"Losing weight isn’t just linked to better management of Type 2 diabetes. Significant weight loss could actually result in lasting remission."
Professor Roy Taylor
A body of research putting people with Type 2 diabetes on a low-calorie diet has confirmed the underlying causes of the condition and established that it is reversible.
The first-year results, which were published on 5 December 2017 in The Lancet, revealed that almost nine out of 10 people (86%) who lost 15kg or more, put their Type 2 diabetes into remission.
The study led by Professor Roy Taylor, from Newcastle University, and Professor Mike Lean from Glasgow University, found that 45.6% of those who were put on a low-calorie diet for three to five months were able to stop their Type 2 diabetes medications.
Professor Roy Taylor’s research revealed that for people with Type 2 diabetes:
- Excess calories lead to excess fat in the liver
- As a result, the liver responds poorly to insulin and produces too much glucose
- Excess fat in the liver is passed on to the pancreas, causing the insulin producing cells to fail
- Losing less than 1 gram of fat from the pancreas through diet can re-start the normal production of insulin, reversing Type 2 diabetes
- This reversal of diabetes remains possible for at least 10 years after the onset of the condition
Importantly, long-term support by routine General Practice staff was given to help the participants maintain their weight loss.
The trial, called DiRECT (Diabetes Remission Clinical Trial) and funded by Diabetes UK, recruited 298 people between the Newcastle and Glasgow University and builds on Professor Taylor’s earlier pilot work.
Professor Taylor, lead researcher of the DiRECT trial, said: “These findings are very exciting. They could revolutionise the way Type 2 diabetes is treated.
“The study builds on the work into the underlying cause of the condition, so that we can target management effectively.
“Substantial weight loss results in reduced fat inside the liver and pancreas, allowing these organs to return to normal function.
“What we’re seeing from DiRECT is that losing weight isn’t just linked to better management of Type 2 diabetes: significant weight loss could actually result in lasting remission."
Remission was defined as having blood glucose levels (HbA1c) of less than 6.5% (48mmol/mol) after a 12 months period, with at least two months without any Type 2 diabetes medications.
Of the 298 people recruited who took part in DiRECT, half continued receiving standard diabetes care from their GP, whilst the other half received a structured weight management programme within primary care without medication.
The programme included a low calorie, nutrient-complete diet for three to five months, food reintroduction and long-term support to maintain weight loss.
Type 2 diabetes remission was found to be closely related to weight loss. Over half (57%) of those who lost 10 to 15kg achieved remission, along with a third (34%) of those who lost 5 to 10kg. Only 4% of the control group failed to achieve remission.
The findings were presented at the International Diabetes Federation Congress in Abu Dhabi by the lead researchers, Professor Taylor and Professor Mike Lean.
Professor Lean said: “Putting Type 2 diabetes into remission as early as possible after diagnosis could have extraordinary benefits, both for the individual and the NHS. DiRECT is telling us it could be possible for as many as half of patients to achieve this in routine primary care, and without drugs.
“We’ve found that people were really interested in this approach – almost a third of those who were asked to take part in the study agreed. This is much higher than usual acceptance rates for diabetes clinical trials."
DiRECT is a two-year trial, which aims to verify and confirm the hypothesis that significant weight loss could actually be an effective and accessible way to put Type 2 diabetes into remission for the long-term.
The trial is delivered through GP practices across Tyneside and Scotland to find out if the benefits of a structured weight management programme can be felt in a real-life primary care setting.
DiRECT also aims to understand why significant weight loss results in remission, to understand which groups might benefit in the future.
Type 2 diabetes is a life-changing condition that progresses over time, which can have devastating consequences. Finding ways to put it into lasting remission could significantly reduce the cost of delivering diabetes care and treating serious complications such as cardiovascular disease, kidney disease or stroke.
Remission could transform the lives of millions of people living with or at risk of Type 2 diabetes.
Isobel Murray, 65, from North Ayrshire, took part in DiRECT from 2014 to 2016. She was on the low-calorie diet programme for 17 weeks and put her Type 2 diabetes into remission after the first four months. Over the two-year trial, Isobel lost more than 21kg and no longer needs to take any diabetes medication. Isobel said: “It has transformed my life, I had Type 2 diabetes for two to three years before the study.
“I was on various medications which were constantly increasing, and I was becoming more and more ill every day. When the opportunity came to go on the DiRECT study, I had absolutely no hesitation.
“When the doctors told me that my pancreas was working again, it felt fantastic, absolutely amazing.
“I don’t think of myself as a diabetic anymore, I get all my diabetes checks done, but I don’t feel like a diabetic. I am one of the lucky ones to have gone into remission.”
Diabetes UK has committed more than £2.8 million to the DiRECT study. Recently, £300,000 has been committed so participants who wish to continue can be followed for up to three years and the full cost-effectiveness of this programme can be evaluated.
The funding will provide further understanding around the longer-term benefits, to see if a treatment of this kind could be offered to people with Type 2 diabetes in the future.
Dr Elizabeth Robertson, Director of Research at Diabetes UK, said: “These first-year findings of DiRECT demonstrate the potential to transform the lives of millions of people.
“We’re very encouraged by these initial results, and the building robust evidence that remission could be achievable for some people.
“The trial is ongoing, so that we can understand the long-term effects of an approach like this. It’s very important that anyone living with Type 2 diabetes considering losing weight in this way seeks support and advice from a healthcare professional.”
Whether putting Type 2 diabetes into remission can protect against diabetes-related complications later in life has yet to be examined, and hence, it is important to expand the DiRECT initiative futher to monitor and study those who achieve remission continue to receive regular health checks.
More research is also needed to find out who could benefit most from these treatments, caution against one size fit all, could Type 1 diabetes patients be worthy of such procedures?
Can you share the science behind the remission?
Type 2 diabetes has been regarded as lifelong and inevitably progressive. However, until recently, approaches undertaken have always been glucose management, to slow down the development of complication of leading to cardiovascular diseases, and kidney failure. In other words, medical professionals have come to accept the fact that there is not yet an effective way to treat Type 2 diabetes.
However, in 2006, blood sugar levels in people with Type 2 diabetes were shown to fall to normal within 7 days after bariatric surgery. Because Newcastle research at that time had managed to establish a link between excess fat in the liver and failure of insulin effects on the liver, the reason for the normalised sugar after bariatric surgery seemed obvious. The people undergoing surgery would suddenly have to stop eating – nil by mouth. That would rapidly deplete liver fat. Then the liver would respond properly to insulin, and stop pumping sugar into the blood.
But could this also explain the problem with the pancreas? Excess fat in the liver causes excess fat in the blood, and leads to excess being delivered to the pancreas. Some early studies had shown that long-term exposure to fat could cause the insulin producing cells to stop working.
These ideas were published as the Twin Cycle Hypothesis - that Type 2 diabetes is caused by excess fat within both the liver and pancreas. Now we had a hypothesis in hands to test.
This causes the liver to respond poorly to insulin. As insulin controls the normal process of making glucose, resulting in too much glucose in the liver. Simultaneously, excess fat in the liver speed up the normal process of export of fat to all tissues. In the pancreas, this excess fat causes the insulin producing cells to fail.
The first test of the Twin Cycle Hypothesis was published in 2011 (Lim, et al., 2011). The Counterpoint study showed that a 700-calorie diet (achieving 15kg weight loss in 8 weeks) would return fasting blood sugar to normal within 7 days. It was shown that was a result of sudden normalisation of liver insulin sensitivity due to the liver fat levels returning to the normal mean for a matched non-diabetic group. However, the most important changes were in the pancreas. Over the full 8 weeks, the level of fat within the cells of the pancreas fell to pre-diabetic levels, and in step with this, the first phase insulin secretion gradually normalised. Watching the beta cells wake up was dramatic - the first time that this had been observed. The study confirmed that if excess food intake were sharply decreased through a very low-calorie diet, all these abnormal factors would be reversed.
Another study published in 2016, tested whether diabetes would stay reversed after resumption of normal eating (but keeping weight steady). Indeed, it remained in remission up to the 6-month final point of the study. This study also established that the condition was reversible in the early years, but after 10 years of diabetes, remissions were very rare.
The ‘One, Two’ approach used in the Counterbalance study was a defined two phase programme. Phase 1 is the period of weight loss – calorie restriction without additional exercise. A carefully planned transition period leads to Phase 2 - long term supported weight maintenance by modest calorie restriction with increased daily physical activity. This approach consistently brings about 15kg of weight loss on average.
“The good news for people with Type 2 diabetes is that our work shows that even if you have had the condition for 10 years, you are likely to be able to reverse it by moving that all important tiny amount of fat out of the pancreas. At present, this can only be done through substantial weight loss.”
For many years, it was thought that the problem in the pancreas was death (apoptosis) of the beta cell. The work of Accili in New York built on earlier work by Ann Clarke of Oxford in establishing the principle that the beta cell defect in Type 2 diabetes was de-differentiation. Under the metabolic stress of too much fat, and coupled with excess glucose, most beta cells lost their specialist function and ceased to produce insulin. Anne showed that this was reversed over days after removing the excess fat. Removal of the excess fat allows resumption of the specialised function to produce insulin. Using human islets, my colleague, Jim Shaw in Newcastle was able to show that islets from people with type 2 diabetes exhibited de-differentiation, and this was not seen in islets from non-diabetic people.
So, type 2 diabetes is a state of chronic beta cell stress and hence de-differentiation. Removal of the excess fat permits re-differentiation - and recovery of function.
What are the next research steps?
Ongoing research will answer the questions of whether diabetes stays away long term, and a formal health economic analysis will determine the cost savings. As prescription of tablets to control blood sugar cost over £1 billion annually in the UK, and as the number of blood pressure tablets required are halved on this programme, the potential savings would be great. But the greatest savings will come in the form of less blindness, less amputation and less kidney failure.
What support is most effective in helping people avoid weight regain? That is an important question.
We will also need to know much more about the insulin producing cells (beta cells) and their de-differentiation.
By Professor Roy Taylor, Newcastle University, UK
- Lim, E. L., Hollingsworth, K. G., Aribisala, B. S., Chen, M. J., Mathers, J. C., & Taylor, R. (2011). Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Diabetologia, 54(10), 2506–2514. https://doi.org/10.1007/s00125-011-2204-7
- Taylor, R. and Lean, M., et al. (2017). Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. The Lancet. doi: 10.1016/S0140-6736(17)33102-1
- Type 2 diabetes is not for life. (2017). Retrieved December 11, 2017, from Newcastle University website: https://www.ncl.ac.uk/press/news/2017/12/directstudy/