Studies of human disease often work from the patient backwards – doctors and scientists take the common symptoms of a particular disorder and use them as clues to figure out what first went awry to spur the disease. For neurological diseases like Parkinson’s or amytrophic lateral sclerosis (aka Lou Gehrig’s Disease), symptoms and brain images have pointed the research at particular parts of the brain, which are then studied in animal models and on the genetic or cellular level. But disease research can also work from the other direction, where a particular cellular process is identified as a potential culprit in the disorder before a patient with that defect is even found.
That’s the case with a paper published this month by a team of University of Chicago researchers studying the cellular mechanisms that underlie diabetes. There are many types of diabetes mellitus, but all can be traced back to the hormone insulin – the body’s signal that cells should soak up sugar from the blood. Most cases of juvenile, or Type 1, diabetes result from the immune system erroneously attacking and killing the Beta-cells of the pancreas, which release insulin. Type 2 diabetes, which often develops in adulthood, results from a reduced sensitivity to insulin and/or a decreased release of the hormone.
But diabetes can also have a genetic origin, in some rare cases, when one of the genes involved in the secretion of insulin is disrupted. Previously on the blog, we’ve talked about the story of Lilly Jaffe, whose diabetes was found to be caused by a rare genetic mutation in a protein called a potassium channel, critical for the release of insulin. The mutated potassium channel seen in Lilly’s case interferes with the trigger of insulin release, causing lower amounts of the hormone to circulate through her blood. Thus, Lilly was treated by daily injections of insulin, until doctors at the University of Chicago detected the mutation and prescribed her a drug that directly targeted the potassium channel.
Now researchers at the University of Chicago have found another ion channel that must function properly for the right amount of insulin to be released. Only problem: there’s no patient.
The laboratories of Deborah Nelson and Louis Philipson (one of the doctors that treated Lilly in 2006) collaborated on the study, published earlier this month in Cell Metabolism. In the paper, a series of experiments show that the ClC-3 channel, a protein that allows chloride ions to pass through cell membranes, is critical for the proper production and release of insulin. Inside the Beta-cells, little bubbles called secretory granules are filled with proinsulin, a precursor of insulin discovered at UChicago forty years ago by Donald Steiner. If the environment inside the granules is sufficiently acidic, that proinsulin is converted to insulin, and the granule moves to the cell surface to release its cargo into the blood.
The ClC-3 protein is known to be present in the membrane of secretory granules, so Ludmila Deriy, a research assistant professor in Nelson’s laboratory, and nine other researchers studied insulin production and release in a mice missing the ClC-3 gene. These mice have many problems – including a propensity for epileptic seizures – but Deriy and her colleagues found that they have very low levels of insulin in their blood, as little as one-fifth of the insulin concentration observed in normal mice.
Looking more closely at the Beta-cells in ClC-3 knockout mice, the researchers found the secretory granules were less acidic than those from normal mice, suggesting that ClC-3 helped make the granules suitable for conversion of proinsulin to insulin. And looking even closer (with the help of an electron microscope), that theory proved true, as the granules from ClC-3 knockouts showed signs of being filled with proinsulin rather than insulin. So ClC-3 is a key player in the story of how insulin is released into the blood, and a person lacking the ClC-3 gene, or possessing a less functional version of the protein, would be expected to show signs of diabetes.
But: “A patient with a CLC-3 mutation may not come to our attention with diabetes,” Philipson says, and thus far there has been no such patient documented. Philipson and Nelson hope that publication of their paper may turn up an example of this rare form of the disease, perhaps in a patient that displays a combination of epilepsy and diabetes. And diabetes registry efforts, such as the recent Illinois law named for Lilly Jaffe, may help researchers discover young patients whose diabetes is caused by previously-unseen genetic mutations. Unlike Lilly, there wouldn’t be an obvious drug treatment for a diabetic with a ClC-3 mutation, Nelson and Philipson said, but a human case would expand their knowledge of how this protein works outside of a laboratory-created mouse model.
Yet it may also be the case that the ClC-3 finding is relevant to more than just rare cases of monogenic diabetes – it could also play a role in the millions of people with Type 2 diabetes. Philipson points out that the disruptions seen in ClC-3 knockout mice – reduced and less efficient insulin production and release – mirror those seen in people who develop Type 2 diabetes. Perhaps, he theorizes, risk factors for diabetes such as obesity could throw off the function of even a normal ClC-3 protein, causing a long-lasting and hard-to-reverse disruption of insulin function.
“”This could be an important pathway in Type 2 diabetes,” Philipson said. “So it’s not just the rare patient that’s affected, it’s 25 million people in the United States.”