Pancreatic Volume and Endocrine and Exocrine Functions in Patients With Diabetes
Philippe, Marie-France MD*†; Benabadji, Salim MD†‡; Barbot-Trystram, Laurence MD§; Vadrot, Dominique MD†‡; Boitard, Christian MD*†; Larger, Etienne MD, PhD*†∥
From the *Service de Diabétologie, Hôtel Dieu de Paris, APHP; †Université Paris 5, René Descartes; ‡Service de Radiologie, Hôtel Dieu de Paris; §Laboratoire de Coprologie Fonctionnelle, Hôpital de la Pitié-Salpétrière, APHP; and ∥INSERM U833, Collège de France, Paris, France.
Received for publication May 26, 2010; accepted October 15, 2010.
Reprints: Etienne Larger, MD, PhD, Service de Diabétologie, Hôtel Dieu, 1, Place du parvis de Notre Dame, F-75004 Paris, France (e-mail: firstname.lastname@example.org).
M.-F.P. and S.B. contributed equally to this work.
M.-F.P. is now with the Service de diabétologie-endocrinologie, Grand Hôpital de Charleroi, Gilly, Belgium.
Objective: Exocrine function has been described in patients with diabetes. We hypothetized that patients with exocrine dysfunction have pancreatic atrophy.
Methods: This is a cohort study of hospitalized patients. Thirty-five patients were selected after detection of impaired exocrine function in routine tests, and 17 patients were matched for age and body mass index to the previous cohort. The pancreatic volume was evaluated on sections of computed tomographic scans of the pancreas. Other investigations included a glucagon stimulation test and determination of fecal elastase-1 concentration and chymotrypsin activity.
Results: Fifty-two patients participated in this study, 24 with type 1 diabetes and 28 with type 2 diabetes. Duration of diabetes was 15 years (5-26 years; median [interquartile range]). The pancreatic volume, 42 cm3 (25-57 cm3), was decreased in most patients. It did not differ in patients with type 1 diabetes compared with those with type 2 diabetes. It was decreased in patients treated with insulin and in those with low elastase-1 concentration or low chymotrypsin activity. In the multiple linear regression analysis, the pancreatic volume correlated with chymotrypsin activity and stimulated C-peptide.
Conclusions: We have unraveled a link between 2 old observations in patients with diabetes: atrophy of the pancreas and exocrine deficiency. These observations give credence to the reality of the exocrine dysfunction in patients with diabetes.
Both type 1 diabetes and type 2 diabetes are chronic inflammatory diseases.1,2 The specificity of both diseases for the endocrine pancreas is uncertain in the long-term. A hallmark of chronic inflammation and scar is fibrosis and atrophy. A reduction in the weight of the pancreas in patients with diabetes has been described for more than 100 years by Cecil.3 In his series of 90 autopsies, Cecil3 stated that the pancreas was small or atrophic in 25% of patients, but this was before insulin has been made available to patients with type 1 diabetes. Other series have confirmed that considerable atrophy occurs in some cases.4 Evaluation of the pancreatic volume has been revisited with the help of computed tomographic (CT) scans in both subjects from the general population and patients with diabetes,5-7 and these data have confirmed that the pancreatic volume is decreased in patients with diabetes. More recently, exocrine dysfunction has been described both in patients with type 1 diabetes and in patients with type 2 diabetes based on the secretin stimulation test in early reports8-10 and then on decreased fecal elastase-1 concentration.11 The frequency of decreased elastase-1 has been evaluated about 26% to 44% of patients with type 1 diabetes and 30% of patients with type 2 diabetes, the decrease being classified as indicating severe pancreatic exocrine dysfunction in one third of cases.12-14 The reality of exocrine dysfunction in patients with diabetes has, however, been recently challenged,15 although the debate is still open.16
As exocrine pancreas accounts for more than 90% of the pancreatic volume, we hypothesized that patients with exocrine dysfunction would be the same to those with atrophy of the pancreas. The objective of the present study was to look for possible endocrine and exocrine correlates of pancreatic volume in patients with diabetes.
MATERIALS AND METHODS
The present work is based on a cohort of hospitalized patients. Two groups of patients were involved in the present study. The first group of 35 patients was selected on the basis of low fecal elastase-1 concentration. These patients were detected because they participated in a cohort study of exocrine function in patients with diabetes (M.-F.P. et al, manuscript in preparation). The second group was composed of 17 patients who were matched for weight and age with patients in the first group. All patients gave written informed consent, and investigations were conducted according to the principles expressed in the Declaration of Helsinki.
The CT images were acquired with standard clinical abdominal CT protocol using a 16-section multidetector CT scanner (Philips Brilliance CT 16-slice; Philips Medical Systems, Best, the Netherlands). The CT parameters were as follows: 0.75-mm slice collimation, 140 kVp, 135 to 200 mA, 0.75-second tube rotation, pitch at 0.9. The entire pancreas was imaged by using a field of view of 300 to 350 mm, depending on body habitus. Conventional processing of reconstructed imaging was used, with soft tissue reconstruction filters, and thickness slice was reconstructed at 1 mm with 0.5-mm overlaps. Patients were administered oral contrast (barium sulfate). When the contrast of the pancreas was insufficient, the CT scan was realized after an intravenous contrast, 80 mL of Xenetix at a rate of 2-mL/s with a 60-second delay.
All images were analyzed at a window of 50 Hounsfield units and a window width of 350 Hounsfield units. The images were analyzed using Brillance Workspace, version 3.5, using quantitative anatomical measurements (Q-CTA; Philips Medical Systems).
The volume of the pancreas was measured after hand outlining of the contour of the pancreas, as described by Saisho,6 on each CT image. Preliminary experiments had shown that the manual technique was more precise than automated detection of contours. Pancreas volume per section was calculated as the product of each pancreas area and the CT section thickness. Total and parenchymal volume of pancreas was computed by summing up the volume from each section that included a piece of pancreas tissue. The measurement of pancreatic volume was carried out by a single investigator (S.B.).
The pancreatic volume was corrected with the formula proposed by Geraghty and colleagues17: Vcorr = Vmes + 11*(1.76-height [m]) + 0.00744*(73-weight [kg]) for men and Vmes − 2.93 (1.63-height) + 0.006214*(60-weight) for women. The corrected volumes were classified in 4 classes according to the distribution observed by Geraghty and colleagues17: below the first percentile when Vcorr was less than 37.9 cm3 in men, less than 22.4 in women; between the first and the fifth percentiles when Vcorr was 37.9 to less than 52.4 cm3 in men, 22.4 to less than 34.7 in women; between the fifth and the 10th percentiles when Vcorr was between 52.4 and 60.1 cm3 in men, 34.7 to less than 41.2 in women; and above the 10th percentile when Vcorr was 60.1 cm3 or above in men, 41.2 or above in women.
The exocrine function of the pancreas was assessed by the measurement of both elastase-1 concentration and chymotrypsin activity on a sample of feces obtained in nondiarrheic patients who had a regular hospital diet. Samples were analyzed the same day or stored in −20°C until analysis. Pancreatic elastase-1 concentration was determined using a "sandwich"-type enzyme immunoassay (Schebo-Biotech, Giessen, Germany), which combines the use of 2 monoclonal antibodies binding to 2 distinct epitopes specific to human pancreatic elastase-1.18,19 Results were expressed as micrograms per gram of stool; the limit of detection was 15 μg/g of stool, and 200 μg/g was the lower normal limit. Fecal chymotrypsin concentration was measured by a colorimetric method using Succ-Ala-Ala-Pro-Phe-p-nitroanilin as substrate.20 The intra-assay variability of the test was 3.3%, and the interassay variability was 9.0%. Results were expressed as units per gram of stool at 25°C. Six units per gram was the lower limit of normal, and values less than 3 U/g were regarded as pathological.
One milligram of glucagon (Novo-Nordisk) was injected intravenously after an overnight fast. Plasma glucose and serum C-peptide were assayed at T0 and T6 minutes. The test was performed only when capillary glucose was less than 250 mg/dL at the time of test. C-peptide was measured by immunoradiometric assay (CIS International, Gif-sur-Yvette, France), as previously described.21 The intra-assay coefficient of variation was 3.7% to 6.6%; the interassay coefficient of variation was 4.4% to 8.0%.
Results are presented as median and interquartile range. Categorical values were compared using χ2 test, numerical values were compared using a nonparametric test, the Mann-Whitney U test, when distribution was not normal, or the Student t test. Correlations were assessed using the Spearman rank order test. A multiple linear regression was performed using variables that were significant in the Spearman rank order test.
The clinical characteristics of the patients are presented in Table 1. The 2 groups of patients were similar with regard to proportion of men/women, age, age at diagnosis, duration of diabetes, body mass index (BMI), proportion of patients with type 1 diabetes/type 2 diabetes, and proportion of patients with first-degree relatives with diabetes.
A CT scan was obtained in 52 patients. The Wirsung was normal in all patients. Calcifications of the pancreas were observed in 1 patient and cysts in another one. There was no renal abnormality suggestive of MODY-5 in any of the patients.
Both the pancreatic volume and the corrected pancreatic volume were similar: 42 cm3 (25-57 cm3; median [interquartile range]). Compared with the distribution of pancreatic volume published by Geraghty et al,17 the size of the pancreas was below the first percentile of the distribution of normal individuals in 18 patients (35%), it was between the first and the fifth percentile in 16 (31%), between the fifth and the 10th percentile in 4 (8%), and above the 10th percentile in 14 (27%) (Fisher exact test compared with the theoretical distribution χ2 = 45, P < 10−4). Only 8 pancreata were considered normal by the investigator (S.B.). Atrophy of the pancreas was diffuse in all other cases except three, with predominant fatty involution in 3 cases. The pancreatic volume did not differ between men and women (Fig. 1A) and patients with type 1 diabetes and patients with type 2 diabetes (Fig. 1C). However, the pancreatic volume was lower in patients without a family history of diabetes compared with those with first-degree relatives with diabetes (49 cm3 [31-61] vs 34 [21-43], P = 0.01; Fig. 1B). Finally, the pancreatic volume was lower in patients treated with insulin compared with patients treated with oral medications (34 cm3 [24-49] vs 69 [60-80], P < 10−6; Fig. 1D). Pancreatic volume was lower in patients with low elastase (34 cm3 [22-47] vs 57 [48-68], P = 0.02; Fig. 2A) or in patients with low chymotrypsin (24 [19-46] vs 43 [32-60], P = 0.03; Fig. 2B).
The pancreatic volume correlated with stimulated C-peptide (Fig. 3A) and with fecal α-chymotrypsin activity (Fig. 3B). Other parameters that were correlated with pancreatic volume were duration of diabetes, maximal weight, present weight (Table 2). Age, BMI, insulin dose, HbA1c, and fecal elastase-1 were not correlated with pancreatic volume. In multiple regression analysis, the pancreatic volume correlated with stimulated C-peptide and with fecal chymotrypsin (Table 3). The same correlation analysis was performed separately in patients with type 1 diabetes and in patients with type 2 diabetes. In patients with type 1 diabetes, pancreatic volume correlated only with fecal chymotrypsin activity (P = 0.03). Correlations with duration of diabetes (P = 0.10) and with stimulated C-peptide (P = 0.08) were close to significance. In patients with type 2 diabetes, the results were different: pancreatic volume correlated with stimulated C-peptide (P = 0.04) and maximal weight (P < 10−6) and was borderline with fecal chymotrypsin activity (P = 0.055). In patients with type 2 diabetes, those treated with insulin had lower pancreatic volume than those treated with oral medications. Pancreatic volume was 43 cm3 (25-48 cm3; insulin treated, n = 21) versus 75 cm3 (61-85 cm3; treated with oral medications, n = 6) (P = 0.0018). There was no correlation with either BMI (P = 0.48) or present weight (P = 0.14).
The main result of the present study is that the pancreatic volume is decreased in patients with diabetes, the more so when exocrine function tests are altered. We found that among the parameters we analyzed, only stimulated C-peptide and fecal chymotrypsin activity correlated with pancreatic volume. Other parameters were of borderline significance, for example, maximal weight ever reached in life in patients with type 2 diabetes and duration of diabetes in patients with type 1 diabetes. We found no correlation between pancreatic volume and either age or BMI. Correlations with these last 2 parameters were observed by Saisho and colleagues.6 But in the latter study, the correlation coefficients were quite low after puberty, 0.1 and 0.3, respectively. In 165 patients with type 2 diabetes, Saisho found modest 7% decreases of pancreatic volume.6
It has been a long-time observation that the pancreas may be small in patients with diabetes. It has been a more recent observation that tests of exocrine function may be altered in patients with either type 1 or type 2 diabetes. The correlation of pancreatic volume with exocrine function test was not unexpected because the exocrine pancreas represents more than 90% of the pancreatic volume.
On autopsy material obtained from 26 patients who died after long-duration type 1 diabetes, Löhr and Klöppel22 found markedly reduced pancreatic volume. There was no correlation with duration of diabetes nor with presence/absence of residual insulin positivity.
Lack of endogenous insulin has been suggested as causing atrophy of the pancreas in chronic diabetes.23 Using the secretin stimulation test, Frier and colleagues9 found a positive correlation of stimulated C-peptide and markers of exocrine function in the C-peptide-positive patients, data that have been confirmed by others in chronic pancreatitis24 and in patients with type 1 diabetes.25
There are few data on the morphology of the pancreas in vivo in patients with diabetes. These have been based on CT scans5-7 or magnetic resonance imaging26 or, more anciently, on ultrasonography.27-29 However, all these investigations have technical limits and have lacked precision in evaluation of the pancreatic volume. A strength of our study was the methodology of evaluation of the pancreatic volume. This was made on contiguous 1-mm-thick images with manual delimitation of the regions of interest. This greatly increases the precision of evaluation compared with previous series. As a consequence, however, it was not applicable to a large series of patients. There have been only few attempts to find clinicobiologic correlates of pancreatic volume in patients with diabetes. In the only previous work,5 exocrine function was evaluated by serum immunoreactive trypsin concentration, a parameter that is now considered only in the context of acute pancreatitis.
Several noninvasive tests are used to assess pancreatic exocrine function. Among them, fecal chymotypsin and fecal elastase are less sensitive but more broadly available than direct tests such as the secretin stimulation test that is considered the criterion standard.30,31 The 72-hour fecal fat assessment is considered less specific, and the difficulty to achieve the 100-g/d fat diet for 6 days has been underlined.31 The superiority of elastase-1 measurement to chymotrypsin determination in feces is debated,30 we thus chose to investigate both tests in patients who participated in the present study, although there have been few evaluations of chymotrypsin in the context of diabetes outside pancreatitis.32 To what extent fecal elastase or chymotrypsin truly reflects pancreatic exocrine function in patients with diabetes is a matter of discussion15,16,33 and will be addressed in a large series of patients (M.-F.P., manuscript in preparation). The morphology of the pancreas has, however, never been evaluated by morphometry in patients with exocrine dysfunction. We felt it was important to exclude other causes of diabetes that can associate with exocrine function, such as chronic pancreatitis, pancreatic cancer that is more frequent in patients with type 2 diabetes, or rare causes like MODY -534 or carboxyl ester lipase mutations.35 Our finding that pancreatic volume correlates with exocrine function in patients with diabetes is another evidence that gives credence to the reality of alteration of the exocrine pancreas in patients with diabetes. More recent evidence come from the anatomical data that are being collected in the nPOD project (www.jdrfnpod.org),36 it is of no doubt that patients with long-term type 1 diabetes can have extensive fibrosis of the pancreas and acinar atrophy. At this point, we can only speculate on the causes of pancreatic atrophy in patients with diabetes. Hypotheses include chronic inflammation,1,2 angiopathy,37 and extension of the autoimmune process to exocrine tissue in patients with type 1 diabetes.38
In conclusion, atrophy of the pancreas and exocrine deficiency are 2 related events in diabetes. Insulin deficiency may be causative. However, the role of other factors, such as angiopathy, needs to be investigated.
The authors thank Dr Ph Boudou for measurement of C-peptide.
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