehm Diabetes Research Center at the University of Michigan. Other co-authors are from Lund University and Skane University Hospital in Sweden and Baylor College of Medicine in Houston.

"The diabetes susceptibility gene Clec16a regulates mitophagy," Cell, published online June 19, 2014.

About The Children's Hospital of Philadelphia:

The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program receives the highest amount of National Institutes of Health funding among all U.S. children's hospitals. In addition, its unique family-centered care and public service programs have brought the 535-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.