News Feature | June 23, 2014

Researchers ID Potential Target Pathway In Diabetes

By Estel Grace Masangkay

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Scientists from the Children’s Hospital of Philadelphia (CHOP) and the University of Pennsylvania announced the discovery of a potential target for protecting insulin-producing cells in Type 1 diabetes.

The team describes how the functions of a diabetes-related gene on a biological pathway affect the release of insulin. The identification of the right drugs that act on the pathway may open the way to a new treatment of T1D.

“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. Now we understand how this gene plays a critical role in regulating insulin metabolism,” said co-study leader Hakon Hakonarson, director of the Center for Applied Genomics at The Children’s Hospital of Philadelphia (CHOP).

Previous research show that variations in the KIAA0305 gene, also known as CLEC16A, correlate with a higher risk of type 1 diabetes along with other autoimmune diseases. Hakonarson’s team developed a strain of mice in which the gene was deactivated and another subset of knockout mice in which only the pancreatic cells were affected.

Findings show that the CLEC16A gene acted on a pathway crucial to insulin secretion, helping protect mitochondria. When deleted, unhealthy mitochondria accumulated and were digested (mitophagy), resulting in the loss of energy output of the cells. As a result, beta cells in the pancreas, responsible for secreting insulin, were disrupted. “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 Doris Stoffers of the Institute for Diabetes, Obesity, and Metabolism of the Perelman School of Medicine at the University of Pennsylvania and a co-senior author in the study.

Inability to properly produce insulin is a hallmark of T1D in humans. The team’s study is the first to link the CLEC16A pathway with regulation of Parkin-mediated mitophagy and to suggest how the process may affect diabetes by throwing a wrench in the cells’ work of insulin secretion. Developing drugs that act on the pathway could present a new targeted therapy for T1D patients with risk variants in the CLEC16A gene.

The scientists’ findings were published online in the journal Cell entitled ‘The diabetes susceptibility gene Clec16a regulates mitophagy’.

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