Residual beta cell mass improves glycaemic control

There are large differences among individuals with type 1 diabetes in their level of glycaemic control, as reflected by glucose variability. An imaging study, reported in a recent issue of Diabetologia, finds that residual beta cell mass plays a role in glucose variability, independent of beta cell function.

It is well known that, despite advances in treatment and technology, only a minority of people with type 1 diabetes actually reach their treatment targets. This is often because optimised glucose control carries a risk of hypoglycaemia. Some people with type 1 do have an HbA1c at or even below target levels without significant hypoglycaemia. Others, however, experience repeated hypos and have poor glycaemic control, including high glucose variability (HGV). While behavioural and psychological factors such as fear and avoidance of hypoglycaemia may account for some of these differences, the underlying mechanisms remain unknown.

The loss of insulin production in type 1 diabetes is generally attributed to destruction of beta cells via autoimmune attack. However, some beta cells do survive – even in longstanding diabetes – and some of them, at least, continue to produce insulin. Evidence of this is seen by the presence of low but detectable C-peptide in people with type 1 diabetes.

It is now possible to detect, monitor and quantify beta cell mass in vivo,with imaging that uses radiolabelled extendin to bind to the glucagon-like peptide 1 (GLP-1) receptor on the beta cell.

Marti Boss at Radboud University Medical Center in the Netherlands and colleagues previously used single photon emission computed tomography (SPECT) imaging to reveal persistent beta cell mass in people with type 1 diabetes of long duration. The extent to which these residual cells might contribute to glucose stability remains unknown, however. So, to investigate further, these researchers used positron emission tomography (PET), which is more accurate than SPECT, with radiolabelled extendin to quantify beta cell mass in people with type 1 diabetes and either low or high glucose variability profiles.

Measuring beta cell mass

Participants in the low glucose variability (LGV) group had HbA1c ≤53 mmol/mol, intact hypoglycaemia awareness and no severe hypos in the last year and no more than two such events overall. Those in the HGV group had either HbA1c ≥69 mmol/mol and reduced hypoglycaemic awareness and/or at least two severe hypos in the last year or HbA1c ≥64 mmol/mol and impaired hypoglycaemic awareness and/or at least two severe hypos in the last year.

Beta cell function was calculated from glucose and C-peptide levels measured after a mixed meal tolerance test (MMTT).

In addition, participants wore continuous glucose monitors for seven to eight days after the MMTT and before the PET scan. Radiolabelled extendin was injected and PET images of the abdomen, including the pancreas, were taken and analysed for the amount of label taken up by the pancreas. This mean standardised uptake value (SUVmean) is known to allow a reliable comparison between individuals and patients with different characteristics – in this study, LGV and HGV – and so was used as a measure of residual beta cell mass. There were nine participants in the LGV group and seven in the HGV group.

Beta cell mass and glucose variability

C-peptide levels as a measure of beta cell function were detectable in around half of all participants. SUVmean (residual beta cell mass) was significantly higher in the LGV group compared with the HGV group. Analysis of the CGM data showed that those in the LGV group also had significantly higher Time in Range and lower mean glucose values than those in the HGV group.

The relationship between beta cell mass and beta cell function was somewhat complex, however. For one of the individuals with LGV had no detectable C-peptide and a similar SUVmean to the individual in this group with the highest C-peptide. And this SUVmean was higher than that of a third individual in the LGV group with no detectable C-peptide. In other words, a high SUVmean did not necessarily correlate with a high C-peptide.

Finally, SUVmean correlated with Time in Range and was inversely correlated with mean glucose levels. However, there was no correlation between SUVmean and BMI, diabetes duration, age at disease onset and blood glucose levels prior to imaging.

The benefits of residual beta cell mass

People with LGV have a higher beta cell mass than those with HGV, according to extendin PET imaging. The findings support the view that preservation of beta cell mass benefits glycaemic stability in people with type 1 diabetes, independent of beta cell function.

There is increasing evidence that some beta cells do survive, even in longstanding type 1 diabetes. In this new study, pancreatic uptake of radiolabelled extendin, consistent with the presence of beta cells, was shown in most of the participants. Their diabetes duration ranged from two to 50 years.

Residual beta cell function, as measured by C-peptide, may contribute towards better glycaemic stability. However, it is unlikely that this explains all the observed benefits of residual beta cell mass because some of the LGV participants, as mentioned above, had undetectable C-peptide – so they enjoyed lower glycaemic variability in the absence of beta cell function. Residual beta cells do not necessarily produce insulin, yet their influence on glycaemic variability suggests some functionality.

The authors suggest that these residual beta cells might be suppressing glucagon release from nearby alpha cells or may induce a lower state of inflammation in the pancreas, both of which would be expected to improve glucose control. These ideas could be tested by experiments measuring glucagon and C-reactive protein in people with type 1 diabetes with different glucose variabilities.

It would also be interesting to measure alpha cell mass in vivo when exploring the association with beta cell mass and glucose variability. Pancreas volume decreases in type 1 diabetes but data from donor pancreases shows that alpha cell mass remains the same. The development of imaging techniques that can measure alpha cell mass is currently ongoing.

In summary, beta cell mass is higher among people with type 1 diabetes and relatively stable glucose control compared with those whose glucose levels are more variable. These findings suggest that residual beta cell mass may play a role in maintaining glycaemic stability and highlights the importance of preserving beta cells, even if they appear to be non-functional. Surviving beta cells are of great interest for novel and future interventions that could restore or extend their functionality, thereby improving glycaemic control. Extendin PET imaging is a valuable tool for detecting beta cells and could be used in future studies monitoring beta cell mass during the course of diabetes or in interventions aimed at preserving beta cell mass.

To read this paper, go to: Jansen T, Brom M, Boss M, Buitinga M, Tack C, van Meijel L, Galan, B, Gotthardt M. Importance of beta cell mass for glycaemic control in people with type 1 diabetes. Diabetologia 17 November 2022. https://link.springer.com/article/10.1007/s00125-022-05830-2

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.