Nov 9, 2016

Interviewer: Someone who is thin can end up with diabetes. And yet an obese person may be surprisingly healthy. Why is that? We'll talk about research today that addresses that question.

Announcer: Examining the latest research and telling you about the latest breakthroughs, the Science and Research Show is on The Scope.

Interviewer: I'm talking with Dr. Scott Summers and Dr. Bhagirath Chaurasia, in Nutrition and Integrative Physiology at the University of Utah College of Health.

You know, I thought one way we could start talking about this is that this type of research has a personal connection for you. If we're talking about thin people who get diabetes, which is kind of not the stereotype, that's something that you've faced in your own life. Not with you personally but with a family member?

Dr. Summers: Yeah. I was 14 years old when my father, somewhat precipitously, developed diabetes. He was 38. He was a fairly athletic individual. And to be honest, after he got diagnosed, he became sort of an exercise addict, and this was the way he would control his diabetes.

But despite all of his efforts and the fact that he was incredible fit and won countless road races, his diabetes worsened and became quite severe. So that was sort of the impetus for me to study diabetes in my career.

Interviewer: Right. So that profile is a surprise, right? Because what's more typical?

Dr. Summers: Yeah, he's an unusual diabetic, but he's not the only one. There's actually a fair number of people that can develop diabetes. We have kids that develop it, a classic type 2 when they're obese and we have adults that develop diabetes when they're thin. I think, actually, what we're learning is that distinction of type 1 and type 2 is much muddier than we realized and there's a lot of types in-between.

Interviewer: So often I think of diabetes as being a problem with the body's management of sugar. It turns out that's part of it. But what you two are looking at is the role of fats in diabetes and maybe it's sort of a mismanagement of the way fats are stored?

Dr. Summers: Yeah, I think so. I think the issue is really what's the type of fat, right? So fat has a lot of different terms, right? Sometimes when we're referring to fat we mean the tissue and sometimes we actually mean the food we're eating. But at the end of the day when fat is eaten, it's converted into something called fatty acids which are then taken up into cells and then they're restored in fat tissue as something called triglycerides.

Ceramides is another way that those fatty acids get metabolized. Instead of getting stored effectively or burned for heat, they sort of spill over into this and they conjugate with a certain protein derivative, protein metabolite. So it's just this different type of fat and metabolite that accumulates and it seems to have a whole series of actions that really are almost part of a universal stress response and a lot of the damage they do seems to be relevant to most of the diseases associated with obesity.

Interviewer: And do we have any idea why one person might be more able to store the fat as triglycerides versus going into that ceramide pathway?

Dr. Summers: Not as much as we need to. No, we really don't. When fat makes the decision to either be stored, burned, or go to ceramides there are some regulatory factors. We know that inflammation, infections will drive it into the ceramide pathway. We know that cortisol stress will.

We don't know as much about the dietary component as we should. We know ceramides are made from saturated fat and a certain type of protein that's a conjugation of those two. We don't as much as one would think about how much you eat, whether that influences it or not. And there may be a genetic component, too. About 20% of Utahans have a mutation in a ceramide synthesizing gene and those that do tend to have diabetes or hyperglycemia.

So I think there are a lot of factors that are driving it and we're trying to . . . that's sort of the holy grail of our research is to figure out those two questions - how ceramide works and what's driving its synthesis.

Dr. Chaurasia: Yeah, and that's exactly the next steps that we are following onto.

Interviewer: So you did some research in mice. What did that work show you? You had too many ceramides in mice.

Dr. Chaurasia: So what we showed is that if you delete out one of the initial enzymes required for ceramide synthesis, specifically in the adipose tissue, these animals tend to be more insulin sensitive. They tend to burn more calories and they tend to deplete out what we call the bad fat, white fat, into something called brown fat which actually turns them to other [inaudble 00:04:30] fat, actually and which allows them to burn more calories. And that's why we think that these animals are much more skinny and much more metabolically healthy.

Interviewer: Okay. And those are the ones where they had less ceramides?

Dr. Chaurasia: Those are the ones where we have less ceramides. And also we found in both the mouse cellular models as was the human cellular models is that if you treat them with increasing concentrations of ceramides, they tend to down-regulate, the expression levels of certain genes which are required for browning and increasing energy expenditure.

Interviewer: Which is actually helpful?

Dr. Chaurasia: Which is helpful, exactly.

Interviewer: Yeah, because it takes that away from white fat which is the more toxic fat.

Dr. Chaurasia: Exactly. Yeah.

Interviewer: Okay. Are you looking into ways to maybe manipulate those pathways to see if that can be used to treat diabetes?

Dr. Summers: Yeah, absolutely. So we've known before that if you treat with . . . there are drugs that you can give to mice but not to people and if you give that to them it prevents diabetes, it prevents fatty liver disease, it prevents hypertension, and cardiomyopathies, and things.

And so we're trying. You know, a part of our lab is trying to develop new drugs that will mimic that. We're testing some natural products that actually are out there that people can eat that might be able to deplete ceramides. And we're looking at dietary interventions, as well. Or we'd like to at some point, at least, look at dietary interventions to see if we can try and modulate this in addition to looking at the genetic components.

Interviewer: And so you think interfering with the ceramide pathway has a potential to help a lot of people?

Dr. Summers: I do. I mean, we've been working on it for a long time now. So it's been 15 years plus.

Interviewer: You're pretty motivated.

Dr. Summers: So, yeah, I'm still a believer at this point. You know, there are a number of things that can prevent diabetes in mice. So the fact that we can do it with this is there are other people that can do it, as well. And turning that into an effective therapy, I'm rather convinced ceramides can contribute to the development of diabetes.

Whether we can actually target that safely in a person is unclear because the reality is ceramides are actually . . . they do good things, too. So it's only when they get above a certain threshold that they become toxic. So can we titrate them in a person? Can we get them to make just, you know, not too little, not too much and remain healthy, is going to be a challenge for us.

But this is what we're trying to do and what I believe passionately we should do.

Announcer: Examining the latest research and telling you about the latest breakthroughs, the Science and Research Show is on The Scope.

For Patients