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.

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.

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 119 patients in the registry belong to 57 independently recruited families, of which 36 families (63.2%) are represented in the present study. The 36 families have a mean of 2.1 participating members (median 1, range 1–9).

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.

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).

The patients with MODY3 with fecal elastase deficiency were significantly older than those with normal fecal elastase (P = 0.002) and had a significantly longer duration of diabetes (P = 0.02) (Table 1). There was no difference between patients with fecal elastase deficiency and normal fecal elastase for BMI or age at diagnosis of diabetes (Table 1). By univariate linear regression, we found that fecal elastase decreased with age and duration of diabetes in patients with MODY3 as well as in subjects with type 1 diabetes but not with BMI (Table 3). Age was also inversely associated with fecal elastase in the control groups and patients with MODY3 combined. In a multivariate linear regression analysis of patients with MODY3 and nondiabetic subjects, having MODY3 was still associated with decreasing fecal elastase after correcting for age (Table 3). After correcting for age, duration of diabetes was not associated with fecal elastase in patients with MODY3 and type 1 diabetic patients but having type 1 diabetes was associated with decreased fecal elastase.

Mean fecal elastase was significantly lower in men than in women with MODY3 (P = 0.02) (Table 2). There was no difference in age at exocrine examination, age at diagnosis of diabetes, duration of diabetes, or BMI between men and women in the study as a whole.

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).

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.

Table 1—

Characteristics of the study subjects

MODY3
Type 1 diabetic subjectsP value*Nondiabetic control subjectsP value*
All patientsFED−FED+P value*
n 63 55 8  140  78  
Male subjects 18 (29) 17 (30.9) 5 (62.5)  70 (50)  36 (46)  
Age at examination (years) 44 ± 16 42 ± 16 58 ± 12 0.002 42 ± 14 0.50 39 ± 14 0.07 
Age at onset of diabetes (years) 21 ± 10 21 ± 10 24 ± 11 NS 20 ± 12 0.60 NA  
Duration of diabetes (years) 22 ± 15 20 ± 14 34 ± 14 0.02 22 ± 13 0.90 NA  
BMI (kg/m2) 25.4 ± 3.5 25.6 ± 3.7 24.3 ± 1.9 NS 26.0 ± 4.0 0.29 24.9 ± 3.4 0.40 
MODY3
Type 1 diabetic subjectsP value*Nondiabetic control subjectsP value*
All patientsFED−FED+P value*
n 63 55 8  140  78  
Male subjects 18 (29) 17 (30.9) 5 (62.5)  70 (50)  36 (46)  
Age at examination (years) 44 ± 16 42 ± 16 58 ± 12 0.002 42 ± 14 0.50 39 ± 14 0.07 
Age at onset of diabetes (years) 21 ± 10 21 ± 10 24 ± 11 NS 20 ± 12 0.60 NA  
Duration of diabetes (years) 22 ± 15 20 ± 14 34 ± 14 0.02 22 ± 13 0.90 NA  
BMI (kg/m2) 25.4 ± 3.5 25.6 ± 3.7 24.3 ± 1.9 NS 26.0 ± 4.0 0.29 24.9 ± 3.4 0.40 

Data are means ± SD or n (%).

*

P values represent unpaired Student's t test for FED+ versus FED−, type 1 diabetic subjects versus all patients with MODY3, and nondiabetic control subjects versus all patients with MODY3, respectively. FED, fecal elastase deficiency; NA, not applicable.

View Large
Table 2—

Pancreatic exocrine dysfunction in adult patients with MODY3 and control subjects

MODY3
Type 1 diabetic subjectsP value*Nondiabetic control subjectsP value*
All patientsWomenMen
n 63 45 18 140  78  
FED† 8 (12.7) 3 (6.7) 5 (27.8) 26 (18.6) 0.42 3 (3.8) 0.06 
    Moderate FED 2 (3.2) 0 (0) 2 (11.1) 10 (7.1)  3 (3.8)  
    Severe FED 6 (9.5) 3 (6.7) 3 (16.7) 16 (11.4) 0.81 0 (0) 0.007 
72-h fecal fat excretion >7 g/day‡ 6 (100) 2 4 13 (68.4)  NI  
Mean fecal elastase-1 (μg/g) (>200) 406 ± 184 442 ± 176 316 ± 176 302 ± 142 0.0001 485 ± 120 0.004 
Fecal fat excretion (g/day) (<7) 13.5 ± 7 10.5 ± 0.7 15.0 ± 8.5 10.9 ± 4.9 0.39 NI  
MODY3
Type 1 diabetic subjectsP value*Nondiabetic control subjectsP value*
All patientsWomenMen
n 63 45 18 140  78  
FED† 8 (12.7) 3 (6.7) 5 (27.8) 26 (18.6) 0.42 3 (3.8) 0.06 
    Moderate FED 2 (3.2) 0 (0) 2 (11.1) 10 (7.1)  3 (3.8)  
    Severe FED 6 (9.5) 3 (6.7) 3 (16.7) 16 (11.4) 0.81 0 (0) 0.007 
72-h fecal fat excretion >7 g/day‡ 6 (100) 2 4 13 (68.4)  NI  
Mean fecal elastase-1 (μg/g) (>200) 406 ± 184 442 ± 176 316 ± 176 302 ± 142 0.0001 485 ± 120 0.004 
Fecal fat excretion (g/day) (<7) 13.5 ± 7 10.5 ± 0.7 15.0 ± 8.5 10.9 ± 4.9 0.39 NI  

Data are means ± SD or means (%). Moderate FED (fecal elastase deficiency) = fecal elastase between 100 and 200 μg/g, whereas severe FED = fecal elastase <100 μg/g.

*

P values represent unpaired Student's t test for type 1 diabetic subjects versus all patients with MODY3 and nondiabetic control subjects versus all patients with MODY3, respectively.

†

The percentage refers to n in each group.

‡

Percentage of patients who underwent the test, i.e., 6 patients with MODY3 and 19 subjects with type 1 diabetes. NI, not investigated.

View Large
Table 3—

Association of fecal elastase to age, duration of diabetes, and BMI

β95% CI*P value
Univariate linear regression    
    Age −3.67 −4.94 to −2.40 <0.001 
Nondiabetic control subjects −2.10 −3.93 to −0.27 0.03 
Type 1 diabetic patients −3.29 −4.94 to −1.65 <0.001 
Patients with MODY3 −4.54 −7.16 to −1.92 0.001 
    Duration of diabetes −3.54 −5.13 to −1.95 <0.001 
Type 1 diabetic patients −2.66 −4.40 to −0.92 0.003 
Patients with MODY3 −5.08 −8.08 to −2.09 0.001 
    BMI −4.54 −9.93 to 0.85 0.10 
Nondiabetic control subjects −3.92 −12.44 to 4.60 0.36 
Type 1 diabetic patients −1.92 −8.00 to 4.17 0.53 
Patients with MODY3 0.35 −13.33 to 14.03 0.96 
Multiple linear regression    
    Comparing patients with MODY3 with nondiabetic control subjects    
Age −3.34 −4.91 to −1.78 <0.001 
MODY3 −62.18 −110.84 to −13.51 0.01 
    Comparing type 1 diabetic patients with nondiabetic control subjects    
Age −2.84 −4.07 to −1.60 <0.001 
Type 1 diabetes −173.07 −209.10 to −137.03 <0.001 
    Comparing patients with MODY3 with type 1 diabetic patients    
Age −2.85 −4.70 to −1.01 0.003 
Duration of diabetes −1.51 −3.48 to 0.46 0.13 
MODY3 107.92 63.82 to 152.03 <0.001 
β95% CI*P value
Univariate linear regression    
    Age −3.67 −4.94 to −2.40 <0.001 
Nondiabetic control subjects −2.10 −3.93 to −0.27 0.03 
Type 1 diabetic patients −3.29 −4.94 to −1.65 <0.001 
Patients with MODY3 −4.54 −7.16 to −1.92 0.001 
    Duration of diabetes −3.54 −5.13 to −1.95 <0.001 
Type 1 diabetic patients −2.66 −4.40 to −0.92 0.003 
Patients with MODY3 −5.08 −8.08 to −2.09 0.001 
    BMI −4.54 −9.93 to 0.85 0.10 
Nondiabetic control subjects −3.92 −12.44 to 4.60 0.36 
Type 1 diabetic patients −1.92 −8.00 to 4.17 0.53 
Patients with MODY3 0.35 −13.33 to 14.03 0.96 
Multiple linear regression    
    Comparing patients with MODY3 with nondiabetic control subjects    
Age −3.34 −4.91 to −1.78 <0.001 
MODY3 −62.18 −110.84 to −13.51 0.01 
    Comparing type 1 diabetic patients with nondiabetic control subjects    
Age −2.84 −4.07 to −1.60 <0.001 
Type 1 diabetes −173.07 −209.10 to −137.03 <0.001 
    Comparing patients with MODY3 with type 1 diabetic patients    
Age −2.85 −4.70 to −1.01 0.003 
Duration of diabetes −1.51 −3.48 to 0.46 0.13 
MODY3 107.92 63.82 to 152.03 <0.001 
*

The 95% CI refers to the regression coefficient β.

View Large

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.

1.
Hardt PD, Krauss A, Bretz L, Porsch-Ozcurumez M, Schnell-Kretschmer H, Maser E, Bretzel RG, Zekhorn T, Klor HU: Pancreatic exocrine function in patients with type 1 and type 2 diabetes mellitus.
Acta Diabetol
 
37
:
105
–110,
2000
2.
Icks A, Haastert B, Giani G, Rathmann W: Low fecal elastase-1 in type I diabetes mellitus.
Z Gastroenterol
 
39
:
823
–830,
2001
3.
Rathmann W, Haastert B, Icks A, Giani G, Hennings S, Mitchell J, Curran S, Wareham NJ: Low faecal elastase 1 concentrations in type 2 diabetes mellitus.
Scand J Gastroenterol
 
36
:
1056
–1061,
2001
4.
Nunes AC, Pontes JM, Rosa A, Gomes L, Carvalheiro M, Freitas D: Screening for pancreatic exocrine insufficiency in patients with diabetes mellitus.
Am J Gastroenterol
 
98
:
2672
–2675,
2003
5.
Hardt PD, Hauenschild A, Nalop J, Marzeion AM, Jaeger C, Teichmann J, Bretzel RG, Hollenhorst M, Kloer HU: High prevalence of exocrine pancreatic insufficiency in diabetes mellitus: a multicenter study screening fecal elastase 1 concentrations in 1,021 diabetic patients.
Pancreatology
 
3
:
395
–402,
2003
6.
Hardt PD, Hauenschild A, Jaeger C, Teichmann J, Bretzel RG, Kloer HU: High prevalence of steatorrhea in 101 diabetic patients likely to suffer from exocrine pancreatic insufficiency according to low fecal elastase 1 concentrations: a prospective multicenter study.
Dig Dis Sci
 
48
:
1688
–1692,
2003
7.
Cavalot F, Bonomo K, Perna P, Bacillo E, Salacone P, Gallo M, Mattiello L, Trovati M, Gaia E: Pancreatic elastase-1 in stools, a marker of exocrine pancreas function, correlates with both residual β-cell secretion and metabolic control in type 1 diabetic subjects.
Diabetes Care
 
27
:
2052
–2054,
2004
8.
Foulis AK, Stewart JA: The pancreas in recent-onset type 1 (insulin-dependent) diabetes mellitus: insulin content of islets, insulitis and associated changes in the exocrine acinar tissue.
Diabetologia
 
26
:
456
–461,
1984
9.
Dyck WP, Rudick J, Hoexter B, Janowitz HD: Influence of glucagon on pancreatic exocrine secretion.
Gastroenterology
 
56
:
531
–537,
1969
10.
Ertan A, Arimura A, Akdamar K, Shibata T, Groot K, Luciano M, Mather FJ, Degertekin H, Agrawal N, Ryan J: Pancreatic immunoreactive somatostatin and diabetes mellitus.
Dig Dis Sci
 
29
:
625
–630,
1984
11.
Nakanishi K, Kobayashi T, Miyashita H, Okubo M, Sugimoto T, Murase T, Kosaka K, Hara M: Relationships among residual β cells, exocrine pancreas, and islet cell antibodies in insulin-dependent diabetes mellitus.
Metabolism
 
42
:
196
–203,
1993
12.
Wang F, Herrington M, Larsson J, Permert J: The relationship between diabetes and pancreatic cancer.
Mol Cancer
 
2
:
4
,
2003
13.
Mitchell RM, Byrne MF, Baillie J: Pancreatitis.
Lancet
 
361
:
1447
–1455,
2003
14.
Layer P, Yamamoto H, Kalthoff L, Clain JE, Bakken LJ, DiMagno EP: The different courses of early- and late-onset idiopathic and alcoholic chronic pancreatitis.
Gastroenterology
 
107
:
1481
–1487,
1994
15.
Bellanne-Chantelot C, Chauveau D, Gautier JF, Dubois-Laforgue D, Clauin S, Beaufils S, Wilhelm JM, Boitard C, Noel LH, Velho G, Timsit J: Clinical spectrum associated with hepatocyte nuclear factor-1β mutations.
Ann Intern Med
 
140
:
510
–517,
2004
16.
Boocock GR, Morrison JA, Popovic M, Richards N, Ellis L, Durie PR, Rommens JM: Mutations in SBDS are associated with Shwachman-Diamond syndrome.
Nat Genet
 
33
:
97
–101,
2003
17.
Zenker M, Mayerle J, Lerch MM, Tagariello A, Zerres K, Durie PR, Beier M, Hulskamp G, Guzman C, Rehder H, Beemer FA, Hamel B, Vanlieferinghen P, Gershoni-Baruch R, Vieira MW, Dumic M, Auslender R, Gil-da-Silva-Lopes VL, Steinlicht S, Rauh M, Shalev SA, Thiel C, Ekici AB, Winterpacht A, Kwon YT, Varshavsky A, Reis A: Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome).
Nat Genet
 
37
:
1345
–1350,
2005
18.
Onishi H, Hanihara T, Sugiyama N, Kawanishi C, Iseki E, Maruyama Y, Yamada Y, Kosaka K, Yagishita S, Sekihara H, Satoh S: Pancreatic exocrine dysfunction associated with mitochondrial tRNALeu(UUR) mutation.
J Med Genet
 
35
:
255
–257,
1998
19.
Scire G, Magliocca FM, Cianfarani S, Scalamandre A, Petrozza V, Bonamico M: Autoimmune polyendocrine candidiasis syndrome with associated chronic diarrhea caused by intestinal infection and pancreas insufficiency.
J Pediatr Gastroenterol Nutr
 
13
:
224
–227,
1991
20.
Mackie AD, Thornton SJ, Edenborough FP: Cystic fibrosis-related diabetes.
Diabet Med
 
20
:
425
–436,
2003
21.
Ræder HJS, Holm PI, Haldorsen IS, Mas E, Sbarra V, Nermoen I, Eide SA, Grevle L, Bjørkhaug L, Sagen JV, Aksnes L, Søvik O, Lombardo D, Molven A, Njølstad PR: Mutations in the CEL VNTR cause a syndrome of diabetes and exocrine dysfunction.
Nat Genet
 
38
:
54
–62,
2006
22.
Bjørkhaug LSO, Bell GI, Njølstad PR, Molven A: A simple test for the high-frequency P291fsinsC mutation in the HNF1α/MODY3 gene.
Diabetologia
 
43
:
818
–819,
2000
23.
Van De Kamer JH: Quantitative determination of the saturated and unsaturated higher fatty acids in fecal fat.
Scand J Clin Lab Invest
 
5
:
30
–36,
1953
24.
Lankisch PG, Schmidt I, Konig H, Lehnick D, Knollmann R, Lohr M, Liebe S: Faecal elastase 1: not helpful in diagnosing chronic pancreatitis associated with mild to moderate exocrine pancreatic insufficiency.
Gut
 
42
:
551
–554,
1998
25.
Rothenbacher D, Low M, Hardt PD, Klor HU, Ziegler H, Brenner H: Prevalence and determinants of exocrine pancreatic insufficiency among older adults: results of a population-based study.
Scand J Gastroenterol
 
40
:
697
–704,
2005
26.
Haaber AB, Rosenfalck AM, Hansen B, Hilsted J, Larsen S: Bone mineral metabolism, bone mineral density, and body composition in patients with chronic pancreatitis and pancreatic exocrine insufficiency.
Int J Pancreatol
 
27
:
21
–27,
2000
27.
Lombardo F, De Luca F, Rosano M, Sferlazzas C, Lucanto C, Arrigo T, Messina MF, Crisafulli G, Wasniewska M, Valenzise M, Cucinotta D: Natural history of glucose tolerance, β-cell function and peripheral insulin sensitivity in cystic fibrosis patients with fasting euglycemia.
Eur J Endocrinol
 
149
:
53
–59,
2003

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.

DIABETES CARE
2008