Diet and exercise

Abstract

Biomedical research and clinical studies provide evidence that a healthy diet and lifestyle along with psychological support could be more efficient in treating and managing metabolic disorders than medication.

Metabolic diseases—a range of conditions associated with abnormal metabolism, notably type‐2 diabetes (T2DB), obesity and irritable bowel disease (IBD)—extract a large societal and economic toll. T2DB is relatively straightforward to diagnose, which has enabled its global prevalence and impact to be accurately quantified: the WHO first Global Report on Diabetes estimates that 422 million adults lived with the condition in 2014, compared to 108 million in 1980 (https://www.who.int/diabetes/global-report/en/). The associated death rate has also been rising to 1.5 million worldwide in 2012 along with an additional 2.2 million from cardiovascular and other diseases caused indirectly by high blood glucose. The report noted that 43% of these 3.7 million deaths occur in people younger than 70, and that during the past decade, the prevalence of T2DB has risen more quickly in low‐ and middle‐income countries as their lifestyles converge with those of more developed nations.

The economic burden of obesity is greater still, already passing the US$2 trillion per year mark in 2014, thus matching the cost of both smoking and armed conflicts.

The pattern is very similar for obesity, which often coexists with or precedes T2DB. The global prevalence nearly doubled from 5% of men and 8% of women in 1980 to 10% of men and 14% of women in 2008, the latest year for which worldwide data exists, according to the World Health Organization (WHO). As with T2DB, obesity is now rising fastest in developing countries where 25% of children under the age of 5 are overweight. This is almost certainly attributable to rising affluence and urbanization, leading to more consumption of processed food and in turn higher intakes of salt, fat and sugar.

Irritable bowel disease is harder to quantify, because there is no firm medical definition and significant variations in reported levels between countries reflect differences in diagnosis. As a result, incidences are usually presented as a range rather than a precise figure. Even so, the pattern is clearly similar to T2DB. The most comprehensive global metanalysis estimates that IBD affects 7–18% of the worldwide population 1. This comprises primarily sufferers from the two main diseases defined within the IBD spectrum: Crohn's disease and ulcerative colitis. The two often exhibit similar symptoms and are both associated with inflammation, but differ in where that inflammation occurs. While Crohn's disease can affect the entire gastrointestinal tract from mouth to anus, ulcerative colitis is restricted to the colon.

A massive economic toll drives public health programs

The associated economic toll of Crohn's disease in the USA alone is US$15.5 billion annually, while ulcerative colitis causes almost US$14.9 billion 2; around a third of these costs are indirect consequences such as missed work. As with other conditions, a small percentage of patients contribute disproportionately to overall healthcare expenditure through repeated admissions and surgery for refractory inflammation, complications, chronic pain or psychosomatic issues.

However, the cost of IBD is dwarfed by that of T2DB, which the American Diabetes Association has predicted will rise globally from US$1.3 trillion per year in 2015 to US$2.2 trillion by 2030 3. This equates to an increased proportion of global GDP from 1.8% in 2015 to 2.2% by 2030. The economic burden of obesity is greater still, already passing the US$2 trillion per year mark in 2014, thus matching the cost of both smoking and armed conflicts (http://www.mckinsey.com/industries/healthcare-systems-and-services/our-insights/how-the-world-could-better-fight-obesity). Societal costs, including early retirement, efficiency at work and diminished prospects of promotion, were estimated to account for 60%, but that still leaves a huge burden on increasingly overstretched national health agencies.

… even surgery achieves only sustained improvement when coupled with significant lifestyle changes.

Given the economic burden, it is hardly surprising that many developed countries have had plans and programmes for combating these metabolic‐related disorders for some years. There has also been direction at a global level from the WHO's executive body, the World Health Assembly, which in 2004 published the “WHO Global Strategy on Diet, Physical Activity and Health”, including prescriptions for healthy diets and regular physical activity. WHO followed up with its “Global Action Plan for the Prevention and Control of Noncommunicable Diseases 2013–2020”, with the target of reducing premature mortality from Noncommunicable Diseases by 2025 and halting the rise of obesity.

This has been backed up by national efforts such as the US Lifestyle Change Program from the CDC, comprising an approved curriculum with lessons, handouts and other resources to help people make healthy lifestyle changes. It includes provision of coaches and distance learning to support people in remote areas and encourage compliance with dietary and exercise regimes. The UK's NHS Diabetes Prevention Programme also focuses on new digital technologies, including wearable devices that monitor exercise, and apps to access health coaches and online peer support groups, along with the ability to set and monitor goals electronically. The obvious conclusion is that such measures are not working given that metabolic diseases are still on the rise, although there may be tentative signals of progress. Furthermore, the CDC and UK NHS contend it is too early to judge the effectiveness of their programmes.

The bottom line is that for these programmes to be effective, they must have rigorous molecular and psychological foundations.

The bottom line is that for these programmes to be effective, they must have rigorous molecular and psychological foundations. Otherwise, patients will tend to drift back towards old habits after some initial success. It was fatuous to set arbitrary targets for reduction in incidence or premature death, while merely issuing vague advice over diet and exercise in particular. At the same time, pharmacological interventions just alleviate symptoms rather than provide sustained remission, never mind a cure.

Ironically, the one therapy that has proved successful for obesity is surgery, which costs around US$10,000 per patient, despite the improvements that came along with laparoscopic techniques introduced in the 1990s. Various options are available, principally biliopancreatic diversion, gastric bypass, sleeve gastrectomy and gastric banding, which all reduce the effective stomach size. But even surgery achieves only sustained improvement when coupled with significant lifestyle changes. The costs along with the risks and side effects associated with surgery are therefore driving the search for non‐invasive methods. “Currently the most effective therapy for weight loss and remission of diabetes is metabolic surgery, but this is an invasive procedure with surgical and non‐surgical risks and hopefully it will become an unnecessary intervention as we develop more success with lifestyle and medical interventions”, said Gary Lewis, Director of the Banting and Best Diabetes Centre at the University of Toronto in Canada.

The impact of weight loss

At least there is mounting evidence that weight loss not only alleviates obesity but also provides relief from just about all other metabolic disorders. The UK Diabetes Remission Clinical Trial (DiRECT) followed people with early‐stage T2DB of whom 64 patients were given a low‐calorie diet and compared to a control group of 26 patients. The result was that for nearly half of those in the intervention group, T2DB can be reduced to long‐term glucose control based largely on diet 4. One key point was that remission of diabetes only occurred if there was a concomitant decrease in liver and pancreatic fat content. Indeed, T2DB remission requires recovery of beta cell function in the pancreas for making insulin; chronic exposure of beta cells to triglyceride or fatty acids decreases their ability to secrete insulin.

The underlying message is that establishing weight loss for patients with T2DB should be given the highest priority, commented Roy Taylor, Professor of Medicine and Metabolism at Newcastle University in the UK and lead author on the DiRECT report. “We demonstrated that substantial weight loss in T2DB normalised liver and pancreas fat in all participants, but the majority who returned to non‐diabetic control exhibited beta cell capacity to return to near normal function”, said Taylor. “This ties in with the work of others on beta cell de‐differentiation explaining T2DB and re‐differentiation once the metabolic stress is removed, explaining reversal to normal”. The urgency then lies in shedding weight before that beta cell capacity to return to near normal function has been lost.

… there is mounting evidence that weight loss not only alleviates obesity but also provides relief from just about all other metabolic disorders.

A key reason for the relative success of DiRECT compared with previous intervention programmes for T2DB was that it adopted evidence‐based measures for weight loss, according to Falko Sniehotta from Newcastle University, who was responsible for the psychological aspects of the project. “Over time, many people accumulate failed attempts while getting heavier and in this case, develop diabetes. There is a lot of frustration about this. Being able to ‘take control’ is a key motivator”, he explained. “So we developed DiRECT based on evidence about what works for weight loss and weight loss maintenance. This includes careful consideration of how the intervention can be faithfully delivered in a primary care setting across two nations, sufficient training of healthcare professionals and sufficient intensity in terms of follow‐up, as well as evidence‐based behaviour change techniques utilized”.

The weight loss diet comprised soups, shakes and fluids, amounting to 800 calories a day for between 8 and 20 weeks. Thereafter, a normal diet was gradually reintroduced with support from the team to maintain weight. “Participants were supported after food reintroduction with sufficient intensity and in line with the theory of maintenance established in a targeted BMJ (British Medical Journal) review”, Sniehotta said. This review concluded that behavioural interventions that deal with both diet and physical activity show small but significant benefits for weight loss maintenance 5.

But it is also highlighted individual differences that require personalized interventions. Indeed, as Taylor noted, people susceptible to T2DB are particularly prone to exercise‐induced compensatory eating, which went some way to explaining disappointing results from an earlier US study called Look Ahead sponsored by the NIH to test whether an Intensive Lifestyle Intervention for overweight or obese T2DB patients would lead to cardiovascular benefits compared with established Diabetes Support and Education. This was conducted on 5,145 persons in 16 centres around the USA with follow‐up over about a 10‐year period. The trial was ended in 2014 after concluding there had been no cardiovascular benefits at all 6. However, the designers of the DiRECT study were not deterred as the NIH trial placed too much faith in the ability of exercise to help prevent patients gaining weight again. “Of course, increased activity is promoted to help maintain weight loss in the long‐term maintenance phase”, Taylor explained. “Certainly, some individuals can lose weight with sufficient exercise, but very few in the middle aged/elderly population with T2DB. If an individual can do it—fantastic. But so few can”.

Another aspect of DiRECT was that it involved giving up oral medications to avoid interfering with the impact of lifestyle change. One unexpected benefit was that this motivated participants to persevere with their lifestyle, instead of resuming their medication. Such oral drugs might include metformin under various names, which reduces glucose production in the liver and improves sensitivity to insulin. Although it was introduced in 1922, its action is still poorly understood, but it certainly activates the enzyme AMP‐activated protein kinase to inhibit liver glucose production. AMPK plays a major role in insulin signalling and whole‐body energy balance, as well as metabolism of glucose and fats. The most recently introduced drug class for T2DB are the SGLT2 inhibitors, which block glucose reabsorption by the kidneys and facilitate its excretion. SGLT2 (sodium‐glucose co‐transporter‐2) is a passive transporter of glucose that plays a key role in its reabsorption in the kidney's proximal convoluted tubule. Inhibiting this transporter has been shown effective in reducing blood glucose levels 7.

Notwithstanding the reluctance of some people with T2DB to take medications, there has been recent progress combining these with lifestyle interventions to either enhance efficacy or achieve more rapid remission. Indeed, SGLT2 inhibitors are designed to operate more effectively in conjunction with diet and exercise.

Lewis cited SGLT2 inhibitors as a significant advance along with the GLP1 (glucagon‐like peptide‐1) receptor agonists. These have the advantage of acting directly on GLP1R, a receptor protein on the beta cells of the pancreas, but concerns over side effects will have to be allayed before it gains widespread approval. Some other therapeutic agents currently under development appear to be even more effective, Lewis commented, but again both long‐term safety and efficacy remain to be proven.

Dietary changes for treating IBD

In the case of IBD, similar advances have been made on the dietary front but with less emphasis on exercise. There are few if any drugs that appear capable of reversing the underlying disease, leaving anti‐inflammatories to alleviate symptoms. These include corticosteroids and aminosalicylates, the choice of which depending primarily on which area of the colon is affected. There has also been some success using immunomodulators to dampen the immune system. One multi‐centre study showed that their use delayed or avoided need for surgery in a number of people with Crohn's disease 8, but as the authors noted, it is not an ideal therapy because it increases vulnerability to infection.

If there is one point underlying lifestyle treatments for these chronic conditions with a metabolic component, it is the motivational psychological aspects…

Meanwhile, there has been growing focus on a semi‐vegetarian diet in treating IBD, with the first evidence of significant efficacy in 2010 9. That small study selected 22 patients with Crohn's disease who had already achieved remission but were deemed at high risk of relapse, which is a common occurrence for more severe cases. Sixteen were given a semi‐vegetarian diet (SVD), comprising a mixture of rice, fermented bean paste (miso) soup, vegetables and fruits. There was also some animal‐based food, including yoghurt and eggs. Fish was served weekly and meat fortnightly, both at half the usual amounts. The other six people were given a standard omnivorous diet. Remission was maintained for 2 years in 15 of 16 patients in the SVD group and two out of six in the control group. Since that 2010 paper, the Japanese team at Akita City Hospital have conducted follow‐up studies. “I now provide plant‐based diet (PBD) to all inpatients with IBD”, said Mitsuro Chiba, a lead author and Chief of the Inflammatory Bowel Disease Section at Akita City Hospital.

The team will shortly publish results of treating IBD with PBD in conjunction with infliximab, a monoclonal antibody against the cytokine tumour necrosis factor alpha (TNF‐α) that is used to treat autoimmune diseases as well as IBD. The key point is that SVD has been shown to induce remission in some patients who fail to respond to respond to drugs such as infliximab 10. Furthermore, the team has recently extended the application of SVD to sufferers from ulcerative colitis, again with some promise. Their trial showed that relapse rates after what they called “educational hospitalization with a PBD” were far lower than for those given medication. The role of educational hospitalization was to help induce and then sustain the dietary changes.

Apart from efficacy, Chiba claimed there was already evidence for potential cost savings through eliminating or at least reducing the use of medications. SVD is most effective when combined with other lifestyle changes, including giving up smoking where relevant and reducing alcohol intake to at least moderate levels. He added though that the success of lifestyle medicine against IBD has been greater than they expected and argued that evidence was now so compelling that the dietary guidance should be covered by health insurance.

If there is one point underlying lifestyle treatments for these chronic conditions with a metabolic component, it is the motivational psychological aspects, according to Volkan Demirhan from the Division of Endocrinology, Metabolism and Diabetes at Istanbul University in Turkey, who helped develop European guidelines for treating obesity. “The patients play a unique central role in obesity management”, he commented, arguing that this needs to be at the forefront of programmes for establishing critical weight loss as soon as possible and maintaining it. He pointed to the growing role of remote management and online support in helping patients keep going through hard times when it may seem they are making great sacrifices without gaining corresponding benefits. While firm evidence for the efficacy of such support programmes has yet to be obtained, it is obvious that interaction with others helps to sustain motivation.

EMBO Reports (2019) 20: e47966