Abstract
Background:
Studies on small intestinal transit in type 1 diabetes mellitus have reported contradictory results. This study assessed the orocecal transit time (OCTT) in a group of patients with type 1 diabetes mellitus and its relationships with gastrointestinal symptoms, glycemic control, chronic complications of diabetes, anthropometric indices, gastric emptying, small intestinal bacterial overgrowth (SIBO), and psychological distress.
Subjects and
Results:
There was a statistically significant increase in OCTT values in diabetes patients (79±41 min) in comparison with controls (54±17 min) (P=0.01). Individual analysis showed that OCTT was above the upper limit (mean+2 SD) in 30.8% of patients. All anthropometric parameters were significantly decreased (P<0.05) in patients with prolonged OCTT in comparison with those with normal OCTT. In contrast, there was no statistically significant association between prolonged OCTT and gastrointestinal symptoms, peripheral neuropathy, diabetic retinopathy, glycated hemoglobin, delayed gastric emptying, SIBO, anxiety, or depression.
Conclusions:
Small bowel transit may be delayed in about one-third of patients with long-standing type 1 diabetes mellitus. This abnormality seems to have a negative effect on nutritional status in these patients.
Introduction
Impaired intestinal motility has been mainly attributed to autonomic neuropathy in DM. 1,2 On the other hand, previous studies in healthy volunteers have shown that other factors may exert a reversible effect on GI transit, including hyperglycemia, 9 psychological, 10 and nutritional 11 factors. Reports on the influence of these parameters on intestinal transit in diabetes are scarce or still lacking.
Another issue that still needs clarification is the relationship between delayed intestinal transit and small intestinal bacterial overgrowth (SIBO) in DM. It has been suggested that delayed intestinal transit is an underlying factor for the presence of SIBO in diabetes. 12 However, one previous study showed a low prevalence of this complication in patients with type 1 DM despite the findings of prolonged OCTT. 13
Therefore, the aims of the present study were to assess OCTT in a group of patients with long-standing type 1 DM and to investigate the association of this parameter with GI symptoms, chronic complications of diabetes, glycemic control, gastric emptying, anthropometric indices, psychological distress, and SIBO.
Patients and Methods
Patients with type 1 DM
Twenty-eight patients with long-standing type 1 DM (22 women, six men; mean age, 39±9 years) attending the diabetes outpatient clinics of the State University of Campinas Hospital participated in the study. The inclusion criteria were patients with type 1 DM, age >18 years, and duration of diabetes >10 years.
Exclusion criteria were previous GI tract surgery, diabetic nephropathy, associated diseases that might cause intestinal dysmotility, use of medications known to influence GI transit, and use of antibiotics during the 2 months preceding the study.
Control group
The reference group for OCTT was the control group of our previous study composed of 24 healthy volunteers (13 men and 11 women; mean age, 34±8 years). 14
Ethical approval
The protocol was approved by the institutional ethics committee. Each patient and healthy volunteer gave written informed consent before participation in the study.
OCTT measured by the hydrogen breath test after lactulose ingestion
The method used for the hydrogen breath test was previously reported. 14 On the day before the test, the subjects were asked to eat a carbohydrate-free diet. After a 12-h overnight fast, they had a mouth washing with 50 mL of a 1% chlorhexidine solution, and a blood sample was taken for determination of fasting blood glucose. Then, two end-expiratory breath air samples were collected with a 10-min interval, using a Quintron GaSampler dual collection device (QuinTron Instrument Co., Milwaukee, WI). Following that, the participants ingested a meal consisting of two scrambled eggs and drank 200 mL of tea containing 20 g of lactulose. Breath air samples were then taken every 10 min for 90 min and after that every 15 min up to 240 min.
During the test period, the participants were not allowed to exercise, drink, eat, or smoke. In each collected sample, hydrogen concentration in parts per million (ppm) was measured on a gas chromatograph (model 12 Microlyzer; QuinTron Instrument Co.). The mean hydrogen concentration of the two fasting samples was taken as the baseline value. OCTT was defined as the time between the lactulose ingestion and a sustained increase in breath hydrogen of at least 10 ppm above the basal values. In addition, the presence of an early peak (>10 mm Hg) detected before 30 min of meal ingestion or baseline H2 level >20 ppm was regarded as suggestive of SIBO.
Clinical and laboratory data
A standardized questionnaire was used to obtain information about sociodemographic data and chronic GI symptoms. Parameters related to DM, including duration of disease, chronic complications such as retinopathy and peripheral neuropathy, and laboratory data, were recorded. Glycemic control was assessed by glycated hemoglobin (HbA1c) obtained by high-performance liquid chromatography analysis (reference range for healthy subjects, 4–6%).
The following GI symptoms were assessed: epigastric pain, early satiety, postprandial fullness, nausea, vomiting, abdominal pain, abdominal bloating, constipation, diarrhea, and fecal incontinence. According to their intensity, these symptoms were classified on the following scale: 0=none; 1=mild; 2=moderate; and 3=severe. For the purpose of data analysis, only symptoms with moderate or severe intensity occurring more than once a week were considered. Constipation and diarrhea were defined according to the Rome III criteria 15 and the Bristol stool form scale. 16
Anthropometric measurements
Anthropometric measurements included weight, height, body mass index (BMI), skinfold thickness, percentage body fat, midarm circumference (MAC), and arm muscle area (AMA). 17 The data on weight and height were used to calculate BMI. 18 MAC was measured using a flexible plastic tape; skinfold thickness at the biceps, triceps, subscapular, and suprailiac was measured with a Lange skinfold caliper (Beta Technology, Santa Cruz, CA). All measurements were taken in triplicate, and the average value was calculated. AMA (in cm2) was calculated using triceps skinfold thickness (TSF) and MAC (in cm) from the following equation: for men, AMA=([MAC−π×TSF]2/4π)−10; for women, AMA=([MAC−π×TSF]2/4π)−6.5. 19 The percentage of body fat was estimated from the patient`s body weight and height and the TSF and biceps, subscapular, and suprailiac skinfold thicknesses using the equations of Durnin and Womersley. 20 Patients were classified as malnourished when at least two anthropometric measures were below the 5th percentile of the reference values of Frisancho 17 (see Gurney and Jelliffe 19 ).
Psychological assessment
The presence of anxiety and depression was assessed by the previously validated Portuguese version of the Hospital Anxiety and Depression (HAD) scale divided into subscales for anxiety and depression. 21 The score for each subscale ranges from 0 to 21. Scores higher than 8 in either HAD subscales were considered to indicate anxiety or depression, respectively.
Gastric emptying study
Gastric emptying of a solid meal was measured by scintigraphy, as previously reported. 22 In brief, patients were studied in the morning, after an overnight fast of at least 12 h. The test meal consisted of an omelet made with 3 eggs, labeled with 185 MBq of 99mTc-sulfur colloid. Simultaneous 1-min anterior and posterior images of the stomach were acquired with the subjects sitting between the two detectors of a dual-head γ-camera. Images were taken immediately after meal ingestion and every 10 min for 120 min. Regions of interest were manually drawn around the whole stomach, and the geometric means of anterior and posterior counts were calculated at each time interval. Time–activity curves for the whole stomach were then obtained by plotting the percentage of the maximal counts against time, and the half-emptying time (T ½) (in min) was determined. The reference values for scintigraphy were determined in our previous study 22 as 88±16 min (median, 83 min), and the upper limit of normal was regarded as 120 min, considering the normal range as the mean±2 SD.
Statistical analysis
Continuous variables were reported as mean±SD or medians, and categorical variables were reported as percentages. Comparisons of the results were performed by the Mann–Whitney U test, Student's t test, and Fisher's exact test as appropriate. Correlations between OCTT values and HAD scores, T ½ values, and HbA1c levels were assessed using the Spearman correlation coefficient. All statistical analyses were carried out using SPSS version 17.0 for Windows (SPSS, Inc., Chicago, IL). A value of P<0.05 was considered to be significant.
Results
Clinical characteristics and laboratory data of diabetes patients are summarized in Table 1. The mean duration of diabetes was 23±7 years. All patients were receiving insulin therapy, and none of them was on combined treatment with metformin. Retinopathy was identified in 85.7% of the patients, and peripheral neuropathy was found in 42.9%. Mean HbA1c was 9±1.7%, indicating poor glycemic control in our study group. The main GI symptoms reported by the patients were abdominal bloating (46.4%) and postprandial fullness (39.3%). According to their bowel habits, five patients (17.9%) had diarrhea, and eight (28.6%) had constipation.
For patients with orocecal transit time (OCTT) results (n=26).
HbA1c, glycated hemoglobin.
OCTT
The mean value of OCTT in the control group was 54±17 min. There was no statistical difference in OCTT values between men and women (P>0.05). Considering the normal range as the mean±2SD, the upper limit of the test was 88 min.
Patients with type 1 DM
Breath hydrogen did not increase above the basal levels in two diabetes patients. They were therefore excluded from the statistical analysis.
The mean value of OCTT in patients with type 1 DM was 79±41 min. There was no statistical difference in OCTT between female (76±42 min) and male (93±37 min) patients (P=0.14).
OCTT values were significantly increased (P=0.01) in diabetes patients in comparison with the control group. Individual analysis showed that eight patients (30.8%) had OCTT above the upper limit of the normal range of the test.
SIBO
SIBO was observed in three patients (11.5%): one with prolonged OCTT (120 min) and two with OCTT values within the normal range.
Gastric emptying
The median T ½ value for the whole group was 83 min. The comparison with the control group showed no significant difference (P>0.05). However, individual analysis identified nine patients (32.1%) with T ½ above the upper limit of normal of the test, indicating delayed gastric emptying.
HAD scale scores
Twenty-seven patients completed the HAD scale. According to the scale scores, 16 patients (59.2%) had some type of psychological distress. Seven patients (25.9 %) had anxiety, two had depression (7.4%), and seven (25.9%) had anxiety associated with depression.
Anthropometric parameters
The mean values of the evaluated anthropometric parameters are shown in Table 2. According to BMI, 13 patients (46.4%) were overweight (BMI between 25 and 29.9 kg/m2), one (3.6%) was obese, and 50% were classified as eutrophic. However, considering TSF, MAC, and AMA values, three patients (10.7%) could be classified as malnourished. There was no significant association (P>0.05) between the evaluated anthropometric parameters and the clinical and laboratory data, T ½, HbA1c level, anxiety, or depression.
OCTT, orocecal transit time.
Associations with delayed intestinal transit
Tables 1 –3 show the comparisons between patients with prolonged or normal OCTT in relation to the variables studied.
n=27.
n=17.
n=26.
OCTT, orocecal transit time; SIBO, small intestinal bacterial overgrowth; T ½, half-emptying time.
Clinical and laboratory features and glycemic control
There was no statistically significant difference between patients with prolonged versus those with normal OCTT in parameters like age, duration of diabetes, presence of peripheral neuropathy or retinopathy, GI symptoms, fasting blood glucose levels measured on the day of OCTT test, and HbA1c levels. OCTT values were similar in patients with constipation (78±39 min) or diarrhea (75±31 min) (P>0.05). In addition, OCTT values did not correlate (P>0.05) with those of HbA1c.
Anxiety and depression
No significant correlation was found between OCTT and the scores for anxiety (P=0.62) or depression (P=0.37). In addition, the prevalence of anxiety and/or depression did not differ (P>0.05) between patients with prolonged or normal OCTT.
Anthropometric parameters
The mean value of OCTT was 78±43 min in overweight and obese diabetes patients and 80±40 min in eutrophic patients (P=0.80).
On the other hand, the values of all anthropometric parameters measured in the present study (i.e., BMI, percentage body fat, MAC, and AMA) were significantly decreased in patients with prolonged OCTT (Table 2).
T ½ values
No significant correlation was found between OCTT and T ½ values (r=−0.10, P=0.65). In addition, median T ½ values were similar in diabetes patients with prolonged or normal OCTT (P>0.05).
Discussion
The present study showed evidence of prolonged OCTT in about one-third of patients with long-standing type 1 DM. This observation is consistent with the data from earlier studies that used the lactulose breath test to assess OCTT. 7,8,12,13
The lactulose breath hydrogen test has been widely used in the assessment of small bowel transit time. 23 Although measures of OCTT may reflect both gastric emptying and intestinal transit, it is accepted that OCTT determined by the lactulose breath test represents intestinal transit times, considering that lactulose leaves the stomach straight away. 24 Our results showed that prolonged OCTT was not associated with delayed gastric emptying, reinforcing the assumption that intestinal transit is in fact delayed in this subgroup of diabetes patients.
Our study confirmed the high prevalence of GI symptoms in patients with DM. 25 Alterations in bowel habits were observed in 46.4% of our patients, but we found no association between delayed intestinal transit and constipation, diarrhea, or any other GI symptom. These results are in keeping with those of other studies showing that the correlation between motor abnormalities and symptoms is poor in DM. 1,8 In fact, the pathogenesis of GI symptoms in DM appears to be multifactorial.
We also investigated whether parameters known to influence intestinal transit were associated with the finding of prolonged OCTT in our study group. It is now recognized that besides autonomic neuropathy, acute hyperglycemia plays an important role in the pathogenesis of the disorders of GI motility. 2,26 Studies in healthy volunteers showed that small intestinal transit time is significantly prolonged during acute hyperglycemia (blood glucose, 12–15 mmol/L) in comparison with normoglycemia. 9,27 On the other hand, the majority of studies in diabetes patients have focused on the inhibitory effects of hyperglycemia (blood glucose, 16–20 mmol/L) on gastric motility, and little is known about the influence of this factor on intestinal motility. The mean blood glucose level (11 mmol/L) measured on the day of OCTT test in our diabetes patients was lower than that previously shown to inhibit small intestinal motility and did not differ between patients with prolonged or normal OCTT. It appears therefore that the fasting blood glucose level did not contribute to the finding of delayed intestinal transit in our study group.
Information about the effect of long-term glycemic control measured by HbA1c on GI motor function is limited. 26 The investigation of the relationship between HbA1c and gastric emptying showed contradictory results. 28 On the other hand, the previous studies on small intestinal transit in diabetes patients did not address the potential influence of chronic glycemic control on the observed alterations. In the present study HbA1c levels were comparable between patients with delayed or normal intestinal transit. This result may suggest that long-term poor glycemic control cannot predict the presence of delayed intestinal transit in type 1 DM. However, it should be noted that HbA1c was elevated in all patients, and therefore we cannot rule out an influence of glycemic control on our results.
Our observation of anxiety and depression in a large proportion of our diabetes patients is also consistent with the observations of several investigators. 29,30 The effect of psychological distress on intestinal transit was investigated by Gorard et al., 10 who reported shortened OCTT in patients with anxiety disorder and a trend for prolongation of OCTT in those with depression. The influence of psychological factors on intestinal transit in type 1 DM has not been previously investigated. In the current study no significant correlation was found between OCTT values and HAD scores, and anxiety and depression scores did not differ between patients with delayed or normal intestinal transit. These data suggest that psychological distress does not play a major role in the pathogenesis of delayed intestinal transit in DM.
However, it should be noted that we cannot exclude the possibility that some negative results of the present study may be related to a Type 2 error. Therefore further studies with a large sample of patients with type 1 DM comprising both patients with well-controlled diabetes and diabetes patients with poor glycemic control are called for to confirm our observations.
Our finding of delayed gastric emptying in 32.1% of diabetes patients is consistent with the results of previous studies showing that gastric emptying is delayed in about 30–50% of patients with long-standing type 1 DM. 31 It is interesting that although the correlation between gastric emptying and OCTT was not statistically significant, our results suggest a trend for an inverse relationship between the two parameters. This would be an unexpected finding, considering that previous studies have shown either a lack of correlation 13 or an association 2 between gastroparesis and delayed intestinal transit in type 1 DM. Thus, additional studies with larger series of patients are needed to clarify this relationship.
The elevated proportion of overweight in our diabetes patients is in agreement with recent reports in type 1 DM. 32 The results of the studies that evaluated the influence of BMI on GI transit are inconclusive. 33 Some studies suggested that gastric emptying is faster in obesity, whereas others showed normal or delayed gastric emptying. 34 One study showed prolonged OCTT in obese patients in comparison with healthy controls, 35 whereas other authors reported faster small bowel transit in women with overweight in comparison with lean women. 36 In contrast, Madsen 11 found no influence of BMI on intestinal transit. The results of the current study suggest that the presence of overweight had no influence on the finding of delayed intestinal transit in our patients with type 1 DM. On the contrary, all evaluated anthropometric indices were decreased in those patients with prolonged OCTT. This indicates that delayed intestinal transit may be associated with an worsening of nutritional status in DM, considering that skinfold thickness is an index of fat storages and that MAC and AMA reflect protein reserves. 19,20 However, it should be emphasized that in the present study the nutritional evaluation was based on a few parameters. A comprehensive nutritional assessment still relies on the analysis of several combinations of anthropometric, biochemical, immunological, functional, and body compositional data, in addition to dietary intake and clinical status evaluation. 17 Therefore additional studies are necessary to obtain a more complete picture of the nutritional deficiencies in these patients.
One possibility to explain the decreased nutritional indices in diabetes patients with delayed intestinal transit could be the presence of SIBO, which has been shown to lead to diarrhea, malabsorption of nutrients, and weight loss. 37 Conversely, it has been suggested that malnutrition itself might lead to delayed intestinal transit. 38 In this case, prolonged intestinal transit would represent an adaptation of the small bowel that would allow more absorption time.
The reported prevalence of SIBO in DM varies depending on the method of investigation, the diagnostic criteria used, and the presence of diabetes complications. Ojetti et al. 39 identified SIBO in 26% of type 1 DM patients in association with autonomic neuropathy. Sarno et al. 13 reported a low prevalence of SIBO despite the findings of prolonged OCTT in patients with type 1 DM. In contrast, other studies concluded that SIBO was related to the altered intestinal motor function in these patients. 12,40 In the present study, the prevalence of SIBO was relatively low (11.5%) but not very different from the 15.5% reported by Rana et al. 12 in type 2 DM. However, the small number of patients with SIBO and the fact that only one of them presented prolonged OCTT do not permit us to draw any conclusion on the potential relationship between these two complications of diabetes.
Conclusions
In conclusion, we found evidence of delayed intestinal transit in about-one-third of patients with long-standing type 1 DM. This abnormality was not associated with GI symptoms, peripheral neuropathy, retinopathy, delayed gastric emptying, psychological distress, HbA1c levels, or SIBO. On the other hand, prolonged OCTT was associated with decreased nutritional parameters, suggesting that delayed intestinal transit may have a negative influence on nutritional status in patients with type 1 DM.
Footnotes
Author Disclosure Statement
No competing financial interests exist.