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The Role of the Liver in Type 1 Diabetes

In part one of this exclusive interview, Dr. Robert Geho discusses the essential role of the liver in metabolizing insulin, and asks why we hear about the artificial pancreas all the time, but never hear anyone talk about an artificial liver?

To view this interview as a video, click here.


 

Steve Freed: This is Steve Freed with Diabetes in Control and we’re here in the Boston, Diabetes Symposium 2016. We have a lot of companies, new products and some great ideas. Today we have a special guest, Dr. Robert Geho. I think I’ll let him introduce himself. He’s the CEO of a company, he works with a number of groups. So why don’t you start and tell us a little bit about yourself and what you do.

Robert Geho: Thank you, Steve, for the invitation to speak with you. As you mentioned I am the CEO of a company called Diasome Pharmaceuticals, which is based in Cleveland, Ohio. We are focused on using a novel globally patented drug delivery system to specifically deliver insulin molecules that are currently sold as commercial insulins from the big three insulin manufacturers to cells in the liver called hepatocytes. Hepatocytes are the major metabolic cells in the liver. They are responsible for managing, storing and then releasing up to 2/3rds of all the sugar that a person eats during the meal. They will only do that if they are getting the insulin signal, which is very difficult to have happen with current injective insulin. So Diasome is a phase 3 enabled technology company, which means the FDA has given us clearance to go into phase 3 with our material, which we call HDV, which stands for Hepatocyte Directed Vesicles.

It can be added to any commercial form of insulin. We are embarking shortly, dosing the first patient in a 200 subject, all type 1s Phase 2b study. So it’s kind of a mini-phase 3 that we’ll take the next year or so to run.

Steve Freed: Can you go into a little bit more detail on the product and how it works, because when most people hear insulin, it’s always the pancreas. Now you are talking about the liver. So maybe you can give us more information?

Robert Geho: It’s a great question. So one of the things I love to ask people with type 1 diabetes is why they’ve never heard the words “Artificial Liver” next to each other. We hear about artificial pancreas all the time, but I’ve never heard anyone talk about an artificial liver. Really the pancreas is important because it produces insulin and glucagon and other things. But insulin is really primarily used by the liver. So it’s been published by various leading researchers fairly recently that 80% of all of the pancreas’ insulin production is actually used by liver hepatocytes. It wasn’t until 1972, so 50 years after the discovery of insulin, that a researcher at Columbia University named Robert Canfield published the first paper that showed that subcutaneously administered insulin when given in therapeutic doses essentially went everywhere in the body except the liver. So it took 50 years from the discovery of insulin for someone to demonstrate this in an animal model that in marked contrast to normal insulin secretion, which by definition goes out of the pancreas through the portal vein directly to the liver. When we inject insulin, this is from every insulin manufacturer and every type of insulin.

There’s so many peripheral insulin receptors in adipose or fat and muscle cells that those cells see the insulin first after subcutaneous injection, and they essentially block the uptake of that injected insulin in the liver. So we’re doing the exact opposite with injective insulin therapy that the pancreas does with endogenous naturally secreted insulin.

That’s a problem because of all the cell types in the body, there is one and only one cell type that can both store sugar and release sugar or glucose on demand. That is the liver hepatocyte. So adipose and muscle cells which have insulin receptors can take insulin out of the blood and burn it and store it, but they have no capacity to release that glucose back into the systemic circulation to counteract hypoglycemia. The liver is uniquely able to do that, and specifically it’s the hepatocyte in the liver that can do that. We want to get type 1 patients for instance back to normal glucose metabolism. The liver has to be a part of that equation. That’s beginning to be more mainstream in terms of the thinking. So, in 2015, the Journal of Diabetes published a paper by Mark Atkinson called the “streetlight effect”. The streetlight cartoon is from the 1920s or 30s of the man looking for his keys under the streetlight.

His keys are two blocks away in the dark and someone comes up to him and says “What are you looking for?” “I’m looking for my keys.” “Where are they?” “They’re up the street.” “Why are you looking here?” “Because the light’s better.” In a commentary article on that publication, Åke Lernmark, who’s a leading diabetes researcher in Europe, called the liver the darkness. He said that the problem is that insulin is the right drug that’s administered at the wrong time and the wrong place and the wrong target. If you want to fix that problem, you basically have to get insulin back to the liver. So that brings us to Diasome’s technology. So we make a 20-50 nanometer carrier. A nanometer is a billionth of a meter. So these are extremely small. They look like small Frisbee shaped discs. They have a liver hepatocyte targeting molecule embedded in that carrier.

The carrier, when it’s added in a liquid form to any commercial vial of insulin acts like nanoVelcro. About 100 insulin molecules will stick to each of the carriers, each of these individual Frisbee shaped discs. What happens is when a person injects that insulin into their body under the skin, just like they would normally do, with a pump or with an old-fashioned syringe, now for the first time some of that insulin is specifically targeted to liver hepatocytes.

What we’ve shown in our Phase 2 data up to this point and all of our pre-clinical animal data is that we have a dramatic improvement in peripheral blood glucose, simply by re-insulinizing the liver in a more normal physiological manner.

Steve Freed: Doesn’t the liver and insulin, when you inject insulin, it causes the glucose to be stored as fat or for it to be utilized as energy? Doesn’t insulin also cause the liver to stop producing glucagon?

Robert Geho: Yes, so 10 years ago, I would say that if we were to go to the Joslin or NYU, or any big medical center here or around the world and ask what the dominant effect of insulin is on the liver, the standard answer would have been: it inhibits hepatic glucose production. So the liver is either storing glucose or releasing glucose in a normal healthy individual. One of the functions of pancreatic insulin is to inhibit hepatic glucose release, thereby keeping peripheral blood glucose levels under control. But the dominant effect of insulin on the liver is not inhibiting hepatic glucose production, it’s stimulating hepatic glucose storage or uptake at the time of the meal. So Alan Cherrington published in 2012 that in a healthy animal, that does not have diabetes, the liver is storing anywhere from 35 to 65 % of a total glucose load, at any given time. So the liver is actually an enormous storage facility, if you will, for all of the carbohydrate that a healthy individual eats. The failure to store glucose in the liver in both type 1 and type 2 diabetes is a huge problem therapeutically.

Continue to Part 2.