Bob has a special mission as CEO of the Cleveland-based startup Diasome. He lives with type 1 diabetes himself, and passionately believes that his company can make injected insulin work better in the bodies of people with diabetes. He has 25 years' experience in diabetes drug development, including involvement and leadership in the execution of more than 20 human clinical studies on improved insulin therapies. As the co-founder and CEO of Diasome, he's responsible for aligning technology, clinical, and business teams in Diasome’s work to achieve the first approved liver-targeted insulin therapyGet their bookView their FacebookView their InstagramView their LinkedInView their Twitter
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Today, he joins DiabetesMine to tell us all about it...
Getting Insulin Where It Needs to Go, by Bob Geho
Imagine a busy intersection in a typical city or town. Gas stations sit on opposite corners, both providing fuel for cars. Same gasoline, same gas pumps. At one of the stations, drivers pull in, open the lids to their gas tanks and insert the nozzle to fill their cars with gasoline. It’s ordinary, routine, very safe, and not a big deal.
At the other station, though, it is an entirely different scene. People still pull their cars in and still take the nozzle out of the pump, but instead of opening the lid to the car’s gas tank, they begin spraying their entire car with gasoline right from the pump nozzle.
“Wait a minute!” someone says. “What in the world is going on here? Why are all these people spraying gas on their cars and not just putting the gas in the tank like everyone else does?”
“Oh,” someone else says, “these drivers have cars without lids to their gas tanks. They still have to get fuel into their tank, but the only way to do it is to spray fuel all over the car itself, in the hope that at least some gasoline will get where it needs to go.” It’s doable, but very inefficient, and potentially dangerous.
This analogy is not perfect, but in certain respects it does depict the difference between the way insulin works in people without diabetes and the way it works in people with type 1 diabetes (T1D). Our body is the car, insulin is the gasoline, our pancreas is the fuel pump at the gas station, and our liver is the gas tank.
Why is it that insulin is such a tricky therapy for people with diabetes? The answer to this question begins with the insulin molecule itself, and to better understand this molecule, we have to consider the fact that insulin is a hormone. The word hormone comes from a Greek word that means “to set in motion,” and a hormone’s job is to interact with specific receptors on specific cells, causing those cells to do very specific jobs.
In a person without T1D, the pancreas makes insulin, and insulin’s primary job is to tell liver, fat and muscle cells to take glucose, or sugar, out of the blood to prevent high blood glucose levels, or hyperglycemia. When the pancreas detects blood glucose levels, it releases its insulin directly to the liver. In a person without diabetes, up to 80% of all insulin produced by the pancreas does its work in the liver, and in response to this insulin signal, the liver will store up to 65% of all the glucose that we eat, keeping blood glucose levels from spiking after a meal. From there, some insulin goes on to help muscle and fat cells absorb glucose from the bloodstream, giving them energy. The hormone glucagon has the opposite effect of insulin; its “setting in motion” job is to tell the liver to release that stored glucose when blood glucose levels start to drop from lack of food in order to prevent hypoglycemia.
But in people with T1D, this system is not functioning properly. Because their pancreas cannot make insulin, they need to inject it peripherally under the skin, where fat and muscle cells soak it up before it can travel to the liver. Peripherally injected insulin in people with diabetes is more like spraying the car with gasoline, resulting in insulin therapies that are inefficient, modestly effective, and potentially unsafe. Without insulin, the liver cannot store glucose physiologically, which then makes it difficult for the liver to release glucose into the bloodstream to prevent lows, and any opportunity to mimic normal blood sugar regulation is lost.
All current strategies for improving the lives of people with T1D are focused on addressing this core issue. We all our working in our own way to restore the body’s ability to manage glucose without people having to actually “manage” it, whether it be with Artificial Pancreas technologies, insulin pumps, connected insulin pens, continuous glucose monitors, islet cell transplant, beta cell regeneration, glucose responsive insulins, faster insulins, slower insulins, or liver-targeted insulins.
In fact, the main premise of all these strategies is to set glucose metabolism in motion in a way that keeps us out of the decision-making process. Our friends and relatives without T1D who don’t have to “manage” their glucose levels have this luxury because their pancreas, liver, peripheral tissues and insulin all work together—almost miraculously.
From time to time in our offices and labs at Diasome, we kick around the phrases “iatrogenic hyperinsulinemia” and “iatrogenic hypoglycemia,” perhaps because they make us feel smart, but perhaps because they are also highly descriptive terms for the problem with current insulins. “Iatrogenic” is a medical term used to describe a therapy or other medical intervention that actually causes harm in the process of treating someone. Insulin is the poster therapy for the word “iatrogenic” because current insulin therapy does often lead to too much insulin, or hyperinsulinemia, and too much insulin relative to glucose can lead to too little glucose, or hypoglycemia.
As a person diagnosed with type 1 diabetes myself a little more than 25 years ago, I have spent my professional life working in support of scientists and clinicians who believe that insulin therapy should mimic pancreatic insulin that reaches the liver more directly. We refer to this as the “where?” question: “Where does insulin go after it is injected?” Just as location is everything in real estate, where insulin works is critically important in developing an effective insulin therapy.
Why does islet cell transplantation work? Because it restores insulin in the liver. Why does a dual insulin/glucagon closed loop system make more sense than an insulin-only system? Because a dual hormone system recognizes the powerful ability of the liver’s glucagon response in counteracting hypoglycemia. These technologies are focused on the goal of restoring normal physiology, but the missing piece is still the availability of an insulin that is liver cell specific.
Interestingly, it took 50 years after the discovery of insulin before researchers at Columbia University found out that injected insulin does not reach the liver. Frustratingly, almost another 50 years have passed, and we still do not have insulin therapies that can set things in motion in the liver the way normal insulin does.
Diasome represents a team of scientists, physiologists, formulation chemists, diabetologists, clinicians and entrepreneurs who are all dedicated to bringing the first liver-targeted insulin to patients. We believe that a Person With Diabetes’ Bill of Rights would begin with having access to insulin therapies that really mimic normal physiology, starting with insulins that “set things in motion” in the right amount and at the right time, but most importantly, in the right place.
Our guiding principles include the recognition that insulin is very powerful and that all injected insulins should be liver targeted because all pancreatic insulin is, by definition, liver targeted. In glucose metabolism, location is everything, and at Diasome #WeTellInsulinWhereToGo.
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Diasome seeks to serve people with diabetes by developing cutting-edge therapies and by serving as a forum for our community to educate and inform others about the challenges and successes in living with diabetes. We actively seek perspectives from the rich and diverse world of clinicians, scientists, thought leaders and people with diabetes. To share your unique perspective with us, email Diasome at firstname.lastname@example.org