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Exocrine pancreas dysfunction is seen in 10-30% of patients with type 1 and 2 diabetes. We have recently identified a syndrome of diabetes and exocrine pancreas dysfunction attributable to mutations in the carboxyl ester lipase (CEL) gene. We wanted to investigate the prevalence of pancreatic exocrine dysfunction in patients with maturity-onset diabetes of the young type 3 (MODY3). All 119 patients with MODY3 in the Norwegian MODY Registry were invited to participate, and 70 (60.5%) responded, among whom 63 were adults. Control groups included 140 subjects with type 1 diabetes and 78 nondiabetic control subjects. Pancreatic dysfunction was defined by fecal elastase deficiency. Fecal fat excretion was measured in 25 patients with fecal elastase deficiency. CEL was investigated for sequence changes. We found a prevalence of fecal elastase deficiency of 12.7% in adult patients with MODY3, compared with 18.6% in patients with type 1 diabetes and 3.8% in nondiabetic control subjects. The six patients with MODY3 with fecal elastase deficiency available for analysis all had increased fecal fat excretion. Fecal elastase decreased with age. Controlled for age, patients with MODY3 still had decreased fecal elastase compared with control subjects. Twelve of 70 patients (17%) had single-base insertions in CEL exon 11. Two of these had fecal elastase deficiency. The prevalence of pancreatic exocrine dysfunction was 12.7% in a cohort of 63 adult patients with MODY3, similar to the prevalence among type 1 diabetic patients. Fecal fat excretion was increased in all patients with MODY3 with fecal elastase deficiency who were investigated, underscoring the potential clinical importance of the exocrine dysfunction.

We found that fecal elastase decreased with increasing diabetes duration in patients with MODY3 and in type 1 diabetic patients, but this effect disappeared when correcting for age. Others have reported weak (5) or no association of fecal elastase deficiency to diabetes duration (1). The prevalence of fecal elastase deficiency was higher in males than in females, confirming previous studies (25), but caution is needed in evaluating this result as the numbers are small. Fecal elastase decreased with increasing age in adult patients with MODY3, in type 1 diabetic patients, and in the pooled analysis of all subjects investigated. However, after correcting for age, the fact of having MODY3 or type 1 diabetes was still associated with decreased fecal elastase.

Those patients with MODY3 with fecal elastase deficiency who delivered stool samples all had increased fecal fat excretion, underscoring the potential clinical importance of the exocrine dysfunction. A majority of the 19 patients with type 1 diabetes and fecal elastase deficiency available for analysis also had increased fecal fat excretion. This result is in line with the findings of Hardt et al. (6), who reported relevant steatorrhea in 39.6% of patients with type 1 or type 2 diabetes and severe fecal elastase deficiency in a prospective multicenter study. Steatorrhea is associated with an increased risk of vitamin D deficiency and osteoporosis (26). Notably, none of the patients in our study reported loose stools, and abdominal pain was not significantly different from that for control groups. This finding underscores why the condition might not be detected in clinical practice.

Previous observations in a cohort of 182 adult patients (mainly with type 1 diabetes) suggested an association between single-base insertions in CEL and exocrine dysfunction (21). In the present study, the number of patients with MODY3 who had CEL mutations was low, not allowing reliable statistical evaluation.

The interaction between the intimately colocalized endocrine and exocrine cells within the pancreas has been discussed in several studies observing the concurrence of diabetes and exocrine pancreatic dysfunction, and exocrine dysfunction (12,13,27), as well as diabetes (7), has been suggested to be the primary event. On the basis of findings of fecal elastase deficiency in young pre-diabetic mutation carriers in the families with the monogenic MODY type 8 syndrome, the exocrine dysfunction seems to be primary in subjects harboring CEL deletions. In this study, we included only patients with an established diagnosis of MODY3 and cannot determine the sequence of development of fecal elastase deficiency and diabetes. Interestingly, however, the patients with fecal elastase deficiency tended to be older, and none of the children had exocrine dysfunction. It seems probable that in patients with MODY3, there is a risk of developing exocrine dysfunction secondary to diabetes. Further studies including larger numbers of patients are required to investigate whether CEL insertions may constitute an additional risk factor. Mutations in HNF1B, a gene involved in pancreatic development and closely related to HNF1A (which is mutated in MODY3), have been suggested to be particularly related to exocrine dysfunction, possibly through a developmental effect. This cross-sectional study does not allow us to draw any conclusions about causality. Further studies are needed to address whether the exocrine dysfunction is a primary or secondary event in the pathogenesis.

We conclude that the prevalence of pancreatic exocrine deficiency in patients with MODY3 is similar to that found in type 1 diabetic patients and higher than in nondiabetic control subjects and that this deficiency seems to be associated with asymptomatic steatorrhea. Hence, clinicians should be aware of the risk of exocrine dysfunction and its complications in their patients with MODY3 as well as type 1 and 2 diabetes, and the need for routine checking for pancreatic exocrine deficiency should be discussed. Treatment with pancreatic enzyme substitution therapy and vitamin supplements may be indicated in patients with steatorrhea.