Remission of type 2 diabetes achieved by a large proportion of patients with a weight-loss intervention in the DiRECT trial emphasized the importance of excess body fat in the disease. Now researchers have been uncovering just how this works.

MedPage Today caught up with DiRECT investigator Roy Taylor, MD, of Newcastle University in England, who recently reported mechanistic findings at the American Diabetes Association annual meeting in Orlando.

he comments that follow have been edited for brevity.

The latest data you’ve reported delved into the mechanisms for the 46% remission rate of diabetes off medication in the diet intervention group. What did you find?

Taylor: What had happened was that we had drastically reduced the amount of fat that was gumming up the liver, we’d reduced the amount of fat that was interfering with the pancreas, and these organs went back to normal function — the liver really fast, 7 days, with the pancreas, much more slowly over 8 weeks. And since then, that was 2011 when we published that work, we’ve been just extending it and finding out more. Last December, we published a big study [DiRECT] that involved not us doing the management of individuals, but just teaching the nurses in primary care how to do this.

So we’ve been able to show that the liver fat level went down from 16%, which was grossly raised. We haven’t previously quite grasped that type 2 diabetes is a disease of too much fat in the liver. So that 16% dropped to 3% — an amazing drop, one of the biggest changes we see in human metabolism. At 12 months, it’s still about 3%, and that is quite remarkable. It causes a small drop in the pancreas fat, but that’s sufficient to allow full function to return in a high proportion of people.

Overall, about two-thirds of people return to nondiabetic blood glucose control, and we can see that the beta cell has woken up, because it regains the all-important first-phase insulin response. When plasma glucose is raised just a little, the beta cell normally produces a rapid surge of insulin, and that’s absent in type 2 diabetes.

It has been thought to be irreversibly lost, but what we’ve shown is that taking away the excess fat allows the beta cell to recover in most cases.

What are the implications of these mechanistic results, knowing how the liver and the pancreas are impacted by weight loss?

Taylor: One of the main implications is that we can talk about type 2 diabetes in a very different way, because we can now see that is a very simple disease process. Hitherto scientists and doctors have referred to type 2 diabetes as a complex heterogeneous disorder. That description is written so often at the beginning of grant proposals, at the beginning of lectures: Type 2 diabetes is a complex and heterogeneous disorder. Well, it isn’t.

Diabetes can now be seen to be a very simple disorder of a person having more fat than they personally can deal with, so it’s a simplification. It’s a simple condition that, of course, is applied to individuals who are heterogeneous. That’s where the complexity comes in and that’s what’s caused the confusion.

So for this one person sitting in front of me in the consultation, that person has acquired more fat than they can cope with. Get rid of their fat, and this disease goes away. Now, knowing the processes allows us to be definitive about that, and that is an enormously welcome message for people with diabetes …

What they say is that hearing firstly, that it’s reversible, and secondly, why it’s reversible — that’s what allows them to be motivated to lose the weight and go on and do it. So studying the mechanisms is really important.

There’s one other important thing that comes out of our work, and that is that the duration of type 2 diabetes really matters. Because the clock is ticking as soon as the diagnosis is made. Even in the first 6 years of type 2 diabetes, which is what was included in this large study, the DiRECT study, even in that time, the people who don’t manage to get back to normal tend to have slightly longer duration of diabetes than those that can easily reverse. So this is important because it changes how we should see that first consultation.

Does this put it more on the patient, that it’s their fault for gaining weight that they have this disease?

Taylor: In fact, it makes it the reverse. One of the most poignant questions asked in the clinic is why me? Why have I got diabetes? All my friends are fatter than me and they don’t have it. Well, unfortunately, we’re all individuals. We all have tendencies one way, advantages other ways. Some people have beta cells that are just more susceptible to a moderate amount of fat than the average. And if we take it to the extreme, many people are completely resistant to the effects of fat in the beta cell. If we look at people with a body mass index over 40, almost three quarters of them don’t have diabetes and are unlikely to get it. And so you see it’s not any individual’s fault. It’s a matter of just having drawn a bit of a short straw with the genes that have set you up in this particular way.

So it takes away the pejorative aspect of type 2 diabetes — you’ve been having a bad diet, you put on too much weight — and really turns it back to the individual. You’re unlucky. You’re drawn the short straw, but the good news is you can deal with it.

What does the DiRECT diet involve?

Taylor: The diet that we used in the initial studies was 600 kilocalories per day together with some non-starchy vegetables. Now we simplified that in order to do our study in general practice and primary care. We moved to an 800 kilocalories per day diet but just from liquid formula products. So it was a packet for breakfast, a packet for lunch, a packet for evening meal. It sounds a bit fierce, but there are two huge advantages of this.

It’s been rather forgotten, even though recognized some time ago, that on an 800 calorie a day diet people are not hungry. You’re not bothered by awful pangs of hunger. Whereas if you cut back by a slice of bread a day, you miss it and you’re a bit peckish. So after the first 36 hours, which are tough, no hunger to note.

The other advantage is one of the real difficulties to losing weight is the day-to-day burden of decisions. How much can I eat, what can I eat, is that a level of spoonful or do I deserve a bit more? … This takes away all that hassle. It’s a packet for your meal and that’s it.

Even though it may seem as though that’s too tough for most people to stick to, in DiRECT we had a flexible period of study. So the basic deal was they would stick with the diet for 3 months, but if they wanted to achieve personal goals, losing a bit more weight, they could choose to extend it. Almost everybody chose to extend it, and the average period of time on the diet was actually 4 months. So that just gives you a hint of how well people feel with this dietary approach.

But then for the weight maintenance phase, we have a slow steady return to eating normal foods.

Were there any surprises?

Taylor: I think one of the most important things in starting out is to have the support of your nearest and dearest, maybe a spouse, partner, or friends. They need to be involved with the quest of this person to get rid of their diabetes. If a person that has that support, they are much more likely to be successful. And so we do go out of our way to involve these significant others in the information about what we’re doing, why we’re doing it.

That has been one of the most important learning points for me. At first I was a bit puzzled, because after being a doctor for over 40 years, I couldn’t accurately predict who was going to do well and who wasn’t. I expect to be able to do that. I know who’s not going to follow my advice too well, but this was a surprise to me.

And then the scales dropped from my eyes. It wasn’t the person I was looking at, it was the person sitting next to them that was actually calling the shots — the husband or wife, the partner, the friends. That led to us paying much more attention to involving them in this grand project to make a step change of getting back to a healthy weight.