The effect of age on beta cell function
The risk of progression to clinical diabetes after initial decline in beta cell function depends on age, according to a paper in a recent issue of Diabetologia. The researchers have mapped the trajectory of beta cell decline over time in autoantibody positive individuals aged from 3 to 45. Their findings will help optimise the timing of interventions to delay progression to type 1 diabetes. Dr Susan Aldridge reports.
Type 1 diabetes involves immune-mediated destruction of pancreatic beta cells and the condition progresses through two stages before clinical diagnosis. Stage 1 is marked by the presence of two or more islet antibodies – signifying the start of the immune attack – but normal glucose tolerance remains. In stage 2, there are multiple islet antibodies and dysglycaemia is present. Stage 3 is clinical diabetes with hyperglycaemia that exceeds the diagnostic threshold.
According to birth cohort data, 70% of those with multiple autoantibodies will go on to develop diabetes within 10 years and 85% will develop it within 15 years, but the timing of this progression can vary widely between individuals. The age at which autoantibodies are first detected is an important factor influencing this heterogeneity. It is widely accepted that age is inversely related to the risk of developing diabetes among autoantibody-positive individuals. Some studies support this by suggesting that loss of C-peptide is more rapid among younger individuals, following the onset of stage 3 type 1 diabetes. Measurable C-peptide and histological evidence of residual insulin-containing islets in diabetes of long duration is also less likely to be observed among those with younger onset.
These findings suggest there may be differences in metabolic patterns, according to age of onset, around or after diagnosis. However, it is not known whether age affects patterns of beta cell decline during the earlier stages of type 1 diabetes.
Understanding whether there are differences in metabolic patterns of progression to diabetes among people with autoantibodies across a range of ages has implications for the timing of interventions intended to slow the immune attack. This is particularly relevant as the anti-CD3 monoclonal antibody, teplizumab, has recently been approved by the US Food and Drug Administration (FDA). Clinical trial data suggest that teplizumab can delay the onset of clinical diabetes by around two years. This period might be extended if the timing of administration of this preventive treatment were optimised.
Accordingly, Ele Ferannini of the Consiglio Nazionale delle Ricerche (CNR) Institute of Clinical Physiology, Pisa, Carmella Evans-Molina of Indiana University School of Medicine and their colleagues have analysed data from longitudinal oral glucose tolerance tests (OGTTs) carried out on participants of varying ages in the Diabetes Prevention Trial – Type 1 (DPT-1) to track changes in beta cell function and insulin sensitivity.
Mining the DPT-1 trial
The DPT-1 trial recruited individuals who had multiple autoantibodies to test the efficacy of either parenteral or oral insulin in delaying progression to stage 3 diabetes. While neither intervention had any impact in this respect, the DPT-1 dataset is a rich resource for understanding the natural history of type 1 diabetes. In the current study, this data was used to look at the impact of age of the participants on the metabolic patterns of progression through beta cell decline before the onset of clinical diabetes.
The DPT-1 study screened 103,391 individuals aged between 3 and 45 years who had either a first- or second-degree relative with type 1 diabetes. Of this initial group, 3483 were islet antibody positive and went on to undergo metabolic, genetic and immunological staging to determine their five-year risk of diabetes. The metabolic part of this staging included C-peptide and plasma glucose measurement, and regular OGTT testing. The researchers based this study data on 658 of these antibody-positive participants.
Mapping beta cell function decline
Beta cell function variables and insulin sensitivity were obtained from OGTT data using a model that describes the relationship between insulin secretion and glucose concentration. Among the 658 participants, 227 (34.4%) went on to develop clinical diabetes at a median time of 2.23 years, while non-progressors were still free of the condition at a median follow-up of 3.41 years.
Risk of progression was inversely related to age, as has been found in other studies. Scanning data for the entire age range of the cohort revealed 14 years to be a significant age. Those aged <14 years were twice as likely to progress to diabetes than those aged ≥14 years.
However, age did not affect the rate of decline in beta cell function or insulin sensitivity among those who progressed to clinical diabetes. This means that although younger individuals are more at risk of progression than those who are older, evolution towards diabetes follows a similar trajectory regardless of age. This pathway takes a relatively stable time course until an inflection point – occurring earlier in younger individuals – beyond which there is a more rapid decline.
These findings could have important implications for the implementation of disease-modifying therapy in early-stage type 1 diabetes. Other research has focused upon individuals who seem to have a more robust response to teplizumab and oral insulin in trials intended to delay progression to type 1 diabetes. These insights, together with the new findings on the impact of age on decline of beta cell function, can be applied to help select those individuals who are most likely to respond to teplizumab and the new immune therapies that are sure to follow.
To read this paper, go to: Ferrannini E, Mari A, Monaco G, Sklyer J, Evans-Molina C. The effect of age on longitudinal measures of beta cell function and insulin sensitivity during the progression of early stage type 1 diabetes. Diabetologia (2023) 66:508–519. https://link.springer.com/article/10.1007/s00125-022-05836-w
Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.