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Pancreatic Exocrine Dysfunction in Maturity-Onset Diabetes of the Young Type 3

¹ Department of Pediatrics, Haukeland University Hospital, Bergen, Norway
² Department of Clinical Medicine, University of Bergen, Bergen, Norway
³ Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
⁴ Gade Institute, University of Bergen, Bergen, Norway
⁵ Department of Pathology, Haukeland University Hospital, Bergen, Norway

Address correspondence and reprint requests to Professor Pål Rasmus Njølstad, MD, PhD, Section for Pediatrics, Department of Clinical Medicine, University of Bergen, N-5020 Bergen, Norway. E-mail: pal.njolstad{at}uib.no

	ABSTRACT

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS-- RESULTS CONCLUSIONS-- References

 
OBJECTIVE—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).

RESEARCH DESIGN AND METHODS—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.

RESULTS—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.

CONCLUSIONS—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.

Abbreviations: MODY, maturity-onset diabetes of the young • MODY3, MODY type 3

	INTRODUCTION

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Although reported to be present in 10–30% of patients with type 1 and type 2 diabetes (1–5) compared with 4% of nondiabetic subjects, severe dysfunction of the exocrine pancreas is often not recognized in clinical practice. Exocrine dysfunction is most frequently diagnosed by fecal elastase deficiency. Studies show that steatorrhea is common in patients with diabetes and fecal elastase deficiency (6), suggesting clinical implications such as increased risk of osteoporosis and other diseases associated with deficiencies in fat-soluble vitamins. Fecal elastase levels have also been reported to correlate with residual β-cell secretion and glycemic control in type 1 diabetic patients (7).

Several mechanisms have been proposed to explain the impaired pancreatic exocrine function in patients with diabetes. Diabetes has usually been regarded as the primary process. Alternative hypotheses that have been presented are 1) insulin deficiency, resulting in a deficit of the trophic action of insulin on acinar cells (8); 2) diabetic microangiopathy, with arterial lesions causing pancreatic fibrosis; 3) diabetic autonomic neuropathy, leading to impaired enteropancreatic reflexes; and 4) hormone suppression caused by high levels of circulating glucagon (9) or other gut hormones such as somatostatin or pancreatic polypeptide (10). Simultaneous damage of the endocrine and exocrine pancreas by a common autoimmune process has also been suggested (11). For other pancreatic disorders, exocrine dysfunction precedes and is suggested to cause the development of secondary diabetes (12–14). The molecular factors involved in connecting the pathogenesis of the endocrine and exocrine pancreatic tissues are, however, not well understood.

Exocrine dysfunction and pancreatic atrophy are strikingly associated with mutations in HNF1B in maturity- onset diabetes of the young (MODY) type 5 (15), and the combination of endocrine and exocrine pancreatic dysfunction has also been observed in other monogenic disorders (16–20). We have recently identified a novel syndrome of autosomal dominantly inherited diabetes and exocrine pancreas dysfunction attributable to mutations in the carboxyl ester lipase (CEL) gene, denoted MODY type 8 (21). Moreover, we have reported an association between exocrine deficiency revealed by fecal elastase deficiency and common variants in CEL in patients with type 1 diabetes (21).

The prevalence of exocrine dysfunction in patients with MODY type 3 (MODY3) has not previously been investigated. As HNF1A encodes a transcription factor that is both related to HNF1B and expressed in the exocrine pancreas, it is conceivable that a mutation in this gene could be directly associated with a defect in pancreatic exocrine function. It is therefore possible that the prevalence of exocrine dysfunction could differ from that of type 1 and type 2 diabetes.

The aim of our present study was, therefore, to investigate the prevalence of pancreatic exocrine dysfunction in patients with MODY3. We screened for fecal elastase deficiency and investigated fecal fat excretion. Moreover, we screened exon 11 of CEL in subjects with MODY3 with and without fecal elastase deficiency to explore whether common variations in CEL were associated with exocrine dysfunction in MODY3.

	RESEARCH DESIGN AND METHODS—

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS-- RESULTS CONCLUSIONS-- References

 
An invitation letter with a questionnaire and a tube for stool sampling was sent to all patients registered with a diagnosis of MODY3 in the Norwegian MODY Registry at the Department of Pediatrics, Haukeland University Hospital, Bergen, Norway. The questionnaire asked about the presence of abdominal pain or loose stools, use of medication for abdominal pain or loose stools, hospital admittance for abdominal pain or for loose stools, frequent defecation or diarrhea, or abdominal surgery. New letters with questionnaires and tubes were sent twice to nonresponders. MODY3 had been diagnosed on the basis of detection of the most commonly found mutation, P291fsinsC, in the HNF1A gene by a simple restriction enzyme-based screening test (22), followed by complete sequencing if the restriction test was negative.

There were 119 patients with MODY3 in the registry (41 men and 78 women) with a mean ±SD age of 37 ±18 years. The response rate for returning both the questionnaire and the initially required stool sample was 72 (60.5%) (22 men and 50 women). Two subjects were excluded because they did not return the second stool sample after a first result of low elastase-1. Thus, the final study comprised 70 patients, of whom 63 were adults (18 men [29%] and 45 women [71%]) with a mean age of 43.7 ± 16.5 years [men 44.7 ± 17.0 years and women 43.2 ± 16.4 years]) (Table 1) and 7 children aged <18 years (3 boys and 4 girls) with a median age of 12 years (5–15).

The control groups consisted of patients with type 1 diabetes (n = 140; median age 41.5 years [range 18–73]) previously collected consecutively from the outpatient diabetes clinic at Haukeland University Hospital (21) and a group of 78 healthy control subjects (median age 34.5 years [18–83]; subjects with diabetes were excluded) collected from the Department of Pediatrics, Haukeland University Hospital, and from Family 1 (spouses and nonmutation carriers) in the study by Ræder et al. (21). None of the subjects had reports of gastrointestinal disease.

Definition of pancreatic exocrine deficiency
Fecal elastase-1 was determined by enzyme-linked immunosorbent assay using two monoclonal antibodies specific for human elastase-1 (ScheBo-Tech, Wettenberg-Giessen, Germany). Results were expressed as micrograms per gram stool. Patients who had one positive test (fecal elastase <200 µg/g) were asked to return a second stool sample for confirmation of the result. Severe exocrine pancreatic dysfunction was defined as fecal elastase <200 µg/g in two tests and <100 µg/g in at least one of these, whereas moderate exocrine pancreatic dysfunction was defined as fecal elastase between 100 and 200 µg/g in two tests. Subjects who had two positive tests were provided with boxes and asked to return 72-h stool samples. Fecal fat excretion was determined after collecting all feces during 72 h while the individuals consumed a normal diet. Food intake was not quantified. Fecal fat was quantified according to Van De Kamer (23), and >7 g fat/24 h was considered a pathological level.

Genotyping
Sequencing of the CEL gene was performed using DNA extracted from frozen blood samples from the Norwegian MODY Registry (21). The region encompassing exon 8–11 was PCR amplified using specific primers to avoid amplification of CEL pseudogene sequence. Nested primers were then used to sequence the variable number of tandem repeats in both directions.

Statistics and ethics
Data are given as mean ± SD or as median (range) for small samples for better robustness. We used two-tailed, unpaired Student's t tests for comparisons of clinical characteristics. We chose a significance level of 5%. Fisher's exact test was used to compare the prevalence of fecal elastase deficiency according to CEL insertion status and between control groups and patients with MODY3. Associations between elastase levels and age, duration of diabetes, and BMI were computed by univariate and multivariate linear regression. We used qq-plots and the Shapiro-Wilks test for normality to evaluate the distribution of elastase. All analyses were performed using Stata 8.0 statistical software (Stata, College Station, TX). The study was approved by the Regional Committee for Research Ethics. We obtained written informed consent from all subjects.

	RESULTS

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Pancreatic exocrine deficiency
We found exocrine deficiency in 11.4% (8 of 70 patients) of all patients with MODY3. Because the number of children with MODY was only seven, we excluded these from the following analyses. None of the seven children had fecal elastase deficiency. In subjects with MODY3 aged >18 years, fecal elastase deficiency was found in 12.7% (8 of 63), compared with a prevalence of 18.6% in adult type 1 diabetic subjects and 3.8% in nondiabetic control subjects (Table 2). There was no significant age difference between patients with MODY3 and either of the control groups (Table 1). Of the patients with MODY3 with exocrine deficiency; two had R229Q mutations in exon 3 of HNF1A; two had S445fsdelAG mutations (exon 7), and the mutations P291fsinsC (exon 4), R263C (exon 4), R131W (exon 2), and P112L were each present in one patient. In patients with normal elastase, P291fsinsC was the most common mutation (28 subjects; 45.2%), followed by R229Q (9 patients; 14.5%), R131W (7 patients; 11.3%), R263C and R171X (4 patients each; 6.5%), S445fsdelAG (2 patients; 3.3%), and some rarer mutations. For adults, the prevalence of fecal elastase deficiency was 27.8% for men and 6.7% for women. Six of the eight patients with MODY3 with exocrine deficiency returned a 72-h stool collection for analysis of fecal fat excretion. All patients who underwent the test had increased fecal fat excretion (steatorrhea) as defined by >7 g/day (mean ± SD 13.5 ± 7 g/day; median 10.5 [range 8–27] g/day).

None of the patients with MODY3 with fecal elastase deficiency reported loose stools, compared with five (9.1%) of the adult subjects with normal elastase. Two patients with fecal elastase deficiency (25.0%) and 16 (29.1%) patients with normal exocrine function had complaints about abdominal pain, for which only one and four patients in each of the two groups, respectively, used over-the-counter analgesics. Abdominal surgery was reported in one patient with fecal elastase deficiency (because of kidney stones) and in nine patients with normal elastase values (cholecystectomies in three patients). Only two patients reported ever having taken medication for loose stools (on time-limited occasions in the past due to infection), both of whom had normal elastase values. We chose not to exclude any of these patients, as it seemed unlikely that their elastase values were affected by these conditions.

CEL variants
Twelve patients with MODY3 (17%) had single-base insertions (the variants ins9, ins10, ins11, and ins12 were found) (21). Two of 8 patients (25%) with fecal elastase deficiency had CEL insertions, compared with 10 of 62 (16%) patients with no insertion (NS). No patients had single-base deletions in the CEL gene. CEL insertions were not significantly more common in MODY3 patients with fecal elastase deficiency. Caution is needed because the number of MODY3 patients with CEL mutations was low, not allowing reliable statistical evaluation. Among patients with type 1 diabetes, 7 of 33 patients (21%) with fecal elastase deficiency had CEL insertions, and overall CEL insertions were found in 23 patients (17%). Data were not available for the nondiabetic subjects, but in a cohort of 97 blood donors and 88 healthy control subjects from the Nord-Trøndelag Health Study (HUNT2), we previously found CEL insertions in 27 of 185 subjects (14.6%) (21).

	CONCLUSIONS—

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS-- RESULTS CONCLUSIONS-- References

 
We have characterized the exocrine pancreatic status in a cohort of patients with MODY3 and found a prevalence of pancreatic exocrine deficiency of 12.7% in the adult patients. This value was similar to previous findings in type 1 and 2 diabetic patients (1–5) as well as to results from our present type 1 control group and three times higher than that in the healthy control subjects. Fecal elastase has been shown to have good sensitivity and specificity for moderate and severe exocrine deficiency, whereas it is criticized as having less sensitivity in mild exocrine deficiency (24). The response rate of 60.5% was satisfactory, and there were no differences in age or diabetes duration between the study population and the subjects with MODY3 in the Norwegian MODY Registry. We therefore conclude that our data are representative.

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.

	Acknowledgments

 
This study was supported by funds from Helse Vest, Haukeland University Hospital, the University of Bergen, Norway, and the Research Council of Norway (FUGE).

We thank Jan Brøgger for sharing his statistical expertise and Bente Berge for practical assistance.

	Footnotes

 
Published ahead of print at http://care.diabetesjournals.org on 5 November 2007. DOI: 10.2337/dc07-1002.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received for publication May 25, 2007. Accepted for publication October 21, 2007.

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This Article Abstract Full Text (PDF) All Versions of this Article: dc07-1002v1 31/2/306    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Vesterhus, M. Articles by Njølstad, P. R. Search for Related Content PubMed PubMed Citation Articles by Vesterhus, M. Articles by Njølstad, P. R. Social Bookmarking                What's this?