In a clinical setting, diabetic autonomic complications (cardiac, gastrointestinal, urogenital, etc.) are often handled as separate entities. We investigated rectal sensitivity to heat, mechanical distension, and electrical stimulations in 20 patients with diabetes and symptoms of gastroparesis, to evaluate the extent of visceral neuronal damage. Furthermore, to evaluate the relation between the nervous structures we examined gastric emptying and cardiac autonomic function with the hypothesis being an association between these. We found that 60% of patients had delayed gastric empting. Rectal hyposensitivity was a general finding as they tolerated 67% higher thermal, 42% more mechanical, and 33% higher electrical current intensity compared to healthy controls. In patients, most heart rate variability parameters were reduced; they reported significantly more gastrointestinal symptoms and a reduced quality of life in all SF-36 domains. Shortened RR interval correlated with reduced rectal temperature sensitivity, and gastric retention rate was negatively associated with symptoms of nausea and vomiting. To conclude, in these patients with signs and symptoms of diabetic gastroparesis, rectal sensitivity was reduced, and heart rate variability was impaired. Thus, we suggest regarding diabetic autonomic neuropathy as a diffuse disorder. Symptoms of widespread autonomic dysfunction and sensory disorders should be expected and treated in these patients.
Gastrointestinal (GI) complaints are more common in all types of diabetes mellitus (DM) patients compared to the general population [
Until now, the majority of studies in this field have focused on diabetes complications of the upper GI tract. Knowledge about the extent of damage to the lower GI tract is sparse; however, in one of our recent studies we demonstrated rectal hyposensitivity in patients suffering from diabetic
We hypothesised that DM patients with upper GI symptoms are hyposensitive in the distal GI tract and that visceral sensitivity, gastric emptying rate, cardiac autonomic function, and clinical symptoms would be associated. Thus, the main aim of this study was to examine the rectosigmoid sensitivity to multiple modalities (heat, mechanical distension, and electrical stimulations) in diabetes patients with symptoms of upper GI dysmotility. Furthermore, we aimed to characterise these patients in terms of cardiac autonomic parameters, gastric emptying rate, quality of life, and GI symptom scores.
Twenty diabetes patients were included between August 2010 and October 2011 from the outpatient clinic at Haukeland University Hospital. Inclusion criteria were upper GI symptoms refractory to treatment, type 1 or type 2 DM, and age between 18 and 65 years. All patients had previously undergone a gastroscopy in order to rule out other causes of their complaints. Major exclusion criteria were implanted gastric electrical stimulation device, nonneuropathic pain conditions, uremia, alcohol abuse, and unwillingness to cease analgesics or prokinetics prior to sensory examinations. Two patients were unable to tolerate the rectosigmoid probe, but completed the other parts of the study. As a control group, 16 healthy volunteers without GI complaints were recruited from the medical departments at Bergen and Aalborg University Hospitals. Clinical characteristics of the study population are summarized in Table
Clinical characteristics.
Variables | Patients ( |
Controls ( |
---|---|---|
Age (years) | 44.5 (±9.6) | 44.8 (±9.3) |
Gender (male/female) | 5/15 | 5/11 |
Body mass index (kg/m2) | 26.5 (±5.1) | 24.4 (±3.4) |
Diabetes duration (years) | 26.5 (±9.9) | — |
Diabetes type (1/2) | 17/3 | — |
HbA1c (%) | 9.7 (±2.1) | 5.6 (±0.2) |
Smoking status (never/past/present) | 10/4/5 | 10/6/0 |
Retinopathy (%) | 65 | — |
Known neuropathy (%) | 55 | — |
Known cardiovascular disease (%) | 20 | 0 |
Creatinine level (IQ-range) ( |
69.0 (58.0–104.0) | 72.0 (66.5–78.0) |
Beta-blocker (%) | 20 | 0 |
ACEI/angiotensin receptor blocker (%) | 45 | 6 |
Statin use (%) | 65 | 6 |
Data are means (±SD) unless otherwise indicated.
ACEI = angiotensin converting enzyme inhibitor.
Prior to the experimental rectal sensory assessments, all patients had their gastric emptying rates evaluated. Twenty spherical radiopaque markers (diameter 4 mm, density 1.27 g/mm3) where given together with a standardized breakfast. The number of markers still present in the stomach was determined by the help of fluoroscopy after 4, 5, and 6 hours, enabling the calculation of an average retention rate. Gastroparesis was defined as a retention rate >26% in males and >63% in females through the 4–6 hour period. The method has a sensitivity of 34% and specificity of 97% compared to scintigraphy and has been further described and validated elsewhere [
On a separate study day, participants were instructed to fast for at least 6 hours prior to sensory examinations. In order to avoid the effect of glucose and insulin levels on GI sensations, both DM patients and healthy controls underwent a euglycemic hyperinsulinemic clamp procedure [
For evaluation of the heart rate variability—a measure of the cardiac autonomic nervous system—a 24 hour Holter ECG recording was performed in all participants (Schiller MT-200, Schiller AG, Baar, Switzerland). The following time-domain parameters where calculated: (1) RR intervals (representing the average heart rate), (2) standard deviation of normalized RR intervals (SDNN—representing the total variability), (3) standard deviation of 5-minute segments of normalized RR intervals (SDANN), (4) root mean square of the differences between successive normalized RR intervals (RMSSD—primarily representing the parasympathetic activity), and (5) the percentage of normalized RR intervals that differ more than 50% compared to the previous ones (pNN50—representing the parasympathetic dominance over the sympathetic activity) [
All participants completed two questionnaires. To evaluate GI symptoms, we used the Patient Assessment of Upper Gastrointestinal Disorder Severity Symptom Index (PAGI-SYM). It consists of 20 questions, and symptoms in the preceding two weeks are graded from 0 (no symptoms) to 5 (very severe symptoms). In addition to a total score, six subscales were calculated: postprandial fullness/early satiety, nausea/vomiting, bloating, upper abdominal pain, lower abdominal pain, and heartburn/regurgitation [
Statistical analyses were performed in SigmaPlot 11 (Systat Software Inc., San Jose, CA, USA), using a
Radiopaque marker (ROM) examination was performed in all patients and was positive for gastroparesis in 60% (12 out of 20). The mean 4–6 hour ROM retention rate in women (
All participants were successfully clamped, and the mean blood glucose levels were similar during testing (patients
(a) The rectal sensitivity to thermal stimulation. Patients showed overall hyposensitivity to heat (
The diabetes patients were also hyposensitive to electrical stimulation and needed significantly higher current intensities to reach the predefined VAS levels. All VAS levels average current intensity was
Technically acceptable 24-hour Holter results were obtained in 18 patients and 11 healthy volunteers. The heart rate was higher in patients (mean RR interval in patients
The patients scored significantly higher in all of the investigated aspects of upper and lower gastrointestinal symptoms (all
PAGI-SYM scores.
Patients | Healthy controls | ||
---|---|---|---|
Subscale item | Postprandial fullness | 3.50 (2.75–4.0) | 0.25 (0.0–0.44) |
Nausea/vomiting | 1.33 (0.50–3.25) | 0.0 (0.0-0.0) | |
Bloating | 3.50 (3.50–4.75) | 0.0 (0.0-0.0) | |
Upper abd. pain | 2.76 (±0.40) | 0.10 (±0.07) | |
Lower abd. pain | 2.00 (1.00–3.50) | 0.0 (0.0-0.0) | |
Heartburn/regurg. | 1.14 (0.86–2.61) | 0.0 (0.0-0.0) | |
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Total score | 2.25 (1.54–2.91) | 0.05 (0.0–0.23) |
Results of the patient assessment of upper gastrointestinal disorder severity symptom index (PAGI-SYM) questionnaire. Twenty patients and 15 healthy controls completed the questionnaire. Abd. = abdominal, regurg. = regurgitation. All
SF-36 scores.
Patients | Healthy controls | ||
---|---|---|---|
Subscale item | Physical functioning | 72.5 (40.0−85.0) | 100.0 (100.0-100.0) |
Role lim. phys. (RP) | 0.0 (0.0−50.0) | 100.0 (100.0-100.0) | |
Bodily pain | 41.6 (±26.6) | 88.5 (±12.6) | |
General health | 33.4 (±19.8) | 85.2 (±16.6) | |
Energy fatigue/vitality | 32.5 (±18.4) | 75.7 (±13.7) | |
Social functioning | 62.5 (37.5−75.0) | 100.0 (100.0-100.0) | |
Role lim. emot. (RE) | 100.0 (33.3−100.0) | 100.0 (100.0-100.0) | |
Mental health (MH) | 76.0 (68.0−80.0) | 84.0 (76.0−92.0) | |
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Summary scores | Physical comp. (PCS) | 33.3 (18.8−39.2) | 55.8 (54.0−57.3) |
Mental com. (MCS) | 47.7 (42.9−50.0) | 53.1 (48.5−55.3) |
Results of the Short Form-36 questionnaire, presented as median (IQ-range) or mean (±SD). Eighteen patients and 15 healthy controls completed the questionnaire. RP = role limitations due to physical health, RE = role limitations due to emotional problems, PCS = physical component summary and MCS = mental component summary.
All
According to our hypothesis, we investigated the associations between rectal sensitivity, gastric emptying, heart rate parameters, and gastrointestinal symptoms. There were no statistically significant correlations between rectosigmoid sensitivity and gastrointestinal symptoms (PAGI-SYM). The gastric retention rate was positively associated with the temperature sensitivity (
We have shown that patients with symptoms and signs of diabetic gastroparesis had sensory deficits in the distal gastrointestinal tract, indicating a widespread nature of visceral neuropathy. Furthermore, patients had reduced heart rate variability and increased mean heart rate, a sign of extensive autonomic dysfunction in DM. Differences in rectosigmoid compliance between DM patients and controls were not detected.
Major limitations include the relatively low number of study subjects and the mixed type 1 and type 2 DM cohort. Although the two conditions share some specific pathogenetic traits (in particular hyperglycemia), the symptom presentation and gastric emptying rate may differ slightly. Type 1 DM patients have been shown to be more prone to vomiting, whereas type 2 patients have relatively more nausea. On average, gastric retention is more pronounced in type 1 DM, although the differences are subtle [
Unlike the colon, the rectum receives innervation from both visceral (sacral) and somatic (pudendal) nerves. In this study we wanted to investigate the visceral afferents specifically, and the probe was positioned at least 15 cm above the anus, thus limiting involvement of the lower somatic nerve afferents. Although rectal sensations by nature primarily deal with the feeling of fullness and the urge to defecate, we chose a multimodal approach in order to obtain a comprehensive sensory profile. Thermal stimulation has the advantage of being highly reproducible. It stimulates the mucosal receptors directly, although it is probably less physiological in nature. Mechanical stimulation, on the other hand, is more physiological but also depends on the varying elastic properties of the rectum, the muscular tone, and neuromuscular feedback loops. Finally, electrical stimulation is highly reproducible; it bypasses the peripheral receptors entirely and depolarizes the nerve endings directly [
Gut sensitivity and motility are subject to modification by glucose and insulin levels. Both act as sensitizers to stretch in the stomach [
Reduced sensitivity in diabetes patients is not necessarily the product of
This study demonstrated that diabetes patients with symptoms of
In this explorative study, we only investigated the associations in line with our hypothesis. Gastric retention showed
Diabetic gastrointestinal complications are challenging to investigate and diagnose. This is partly not only due to the inaccessibility of GI organs but also due to the imprecise nature of GI motility measurements and the poor correlation between symptoms, GI dysmotility, and autonomic neuropathy [
In conclusion, this study provided evidence of the generalized nature of diabetic autonomic neuropathy. Diabetes patients with signs and symptoms of upper GI dysfunction displayed reduced rectal sensitivity to heat and mechanical and electrical stimulation. Also, the heart rate variability was impaired. In a clinical setting, the presence of autonomic dysfunction could be regarded as a diffuse neuropathic complication.
Analysis of variance
Body mass index
Diabetes mellitus
Electrocardiography
Gastrointestinal
Interquartile range
Magnetic resonance imaging
Patient assessment of upper gastrointestinal disorder severity symptom index
Radiopaque marker
Standard error of the mean
Standard deviation
Short Form-36
Visual analogue scale.
The authors declare that they have no conflict of interests.
Christina Brock, Magnus Simrén, Jens B. Frøkjær, and Asbjørn M. Drewes participated in study design; Eirik Søfteland, Christina Brock, Jens B. Frøkjær, and Georg Dimcevski participated in data collection; Eirik Søfteland, Christina Brock, and Georg Dimcevski participated in data analysis; all coauthors participated in interpretation of results; Eirik Søfteland and Georg Dimcevski participated in paper preparation. All coauthors participated in critical revision of paper. Eirik Søfteland is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
The authors would like to acknowledge the invaluable assistance of the Clinical Research Unit at Haukeland University Hospital. The research leading to these results has received funding from the European Community’s Seventh Framework Programme FP7/2007–2013 under Grant Agreement no. 223630 and from the Norwegian Diabetes Association.