Twin cycle theory and beta cell function

Knowledge and understanding of the onset of type 2 diabetes has progressed over the past two decades. Beta cells in the pancreas are responsible for the production and secretion of insulin, which is essential for the regulation of glucose levels in the blood (Marchetti et al 2017). Previously it was believed that beta cell death or dysfunction led to the onset of type 2 diabetes, but the ‘twin cycle’ theory has enhanced understanding of this process (Taylor 2008). Research had shown that bariatric surgery (weight loss surgery) could reverse the metabolic abnormalities associated with type 2 diabetes in obese patients within weeks (Gumbs et al 2005); however, the mechanisms by which the weight loss following this surgery affected beta cell function were not understood. The twin cycle theory suggests that long-term consumption of surplus calories results in accumulation of fat in the liver which induces insulin resistance and hyperinsulinaemia (excess levels of insulin in the blood), leading to a cycle in which insulin stimulates fat production that results in the accumulation of fat in the pancreas, causing type 2 diabetes (Taylor 2013).

Evidence to support the twin cycle theory was identified in the Counterpoint study (Lim et al 2011), in which the researchers tested the hypothesis that beta cell failure and insulin resistance could be reversed by dietary restriction of energy intake. Participants in the Counterpoint study were given a very-low-calorie diet for eight weeks. Over this period their mean weight loss was 15kg – similar to that achieved over the same period by patients who had undergone bariatric surgery – their liver fat levels dropped considerably and their insulin sensitivity improved (Lim et al 2011). The study also showed that people could tolerate a very-low-calorie diet for a short period of time (Steven et al 2016).

Research has suggested that beta cells can dedifferentiate – that is, changes in the gene-expression alter the structural and functional elements of the cell – following exposure to excess fat, resulting in an inability to secrete insulin. However, once an individual achieves normal fat levels there is potential for beta cell recovery (Cinti et al 2016). Other studies have shown that beta cell function in people who have achieved remission of type 2 diabetes appears to remain stable if weight loss is sustained; however, if an individual returns to their previous weight it is likely that type 2 diabetes will return due to dedifferentiation of the cells (Taylor and Barnes 2019). Therefore, it is crucial that people who achieve remission of type 2 diabetes continue to have their risk factors monitored and should be supported to avoid long-term weight gain (Nagi et al 2019).

While not everyone with type 2 diabetes is obese, each individual has a ‘personal fat threshold’ which, if exceeded, makes development of the condition more likely and explains why some people with a healthy body mass index (BMI) develop type 2 diabetes (Taylor and Holman 2015).

Weight loss and remission of type 2 diabetes

Following the Counterpoint study, public interest in the potential for remission of type 2 diabetes using a very-low-calorie diet to support weight loss prompted Steven et al (2013) to post general information about reversing diabetes on a website. The researchers collated self-reported data from a group of 77 people with type 2 diabetes who had followed the advice on the website, using either liquid meal replacements or restricted calorie intake. The group’s self-reported weight loss and fasting blood glucose levels showed that 61% attained remission, defined as achieving fasting capillary blood glucose <6.1mmol/L and/or HbA1_c <43mmol/mol (Steven et al 2013). This informal study suggested that remission should be a goal in the management of type 2 diabetes. However, because the participants were highly motivated individuals there is potential for bias, so further research was required to support the results.

Lean et al (2018) conducted the Diabetes Remission Clinical Trial (DiRECT), a randomised controlled trial in primary care which aimed to evaluate the effectiveness of a low-calorie diet with structured follow up compared with conventional best practice management for people with type 2 diabetes. Participants had had a diagnosis of type 2 diabetes for less than six years. The intervention included:

The average weight loss after 12 months in the intervention group (n=149) was 10kg compared with 1kg in the control group (n=149), with 46% (n=68) of the intervention group achieving remission of type 2 diabetes at 12 months (Lean et al 2018). After 24 months, 36% (n=53) of participants in the intervention group remained in remission (Lean et al 2019). The study confirmed that beta cell function was normalised in people who maintained their weight loss.

The pancreas in people with type 2 diabetes is smaller than in those without the condition and is an irregular shape (Macauley et al 2015). Some of the researchers from the DiRECT trial team used a subset of participants from the original study to examine the effect of remission on the pancreas by comparing groups of people with and without type 2 diabetes (Al-Mrabeh et al 2020). At baseline, the pancreas in those with type 2 diabetes was significantly smaller than the pancreas of those without the condition and had irregular borders. Two years after the initial DiRECT trial, the size and shape of the pancreas in participants who had progressed to remission had normalised (Al-Mrabeh et al 2020).

The DiRECT trial showed that weight loss was the best predictor of remission, with 36% of participants who had achieved a weight loss of 10-15kg still in remission after two years (Thom et al 2021). Following weight loss, the next best predictor was number of prescribed diabetes medicines at baseline, with those taking fewer medicines more likely to progress to remission. People who experienced symptoms of anxiety or depression were less likely to achieve remission. Baseline BMI, fasting insulin levels and duration of type 2 diabetes did not predict remission (Thom et al 2021).

Diet programmes

While the evidence suggests that weight loss is the best predictor of remission of type 2 diabetes (Thom et al 2021), there is uncertainty about the most effective weight reduction programmes. An umbrella review of meta-analyses and systematic reviews of dietary approaches for weight loss and remission in people with type 2 diabetes found the highest remission rates were related to total diet replacement programmes (Churuangsuk et al 2022). The review concluded that no one macronutrient profile or style could be considered more effective than others, although the research examined was not always comparable. For example, low carbohydrate diets were not found to be more effective than high protein diets, Mediterranean diets or low glycaemic diets. Total diet replacement programmes were found to be cost-effective and participants on these programmes achieved the greatest weight loss, had reduced need for diabetes medicines and developed fewer diabetes-associated complications (Churuangsuk et al 2022).

The safety and effectiveness of a total diet replacement programme for obese patients was investigated in a randomised controlled trial conducted in primary care – the Doctor Referral of Overweight People to Low Energy total diet replacement Treatment (DROPLET) trial (Astbury et al 2018). The trial evaluated the merits of implementing a total diet replacement programme with weekly support from a practice nurse compared with a ‘usual care’ diet programme with reduced calorie intake. The results showed that the total diet replacement programme supported participants to achieve significant weight loss over a 12-week period and was well tolerated (Astbury et al 2018). Although it was not documented whether or not the participants had type 2 diabetes, the study supports the effectiveness of using a total diet replacement programme in a primary care setting.

Other types of weight loss interventions have been shown to be successful. For example, a population-based cohort study assessed the five-year outcomes for patients (n=867) aged between 40 years and 69 years who were newly diagnosed with type 2 diabetes (Dambha-Miller et al 2020). Participants were randomised into an intervention group (multifactorial treatment) or control group (routine care). Those in the intervention group received intensive support to achieve behaviour changes, including more frequent consultations and education, but were not specifically encouraged to follow a total diet replacement programme. Diabetes remission was achieved in 30% (n=257) of participants in the intervention group after five years (Dambha-Miller et al 2020). The study showed that weight loss of >10% of a person’s body weight soon after diagnosis was effective in achieving remission of type 2 diabetes and that this could be accomplished without severe calorie restriction. The study also showed that for each kilogram of weight lost there was an associated 7% higher chance of remission (Dambha-Miller et al 2020).

Unwin et al (2020) undertook a service evaluation in a GP surgery in England where patients with prediabetes (n=71) and patients with existing or newly diagnosed type 2 diabetes (n=128) were advised and supported to follow a low carbohydrate diet of 50-130g per day. They identified positive long-term results with significant reduction in weight, HbA1_c levels and cardiovascular risk factors. Of the patients with prediabetes, 93% returned to a non-diabetic threshold within 23 months, while 46% of those with existing type 2 diabetes were considered to have achieved remission after 23 months. Although this was not a randomised controlled trial, the findings illustrate the positive effects that motivated healthcare professionals can have on patients in a community clinical setting and the effectiveness of supporting patients to adhere to a low carbohydrate diet (Unwin et al 2020).

Taylor et al (2021) acknowledged that no single diet programme or intervention is suitable for all patients and that it is possible to achieve remission of type 2 diabetes using a variety of dietary interventions. The evidence discussed previously suggests that remission of type 2 diabetes is dependent on the amount of weight lost by patients – ideally >10% of their body weight – and the maintenance of this weight loss.

Role of the nurse in supporting patients to achieve remission

Evidence suggests that remission should be a primary goal in the management of patients with type 2 diabetes (Steven et al 2013). Nurses have an important role in providing people with evidence-based information about the amount of weight loss required to achieve remission and in motivating people to make behaviour changes (Steven et al 2013). For some people, achieving any amount of weight loss can be challenging, but promoting this is essential because even a 5% weight loss can have a significant positive effect on the reduction of HbA1_c, cholesterol and blood pressure levels and insulin sensitivity (Ryan and Yockey 2017).

Patients may approach nurses and other healthcare professionals for advice on what changes they should make to their diet. There has been much debate about low carbohydrate diets compared with low fat diets and various intermittent fasting diets (Pagoto and Appelhans 2013). Following a review of dietary approaches, Diabetes UK (2018) developed evidence-based nutrition guidelines for the prevention and management of diabetes. These guidelines recommend that overweight and obese people with type 2 diabetes should aim for a weight loss of 15kg as soon as possible following diagnosis to achieve remission and weight loss of at least 5% to improve glycaemic control and reduce the risk of diabetes-associated complications. This should be achieved through an individualised, person-centred plan that takes into account an individual’s lifestyle and cultural factors and incorporates joint decision-making. Further, the guidelines identify that no single approach to weight loss is significantly superior to others, but recommend that people reduce their energy intake and total and saturated fat intake while increasing their fibre intake and physical activity levels. The consumption of red and processed meat and refined carbohydrates are discouraged (Diabetes UK 2018).

Primary care nurses have an important role in supporting the NHS Low Calorie Diet Programme – also known as the ‘soups and shakes’ diet programme – which has been launched in several areas across England (NHS England 2022b). People who are eligible are offered total diet replacement products of 900 calories per day for up to 12 weeks and supported either on a one-to-one basis, in groups or virtually via an online platform. Early pilot data has shown an average weight loss of 13.4kg after three months (Diabetes UK 2022). Eligibility criteria include having a BMI of ≥27; however, further research is underway to investigate the effect of weight loss in people with a BMI of <27 and early results are encouraging (Diabetes UK 2021).

Achieving significant weight loss will have many health benefits, but it is vital that weight loss and lifestyle changes are maintained and supported by regular physical activity (Wing and Phelan 2005). Where possible, nurses should attempt to engage with patients about these subjects, making use of all opportunities to provide information and promote behaviour changes that will have a positive effect on their health and well-being (Health Education England 2022).

Regaining weight soon after the initial loss is a common occurrence among all patient populations, not just in those with type 2 diabetes. Participants in the DiRECT study who gained 2-4kg were offered a ‘rescue plan’ involving either partial or total meal replacement to assist with reducing their weight (Lean et al 2019). This demonstrates the need for long-term commitment from patients and nurses to sustain lifestyle changes and resultant weight loss.

Conclusion

Evidence shows that it is possible to achieve remission of type 2 diabetes, particularly in people who are newly diagnosed or who have had the condition for less than ten years. This has significant implications for reducing the risk of microvascular and macrovascular complications associated with type 2 diabetes. Nurses have a central role in ensuring patients are aware of the research on remission of type 2 diabetes and in supporting them to achieve weight loss to improve their health outcomes. This support needs to be sustained to reduce the likelihood of patients regaining weight and subsequently developing type 2 diabetes.