Early Beta Cell Function Recovery May Underpin T2D Remission

Liam Davenport

August 02, 2018

Type 2 diabetes (T2D) patients who achieve remission following weight loss recover their pancreatic beta cell function early on and maintain it over time, a planned analysis of UK trial data reveals in findings that could lead to changes in diabetes management.

The results follow that of a landmark study in which an intensive primary care-led weight management programme achieve remission in 46% of 306 T2D patients versus standard care.

Now, the researchers have found that patients who achieved remission had a significant improvement in first-phase insulin response, which is a brief spike in insulin levels that is typically lost in diabetes patients.

Responders also had greater reductions in liver fat content and liver production of triglycerides, although both responders and non-responders had similar overall weight loss and loss of pancreatic fat.

Rescuing Beta Cells

The research, which was published online by the Cell on 2 August, was led by Prof Roy Taylor, Director of the Newcastle Magnetic Resonance Centre at Newcastle University.

In a press release, he said that the results have "potentially important implications for the initial clinical approach to management".

He added: "At present, the early management of type 2 diabetes tends to involve a period of adjusting to the diagnosis plus pharmacotherapy with lifestyle changes, which in practice are modest."

"Our data suggest that substantial weight loss at the time of diagnosis is appropriate to rescue the beta cells."

These findings, Taylor suggested, "will lead to further targeted work to improve understanding of the process [and] provides a major focus for cell biologists to make specific advances".

Speaking to Medscape News UK, he explained that, for a long time, it was believed that insulin-producing cells steadily died in T2D, "and that underlay the steadily downhill progress".

"But recently it's been shown that there's actually switching off of the insulin-producing genes and when you take away the metabolic stress, they can notionally be switched back on again," he says.

For some patients, that process "can gallop a little faster, and so some people don't manage to get back to normal, whereas other people can get back to normal once the stress has been removed".

DiRECT Research

The original Diabetes Remission Clinical Trial (DiRECT) involved 306 patients aged 20–65 years diagnosed with T2D within the previous 6 years and with a body mass index of 27–45 kg/m2 from 49 general practices in Scotland and northern England.

Patients from 23 practices were assigned to an intervention in which antidiabetic and antihypertensive drugs were withdrawn and their diet was replaced with a 825–853 kcal/day formula diet for 3–5 months.

This was followed by stepped food reintroduction over 2–8 weeks with structured support. Patients from the remaining 26 practices served as controls.

At 12 months, 24% of patients in the intervention group lost ≥15 kg of weight versus none in the control group (p<0.0001).

Diabetes remission was achieved by 46% of intervention patients, compared with 4% of control participants, at an odds ratio of 19.7 (p<0.0001).

New Analysis

For the current analysis, the team performed detailed metabolic studies on 64 patients from the intervention group and 26 from the control group, focusing on liver fat content, liver export of triglyceride, pancreatic fat content, and beta cell function.

At baseline, there were no significant differences between responders, defined as patients who returned to non-diabetic glucose control after weight loss, and non-responders in terms of age, weight, sex and any of the parameters being studied.

However, responders had a shorter duration of diabetes than non-responders, at 2.7 versus 3.8 years (p=0.02), and had higher fasting plasma insulin levels, at 108.3 pmol/l versus 77.2 pmol/l (p=0.02), and plasma alanine aminotransferase levels, at 34.1 pmol/l versus 26.3 pmol/l (p<0.005).

During the weight loss phase, there was no significant difference in the degree of weight loss between responders and non-responders, at 16.2 kg versus 13.4 kg (p=0.14).

Over the 12 months of the study, responders nevertheless had a greater change in weight than non-responders, at -14.1 kg versus -9.4 kg (p=0.02).

At 12 months, responders also had lower liver fat content than non-responders, at 3.0% versus 6.1% (p=0.04), and lower production of triglyceride in the liver, at 437.5 mg/kg/day versus 649.6 mg/kg/day.

While both responders and non-responders had a significant reduction of in pancreatic fat content during the weight loss phase, there were no significant differences between the groups, and fat content remained stable during follow-up.

Notably however, first-phase insulin secretion increased in responders following weight loss, from 0.04 nmol/min/m2 to 0.11 nmol/min/m2 (p<0.0001), while there was no change in non-responders, a difference that was maintained during follow-up.

Responders also experienced a gradual increase in maximal insulin secretion following weight loss that reached significance by 12 months (p<0.04 versus baseline), an effect that was not seen in non-responders.

The team concludes that "weight loss in early type 2 diabetes brings about similar correction of intra-organ fat content in all, but the defect in those who do not return to non-diabetic glucose control appears intrinsic to the beta cell".

They note, however, that 98% of the participants were white and therefore "comparable studies in other ethnic groups are required".

Substantial Weight Loss Needed

Examining the implications of the findings, Taylor emphasised that, while weight loss clearly the goal, he "would personally avoid the term 'lifestyle'" when discussing what changes are need to achieve that weight loss.

He said that the term "implies something 'fuzzy' that is difficult to change", adding: "What we're talking about here is substantial weight loss, and so I think it's helpful to be absolutely emphatic that it's weight loss."

"It's not going for a walk in the morning. It's not putting on Lycra and going for a jog. That may contribute, but it may make things worse, and it takes away from the simplicity that we've been able to identify."

Taylor continued: "This isn't a disease of lifestyle, something mysterious. This is a disease of being fatter than your body can cope with, so it's a very individual matter."

He therefore believes that the typical approach to weight loss via lifestyle changes is "too nebulous", and that trying lose a little weight over long period of time is "simply unfeasible".

He added: "Weight loss clinics up and down the land are achieving average weight losses that aren't much different from zero because the basic understanding isn't right."

Pointing out that half of all people in the UK with T2D are not obese, he said that "we need to approach this matter with absolute clarity of thought and not adopt fuzzy thinking".

He concluded: "It's very important for all to realise that the actual cause of type 2 diabetes can now be defined and, having defined it, we can do something about it because, at last, we have a practical way of doing that."

The study was funded by a grant from Diabetes UK. The formula diet was donated by Cambridge Weight Plan.

Naveed Sattar reports grants and personal fees from Boeringer Ingelheim; personal fees from Janssen, Eli Lilly, and NovoNordisk; and grants unrelated to the present work from AstraZenica. Michael Lean reports personal fees from Counterweight and Cambridge Weight Plan not related to the present work. All other authors declare no competing interests.

Cell Metabolism 2018; 28, 1–10.  doi: 10.1016/j.cmet.2018.07.003


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