Visceral perception and gut changes in diabetes mellitus

Neurogastroenterol. Mot . 11994) 6,85-94

Visceral perception and changes in diabetes mellitus

S. SARNO,' L . P. ERASMUS,' M. HASLBECK' & R. HOLZL'

'Klinische Psychologie, Universitat Mannheim, Germany 'Forschungsgruppe Diabetes 111. Medizinische Abteilung Krankenhaus Munchen-Schwabing, Germany

Abstract Colonic perception threshold and pain threshold for distension stimuli were measured in 19 healthy subjects and in 19 long-standing insulin- dependent Type I diabetics who had autonomic and peripheral neuropathy and complained of gastrointestinal symptoms. The age range 26-72 years in both groups. Neither perception threshold nor pain threshold was significantly different between patients and controls. Abnormal delay of the primary evoked contraction after stimulus was found in 44% of the patients and abnormal colonic oscillation after stimulus was recorded in 53% of the patients. The colonic wall trended to higher compliance in diabetics. These abnormalities did not correlate with perception or pain threshold, suggesting that the sensory afferent and motor efferent systems work relatively independently. Also, the abnormalities did not correlate with the type of gastrointestinal symptom, metabolic state or half- time gastric emptying. Results suggest a substantial integrity of the colonic afferent system, a local derangement of the colonic wall with an impairment of the enteric system and a probable derangement of efferent pathways.

Keywords colonic motility, diabetes mellitus, interoception, visceral nociception.

INTRODUCTION

Investigation of colonic perception and nociception can improve our understanding of the brain-gut interaction and of the feedback mechanisms regulating gastrointestinal motility. Visceral sensation is mediated by the vagal and spinal afferent innervation and is involved in multiple reflex loops regulating gastrointestinal effector function as smooth muscle contraction, se-

Address for correspondence Dr Stefania Sarno, Universitat Mannheim, Klinische Psycholo- gie, Im Schloss, D-68 13 1 Mannheim, Germany. Received: 13 September 1993 Accepted for publication: 7 January 1994

cretion, absorption, and blood flow.' Vagal afferent innervation has been found in the oesophagus, stomach, small intestine, proximal colon and caecum' whereas the distal colon is supplied by two separate afferent pathways that project through the colonic nerves to the thoracolumbar segments and through the pelvic nerves to the sacral segments of the spinal ~ o r d . ~ - ~ In particu- lar, perception and nociception in distal colon mainly depend on the integrity of the sacral primary afferent innervation, which is generally thought to be of great importance not only for colonic sensation but also for reflex control of bowel motility, including peristalsis and sphincter control.'

In vivo studies in humans which are able to verify the reciprocal influence of visceral afferent input and main- tenance of bowel functional homeostasis are rare. A long-standing diabetic population with autonomic and peripheral neuropathy, and complaining of gastrointestinal symptoms seemed to us a good model for the investigation of (a) eventual impairment of perception and nociception in the lower gut and (b) influence of such impairment on the feedback mechanisms regulating intestinal motility and functions.

MATERIALS AND METHODS

Perception threshold and pain threshold in the colon were measured in 19 Type I diabetic patients and 19 healthy controls. Assessment of local (motor) and central (sensory) response to phasic and tonic distension of the gut was possible by means of a computerized pumping system and a special colon probe.7

Before the examination of colonic perception, patients underwent a routine clinical diagnosis. Auto- nomic neuropathy was assessed using Ewing's index' of respiratory sinus arrhythmia. A bidirectional thermal stimulation unit (Path-tester, Toennies Inc., Hochberg, Germany) was used to acquire cold and warm thresholds of the feet, which is a valid clinical diagnostic method for peripheral neuropathy.' Gastric emptying (half-time) of a semi-solid meal was assessed with scintiscanning

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Figure 1 Colonic probe: the silcolatex balloon is inflated through a catheter inside the probe which is connected with

E x t e r n a l t u b e I I the computerized pumping system

method. Metabolic state (HbA1,) was also examined. As all these clinical parameters were not acquired in the control group, results were compared with known norm value^.^,^

Apparatus

The colon probe is a flexible silcolatex tube with a 14- mm external diameter (Fig. 1). A ballon tube is fixed at both ends on the carrier tube and inflated trough a PVC catheter inside the probe. It can be easily inserted into the rectum and sigma-colon using a smoothing gel. The stiffness of the probe is optimized to allow comfortable insertion without endoscopical or radiological control7 In this study we inserted the probe 35 cm ab ano, thus positioning the balloon in the sigma-colon.

The pumping system consists of a syringe-type pump driven by a stepping motor and a programmable control unit. It allows the pumping of volumes up to 500 ml with a resolution of 0.1 ml. Speed is adjustable from 0 to 50 ml sec-' in steps of 0.1 ml sec-'. We used 50 ml sec-' for application of phasic stimuli and 20 ml sec-' for tonic stimuli. The balloon predistension before application of the stimuli was performed at a speed of 0.2 ml sec-'. Pressure is measured in the catheter, at the conjunction between probe and pump. Influence of the elastomer characteristics of the balloon was noted by

individual calibration of the balloon at nine volume steps (5, 10, 15, 20, 40, 60, 110, 160 and 200 ml), which was performed before each examination.' Dynamic characteristics allow the evaluation of pressure values from 1.5 sec after inflation, i.e. after end of inflating due to pneumatic resistance of the probe catheter.

A specially developed software allows the application of well defined stimuli as well as simultaneous recording of intraluminal pressure, additional biosignals such as heart rate, respiration and the subject's answers given by means of a key-board after each trial.

Patients and subjects

Nineteen long-standing Type I insulin-requiring diabetic in-patients, and 19 healthy controls (8 males and 11 females in each group), participated to this study. The 19 patients were selected among a larger number of diabetics who took part in our study, to build an homo- geneous group in respect to severity of impairments. All patients had peripheral and autonomic neuropathy and complained of gastrointestinal symptoms: 7 patients complained of diarrhoea, 8 of constipation, and 4 patients of alternating diarrhoea/constipation. Para- meters describing the patients' state are reported in Table 1.

Table 1 Description of patients and Group Mean f SD Range controls

Patients n Male/female Age (years] Diabetes duration (years) Diarrhoea/constipation/both Gastric emptying' (min) RSA' HbA,,' (Yo)

Controls n Male/female Age (years ]

19 8/11

48.6 f 11.1 26-72 18.3 f 7.0 9-36

39.3 f 20.3 8.3-78.0 6.1 f 1.5 4-9 9.0 f 1.9 5.5-12.2

71814

19 8/11

41.6 f 11.4 26-72

'Normal values: gastric emptying: 12-19 min, RSA: 114, HbA,,: 4-6Y0."'

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Volume 6, Number 2, June 1994 Visceroception in diabetes mellitus

PROCEDURE

Tests started at 07.30 hours after a 12-h fast. Enemas were given to all subjects 1 h before testing. Patients received 1/3 of their usual insulin doses, and blood glucose was measured after 2 h. None of the sessions had to be suspended because of hypoglycemia. All subjects were in a supine position. The application of the probe caused an initial discomfort, as a cold, foreign body was inserted into the lower intestinal tract. Adaptation fol- lowed in a few minutes and no subject reported further complaints during the test.

Test consisted of a staircase procedure (SP) in two runs, which measured the perception threshold in colon at two different predistension levels (10 ml and 60 ml), and of a stepwise distension test (SWDT) which measured the pain threshold. Different predistension levels in the SP were used to test effects of colonic stretching on intraluminal perception.

In the SP, 30 stimuli in each run were presented to the subjects, and their detection was tested. Stimuli were phasic volume increases of the balloon, lasting 5 sec each. They ranged between 1 and 50 ml and were logarithmically scaled in 30 steps. Stimulus volume was increased if the stimulus was not perceived and reduced if perceived, so that after a while volume and pressure of stimuli represented the threshold intensity which was then tracked continuously. It is known that perceptual judgements are influenced by some non-perceptual variables which are collectively called response bias. Thus, in order to avoid psychological effects of personality traits on the judgments, we used a special forced-choice- design, which was developed by Wetherill et al." and first applied by Jamal," to determine thermal sensitivity.* In this design each of the 30 trials consisted of three subtrials A, B and C. The stimulus was presented either in A or B. In interval C questions appeared on a screen facing the subject, asking whether the subject had perceived the stimulus in A or in B. Subjects were instructed to guess if not sure, and to give answers using a key-board. Stimulus volume was decreased after three successive correct answers, and increased after one wrong answer. Perception threshold was defined as the median volume of the last 15 stimuli. The volume of the first stimulus was 19.8 ml for all subjects and patients.

The SWDT consists of a progressive inflation of the balloon with air in 20-ml steps given at 120-sec intervals on a balloon predistension level of 10 ml. After each inflation step the subjects were asked about any sensa- tions by means of the screen. If the subjects rating on the key-board corresponded either to a 'definitely unplea-

'The procedure was adapted to interoception measurement and expanded in related studies by Holzl and co-workers.

sant' or to a 'slightly painful' sensation, the SWDT was stopped and the balloon was deflated totally. A maximal volume of 210 ml (10 stimuli] was never exceeded in order to protect subjects' colons from being over- stretched.

EVALUATION

Data recording

Continuous digital recording of balloon volume, pressure, heart rate, and respiration was obtained by means of a laboratory computer (LS/11, DEC) and, simul- taneously, by means of a writing-recorder (ES 1000, Gould) (1 mm sec- ', 1 mbar mm-I). As reliable standard computerized methods for global evaluation of such data do not exist as yet, results presented in this paper were obtained by means of manual evaluation based on paper recordings. All pressure values were corrected by subtraction of corresponding values of the balloon in normal atmosphere measured immediately before inserting the probe.

Definition of pressure parameters

Components of the staircase procedure tracing Figure 2 shows the components of a stimulus in the SP: (a) baseline immediately before volume increase; (b) artefact due to sudden pressure rise in the catheter during inflation; (c) minimum, or short plateau immediately after inflation artefact; (d) maximum before volume decrease; (e) artefact during deflation of the balloon; ( f ) first maximum after the stimulus; (g) end of stimulus evoked activity.

For evaluation we used pressure before stimulus pa, which was considered as an index of tonic reaction to predistension and pressure during the stimulation (pc + pd) 2T1, which contains information about response to phasic stimuli. As the primary contraction (phasic response, d-f) is interrupted by the second artefact (e), its maximum could not be interpreted.

Components of the SWDTrecording Figure 3 shows the components of a stimulus in the SWDT: (a) baseline immediately before inflation step; (b) pumping artefact; (c) minimum or short plateau immediately after inflation artefact; (d) maximum of PC (primary contraction); (e) first minimum after the PC; ( f ) and (8) secondary contractions; (h) baseline reached after 120 sec, just before next stimulus.

In the SWDT we could take into account all parameters, with the exception of the pump artefact (b), of course. We considered the difference of pressure P h - pa as a static reaction of the bowel to the stimulus; the

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60

50

k 40 E

- 9

4

30 3 Y) ul

E 20 4

10

0

j t a

I d

f

n Figure 2 Components of a stimulus in the Staircase Procedure: [a) baseline immediately before volume increase; (b) I artefact due to pressure rise in the catheter during inflation; [c) minimum or short plateau immediately after inflation artefact; Id) maximum before volume

9

0)

3 ul ul 40 E

20

0

4

I I I I I I I I i decrease; [e) artefact due to volume decrease in balloon; ( f ) first maximum

0 10 20 30 40 after the stimulus; [g) end of stimulus- Time Is1 evoked activity.

Jb

‘a

Figure 3 Components of a stimulus in the SWDT: (a) baseline immediately before inflation step; (b) aretfact due to pressure rise in the catheter during inflation; [c) minimum or short plateau immediately after inflation artefact; id) maximum of orimarv contraction: [el first minimum

‘h

I I . I

1 1 1 1 1 1 1 1 1 1 1 1 after the primary contraction; ( f ) and (g) secondary contractions; [h) baseline

0 30 60 90 120 reached after 120 sec, just before next Time [sl stimulus.

difference of pressure pd - p , as the amplitude of the PC; pd - pc as the active dynamic reaction; pc - pa as the passive elastic reaction. We also took into account the latencies t d - t , and t , - t,.

Statistics

Statistical analysis was done using the SPSS - PC+

program. Group differences were tested by means of Mann-Whitney U-test. ANOVA was also performed in order to test the influence of sex and age. Pearson’s r test

was calculated for correlations between diagnostic results. occurrence of colonic oscillation was tested by$ test.

R E S U L T S

Staircase procedure

At both predistension levels volume and pressure of perception thresholds did not significantly differ between patients and controls: 10 controls and l l

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Table 2 Volume thresholds and threshold pressure in staircase procedure Volume Threshold

threshold (ml) pressure (mbar)

Basal volume (ml) Mean (7 Mean U

Controls 10 16.0 13.2 21.1 18.3 Diabetics 23.0 15.8 18.7 13.9 Controls 60 15.2 12.0 13.3 10.4 Diabetics 19.2 12.2 12.5 10.4

diabetics had a lower threshold with 60 ml predistension volume, 7 controls and 7 diabetics with 10 ml volume, and 2 controls and 1 diabetic had the same perception threshold at both predistension levels. Intraluminal pressure had a trend to be lower in diabetics, but the difference was not significant (Table 2). Influence of age on threshold volumes was highly significant ( P < 0.001 at both predistension levels). Distri-

Controls

1 Diabetics

3.5- 5.2- 7.8- 11.6- 1713- 2518- 3814- 4.6 6.8 10.2 15.2 22.6 33.6 50.0

Threshold Volume [mil I10 ml base vol.)

Controls

1 Diabetics

0-’10 11L20 21-30 31-40 41150 51L60

Phasic pressure [mbarl I10ml base vol.1

bution of threshold parameters is illustrated in Fig. 4). Within the patients’ group no significant correlation

was found between the variables: respiratory sinus arithmia (RSA), HbA1,, time of gastric emptying, perception thresholds, intraluminal pressure, gastrointestinal symptoms, colonic changes. Perception thresholds of the patients did not correlate with type of gastrointestinal symptoms.

3.5- 5.2- 7.8- 11:s- 17:3- 2518- 38:4- 4.6 6.8 10.2 15.2 22.6 33.6 50.0

Threshold Volume Imll 160 rnl base vol.)

0-10 11-20 21-30 31-40 41-50 51-60

Phasic pressure Imbarl (60 ml base vol.)

Figure 4 Distribution of threshold parameters in the two groups (a) threshold volume at 10 ml predistension level, (b) threshold volume at 60 ml predistension level, (c) phasic pressure at 10 ml predistension lcvel, (d) phasic pressure at 60 ml predistension level

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Respiration

'"U

Control r- iiiiiaiurninai pressure

--

Heart rate F- ~ . . -- .-,-La &

Controls Diabetics

Mean U Mean U

Maximum tolerated volume (mi] 139.5 48.7 147.8 46.6 Maximum tolerated pressure (mbar] 43.6 17.8 36.7 10.5 Compliance index (mbar ml-'] 0.29 0.18 0.18 0.15

Intraluminal pressure recordings, however, deliver more informations on the state of the gut. Figure 5 shows an example of recordings from a control subject (left] and from a diabetic patient (right).

The control subject's pressure course corresponds to the pattern of Fig. 2 (positive artefact/minimum/PC, interrupted by negative artefact/final return to baseline within a few seconds]. The patient's record shows repeated contractions after the end of stimulus. As this pattern was never observed in the healthy controls of this study, nor in control subjects who took part in other studies of our research group (unpublished data)

90

Figure 5 Records of the SP from a control subject (a] and a diabetic patient (b]. The control subject's pressure tracing corresponds to the pattern of Fig. 1 (positive artefact, minimum, primary contraction, interrupted by negative artefact, finally retum to baseline within a few seconds). The patient's record shows repeated contractions after the end of stimulus.

Table 3 Results of stepwise distension test in controls and diabetics

with a total number of examinations >loo, it was regarded as irregular. Such an irregular pressure course and an abnormal development of the dynamic reactions evoked by stimuli have been found in 10 out of 19 patients I%%), at the low predistension level of 10 ml ( P < 0.001, 2-tailed ?-test).

Stepwise distension test

Like the perception thresholds, pain threshold as measured by means of the SWDT did not differ between the two groups (Table 3) .


Mean of colonic compliance, defined as tonic adaptation of the bowel to distension (compliance index measured as change of balloon pressure in relation to volume increase) was slightly higher (low compliance index) in the patient group, but the difference was not significant ( P >0.05, 2-tailed U-test). Histograms of these data are presented in Fig. 6.

Figure 7 shows an example record taken from a control subject (top) and a diabetic subject (bottom).

In the patient's tracing we can notice an abnormal delay of the PC. Latency of the PC, defined as interval between stimulus begin and peak of the PC, ranges between 5-13 sec in normal subjects and is not influenced by age. In the patient's group latency reached 40 sec, in some cases; 3 patients and 3 controls did not show a PC in the SWDT. Of the remaining patients, 44% had latencies higher than the maximum of the controls (P < 0.002, %tailed U-test). Figure 8 summarizes these results.

No correlation was found between abnormal latencies, abnormal oscillation pattern and type of gastrointestinal symptoms, metabolic state or time of gastric emptying, nor between latencies of the dynamic reaction and perception threshold.

DISCUSSION

The main result of this study is that colonic perception and nociception are preserved in diabetics with autonomic and peripheral neuropathy despite pronounced gastrointestinal symptoms. A clear explanation of these results is not easy, because: (a) colonic perception and nociception in diabetic neuropathy have been very little investigated until now in human in vivo studies; and (b) no correlation was found in our study between gastrointestinal symptoms, metabolic state, perception and nociception thresholds, and tracing abnormalities.

The not impaired colonic perception and nociception sustains the hypothesis of an integer afferent system. However, since we have not measured concomitant evoked potentials (EP), we do not know if the travel speed of the afferent information is normal or delayed. The prolonged latencies of the PC in the SWDT which were found in 44% of the patients resemble delays of many EP components found in similar percentages of diabetics in different studies using acoustic, visual and somatosensory EPs. Such delays have been interpreted as signs of central nervous system (CNS] lesions by some a~thors'"~' and of peripheral lesions by others. 19,20

At least two not mutually excluding hypotheses might explain our results: (a] as the PC evoked by the

1 Controls a1

30150 7&90 1101130 1501170 190-210

Max. tol. volume [mfl

12--$ Diabetics Con f ro 's b l

10-23 24-37 38-51 52-65 66-79 80-92

Max. tol. pressure lrnbarl

l 2 1 Controls c l

0-125 126-250 251-375 376-500 501-625

Compliance index Imbar/ll

Figure 6 Maximal tolerated volume (a), maximal tolerated pressure {b) and compliance index (c) in the two groups.

stimulus has the pattern and functional features of the spontaneous peristaltic reflex, which is regulated by the enteric nervous system (ENS],2G24 a derangement in the colonic intrinsic innervation can be inferred. This

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S. Samo et al .

I I ! I

Neurogastroenterology and Motility

I i

15

60 cn u)

0 45

.$ 30 t

\r

s 15

0

Figure 7 SWDT records from a control subject (top) and a diabetic patient (bottom). The patient’s curve shows a high delay of the primary contraction.

Controls

1 Diabetics

peripheral hypothesis is also supported by the oscil- lations noticed in 53% of the patients in the SP. Morpho- logical animal studies have already shown alterations of the intrinsic nervous system in the intestine as a conse- quence of diabetes, e.g. reduced number of Auerbach’s plexus and degenerated intrinsic axons, as well as extrinsic nerves of the gastrointestinal t r a ~ t . ’ ~ Diabetic changes in the gut are not limited to the nervous system, but extend to other tissues, such as deformed villi, lymphocyte aggregation, blood vascular lesions, increased mucosal weight, decreased muscle thickness,

An interesting hypothesis of main local damage defined as pacemaker disturbance has been made,28,’9

0

6o 1 50

cn f 4 0 0 4

30 B 9 g 20 z

10

0

10 20 30 40 50 which seems to us useful in explaining our results. (b) Although the peristaltic reflex can be elicited at local

Latency of PC Maximum [secl sites in the absence of signals from the CNS, the bowel does not normally function without such signal^.^^,^' Distal colon receives both sympathetic and parasym- pathetic innervation, the former supplied by nervus Controls

splanchnicus, the latter by the pelvic nerve. Thus, cen- trally mediated reflexes, as well as locally mediated reflexes, are important in normal gastrointestinal function. Basic motor patterns may be dependent on the activity of intrinsic neurons, but are subject to modifi- cation by signals from the CNS acting on command neurons controlling intrinsic enteric circuits?’ Indeed, in diabetes mellitus vacuolation of cell cytoplasm and degeneration of cell bodies has been described in the sympathetic ganglia, together with segmental demyelinization and axonal degeneration in the rami

I I I I

0 20 40 60

Latency of PC End [secl c o m m u n i ~ a n t e s ; ~ ~ ~ ~ morphological changes in the splanchnic nerve, with loss of fibres and paranodal and segmental demyelinization have also been f0und.3~ Therefore, we cannot exclude a damage of the efferent

Figure 8 Latencies of the evoked responses in the two groups: (a) latency of the primary contraction maximum; (b) latency of extinction of primary contraction.

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nervous pathways controlling the intrinsic enteric circuits at an higher hierarchical level.

Unfortunately, in none of the above mentioned studies nor in our own study could a correlation be unequivocally assessed between structural and functional damages, and the role of the neurological impairment in the pathogenesis and decourse of the diabetic gastrointestinal complications remains unclear, also because similar symptoms are often common to other clinical patient subgroups, e.g. irritable bowel syn- drome, in which such impairments were not f ~ u n d . ~ "

ACKNOWLEDGEMENT

This study was supported by the Deutsche Forschungsgemeinschaft-DFG [Contr.-no.: Ho 904/4 and 5 J, the Max-Planck-Gesellschaft-MPG, and the Ministerium fur Wissenschaft und Forschung Baden Wiirttemberg (Focal Funding Program).

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Visceral perception and gut changes in diabetes mellitus