Diabetes and the Body Clock
People often say that time rules our lives; but time, it turns out, also rules the pancreas, because the function of the body clock - or circadian rhythm - is tightly linked to the release of the glucose control hormone insulin. And, by tracking the two systems, Joe Bass, at Northwestern University, has been screening drugs to find molecules that can manipulate insulin levels by tweaking the action of the clock…
Joe - A number of years ago, we began to investigate the connection between the body's internal clock and organs in the body that respond to the clock and are important in maintaining energy balance and metabolism. One of the organs is the pancreas. A surprise for us was the discovery that the very same mechanism that causes us to wake up each day also induces the pancreas to produce insulin, which controls blood sugar. So, the real purpose of our work has been to try to understand, at the most basic level, what are these connectors that links the sleep cycle to the release of insulin.
Chris - And I suppose it's not a coincidence that we know that diabetes, or at least an exacerbation of diabetes, and sleep deprivation slash when people sleep at the wrong times and eat the wrong things. They're all interlinked, then?
Joe - That's right. We know from epidemiologic studies that there's an association between things like shift work and even exposure to blue light at night which occurs when you spend a lot of time on computer screens. That kind of light triggers the brain to think that it's daytime even when it's night and it scrambles the signals internally that normally align our sleep cycle and all of our physiology with the light/dark cycle with the rising of the sun. And one of the key things that gets scrambled is the ability to metabolise sugar.
Chris - So is it that the pancreas knows the time and is doing this itself, or is there literally a connection between what the brain is doing and what the pancreas should be doing?
Joe - The problem, like many things in science, doesn't have a simple answer. Both connections are present. In other words, under normal conditions in evolution, in the context of the wild so to speak, normally, the brain sends signals to the pancreas that entrain the pancreas to function at the right time each day. However, the pancreas has its own internal clock. We believe that one of the things that happens with, say, shift work is that it's the alignment between that brain clock which responds to the light cycle and the pancreatic clock that become misaligned. So, if we understand how the clock works within the pancreas, we may begin to identify pathways that we could manipulate to realign or fix the broken clock.
Chris - And how did you go about doing that?
Joe - Well, the first thing is we have to have the tools to measure both the clock and its output. We use genetic approaches to insert what's called luciferase, which is an enzyme that's normally made in fireflies. We took a small piece of that gene and stuck it in the middle of insulin, which is the major hormone produced by the pancreas that controls blood sugar. Now, when we do that, that means that every time the pancreatic cells, the beta cells, are stimulated to release insulin - and they are stimulated primarily by glucose but also by other metabolites and molecules - every time the cell is stimulated, we have an instrument that can detect the release of the luciferase enzyme. So, instead of having to measure insulin, we measure luminescence from this luciferase.
Chris - And how do you line that up with what the clock is doing?
Joe - We take another approach using genome editing to go into the genes in the beta cell and twist around the core genes that control the clock to either eliminate or alter the function of the clock mechanism. And with those two instruments, we can now, in a very high throughput way, screen thousands of compounds to ask, "Do any of the drugs that we have in our libraries influence the release of insulin when the clock is not working?"
Chris - Did you find any?
Joe - We found a number. We screened about 3000 known drugs. Among these, we identified a handful, and then we used a number of criteria to further select those that we would advance to studying in the animal.
Chris - Any that are in common parlance or any we'll be familiar with?
Joe - One of the main hits that we had is a somewhat infamous drug at this point: it's called ivermectin. It is an anti parasitic drug, and it acts on a special ion channel in an infectious organism that is unique to that animal. But, it turns out that it's in a class of what we call metabotropic receptors, and those receptors turn out to be abundant in the pancreas. And so, for reasons that we don't entirely understand, this molecule is activating a chloride channel that's expressed within the pancreas, and that chloride channel is an important target of the clock. That was a surprise for us to find.
Chris - So the chloride channel is affected by the clock and that in turn affects the secretion of insulin. So, therefore, you've now got a molecule that can affect the output of insulin from the pancreas when the clock goes wrong. So if you've got people who've got clock related metabolic syndrome, you could potentially give them this. It might put things right?
Joe - What we would do is use this as a so-called 'scaffolding' to give us molecular insight; both into the kind of chemistry that could be used to target the pancreas, and also those molecules expressed in the pancreas that are regulators of insulin release. That latter idea that this set of receptors are insulin atrophic, which means that they induce the release of insulin, is something that we found to be interesting, and there's evidence in the literature for this. There's also evidence that in obesity, for instance, there may be substances that are produced in fat that interfere with the function of this particular channel. So it's an entire range of factors that control insulin that we stumbled upon and they appear to be controlled by the clock system.