RESET: REmission of diabetes and improved diastolic function by combining Structured Exercise with meal replacemenT and food reintroduction.

Lay title: Reversing type 2 diabetes through a low calorie diet and supervised exercise

What is the problem?
Type 2 diabetes is becoming more common and adults are getting it earlier (aged between 18-40). This is worrying because people who get type 2 diabetes earlier are very likely to have heart, kidney and physical function problems at an early age. However, many of these effects have been shown to be reversible, either through weight loss caused by a low calorie diet or structured exercise. However, we don't know if combining weight loss and exercise leads to even greater improvements in young adults with type 2 diabetes.

What have we done so far?
Previous research, including by our group, have shown that low calorie diets lead to over half of people reversing their type 2 diabetes. Despite this, we have shown that there is no change in the structure or function of the heart. On the other hand, 12 weeks of structured exercise improved the pumping function of the heart.

What are we going to do?
The overall aim of the RESET programme is to assemble a team of experts in nutrition, exercise, heart disease and diabetes who, along with our patient partners, will investigate whether the combination of a structured exercise programme and a low calorie diet reverses diabetes and improves heart function, fitness, and other aspects of health when compared to standard care.

How will we do it?
In total, 80 people will be randomly assigned to: either usual standard care or a combination of an exercise programme and a low calorie diet.
Standard care - This group will receive their normal diabetes care and will be provided with a leaflet outlining the benefits of diet and exercise. They will also be offered the low calorie diet at the end of the trial.

Low calorie diet and exercise - These participants receive shakes that will replace all meals for two weeks and then all but one meal of the day for 10 weeks. After 12 weeks, participants will slowly return to their normal diet. The participants will have regular contact with the dietitian and study doctor throughout the 24 weeks.

Under the supervision of an exercise specialist, participants will also take part in exercise three times each week (from week 3 to week 12). They will use a treadmill, bike, weights, and resistance bands. The time exercising at each session will gradually be increased up to 60 minutes. They will be encouraged to continue exercising regularly for the remaining 12 weeks (weeks 13-24), but this will not be directly supervised. Participants will still have free access to exercise equipment and will still stay in contact with the exercise specialist who will track their activity and heart rate remotely. If the amount of exercise reduces, they will be invited back for supervised sessions. Additional calories will be allowed on exercise days to compensate for the extra energy expended.

What are we measuring?
We will look at how many people reverse status their type 2 diabetes across the 24 weeks .This means returning their sugar levels to normal ranges whilst not being on diabetes medications. We will also look at changes in the heart by performing detailed scans of the heart's structure and pumping function. In addition we will also measure fitness, physical function, the amount of fat and muscle and whether there is any change in mood or quality of life.

Who will we include?
Adults aged 18-40 who have had type 2 diabetes for between 3 months and 6 years and are classed as having more weight than is generally good for health. Participants should be on tablet (but not insulin) treatment for their diabetes.

What will we do with the results?
We will share our results with participants, the public and health care providers. If the study is successful, it will lead to another study to compare the diet plus exercise approach to diet alone. We will also look at how we could deliver the programme beyond a research study.

Background: Early onset type 2 diabetes (T2DM) is associated with an aggressive disease phenotype and a magnified lifetime risk of cardiovascular disease. Although diabetes remission can be achieved through low energy diets (LED) incorporating meal replacement products (MRP), our research suggests that such approaches do not lead to anticipated improvements in diastolic function or cardio-respiratory fitness, whilst lean mass is lost.
Aim: To establish a UK (Leicester)-Canada (Montreal, Edmonton) team of experts to investigate whether combining MRP with structured exercise leads to T2DM remission in younger adults over 24 weeks, whilst also improving diastolic function, cardiorespiratory fitness and supporting lean mass preservation.
Design: Prospective, randomized (2 arm) open-label, blinded-endpoint trial.
Participants: Obese individuals with T2DM (3 months-6 years), aged 18-40.
Control: Standard T2DM care.
MRP plus EX: LED with total and partial MRP (900kCal/day) for first 12 weeks followed by individualised food reintroduction (weeks 13-24); combined with supervised aerobic and resistance exercise (weeks 3-12), transitioning to home-based exercise (weeks 13-24).
Primary outcomes: Diabetes remission (A1c<6.5% without antihyperglycemic medication).
Key secondary outcomes: MRI-defined measures of cardiac function/structure including circumferential peak early diastolic strain rate (diastolic function); peak VO2; visceral/hepatic fat (MRI); body composition, blood pressure; objectively assessed sleep, sedentary time and physical activity; depression, anxiety and quality of life; process evaluations.
Sample size: With a conservative 45% remission rate in the intervention group and 5% remission rate in controls (power=90%, alpha=<0.05, 30% dropout), we will recruit 80 individuals (40 UK,40 Canada).
Importance: This work will establish whether diabetes remission is possible with early onset T2DM whilst also optimising whole body and cardiovascular health.

Burden - individual level

Young adults (18-40 years) with type 2 diabetes (T2DM) will directly benefit from this research. Years without T2DM translate into years without an increased risk of blindness, amputation, heart attack, stroke, heart failure, kidney disease requiring dialysis or transplant, liver failure and problems with physical function. The effects of low energy diets, which replace some or all daily meals with pre-packaged products, have been shown to reverse T2DM. However, we do not know if combining exercise with low energy diets leads to even greater improvements in young adults with T2DM. Just as a drastic reduction in energy intake causes weight loss and reverses T2DM, an increase in physical activity and muscle strengthening exercises have the potential to lead to a healthier, longer lasting form of T2DM reversal, with added benefits to the heart, the amount of muscle maintained with weight loss and physical functionality. This means better productivity, quality of life, and happiness. Being able to enhance T2DM reversal with improved heart and physical health is likely to be particularly important for young adults; with families, friends, and communities also set to benefit. Better quality of life of the people in our close and wider circle enhances our own. People under 40 years of age are often involved in key societal roles including building families, raising children, looking after aging parents, financially supporting themselves and their households, and driving the economies of their societies.

Burden - health care

Based on current projections, the costs for diabetes management is expected to increase by over 50% in the next 20 years. Therefore developing treatments that will reverse or minimise these costs is important in publically funded health care settings, such as the UK and Canada. Our grant will look at the cost-effectiveness of a combined diet and exercise approach to T2DM reversal in a group poised to contribute the most to the future burden of T2DM and its complications (young adults). We will capture all study and health care related costs to inform future economic analyses for which we will apply for additional funding.

Healthcare professionals and options for T2DM management

Doctors, dietitians, exercise specialists, and psychologists will benefit from the evidence generated. T2DM management currently focuses primarily on diagnosis and medication or surgery. We are looking at structured approaches that are delivered by experts in nutrition, physical activity, and behaviour change. If successful, the study has the potential to create opportunities for collaborations with health care organizations in future projects. This will allow us to explore how we could deliver the programme beyond a research study. The investigators on this trial will also work to ensure the results influence future guidelines on how to manage T2DM in younger adults. The diet and health industry is also set to benefit. This trial will inform industry about how well their product works as well as contributing to future product development. Fitness centres may also benefit if the approach used in this study is adopted more widely, as facilities are required for supervised exercise programmes.

Academic and research

The proposed study is anticipated to lead to a larger, longer-term effectiveness study, which will also include a cost effectiveness component. These in turn will lead to implementation initiatives and evaluation studies. The link with the NIHR Leicester BRC and NIHR Diet and Activity Research Translation (DART) Collaboration will also allow us to explore whether other dietary approaches can be used to support T2DM reversal. Our team will also explore other lifestyle-based strategies for T2DM prevention, reversal, and management, as the goal is to run not just a single research project but a comprehensive, long term programme of research.