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Newswise Philadelphia, June 19, 2014 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 (www.caglab.org) at The Childrens 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.

Hakonarsons 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.

Read more from the original source:
Gene Study Points to Novel Pathway for Diabetes Treatment

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