In part 1 of this Exclusive Interview, Aaron Vinik talks with Diabetes in Control Publisher Steve Freed during the AACE 2018 convention in Boston, MA about the latest on his INGAP research and understanding the role of the brain in diabetes.
Aaron Vinik MD, PhD, FCP, MACP, FACE is the Director of Research at Eastern Virginia Medical School in Norfolk, VA.
Transcript of this video segment:
Freed: This is Steve Freed with Diabetes In Control and we’re here at AACE 2018 with a special guest, Dr. Aaron Vinik. Dr. Aaron Vinik is on our board because we appreciate what he does. Now, I can go into all the details about his background but it would be a waste of time because it’s just too long. Basically, he is an expert in neuropathy, he is known for it all over the world, not just in the U.S., so it is really an honor to have you here. I got to know Dr. Vinik because back a couple of years when he was doing research and discovered a protein called InGaP, which at the time, we thought might be a cure for different types of diabetes. So maybe we can start off with that. Since then, a lot of things have changed. Where do you stand now with InGaP?
Vinik: Steve, it is a pleasure to be on again with you, I will just have to be careful with what I say because when I hear of it, it comes back again and it gets quoted in so many different ways. The InGaP situation is tricky right now, the issue is being shown in InGaP itself; the small peptide has been shown to stimulate growth and proliferation of stem cells and they differentiate into pancreatic beta cells and they get the whole quandary of the glucagon cells, somatostatin, pancreatic peptide and it becomes a functioning islet and we have shown that that will occur in almost every species we’ve done – all the animal species including monkeys and dogs. We have also shown that it is active in humans, both in type 1 and type 2 diabetes. The only problem we have encountered is what most people encounter when you stimulate regeneration of islets: is that these newly formed islets are attacked as foreign and the body turns against them and causes a lysis of them, autophagy or whatever words you want to use for killing of beta cells. So if we could stop the killing, we’d be a long way. We have now tried a number of different anti-inflammatory agents – all of them supposed to be God’s gift to mankind but none of them have worked so far. We have hopes that there are a couple of new ones around that are, right now, in clinical trials and we will see. It’s not the inability to stimulate the growth, we can do that, and we can regenerate islets, but, we need to stop the killing.
Freed: Well, thank you. Couple of questions I know your expertise in – one of the questions is: Why was the brain the last organ to be implicated in the pathogenesis of diabetes?
Vinik: Everybody has thought of diabetes as an absolute or relative deficiency of insulin. So the whole idea had been in the discovery of the pathogenesis, the development of diabetes, was to look for anything that would affect beta cells that made insulin – anything that would cause a loss of beta cells or beta cell destruction. And then it emerged that the major factors that contributed to that were hormones produced, in the intestine for example, glucagon-like-peptide-1 (GLP-1) – anything that acted on a pancreatic beta cell to stimulate its growth and proliferation, but, in addition, to enhance insulin secretion. It took quite a long time to discover that that wasn’t the only mechanism because if you express or secrete insulin that is what has to be biologically active in many different forms, rather than the native form. A whole new science emerged and that was related to insulin resistance – what turned the body off of insulin. So now we got on the whole quandary of studies and research, all the factors that could affect resistance to the action of insulin. Now we have all the beta cell factors, all the insulin resistance factors and lo and behold, people said, “Oh well it happens in the liver, so they studied the liver; it happens in the muscle, so they studied the muscle; it happens in the GI tract, so they studied the GI tract; it happens in the kidney, so they studied the kidney.” So we’ve got the explosion of factors that can affect diabetes. From my early days where I knew about sulfonylureas and metformin or phenformin in the early days, and insulin and early crude versions of insulin and now, just taken off now, we have 14 different classes of drugs and they act on all those different areas. So, if you take my friend, Ralph DeFronzo, he went from the duet to the triad to the tetret to the pentet to the sextet to the octet and now to the dreadful dectet, and creeping into even his diagram now is the brain.
Freed: When it comes to diabetes, nutrition and metabolism play major roles obviously. We know that the gut plays a role, we know the stomach and the hormones that are released. Maybe you can talk a little bit about the brain – where the brain comes into our metabolism.
Vinik: So, the brain to me is actually the conductor of the autonomic orchestra. The brain controls just about every hormone that is produced in the central nervous system. In the pituitary, there’s growth hormone, there’s HETH, which stimulates cortisol secretion. But more than that, it also controls all the hypothalamic nuclei – the supraventricular, the paraventricular, the nuclei – and those regulate the release of acetylcholine, norepinephrine and epinephrine. So those, we’ll call them hormones, actually regulate all your metabolism. So, if you turn them on like with the sympathetic nervous system activation, you’ll increase the glucose levels and increase liver production of glucose. The glucose itself not only is produced in the liver, but the sympathetic nervous system acts on adipose tissue, adipose tissue causes breakdown of triglycerides, the release of free fatty acids, the free fatty acids then contributing to neoglucogenesis, new glucose formation. All driven by what is happening here, [points to the brain\ in your hypothalamus at the base of the brain. On the other hand, there’s a counterbalancing hormone that is acetylcholine, the parasympathetic nervous system. The parasympathetic nervous system does just the opposite of everything of the sympathetic nervous system. The sympathetic nervous system is “fight or flight,” and the parasympathetic nervous system is quiet and peacefulness – just when you want to drift off. That’s a very nice balance.
The next question you have to ask is, and I’ll ask it for you, is to say: If this control is centralized, in a very small area in the brain, there must be some very powerful substance or substances that act on that area, and they must be defective in obesity and diabetes. Now, we’ve taken everything away from a beta cell, taken it away from the pancreas, taken it away from the liver, from the production of glucose or adipose tissue, production of free fatty acids, and so forth, and we’ve said there is something happening right there. Lo and behold, brain dopamine is deficient in obesity and is deficient in obese diabetics. Just a little molecule, just a few tiny smidgens of this molecule, is required to activate that whole system and we are deficient in it. What is even more interesting about this, is that you will have a circadian rhythm. So, you’ve got a clock that ticks for when the dopamine level must go up and when the dopamine level must go down. So, what goes wrong, is when you’re deficient, your clock is not set properly. As you know, Steve, if you look at your rhythm of glucose, it goes up just before breakfast time, reaches a peak, then goes down, then goes up again, just before lunch, then goes down and then it drops to a nadir between about two and four in the morning. And that clock is regulated but the dopamine clock here (points to brain). Isn’t that cute? So, all we have to know is how we can reset this clock.