New Horizons In Type 2 Diabetes Research Two papers published in the journal Cell Metabolism present different approaches to controlling glucose levels in people with Type 2 diabetes — the form of diabetes in which the body gradually loses the ability to use insulin to control sugar levels in the blood.
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New Horizons In Type 2 Diabetes Research

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New Horizons In Type 2 Diabetes Research

New Horizons In Type 2 Diabetes Research

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This is Talk of the Nation: Science Friday. I'm Ira Flatow. Up next, the latest in diabetes news. This week, two research groups are reporting progress in treating diabetes, at least in mice. Researchers in France say the hormone apelin can lower blood sugar in mice.

Apelin is a naturally-occurring hormone put out by fat cells, and it's found in both mice and in humans. In another study, researchers made a synthetic protein, modeled after ingredient - the common ingredient found in red wine. We know it all. It's resveratrol. When they injected mice with the protein, they found it warded off weight gain. It improved exercise endurance. It lowered insulin resistant in the mice. And both of those groups reported their findings in the most recent issue of the journal Cell Metabolism. So how or do these findings translate to humans?

There are an estimated 246 million adults worldwide who suffer from diabetes, mostly type 2 diabetes. Talk - joining me now to talk more about is my guest, C. Ronald Kahn. He is the professor of medicine at Harvard Medical School, and also the vice chairman of the board, and section head of the Joslin Diabetes Center in Boston. Thanks for talking with us today, Dr. Kahn.

Dr. C.RONALD KAHN (Medicine, Harvard Medical School): Glad to be here, Ira.

FLATOW: Both of these new reports relate fat and diabetes. Give us a little more insight on the relationship between the two. Are we finding out that we have a lot more to learn about diabetes here?

Dr. KAHN: Oh, there's actually very good news on that front. There is a lot more to learn about - particularly about what causes type 2 diabetes, and this problem of insulin resistance. As you commented that many people with diabetes actually make insulin, but their tissues don't normally respond to it. And both these articles, as well as a lot of other research is trying to address that problem.

FLATOW: Mm-hmm. Let's talk about the two separate - let's talk about the apelin. It's a hormone, right?

Dr. KAHN: Right. Yeah, so, what we've learned both in this study and in several studies that preceded this study, is that we used to think about fat as just a kind of a storage depot for extra calories, when we didn't have a chance to eat. But it turns out that fat is a very active tissue. And it's actually making a number of different hormones that affect metabolism.

FLATOW: Mm-hmm. And what does the fat do? It puts out this hormone?

Dr. KAHN: So, fat releases these different hormones, apelin is one of them, another one is called leptin.

FLATOW: Mm-hmm.

Dr. KAHN: Another one is called adiponectin. And different fat stores, make different amounts of these different hormones. As you know, obesity is particularly bad when it's inter abdominal, when it's called apple-shaped obesity, or central obesity.

FLATOW: Mm-hmm.

Dr. KAHN: And some of these hormones are made at higher levels by that inter-abdominal fat. And some made more by subcutaneous fat.

FLATOW: Mm-hmm. And the researchers found that apelin helped to move glucose into cells, just like insulin does.

Dr. KAHN: Right. So apelin is one of the good fat hormones, or adipokines. Another one that's generally good on metabolism, is called adiponectin. And it also comes out of fat, and stimulates metabolism more in the liver. Apelin seems to work more on the muscle.

FLATOW: And so could apelin be taking over when the insulin isn't working?

Dr. KAHN: So, we believe that these adipose hormones like apelin have - and adiponectin and another - the other one, leptin. All have kind of long-term effects. Insulin works more in the short term. It more responds to individual meals at a feeding - short periods of feeding and fasting, where as these fat cell hormones seem to more respond to bigger changes in body weight over longer periods of time.

FLATOW: Mm-hmm. And the other compound is modeled on a molecule found in red wine. We're heard a lot about it over many years, resveratrol. It's the one we hear that protects, you know, about - from heart disease. Why you should be drinking a glass or two of wine every day.

Dr. KAHN: Right.

FLATOW: And what is happening there?

Dr. KAHN: Well, what's exciting in this particular area is that the class of molecules that are the cellular targets of resveratrol, is a new - a kind of group of intracellular regulators, they're called sirtuin proteins, or sirt for short. Sirt 1, 2, 3, 4, there's a whole family of these. And what's being learnt is that these are important controllers of metabolism, and even aging. And if we can find drugs that will lead, or activate, or inhibit different sirtuins, we may have approaches to diseases like diabetes, obesity, and perhaps even other important diseases.

FLATOW: Mm-hmm. And is this a - is this an opportunity to make a lot of resveratrol, or to find out the mechanism by which it works? Or go in that direction?

Dr. KAHN: Well, yeah. I think that the idea is - and this is actually in part based on work by an academic lab - but it was in collaboration with a biotechnology company, Sirtris Pharmaceuticals, that is interested actually in making small molecules that could be orally absorbed, that would actually stimulate one member of the sirtuin family, called SIRT1, which appears to have very beneficial effects on metabolism, and that's what the story is about.

FLATOW: Mm-hmm. Well, you know, I can imagine the headlines and you can see some of them already. Saying things like, apelin to save diabetics. You know, they just go get some, and you don't need to get - take insulin anymore. Will that be over the top or true?

Dr. KAHN: Well, I think eventually we will find new drugs in both categories of adipokines, that is the fat-cell hormones, and in the sirtuin activators and inhibitors. Of course, it's still early to know what the long-term effects of this would be. How is the best the way to give them? What are the very - most important targets and tissues to be acted upon? But I think that this is actually - both of these areas are exciting developments for the future.

FLATOW: Mm-hmm. In researching this week, we Googled apelin, and see that it is known as a cardiac hormone. So, if were to give people this hormone, and reduce their blood sugar levels, do we know how it's going to effect the heart in some ways?

Dr. KAHN: I don't think we do. And in fact, that is one of the reasons that it - I would call these kind of early - particularly the apelin story, is a molecule that we still don't know a lot about. And many of these molecules may have beneficial effects on other tissues, but may also have some detrimental effects. So we need to find what is the full series of effects, to decide whether these are going to be good therapeutic - or therapeutic alternatives.

FLATOW: Mm-hmm. So the take home on that would be don't wait for all this to develop out. Do something now on your own.

Dr. KAHN: Well, I think that the take home is, yeah, we still have things we can do now, and both the current pharmacological therapies we have for diabetes, but also of course, for type 2 diabetes. So much is involved with lifestyle, keeping your weight down, keeping active, and these are very important modifiers of the disease.

FLATOW: Mm-hmm. We've been hearing more and more about something called metabolic syndrome.

Dr. KAHN: Yes.

FLATOW: Tell us what that is.

Dr. KAHN: Well, metabolic syndrome is actually a clinical cluster of diseases that seem to kind of come together. Diabetes, central obesity, the tendency to hypertension, accelerated arthrosclerosis, fatty liver, even gall stones. Diseases also like Alzheimer's disease, and polycystic ovarian disease are also related. And all of these diseases cluster around the fact that all of these diseases have - as part of their problem, insulin resistance. That is the tissues of the body don't fully respond to the hormone insulin, which is the normal hormone that controls glucose and metabolism. So, these are insulin-resistance states.

FLATOW: Mm-hmm.

Dr. KAHN: And there are different levels of insulin resistance in different tissues and different diseases, but all of them kind of come together in this cluster of metabolic syndrome.

FLATOW: Mm-hmm. Would any of the research we were talking about today apply to the severe cases, the type I cases of diabetes?

Dr. KAHN: Well, it's not likely that either of these approaches are going to be the answer for type I diabetes. For type I diabetes, we're dealing with a disease where the insulin-producing cells have been destroyed by an auto-immune process. And so our goal is not only initially to replace insulin by injection, but eventually to develop either transplant or genetic therapies to actually restore insulin secretion.

But there we have to deal first with the immune response, which is destroying the insulin-producing cells. In type 2 diabetes, we have a different problem. The body makes insulin, but the tissues don't respond to it. The body tries to make more insulin. It can't make enough more to overcome this, so there's a problem of both making enough insulin, but also this problem with insulin resistance, that is really - needs to be addressed in treating type 2 diabetes.

FLATOW: Hmm. Mm-hmm. And how soon might we expect to see this mice research trickled down into the human?

Dr. KAHN: Well, I believe that with drugs like in the class of the sirtuin activators, these are already an early-stage human clinical trials. And so I think that we're going to know over the next few years whether either the particular compound that was mentioned in this article or others like it will have effects - beneficial effects on metabolism.

I think with apelin - with the adipose hormones like apelin, there's a bigger challenge, because these are protein or peptide hormones. These would probably have to be given by injection where the sirtuin activators could potentially be given orally...


Dr. KAHN: In fact, they are given orally. So, I think that there's of course going to be more rapid acceptance if we can find orally therapies. But injectable therapies, also would be acceptable if they really work.

FLATOW: Mm-hmm. Do you think that people should expect to just continue if they have - if they're diabetic type 2, their lifestyles and say, when these drugs are available, I'm just going to, you know, take these drugs'? Or do they still have to change their lifestyles?

Dr. KAHN: Well, I think it's very important for anybody who currently has type 2 diabetes, or people who are at high risk to be addressing the problem now, and not wait for the future. If you've got diabetes, we know that all the long-term complications on vascular tissues that lead to amputations, blindness, kidney disease...

FLATOW: Mm-hmm.

Dr. KAHN: All of these complications are representing cumulative damage over time from abnormal metabolism. And the sooner the diabetes is under control, the better it's under control, generally, the better the outcome. With people even who are at risk for developing diabetes, we know that lifestyle changes, like keeping your body weight down by diet and exercise, makes a huge difference in your ultimate risk of ever getting the disease.


Dr. KAHN: So, I don't tell people to wait. I tell them to attack the problem now.

FLATOW: And how much of this is hereditary type 2 diabetes?

Dr. KAHN: Type 2 diabetes has a very strong hereditary component. It's actually though what we call a polygenic disease. That is it's not one gene that you're inheriting, but probably a cluster. In fact, now there's as many as 20 different genes that have been identified to contribute each a small amount to type 2 diabetes.


Dr. KAHN: So, the problem with this is that many of us have some of these genes. Very few people have none...

FLATOW: Right.

Dr. KAHN: And very few people have all, but there's a lot of them that are very common. So I think we're going to - while the genetics are interesting from a medical-research perspective, right now, we have to deal more with the environment, which we can control.

FLATOW: I'm talking with Dr. Ronald Kahn on this hour on Talk of the Nation: Science Friday from NPR News, talking about diabetes. We did a segment a while back in the show talk - where the first human genome with a cancer patient was identified.

Dr. KAHN: Mm-hmm.

FLATOW: And they compared it to - they took some genes out of her tumor and some out of her skin cells, and found the exact differences in those genes that might have caused the cancer. Do we know enough about the exact genes of diabetes 2, that this might help, or might not help, or might not be needed?

Dr. KAHN: Well, I think for diabetes, it's going to be - it has some similarities with cancer, in that cancer is often multiple genes...

Dr. KAHN: Mm-hmm.

FLATOW: And diabetes is often multiple genes. But in cancer, what we have are real mutations in genes. That is something that really turns them on or off in a very dramatic way. Probably in diabetes, we have what we call quantitative traits. That is a quantitative difference in a gene. It might be on a little bit more, or on a little less, or a little bit more active, so it's going to be a much more subtle, genetic effect. I don't think yet we're at a point - although you can now go and buy a test for diabetes genes.

You can order it. You know, send some blood or DNA...

Dr. KAHN: Mm-hmm.

FLATOW: And get a test for it. I don't actually think that they're going to help...

Dr. KAHN: Yeah.

FLATOW: At this point decide yet quite what to do about therapy.

Dr. KAHN: Mm-hmm.

FLATOW: We do know that certain kinds of therapy responses are also genetically controlled. And eventually, this will make a big difference even in diabetes, to know which therapies you're most likely to respond to.

FLATOW: One last question from (unintelligible) in Second Life, does red-grape juice work?

Dr. KAHN: Does red-grape juice - well, yeah. There's nothing about the alcohol in red wine that's essential, and at least for this particular compound, resveratrol, that's been talked about, it is more in the Pinot Noir grapes, so if you're going to get grape juice, I guess you should look for Pinot Noir. But it would take a heck of a lot of grape juice to get this active compound. It's going to probably take something more developed as a pharmaceutical agent to get you what you need.

FLATOW: Something that's a lot more concentrated.

Dr. KAHN: More concentrated and more powerful, yeah.

FLATOW: More powerful. And the drug companies are working on that stuff?

Dr. KAHN: Yes, they are. Yeah, there are several actually.

FLATOW: All right. Dr. Kahn, I want to thank you for taking time to be with us.

Dr. KAHN: Thank you for having me.

FLATOW: Good luck to you. Have a good weekend.

Dr. KAHN: Thanks now. Bye bye.

FLATOW: Dr. C. Ronald Kahn is the Mary K. Iacocca professor of medicine at Harvard Med School. Also, the vice chairman of the board and section head of the Joslin Diabetes Center in Boston, talking about diabetes research that appeared in this week's journal, Cell Metabolism.

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