New research from The Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania details how a diabetes-related gene functions on a biological pathway that affects the release of insulin. 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, MD, PhD, director of the Center for Applied Genomics at CHOP. “Now we understand how this gene plays a critical role in regulating insulin metabolism.”
The current finding builds on a 2007 genome-wide association study by Dr. 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.
The research team subsequently developed a strain of mice in which the CLEC16A gene was deactivated. They then collaborated with endocrinology expert Doris A. Stoffers, MD, PhD, of the Institute for Diabetes, Obesity and Metabolism at UPenn to breed a subset of the knockout mice in which only the pancreatic cells were affected. Dr. Stoffers was co-senior author with Dr. Hakonarson, and is the corresponding author of the study, which appears online in the journal Cell.
The investigators show that the CLEC16A gene acts upon a pathway crucial to insulin secretion. The gene normally helps protect mitochondria, the tiny energy-producing components of cells, but when the CLEC16A 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 Dr. Stoffers.
In humans, an 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 called 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.
More information about the study is available here.