In this cross-sectional cohort of 443 individuals with type 1 diabetes, we assessed the association of FE levels with type 1 diabetes parameters and clinical features. In addition to the known associations of FE levels with disease duration and smoking [10], lower FE levels were associated with a higher HbA1c, older age and male sex. We found no evidence of independent associations between FE levels as a continuous variable and other glycaemic markers, liver and kidney function, liver fibrosis score or dietary intake. However, when dichotomising FE levels according to international guidelines, we found an EPI prevalence of 17%, which was associated with a higher HbA1c, a higher mean glucose, a lower fibre intake and a lower total energy intake, which has not been described previously. The association with HbA1c and mean glucose is remarkable as we found no evidence of association with CGM metrics, but the ranges for the CGM metrics (e.g. TIR 4–10 mmol/l) may be too broad to detect subtle differences in glycaemia. Taken together, these findings do not justify routine measurement of FE levels in individuals with type 1 diabetes, although clinical awareness of EPI and its complications may be warranted, especially in individuals with longer diabetes duration. Individuals with type 1 diabetes and EPI may be difficult to identify in clinical practice as we found no difference in abdominal complaints between the EPI and non-EPI groups. Previous studies reported that individuals with type 1 diabetes had a lower bone mineral density than healthy control individuals [14], and, in a study of individuals with EPI due to chronic pancreatitis, EPI was associated with a higher risk of osteoporosis (43% vs 6% in those without EPI) and with vitamin deficiencies [24]. These observations, together with our data, raise the possibility that the lower caloric intake observed in individuals with EPI reflects food avoidance due to (subclinical) malabsorption and related symptoms, and these individuals are therefore at risk for complications of EPI.

However, studies involving FE levels, measurements of bone mineral density and plasma vitamin levels in individuals with type 1 diabetes should be conducted to shed further light on this hypothesis. The EPI prevalence in our cohort (17%) is lower than that reported in other cohorts. Indeed, in a cohort of 320 individuals with type 1 diabetes, FE levels <200 µg/g faeces were reported in 51% of participants [10]. Another study in 195 individuals observed FE levels <200 µg/g faeces in 34% of individuals with type 1 diabetes [12]. These studies used a similar measuring technique (polyclonal ELISA), and the diabetes duration was also similar to that in our cohort (median of approximately 15 years). The difference in observed EPI prevalence may be explained by the number of male participants in both populations (64% and 54% vs 37% in our cohort); the number of smokers was not reported in those studies. In an earlier study in the GUTDM1 cohort, we found that higher fibre intake was associated with improved glycaemic management [17]. Remarkably, in the current work, having EPI was found to be associated with both a lower fibre intake and a higher HbA1c. Although causality cannot be proven in our study, we speculate that a higher fibre intake attenuates inflammation through the production of short-chain fatty acids, with favourable effects on exocrine function and glycaemic management. To test this hypothesis, the effect of fibre intake on inflammatory parameters and exocrine function should be studied in interventional studies. The fact that several associations observed in the dichotomised analyses were not observed in the linear analyses may indicate a non-linear relationship of FE levels with digestive capacity. In support of a non-linear relationship, the cut-off of 200 µg/g faeces is also recommended by international guidelines [23]. The association of exocrine dysfunction with diabetes duration may be visualised as a gradual decrease, in contrast to the rapid, biphasic loss of C-peptide and proinsulin in type 1 diabetes that we and others have described previously [25, 26]. Our findings imply that clinicians should be aware of the possibility of EPI, especially in older individuals with type 1 diabetes, those who are male and smokers, regardless of the presence of residual beta cell function. Emphasising the entanglement of endocrine and exocrine disease activity in type 1 diabetes, elevated amounts of dendritic cells, CD8-positive T cells [6] and neutrophils [27] have been observed in the exocrine compartment of individuals with type 1 diabetes compared with healthy individuals, and specific antibodies against exocrine enzymes have been described [28]. Pancreatic size is also known to be reduced at the time of type 1 diabetes diagnosis and continues to decline in the years after diagnosis [29]. However, whether exocrine involvement in type 1 diabetes is a consequence of T cell-mediated beta cell destruction or whether exocrine acinar cells are direct targets of autoimmunity remains to be elucidated. The gradual decline in FE levels that we observed, in contrast to the rapid, biphasic decline of endocrine function (as reflected by C-peptide), may hint at separate pathophysiological processes in the exocrine pancreas compared with the endocrine pancreas, but may also simply reflect a larger functional reserve capacity of the exocrine pancreas compared with the endocrine pancreas. We did not observe the classical signs of weight loss and steatorrhea in the EPI group. However, clinically relevant malnutrition may occur before overt clinical symptoms, and steatorrhea only occurs when pancreatic enzyme secretion falls below 10% [30]. In this regard, our finding of a lower caloric intake in the EPI group may suggest undetected EPI, which may be even harder to uncover as individuals with type 1 diabetes have been found to have a tailored, distinct eating pattern compared with healthy control individuals [31]. Given that Whitcomb et al showed that pancreatic enzyme replacement therapy increases protein absorption (determined using a nitrogen absorption coefficient) in individuals with EPI after pancreatectomy [30], individuals with type 1 diabetes and EPI with low protein intake may benefit from pancreatic enzyme replacement therapy. Hence, our findings open the possibility of a trial using pancreatic enzyme replacement therapy in individuals with type 1 diabetes and EPI. The results of such a study could shed light on our hypothesis that the lower caloric intake in our cohort reflects food avoidance due to (subclinical) malabsorption and related symptoms.

Our cohort is the largest to date to assess EPI prevalence on the basis of FE measurements, and the first to relate EPI in type 1 diabetes to CGM metrics, residual beta cell function and macronutrient intake. However, the current study has several limitations. The cross-sectional design of our study prevents inference of causal relationships. Also, we did not assess other common causes of EPI, such as chronic pancreatitis and cystic fibrosis. However, we believe that the observed EPI prevalence is primarily associated with type 1 diabetes, as the prevalence of EPI in our cohort greatly exceeds the prevalence of these conditions [32, 33]. The high EPI prevalence in other type 1 diabetes cohorts [10, 12] and the absence of an association of EPI with alcohol intake and markers of cholestasis, which are commonly associated with chronic pancreatitis, supports this conclusion. The similar levels of autoantibodies between the EPI and non-EPI groups in our cohort further argue against a higher rate of misdiagnosed individuals with chronic pancreatitis in the EPI group. Furthermore, food intake is known to be under-reported in general [34], and, although we assume that this occurs to a similar extent across the EPI and non-EPI groups, reporting bias cannot be fully excluded, as in most studies using self-reported data. Additionally, we did not directly assess osteoporosis via DEXA scans, which could have shed further light on the relationship between type 1 diabetes and EPI and its complications. Although initially all individuals collected faecal samples, material for elastase measurement was only available in 452 individuals, of which nine were excluded for having self-reported watery stools during sample collection. As seen in ESM Table 5, the excluded group had a higher HbA1c, shorter diabetes duration, and, as expected, a higher proportion of self-reported diarrhoea. These exclusions may have introduced bias into the estimated associations, although the direction of this bias is unknown. Age, sex and BMI (as an estimate of adiposity) are well-known factors related to metabolic health, and were therefore included in the models as potential confounders. Diabetes duration is a marker of disease progression and severity, and strongly influences clinical outcomes, and was therefore added as a potential confounder. Alcohol use and smoking are known to be associated with exocrine pancreatic function and are also therefore potential confounders. However, there may be a risk of residual confounding by variables that could not adequately be addressed in our cohort due to its composition and sample size (e.g. ethnicity and family history of diabetes). This should be considered when interpreting the results.

The lack of evidence of associations of FE levels with clinical parameters in this relatively healthy population of individuals with type 1 diabetes does not support the use of FE measurement for routine screening for EPI. However, the high prevalence of low FE levels and their association with lower food intake and higher glucose levels justify clinical awareness for EPI and its complications. Furthermore, smoking cessation in individuals with type 1 diabetes may not only improve cardiovascular risk but also contribute to preservation of exocrine pancreas function.