TY - JOUR
AU - MD, Cornelius L Bollheimer,
AB - Background Pancreatitis and exocrine pancreatitic insufficiency have been described as extraintestinal manifestations of inflammatory bowel disease. In this study, we investigated whether the endocrine pancreatic function is also disturbed in patients with inflammatory bowel disease. Methods Seventeen patients with Crohn's disease and 13 healthy volunteers participated in the study. We analyzed the plasma insulin response in a 75-g oral glucose tolerance test. Glucose and insulin levels were determined at time 0 (fasting levels) and 30, 60, 90, 120, 180, 240, and 300 min after glucose uptake. Insulin resistance and β cell function (BCF) were analyzed by calculating respective indices. Results Fasting and oral glucose-tolerance test glucose levels appeared to be similar in patients with Crohn's disease and in the controls. Impaired fasting glucose, impaired glucose tolerance, and/or overt diabetes mellitus were not observed in the volunteers. Insulin as well as the index for BCF were significantly increased in patients with Crohn's disease. In addition, insulin resistance was shown to be significantly elevated in Crohn's disease. Conclusions Patients with Crohn's disease reveal an increased insulin secretion caused by an enhanced BCF, which may be induced by an up-regulated enteropancreatic axis. This hypersecretion may override the insulin resistance given by the chronic inflammatory state. Crohn's disease, endocrine pancreas function, oral glucose tolerance test Inflammatory bowel disease (IBD) may have many extraintestinal manifestations, including pancreatitis and exocrine pancreatic insufficiency.1,–4 Based on autopsies, Ball and Bargen observed concomitant subclinical pancreatitis in 46 of 84 (55%) patients suffering from IBD.4 Hegnhoj and colleagues investigated the exocrine pancreatic function of 143 patients with Crohn's disease (CD) and found 2 factors to be responsible for impaired pancreatic function: disease activity and localization or extent of disease.5 In contrast to the exocrine function, data about the endocrine function of the pancreas in patients with IBD are rare and inconclusive. The topic was first investigated by Angelini et al, who performed oral glucose-tolerance tests (OGTTs) on 27 IBD patients, and no significant differences in comparison to healthy controls were noted.6 Bendet and coworkers investigated insulin secretion in patients with CD during a 3-hour OGTT and reported that the values of the homeostatic model assessment (HOMA; see below) were decreased in patients with CD.7 The normal uptake of glucose from the blood (i.e., the glucose tolerance) depends on the insulin sensitivity of the peripheral tissue (e.g., muscle) and on the height of the β cellular insulin secretion. Progressive impairment of these 2 processes can lead to glucose intolerance and eventually to full-blown type 2 diabetes mellitus. An expanded OGTT with a 5-hour measurement of blood glucose and insulin is a simple approach for estimating both insulin sensitivity and β cell function (BCF) in a clinical setting.8 In the present study, we employed the OGTT to evaluate the endocrine pancreatic function of patients with CD. Methods Patients Seventeen patients with CD (8 men, 9 women) were enrolled in our study. Patients have been recruited while hospitalized or visiting our outpatient clinic. Diagnosis had to be certain for at least 1 year. Thirteen healthy (8 men, 5 women) volunteers served as controls (Table 1). Table 1. Clinical Baseline Characteristics of Study Participants     View Large Table 1. Clinical Baseline Characteristics of Study Participants     View Large Methods Family history, general history, drugs used, and so forth were monitored by a questionnaire. The activity of the disease was evaluated by the CD activity index (CDAI).9 C-reactive protein and total white blood cell count were used as markers for inflammation. All of the patients and healthy volunteers were subjected to a 5-hour OGTT after fasting overnight. After obtaining fasting serum (pending analysis of glucose and insulin), a standard OGTT was performed by having the patients ingest a liquid solution containing 75-g glucose. Then glucose, insulin, and C-peptide levels were measured after 30, 60, 120, 180, 240, and 300 min (normal range for fasting insulin: 2-25 μU/mL). For insulin resistance, the HOMA index was generated according to the following formula: HOMA = | (Fasting Glucose [mg/dL] × Fasting Insulin [μU/mL]) ÷ 22.5 |. High levels of the HOMA index (normally <2.4) indicated insulin resistance. The assessment of the pancreatic BCF was based on the concept of the insulinogenic index (IGI) and was calculated by an area under the curve analysis (AUC) of insulin secretion divided by the AUC value of corresponding glucose during the first 120 min of OGTT.10,–12 Statistics The statistical SPSS package version 11.0 (SPSS, Chicago, Ill) was used for the statistical analysis. Comparisons were made using the Mann-Whitney U test and the χ2 test to analyze qualitative data. Pearson's correlation coefficient was used to measure the strength of the association between 2 variables. Statistical significance was established at P < .05. Ethical Considerations The study was approved by the local Ethics Committee. Results Characterization of the Study Population Patients with CD and controls were comparable in terms of age, sex, and body mass index (BMI). The mean CDAI of the patients with CD was 214 (range 68-510). Ten patients were in remission (i.e., CDAI < 220), 6 were moderately active (i.e., CDAI 220-450), and 1 patient had severe disease (i.e., CDAI > 450). None of the patients showed abnormal serum lipase levels (Table 1). Seven patients were treated with steroids (average 15 mg/day [range 5-60 mg/day]) and 1 patient was treated with 3-mg budesonide daily. Glucose Fasting glucose levels in all patients and in all controls were within the physiological range of <110 mg/dL. There were no quantitative differences between the patients and the controls either in terms of fasting glucose nor within the time course during OGTT (Fig. 1). When comparing the basal glucose levels and the glucose course during OGTT in patients with active and inactive disease, we found comparable basal glucose levels and significantly decreased glucose levels in patients with active disease after 30 min (t0: P = .07; t30′: P = .01; t60′: P = .11; t120′: P = .96; t180′P = .42; t240′: P = .48; t300′: P = .54). In patients with and without steroid medication, basal glucose levels and glucose course during OGTT were comparable. Insulin When comparing the basal insulin and the insulin course during OGTT, patients with CD revealed significantly higher levels than healthy controls (t0: P = .002; t30′: P = .057; t60′: P = .019; t120′: P = .028; t180′P = .016; t240′: P = .057; t300′: P = .052; Fig. 1). Figure 1. View largeDownload slide Glucose and insulin during a 5-hour OGTT: 17 CD patients (▪) and 13 healthy controls (○) received 75-g glucose after an overnight fast. The 5-hour time course for serum glucose and corresponding serum insulin are depicted as mean ± standard error. Figure 1. View largeDownload slide Glucose and insulin during a 5-hour OGTT: 17 CD patients (▪) and 13 healthy controls (○) received 75-g glucose after an overnight fast. The 5-hour time course for serum glucose and corresponding serum insulin are depicted as mean ± standard error. HOMA Index Although the mean of the HOMA values (derived from fasting glucose and fasting insulin) among the patients with CD was still within the generally accepted normal range of <2.4, it was significantly higher than that of the controls, indicating a higher insulin sensitivity (P = .009; Fig. 2A). Interestingly, patients with active disease (CDAI ≥150) showed significantly (P = .01) lower values for HOMA (i.e., had a lower degree of insulin resistance) than the patients with inactive disease (CDAI <150; Fig. 2B). It must also be emphasized that the HOMA of patients using steroids did not differ from the HOMA of patients who were not using steroids. The steroid dose used (P = .851; r = −0.09) and the BMI (P = .343; r = 0.18) had no relevant influence on the HOMA. Figure 2. View largeDownload slide HOMA index as a measure for increased insulin resistance in CD patients. The HOMA index was calculated using the fasting glucose and its corresponding serum insulin as described in Methods. A, Comparison of healthy volunteers (N = 13) and CD patients (N = 17). B, Comparison of healthy controls and patients with a CDAI ≥150 (N = 10) to patients with a CDAI <150 (N = 7). Data are depicted as Turkey's box and whisker blots. Figure 2. View largeDownload slide HOMA index as a measure for increased insulin resistance in CD patients. The HOMA index was calculated using the fasting glucose and its corresponding serum insulin as described in Methods. A, Comparison of healthy volunteers (N = 13) and CD patients (N = 17). B, Comparison of healthy controls and patients with a CDAI ≥150 (N = 10) to patients with a CDAI <150 (N = 7). Data are depicted as Turkey's box and whisker blots. IGI Index The IGI index, which is a parameter for BCF, was significantly increased in patients with CD compared with that in healthy volunteers (P = .025; Fig. 3A). In contrast to the HOMA, however, the IGI index did not differ significantly between patients with high and low activity (Fig. 3B; P = .89; r = −0.09). There was also no significant difference between the IGI of patients taking steroid medication and that of patients not taking steroids. The steroid dosage used (P = .836) and the BMI (P = .559; r = 0.11) did not significantly influence the IGI in our study population. Figure 3. View largeDownload slide IGI index as a measure for an increased β cell activity in CD patients. Based on the 120-min time course for glucose and the corresponding insulin after an oral glucose load, the IGI index was calculated as described in Methods. A, Comparison of healthy volunteers (N = 13) and CD patients (N = 17). B, Comparison of healthy controls and patients with a CDAI ≥150 (N = 10) to patients with a CDAI <150 (N = 7). Data are depicted as Turkey's box and whisker blots. Figure 3. View largeDownload slide IGI index as a measure for an increased β cell activity in CD patients. Based on the 120-min time course for glucose and the corresponding insulin after an oral glucose load, the IGI index was calculated as described in Methods. A, Comparison of healthy volunteers (N = 13) and CD patients (N = 17). B, Comparison of healthy controls and patients with a CDAI ≥150 (N = 10) to patients with a CDAI <150 (N = 7). Data are depicted as Turkey's box and whisker blots. Discussion Although impairment of the exocrine pancreatic function in inflammatory bowel disease has been acknowledged by many authors,1,–6 its endocrine function in IBD has been addressed by only 2 groups-Angelini and coworkers in 1988 and Bendet and coworkers in 2004. In the first study,6 patients with IBD were found to have a normal glucose tolerance and showed no difference from healthy controls (normal glucose tolerance = blood glucose <140 mg/dL after a 2-hour OGTT). A more detailed analysis of insulin sensitivity and/or BCF was not performed in that study, however.6 In a later study, Bendet and coworkers found increased insulin secretion during a 3-hour OGTT.7 They also reported decreased HOMA values in patients with CD, which appeared to be accidentally interpreted by the authors as a sign of decreased insulin sensitivity (i.e., increased insulin resistance).7 It was further proposed that such an increase of insulin resistance in CD may be caused by the chronic inflammatory status. Bendet et al investigated the levels of glucagon-like peptide-1 (GLP-1) in their patients and found enhanced secretion of GLP-1 in patients with CD, which was associated with higher plasma insulin.7 GLP-1 is known to develop a most profound glucose-lowering effect, which is derived from1 the stimulation of insulin release,2 an inhibition of glucagon release,3 slowing of gastric emptying,4 and a decrease in appetite mediated at the level of the hypothalamus.13,–16 In comparison to these 2 studies, the present study confirmed the findings of Angelini et al. No significant difference in fasting glucose and glucose levels during the OGTT suggests similar glucose tolerance in patients with CD when compared with healthy controls. Glucose tolerance may, however, only be a rough parameter for insulin sensitivity. When calculating the HOMA index we found it increased (not decreased) in patients with CD, which suggests decreased insulin sensitivity (i.e., increased insulin resistance). It is noteworthy that the HOMA values (i.e., insulin resistance) were found to be lower in patients with active CD (CDAI ≥150) than in patients with inactive disease (CDAI <150). This argues against chronic inflammation as a possible cause for insulin resistance and requires further investigation. Despite insulin resistance, an additional up-regulation of the enteropancreatic axis as proposed by Bendet et al7 may explain the hypersecretion of insulin, which obviously overrides insulin resistance as demonstrated by the elevated IGI in the present study. Here, it should be emphasized that the fasting and OGTT glucose levels were within the normal range and were not elevated for impaired fasting glucose and/or impaired glucose tolerance levels. Increased insulin secretion and increased insulin resistance can therefore not be interpreted as indicators of a prediabetic state in patients with CD. Instead, the increased insulin secretion may indicate an increased risk of hypoglycemia and may explain the difficulties in terms of a sufficient metabolic control during parenteral nutrition in highly active CD. References 1. Axon ATR, Ashton MG, Lintott DJ. Chronic pancreatitis and inflammatory bowel disease. Clin Radiol.  1979; 30: 179– 182. Google Scholar CrossRef Search ADS PubMed  2. Eisner TD, Goldman IS, McKinley MJ. Crohn's disease and pancreatitis. Am J Gastroenterol.  1993; 8: 583– 586. 3. Herrlinger KR, Stange EF. The pancreas and inflammatory bowel disease. Int J Pancreatol.  2000; 27: 171– 179. Google Scholar CrossRef Search ADS PubMed  4. Ball WP, Bargen JA. Pancreatic lesions associated with chronic ulcerative colitis. Arch Pathol.  1950; 50: 347– 358. 5. Hegnhoj J, Hansen CP, Rannem T, et al. Pancreatic function in inflammatory bowel disease. Gut.  1990; 31: 1076– 1079. Google Scholar CrossRef Search ADS PubMed  6. Angelini G, Cavallini P, Bovo P, et al. 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Fehmann HC, Göke R, Göke B, et al. Proming with GLP-1 (7-36) amide, GIP and CCK-8 enhances glucose induced insulin secretion from the isolated perfused rat pancreas. Digestion.  1990; 46( Suppl. 1): 32– 33. Google Scholar CrossRef Search ADS   16. Mojsov S, Weir CG, Habner JF. Insulinotropin: glucagon-like peptide 1 (7-36) co-encoded in the glucagon gene is a potent stimulator for insulin release in the perfused rat pancreas. J Clin Invest.  1987; 79: 616– 619. Google Scholar CrossRef Search ADS PubMed  Copyright © 2005 by Lippincott Williams & Wilkins.
TI - Increased Insulin Resistance and β Cell Activity in Patients With Crohn's Disease
JF - Inflammatory Bowel Diseases
DO - 10.1097/01.MIB.0000195975.97673.f5
DA - 2006-01-01
UR - https://www.deepdyve.com/lp/oxford-university-press/increased-insulin-resistance-and-cell-activity-in-patients-with-crohn-1n2RYR04vl
SP - 53
EP - 56
VL - 12
IS - 1
DP - DeepDyve
ER -