Gut 1996; 39: 748-756

Rapid distal small bowel transit associated withsympathetic denervation in type I diabetes mellitus

L Rosa-e-Silva, L E A Troncon, R B Oliveira, M C Foss, F J H N Braga, L Gallo Jr

Department of ClinicalMedicine, RibeirAoPreto Medical School,University ofSfoPaulo and Hospital dasClinicas Campus daUSP, Ribeirao Preto,SP, BrazilL Rosa-e-SilvaL E A TronconR B OliveiraM C FossF J H N BragaL Gallo JrCorrespondence to:Dr L E A Troncon,Department of ClinicalMedicine, Hospital dasClinicas, Campus da USP14048-900, Ribeirao Preto,SP, Brazil.

Accepted for publication1 1 June 1996

AbstractBackground-The pattern of progressionofa meal from the stomach to the caecumin diabetes mellitus is controversial andthe differential roles oftransit through thejejunum and the ileum have not beeninvestigated in diabetes.Aims-To determine gastric emptyingand transit rates through proximal anddistal regions of the small bowel in type Idiabetic patients.Subjects-The study included six diabeticpatients with evidence ofautonomic neur-opathy (DM-AN group), 11 diabetics with-out autonomic dysfunction (DM group),and 15 control volunteers.Methods-Gastric emptying and smallbowel transit of a liquid meal were evalu-ated scintigraphically in these subjects.Transit through regions ofinterest corres-ponding to the proximal and distal smallintestine up to the caecum was deter-mined and correlated with gastric empty-ing rates, cardiovascular measurementsof autonomic function, and the occur-rence of diarrhoea.Results-Gastric emptying and transitthrough the proximal small bowel weresimilar in the three groups. The mealarrived to the caecum significantly earlierin DM-AN patients (median; range: 55min; 22->180 min) than in the DM group(100 min; 44->180 min, p<0.05) or in con-trols (120 miin; 80->180 min, p<0.02).Accumulation ofchyme in the distal smallbowel was decreased in DM-AN patients,who showed values for peak activity (30%;10-55%) significantly lower than in theDM group (49%; 25-77%, p=0.02) and con-trols (50%; 30-81%, p=0.02). In DMpatients (n=17), the time ofmeal arrival tothe caecum was significantly correlatedwith both orthostatic hypotension (co-efficient of contingency, C=0 53, p<0.01)and diarrhoea (C=0.47, p<0.05), but notwith gastric emptying rates.Conclusions-Patients with type I diabetesmellitus and sympathetic denervationhave abnormally rapid transit of a liquidmeal through the distal small bowel, whichmay play a part in diarrhoea production.(Gut 1996; 39: 748-756)

Keywords: diabetes mellitus, gastrointestinal transit,gastric emptying, small bowel transit, autonomicneuropathy, diabetic diarrhoea.

Abnormalities of gastrointestinal motilitycausing troublesome symptoms are wellknown complications of longstanding diabetes

mellitus.' 2 These motor disorders seem to bemore frequent in patients with evidence ofautonomic neuropathy,'-5 which suggests a rolefor gut denervation in symptom production.

Involvement of the small bowel, in par-ticular, has been thought to contribute to thepathophysiology in diabetic diarrhoea,' 2 5 6and it has been proposed that abnormal smallbowel motility and transit could cause diar-rhoea through a number of mechanisms.' Slowintestinal transit might be responsible forbacterial overgrowth7 whereas rapid transitwould lead to diarrhoea due to 'intestinalhurry'.6 Nevertheless, studies concerning smallintestinal transit in diabetic patients are notextensive and have produced conflictingresults. Mouth to caecum transit time assessedby the hydrogen breath technique has beenfound to be prolonged2 8 or normal.' 9 '0 Onthe other hand, the passage of a barium mealthrough the gastrointestinal tract was reportedto be accelerated in some patients with diabeticdiarrhoea.6 Regardless of these discrepancies,the relation between gastric emptying andsmall bowel transit rates has not beenextensively evaluated in diabetics.

In a previous study we found that patientswith type I diabetes mellitus associated withautonomic neuropathy have abnormally rapidgastric emptying of liquids.4 We hypothesisedthat this abnormality could lead to acceleratedtransit through the entire length of the smallbowel, thus contributing to diarrhoea pro-duction. This study therefore aimed to measuregastric emptying and transit through the smallbowel after the ingestion of a liquid nutrientmeal in type I diabetic patients with evidenceof autonomic neuropathy. As there is evidencethat the jejunum and the ileum display differenttransit patterns,"1 we assessed the differentialroles of proximal and distal small bowel indetermining small intestinal transit.The relations between gastrointestinal

transit, signs of autonomic dysfunction affect-ing the cardiovascular system, and the occur-rence of diarrhoea were also evaluated.

MethodsThis study was carried out according to aprotocol previously approved by the localethics committee, with informed written con-sent obtained from each subject.

SUBJECTS

PatientsSeventeen unselected, insulin dependent typeI diabetic men attending the diabetes mellitus

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outpatient clinic ofthe Hospital das Clinicas deRibeirao Preto were included in this study.None of them had undergone previous oper-ations on the gastrointestinal tract or a historyof chronic alcoholism or pancreatic disease.None of the patients were taking any medi-cation other than insulin.Symptoms suggestive of autonomic neuro-

pathy,12 such as postural hypotension, neuro-

genic bladder symptoms, sexual impotence,dysphagia, early satiety, nausea, vomiting, di-arrhoea, constipation, and faecal incontinencewere recorded using a specifically designedquestionnaire. These symptoms were onlyattributed to diabetic neuropathy after exclud-ing other conditions by the appropriate investi-gations. Six patients had symptoms suggestiveof postural hypotension, two had evidence ofneurogenic bladder, and four had sexualimpotence. The only gastrointestinal symptomfound in our patients was diarrhoea. Sevenpatients had occasional diarrhoea, with one totwo days of elimination of liquid stools every15-60 days, and one had chronic, continuousdiarrhoea. However, this symptom was not thereason for seeking medical care except in thecase with continuous diarrhoea.Autonomic nerve function was assessed by

three standardised cardiovascular reflex tests,which provided five measurements ofvagal andsympathetic activities. On the basis of both theresults of these tests and the questionnaire,diabetic patients were assigned to one of twogroups. Six patients with at least one symptomsuggestive of autonomic dysfunction plusabnormal results in at least two measurementsin the cardiovascular nerve function testsrepresented a group of diabetics regarded as

having autonomic neuropathy (DM-AN). Theremaining 11 diabetics represented a groupwithout autonomic neuropathy (DM). Table Igives the clinical data of the patients studied.No patient presented evidence of renal failure.All patients were regarded by their attendingphysicians as being fairly stable, as far asdiabetes control was concerned, with norecords of clinical or laboratory decompen-sation or increase in the usual insulin dose inthe six month period preceding the study. Onthe morning of the day of the study, fastingplasma glucose concentrations (Table I)ranged from 3-8 to 14-0 mmol/l (median=6.2mmol/l) for group DM and from 3-6 to 13.0mmol/l (median=8.3 mmol/l) for group DM-AN. Urinary glucose excretion during the 24hours preceding the gastrointestinal transit

study ranged from 0 to 12 g/24 h (median=4g/24 h) for group DM and from 0 to 12 g/24h (median=5-7 g/24 h) for group DM-AN.

ControlsFifteen non-diabetic, healthy male volunteersselected from the medical staff formed thecontrol group. Median age in this group was 27(range 18-45). No control patient was takingany medication or had clinical or laboratoryevidence of diabetes mellitus or digestivediseases. Complaints of diarrhoea, consti-pation or changing bowel function were

specifically denied by all control subjects. Allcontrols were submitted to the cardiovascularautonomic nerve function tests. The gastro-intestinal transit study was performed on 10volunteers.

STUDY DESIGN

Cardiovascular autonomic nervefunction testsAutonomic nerve function was assessedby three standardised cardiovascular reflextests: tilting test, detection of respiratorysinus arrhythmia (RSA), and the Valsalvamanoeuver.

The head up tilting test with an inclinationof 70° was performed by means of a speciallydesigned tilting table, which permitted acutepassive changes in body position withoutmuscular effort by the subject.`3 Heart rate wasmonitored by continuous electrocardiographic(ECG) recording (Siemens-Elema Mingograf34) and arterial blood pressure was measuredin the right arm with a sphygmomanometer bythe auscultation method.RSA magnitude was determined in the

supine position with the subjects breathing ata fixed respiratory rate of six cycles per minute.Instantaneous heart rate (R-R interval) was

measured with a cardiotachometer (Hewlett-Packard, model 8812-A) and recorded on heatsensitive paper (Hewlett-Packard, model7754-A). Beat to beat variation was reportedas the mean value of the differences betweenmaximum and minimum instantaneous heartrate during six respiratory cycles.'4The Valsalva manoeuver was also performed

in the supine position by maintaining the intra-thoracic pressure fairly constant at 40 mm Hgfor 15 seconds. Heart rate was continuouslyrecorded on the ECG throughout the test. Theratio of the shortest R-R interval during the

TABLE I Characteristics ofdiabetic patients with and without autonomic neuropathy (AN) as defined by suggestivesymptoms plus abnormal cardiovascular nerve function tests. Nephropathy was indicated by persistent microalbuminuria.Peripheral neuropathy (PN) was indicated by sensory and motor disturbances in a detailed physical examination

Blood Symptoms ofANDuration of sugar

Diabetic Age (y) diabetes (mmolAl) Nephropathy Retinopathy PN PH NB SI Dpatients m (r) (y); m (r) m (r) (n) (n) (n) (n) (n) (n) (n)

Without AN 33 9 6-2 - - - 1 - 1 3(n=3) (18-45) (2-31) (3-8-14-0)With AN 37-5 12 8-3 4 4 4 5 2 3 5(n=6) (27-40) (11-13) (36-13.0)

m=median; r=range; n=number of patients. PH=postural hypotension; NB=neurogenic bladder; SI=sexual impotence;D=diarrhoea.

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manoeuver to the longest R-R interval 30seconds after this manoeuver (Valsalva ratio)was calculated.'3 15These three cardiovascular tests yield five

variables for the assessment of autonomiccontrol: (1) heart rate variation during the first10 seconds after tilting, for assessing vagalactivity on sinus node`5; (2) heart rate variationfrom the first to the fifth minute after tilting, forassessing sympathetic mechanism of heart rateincrease'5; (3) arterial pressure response tostanding in the tilting test, for assessingperipheral sympathetic function'5; (4) beat tobeat variation in the RSA test, as an index ofvagal activity,'4 and (5) Valsalva ratio, forassessing sympathetic and vagal controlmechanisms. '3 15 `Withthe exception ofbloodpressure levels after tilting, results for diabeticswere regarded as abnormal when an observedvalue was out of the range obtained for thecontrol group. For arterial blood pressure, a fallin systolic levels of 30 mm Hg or more or a fallin diastolic values of 10 mm Hg or more, orboth, were regarded as abnormal.'6

Gastric emptying and gastrointestinal transitGastric emptying and gastrointestinal transitwere determined at 1 00 pm, six hours after alight breakfast, which was preceded by theusual morning insulin dose. No food intakewas permitted during this period.A liquid test meal was prepared by mixing

10 g of wheat flour, two eggs, 15 g of dextrose,40 g of sucrose, 10 g of chocolate, 15 g ofcasein, 250 ml of water, and 18 g of lactulose(Epalfen, Zambon Farmaceuti, in Spa, Vicenza,Italy) in a food processor. This meal (800mOsm) contained 437 Kcal, 64 g of carbo-hydrate, 20 g of protein and 11 g of fat and waslabelled with 18 MBq of99mTechnetium-sulphurcolloid (Sulfursyd, Sydma Medical Equipmentsand Reagents, Ribeirao Preto, SP, Brazil) imme-diately before ingestion.

After ingestion of the liquid test meal wascompleted, the subject was placed upright infront of the hexagonal hole, low energy, highsensitivity collimator of a gammacamera(Orbiter Stand, Siemens Gammasonics, USA)coupled to a computer (Microdelta System,Siemens Gammasonics, USA). Externalmarkers (plastic needle cover containing cottonsoaked in 99mTechnetium-sulphur colloid) werefixed to the skin, one on the right hypo-chondrium and the other on the right lowerquadrant, 2 cm medially to the anteriorsuperior iliac spine. The first marker allowedcorrection for body movements, whereas thesecond established the anatomical reference tothe caecum.'7 Serial images of the distributionof the ingested radioactivity over the anteriorand posterior views of the abdomen wereobtained every five minutes for the first 30minutes and every 10 minutes for 180 minutesthereafter. Time zero was defined as the timeof meal completion. Concomitantly, endexpiratory breath air samples were collectedimmediately before and every 10 minutes afteringestion of the test meal for 180 minutes.'8Hydrogen (H2) excretion was measured in each

breath sample by means of a Microlysergas chromatograph (Model 12, Quintron,Milwaukee, Wisconsin, USA).

DATA ANALYSIS

Gastric emptyingRegions of interest (ROIs) for the anterior andthe posterior views of the stomach were definedon each scintigram. Decay corrected counts forboth anterior and posterior gastric ROIs weregeometrically averaged to correct for theposterior-anterior movement of the markerwithin the stomach.`' A time activity curve forthe stomach was derived from these correcteddata. Three parameters were determined byanalysis of this curve. The percentages of initialactivity remaining in the gastric area 15minutes and 120 minutes after the meal weretaken as indicating early and late gastricemptying (GE), respectively. The tl,2 wasdefined as the period of time necessary for theactivity in the gastric area to fall 50/o from theinitial levels.

Gastrointestinal transitROIs for the anterior view of the proximal anddistal segments of the small bowel and thecaecum were defined on each image accordingto procedures recommended by others," 20 aspreviously described.'8 Initially, the progression*of the radiolabelled meal was visually assessedby replaying the successive frames on the videomonitor. Immediately after meal ingestion, thetypical image of the stomach was seen in thefirst frames. Thereafter, activity leaving thestomach was seen on the left and immediatelybelow the gastric area. As gastric emptyingproceeded, activity was detected only briefly inthis region, which remained nearly emptythroughout the study. From this region, theradioactivity moved to the right and downwardto the pelvic area, where it seemed to accumu-late, forming a nearly round image beforestarting to ascend towards the caecum (Fig 1).Activity in each of these ROIs was expressed asthe percentage of total abdominal activity so as

Figure 1: Scintigraphic image of the anterior abdomen afteringestion ofa liquid meal tagged with 99`Tc illustrating theROIs definedfor the stomach (S), proximal (P) and distal(D) small bowel, and the caecum (C).

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TABLE II Results of the cardiovascular tests in the control group and diabetic patients without (DM) and with autonomicneuropathy (DM-AN). Patients in the second group had at least one suggestive symptom plus abnormalities in at least twocardiovascular measurements

HR d,o HR d, s Postural RSA VRGroups m (r) m (r) hypotension m (r) m (r)

Control 18.0 (8-0-27-0) 16.0 (7-0-26-0) -) 180 (60-37-0) 1.9 (1-3-2.5)DM 16.0 (9-0-25-0) 13.0 (7-2-23.0) (-) 175 (7-0-29-0) 1-8 (14-2-0)DM-AN(patient number) Individual data1 3-2 134 (+) 268 1.62 8-9 155 (+) 43 1.23 11.0 172 (+) 40 1.44 0-0 10.0 (+) 21 1.05 6-0 216 (+) 63 1.96 6-0 60 (+) 20 1.1

HR d,o=heart rate variation during the first 10 seconds in the tilting test. HR dl,s=heart rate variation from the first to the fifthminute in the tilting test. Postural hypotension was defined as a fall of at least 30 mm Hg in systolic levels or 10 mm Hg in diastoliclevels in the tilting test, or both. RSA=beat to beat variation in the respiratory sinus arrhythmia test. VR=valsalva ratio.m=median; r=range. (-)=absent; (+)=present.

to avoid further corrections. Counts from theseROIs were used to draw time activity curves foreach intestinal segment. Analysis ofthese curvesprovided data for assessing both gastricemptying and the progression of the front of themeal throughout the small bowel up to thecaecum. The time ofmeal arrival to the caecum(tc) was defined as the time required for the firstappearance in the corresponding ROI of at least10% of total abdominal activity. The tc valuesdetermined according to this definition werefound to be highly correlated with orocaecaltransit time, as determined by the H2 breathtest. By analogy, the time of meal arrival to theproximal and distal small bowel was alsodefined as the time required for the firstappearance of at least 10% of total abdominalactivity in the corresponding ROIs. The transitofthe bulk ofthe meal in the proximal and distalsmall bowel was assessed by computing thevalues for the activity remaining in each of theseROIs in each frame. Particularly, accumulationof the bulk of the meal in the distal small bowelwas estimated by recording the peak activity forthe corresponding ROI, which was defined asthe highest count observed in this ROI at anytime during the study.

Orocaecal transit time (OCTT)This was defined as the time between mealintake and the first rise in H2 concentration ofat least 5 ppm above fasting values in at leastthree consecutive samples.'8

STATISTICAL ANALYSISNon-parametric tests were used to analyse theresults.2' The significance of the differences

TABLE iII Gastric emptying (GE) ofa liquid meal in controls and diabetic patientswithout (DM) and with (DM-AN) evidence ofautonomic neuropathy. Early and late GEcorrespond to the percentages of initial activity in the gastric area 15 minutes and 120minutes after meal ingestion, respectively. T,,2 is the time necessaryfor the activity in thegastric area to fall 50% from the initial levels. Data are reported as median and (range)

Subjects Early GE (%/5) Late GE (%o) t,,1 (min)

Controls 79.8% 21-8% 58-5 min(n=10) (51-3-84-4) (14-6-30-6) (16-0-83-0)DM 68 2% 11-0% 40-0 min(n=11) (39-8-89 5) (5.2-39 3) (5 0-95-0)DM-AN 67.6% 12.6% 49.5%(n=6) (53-4-81-8) (5.3-60.5) (16-0->180-0)

n=number of subjects.

between the three groups of subjects con-cerning each of the gastric emptying andgastrointestinal transit parameters was assessedby the Kruskal-Wallis test. Subsequent com-parisons between pairs of groups were per-formed by the Mann-Whitney U test.

Correlations between gastric emptying andgastrointestinal transit data and between theresults of cardiovascular tests and gastro-intestinal transit data were assessed by theSpearman correlation coefficient (r). The con-tingence coefficient (C) was used to analyse thecorrelations involving categorical data such aspresence or absence of evidence of autonomicneuropathy, diarrhoea, and postural hypo-tension. For this correlation analysis, the dataobtained for the two groups of diabetes werepooled.

Differences were taken as statisticallysignificant for p values of less than 0 05.

Results

CARDIOVASCULAR AUTONOMIC FUNCTIONThree patients in the DM-AN group had ab-normalities in three to five measurements ofcardiovascular autonomic function. The remain-ing three patients in this group had abnormalresults in only two measurements (Table II).Orthostatic hypotension, in particular, wasdetected in all patients in this group. On thecontrary, none of the patients allocated to theDM group had abnormal results for any of thefive cardiovascular measurements performed.

GASTRIC EMPTYINGTable III shows the results concerning thevarious parameters. Values for the activityremaining in the stomach in both groups ofdiabetics tended to be lower than thoseobtained in controls, but no statistically signifi-cant differences were observed regarding any ofthe parameters.

GASTROINTESTINAL TRANSITAnalysis of the sequential images obtained foreach subject revealed distinct patterns ofgastrointestinal transit (Fig 2). In all controlsand in nine DM patients, the stomach emptiedevenly and the front of the meal travelled

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Figure 2: Serial gammacamera scans at different times (0, 30, 60, and 120 minutes) after meal ingestion in three diabetics(A, B, and C). In patient A, gastrointestinal transit was steady with accumulation ofmeal marker in the distal small bowelbefore caecalfilling. In patient B both gastric emptying and small bowel transit were very fast, with the tracer reaching thecaecum at 30 minutes, without previous accumulation in the distal area. In patient C, the front of the meal emptied rapidlyfrom the stomach and also reached the caecum rapidly. However, there was no subsequent gastric emptying nor anyfurtherprogression of the marker through the small bowel. EM=external marker.

rapidly across the proximal small bowel andseemed to accumulate in distal segments,before the caecum was reached (Fig 2A).Seven diabetics (five from group DM-AN)showed a completely different pattern, with atrend towards more rapid gastric emptying andrapid transit through both proximal and distalsmall bowel segments. None of these patientsshowed evidence of accumulation of the tracerin the ileal region (Fig 2B). Lastly, anotherpattern was observed in one DM-AN patientwith a biphasic pattern of gastric emptying. Inthis patient, the front of the meal emptiedrapidly from the stomach and quickly reachedthe caecum. Therafter, no subsequent gastricemptying was noticeable nor was there anyprogression through the small bowel (Fig 2C).

Figure 3 shows the results concerning thetime of meal arrival to the ROIs correspondingto the proximal and distal small bowel and tothe caecum. There were no significant differ-ences between the three groups regarding thetime of meal arrival to the proximal and distal

small bowel. However, the time of meal arrivalto the caecum was significantly shorter in theDM-AN group (median; range 55 min;22-> 180 min) than in the controls (120 min;80->180 min; p<0025) or the DM group (100min; 44->180 min; p<005).

Figure 4 shows the activity versus timecurves constructed, for the ROIs corres-ponding to the stomach, the proximal and thedistal small intestine, and the caecum. Therewere no significant differences betweendiabetics and controls regarding the values foractivity in the ROI for the stomach (Fig 4A)and the proximal small bowel (Fig 4B) at anytime point during the study. However, in theDM-AN group, activity in the ROI for thedistal small bowel was consistently lower thanin both the control and DM groups, withdifferences reaching statistical significancefrom 90 minutes up to the end ofthe study (Fig4C). Activity in the ROI for the caecum in theDM-AN group was consistently higher than inboth the controls and DM patients (Fig 4D).

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m

Aa

*' 4.s

C DM DM-ANDSB

* Visual analysis of gammacamera scans and* A A inspection of activity versus time curves

suggested that, unlike controls and diabeticsA i' without autonomic neuropathy, diabetes

mellitus patients with evidence of disautonomyA lacked accumulation of chyme in the ileum

with increased caecal filling (Fig 2 and Fig 4).-A This suggestion was supported by the fact that

activity in the ROI for the distal small bowelUH by the time the tracer reached the caecum was* A significantly smaller for the DM-AN group

A (median; range: 23%; 10-32%) than for theA * controls (38%; 27-81%; p<001) and DMA group (36%; 15-78%; p<0 05). Also, peak

A activity in the ROI for the distal small bowelA in the DM-AN group (median; range: 30%;

10-55%) was significantly lower than in bothC DM DM-AN the control (50%; 30-81%, p=0.025) and DM

Caecum groups (49%; 25-77%, p=0.025).

*p<0.025 vcontrols; p<0.05 vDM

Figure 3: Time ofmeal arrival to proximal (PSB) and distal (DSB) small bowel segments,and to the caecum in controls (C) and in diabetic patients without (DM) and with evidenceofautonomic neuropathy (DM-AN). Median values are given by the horizontal bars. Insix cases (2 C, 3 DM, and 1 DM-AN), activity in PSB throughout the study have notreached the minimum requiredfor definition of the time ofmeal arrival.

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OcTTThe results concerning the arrival of the mealto the caecum were confirmed by the H2 breathtest, although a clearly interpretable H2 profilewas obtained in only seven controls and ninediabetic patients. Values for OCTT in theDM-AN group (median; range: 40 min; 30-70min) were significantly shorter than in controls(150 min; 100-160 min; p=0008) but were

not significantly different from the DM group(90 min; 50-170 min). Also, there was no

difference in OCTT values between DM andcontrol groups.

80

60 hCORRELATION BETWEEN OCTT AND tcThere was a significant correlation (r=0.79;p<0001) between tc obtained by scintigraphyand OCTT obtained by the H2 breath test.

40 h-

2C

30 60 90 120 150 180

Time (min)

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Figure 4: Activity time curvesfor the stomach (A), the proximal (B) and the distal (C)small bowel, and the caecum (D) in controls and in diabetic patients without (DM) andwith evidence ofautonomic neuropathy (DM-AN). Data are presented as median values ofactivity at each time point, expressed as percentage of total abdominal activity.

CORRELATIONS BETWEEN GASTRIC EMPTYING

AND GASTROINTESTINAL TRANSIT TIME

There was a significant correlation betweenearly GE and the time of meal arrival to theproximal small bowel both in controls (r=0.73;0 02<p<0 05) and in diabetic patients (r=0.76;p=0002). However, no significant correlationwas found between the remaining gastricemptying and intestinal transit data in any ofthe groups studied.

CORRELATIONS BETWEEN CARDIOVASCULAR

AND GASTROINTESTINAL PARAMETERS

There were no significant correlations betweenany of the cardiovascular and the gastro-intestinal parameters, except for that betweenpostural hypotension and the time of mealarrival to caecum (X2=6.8; C=0 53; p<0O01),which was not surprising, because all DM-ANpatients had postural hypotension.

CORRELATIONS BETWEEN DIARRHOEA,EVIDENCE OF AUTONOMIC NEUROPATHY, AND

GASTROINTESTINAL TRANSIT

Diarrhoea was found to be significantly corre-

lated with both the presence of cardiovascular

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evidence of autonomic neuropathy (X2=4.898;C=047; p<0 05) and the values for the timeof meal arrival to the caecum (x2=4.898;C=0 47; p<005).

DiscussionIn this study, the application of a suitablescintigraphic technique to assess gastro-intestinal transit allowed us to show that maletype I diabetes mellitus patients with auto-nomic neuropathy have abnormally earlyarrival of the head of a liquid meal to thecaecum and diminished accumulation ofchyme in the distal small intestine.A significant correlation between tc assessed

by scintigraphy and OCTT measured by H2breath test indicates that the isotope techniqueprovides a valid way to estimate the arrival ofthe head of a test meal to the caecum, thusconfirming previous observations.20 As far asthe proximal and distal small bowel isconcerned, no such validation is available, asthere are no independent, physiological tech-niques to assess segmental small bowel transit.Nevertheless, the ROI for both the proximaland distal small bowel were defined accordingto the visual resolution of the progression oftheisotope through successive segments andconformed with accepted topographic dis-position for the jejunum and the ileum.22Although there was a trend toward more

rapid gastric emptying in both groups ofdiabetics compared with controls, no signifi-cant differences in gastric emptying rates werefound between either group of diabetics andcontrols. This finding, as well as the lack ofcorrelation between data for gastric emptyingand intestinal transit measurements, indicatethat the rapid gastric emptying of liquids thatwe4 and others23 have previously found indiabetes mellitus does not seem to be involvedin the production of abnormally fast smallbowel transit in patients with autonomicneuropathy.Our findings of accelerated small bowel

transit in diabetic patients with autonomicdysfunction are in agreement with thepioneering study by Malins and French,6 whoused a radiological technique. Also, rapid smallintestinal transit has been previously observedin some patients in a large group of diabetics.9However, a number of other studies havedemonstrated normal5 9 10 or delayed2 8 smallintestinal transit in diabetics. A potentialsource for such discrepancies is diversity ofcriteria for patient selection. In an attempt tominimise variability caused by sex,24 type ofdiabetes mellitus,25 and age,26 we have studiedonly male type I diabetics within a relativelynarrow age range. Interestingly, the finalcomposition of our group of diabetics had afew unexpected features. Firstly, we found arelatively high proportion of patients with diar-rhoea in our previously unselected sample ofmale type I diabetes, even though diarrhoeawas not a major clinical problem in thesepatients. This relatively high frequency of diar-rhoea might be explained by either a particularpattern of referral of outpatients to our

teaching hospital or by the fact that clinicalevaluations were performed by physiciansmore prone to detect and record any minordigestive manifestation. Secondly, we foundthat all patients meeting the criteria forinclusion in the group with autonomicneuropathy (DM-AN) had objective evidenceof orthostatic hypotension, which is known toindicate sympathetic dysfunction.'3 15 16 Thesefindings enabled us to suggest a causativeassociation between sympathetic denervation,rapid distal small bowel transit, and diarrhoeain diabetics.The results of our transit study show that the

proximal and distal regions of the small bowelhave different roles in determining the abnor-mally fast arrival of the meal to the caecum. Aspreviously shown by others," the jejunum andthe ileum display different transit patterns afterthe ingestion of a liquid caloric meal. Chymepasses rapidly through the jejunum whereas theileum seems to be a zone of accumulation.Accordingly, in all our controls and in nine of11 diabetic patients without evidence of auto-nomic neuropathy, transit through the proxi-mal and distal small bowel conformed to thesepatterns. In contrast, in the group of diabeticswith autonomic neuropathy there was noevidence of accumulation in the distal smallbowel, even though transit through the proxi-mal intestine seemed to be preserved. Thisfinding suggests that early arrival of the headof the meal to the caecum in diabetics withautonomic dysfunction is probably caused bymotor disturbances affecting predominantlythe ileum or the ileocolonic junction, or both.We cannot rule out, however, the possibilitythat accelerated distal small bowel transit is aconsequence of impaired sodium and waterabsorption caused by sympathetic denervationof the ileum known to occur in diabetic neuro-pathy.27 The addition of lactulose to our testmeal as a substrate for the H2 breath test mightalso have caused an accelerating effect ongastrointestinal transit due to its osmoticaction. This passive effect, however, would besimilar for normal subjects and diabeticpatients and therefore could not be taken as thecause of the differences in transit hereinshown.The factors influencing transit through the

more distal segments of the small bowel undernormal conditions and the patterns of ilealtransit in different diseases are still poorlyunderstood. Greydanus et a128 studied colonicfilling after the ingestion of a solid meal andfound that in healthy volunteers the ileocolonictransfer of chyme is characterised by bolusmovements followed by plateaus, when notransfer was observed. Although our studyassessed small bowel transit rather than colonicfilling, it is plausible to assume that accumu-lation in the distal small bowel may correspondto the plateaus described by Greydanus et al.28A few studies using scintigraphic tech-

niques28 29 have shown that small bowel transitand colonic filling after the ingestion of a solidmeal are delayed among some diabetic patientswho included a larger group of patients withintestinal pseudo-obstruction. The discrepancy

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Intestinal transit in diabetes 755

between these results and ours might be due todifferences in the pattern of gastrointestinalinvolvement in diabetes, because none of ourpatients had any evidence of obstructivefeatures in their clinical picture. It is alsonoteworthy that, in contrast with others,28 29 weassessed gastric emptying and small boweltransit only after the ingestion of a liquid mealwith a relatively low fat concentration andcontaining lactulose. Our results thereforecannot be generalised to a solid, ordinary mealwith higher lipid content. On the other hand,it is fairly well known that a solid test meal ismore likely to disclose gastroparesis in diabeticpatients than a liquid meal, which mightaccount for delayed small bowel transit andcolonic filling, as found by others.28 29The lack of a close correlation between data

for the cardiovascular and gatrointestinalmeasurements is not surprising and has beenreported in other studies.'0 This could beexplained by regional differences in nerve dys-function or low sensitivity of cardiovasculartests in detecting widespread denervation indiabetics. Nevertheless, there was a significantcorrelation only between orthostatic hypo-tension and early arrival of the meal marker tothe caecum in the overall group of diabetics. Asorthostatic hypotension in diabetics is thoughtto be caused by efferent sympathetic dys-function,'3 15 16 it is possible that impairment ofadrenergic influences on distal small bowelmotor activity may be involved in theproduction of rapid distal small bowel transitin diabetics with autonomic neuropathy. Thisinterpretation is consistent with previousfindings suggestive of a prominent role ofsympathetic influences in the control ofhumangastrointestinal transit.30 It has also beenshown that sympathetic deprivation is probablyinvolved in the production of upper gut dys-motility in diabetic patients with gastro-paresis.3133 and in water and chloride mal-absorption in diabetic diarrhoea.34

Postprandial hyperglycaemia is an additionalfactor that could possibly contribute to smallintestinal transit disorders in diabetic patients.Induced hyperglycaemia has been shown toinhibit gastric motility and emptying in healthysubjects35 36 and to slow gastric emptying indiabetics.37 We attempted to reduce thisputative influence of hyperglycaemia in ourresults by including only patients with satis-factory metabolic control. Also, fasting plasmaglucose and urinary glucose excretion concen-trations before the test in the group of diabeticpatients with evidence of autonomic neuro-pathy were similar to those observed in theremaining patients. Although we cannot ruleout an influence of hyperglycaemia on ourresults, it is unlikely that this factor contributedto transit acceleration, because at least inhealthy volunteers small bowel transit is signifi-cantly prolonged during hyperglycaemia.38The association between rapid small

intestinal transit, autonomic dysfunction, anddiarrhoea herein shown has already been rec-ognised in a number of different conditionsincluding diabetes6 39 and postvagotomy diar-rhoea.40 41 More recently, abnormally fast

small intestinal transit of a liquid meal has beenreported in eight patients with chronic diar-rhoea and some form of autonomic dysfunc-tion related to systemic disease, includingdiabetes mellitus.42A number of mechanisms might be involved

in the production of diarrhoea associated withautonomic dysfunction in diabetics. It isplausible that deranged small bowel motilitycaused by impaired neural influences on thegut may lead to exceedingly early transfer ofchyme to the caecum, which would overloadthe large bowel and contribute to diarrhoeaproduction, particularly when a hyperosmolarmeal is ingested. Bile malabsorption43 mightalso be involved because decreased accumu-lation of chyme in the distal small bowelprobably reduces the re-absorption of bile saltsin the ileum. Impaired absorption of water andelectrolytes associated with reduced (X2adrenergic activity,27 which has been proposedas a key factor in diarrhoea production indiabetic patients,34 might also result fromdiminished accumulation ofchyme in the distalsmall bowel. Thus, rapid transit through themore distal segments of the small bowel couldbe a common component in the multifactorialorigin of diarrhoea production in patients withdiabetic autonomic neuropathy.Rapid small intestinal transit and reduced

accumulation of chyme in the distal smallbowel of diabetic patients are unlikely to affectthe absorption ofnutrients and drugs that takesplace mostly in the more proximal segments ofthe small bowel. It is plausible, however, thatthe transit abnormalities herein shown mightinterfere with the release of ileal neuropeptides,such as enteroglucagon,44 which are known totake part in glycaemic control.45

In conclusion, our findings indicate that typeI diabetic patients with evidence of autonomicneuropathy have abnormally rapid progressionof a liquid meal through the small bowel. Theearlier arrival of chyme to the large bowel doesnot seem to be due to accelerated gastric empty-ing, but rather to a reduced accumulation in themore distal segments of the small intestine.These transit abnormalities in diabetic patientswere found to be correlated with both thepresence of orthostatic hypotension and theoccurrence of diarrhoea. Although our findingscannot be fully generalised to an ordinary diet,it is suggested that impairment of sympatheticinfluences on distal small bowel motility mightplay a part in the acceleration of intestinaltransit, which in turn might be involved in theproduction of diarrhoea in diabetes.

We are indebted to Mrs Christiane Souza e Silva and to Mr CR Cambrea for excellent technical assistance. We also thankProfessor J E Dutra de Oliveira and Dr N Iazigi, who allowedus to use equipment from their laboratories.

This study was supported by grants from CNPq-ConselhoNacional de Desenvolvimento Cientifico, FAPESP-Fundai;ode Amparo a Pesquisa do Estado de Sao Paulo, FAEPA-Fundacao de Arnparo ao Ensino, Pesquisa e Assistencia doHospital das Clinicas de Ribeirao Preto.

1 Feldman M, Schiller LR. Disorders of gastrointestinalmotility associated with diabetes mellitus. Ann Intern Med1983; 98: 378-84.

2 Dooley CP, El Newhh HM, Zeidler A, Valenzuela JE.Abnormalities of the migrating motor complexes motorcomplex in diabetics with autonomic neuropathy anddiarrhea. ScandJ3 Gastroenterol 1988; 23: 217-23.

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756 Rosa-e-Silva, Troncon, Oliveira, Foss, Braga, Gallo r

3 Rundles RW. Diabetic neuropathy: general review withreport of 125 cases. Medicine 1945; 24: 111-60.

4 Oliveira RB, Troncon LEA, Meneghelli UG, Dantas RO,Godoy RA. Gastric accommodation to distension andearly gastric emptying in diabetics with neuropathy. Braz3rMed Res 1984; 17: 49-53.

5 Wegener M, Borsch G, Schaffstein J, Luerweg C,Leverkus F. Gastrointestinal transit disorders in patientswith insulin-treated diabetes mellitus. Dig Dis 1990; 8:23-6.

6 Malins JM, French JM. Diabetic diarrhoea. Q J3 Med 1957;26: 467-80.

7 Goldstein F, Wirts CW, Kowlessar OD. Diabetic diarrheaand steatorrhea: microbiologic and clinical observations.Ann Intern Med 1970; 72: 215-8.

8 Scarpello JHB, Greaves M, Sladen GE. Small intestinaltransit in diabetics. BMJ 1976; 2: 1225-6.

9 Keshavarzian A, Iber FL. Intestinal transit in insulin-requiring diabetics. Am J Gastroenterol 1986; 81: 257-60.

10 Werth B, Meyer-Wyss B, Spinas GA, Drewe J, Beglinger C.Non-invasive assessment of gastrointestinal motilitydisorders in diabetic patients with and without cardio-vascular signs of autonomic neuropathy. Gut 1992; 33:1199-203.

11 Jian R, Pecking A, Najean Y, Bernier JJ. Etude de laprogression d'un repas dans l'intesin grele de l'homme parune methode scintigraphique. Gastroenterol Clin Biol1979; 3: 755-62.

12 Unger HR, Foster DW. Diabetes Mellitus. In: Textbook ofendocrinology. Wilson JD, Foster DW, eds. WB SaundersCompany, Philadelphia. 1985: 1018-80.

13 Marin Neto JA, Gallo Jr L, Manco JC, Rassi A, Amorim DS.Postural reflexes in chronic Chagas's heart disease.Cardiology 1975; 60: 343-57.

14 Santos e Fonseca CMC, Manco JC, Gallo Jr L, Barreira AA,Foss MC. Cholinergic bronchomotor tone and airwaycaliber in insulin-dependent diabetes mellitus. Chest1992; 101: 1038-43.

15 Marin Neto JA, Gallo Jr L, Mango JC, Rassi A,Amorim DS. Mechanisms of tachycardia on standing:studies in normal individuals and in chronic Chagas'sheart patients. Cardiovasc Res 1980; 14: 541-50.

16 Ewing DJ, Clarke BF. Diagnosis and management ofdiabetic autonomic neuropathy. BMJ 1982; 285: 916-8.

17 Read NW, Al-Janabi MN, Holgate AM, Barber DC,Edwards CA. Simultaneous measurement of gastricemptying, small bowel residence and colonic filling of asolid meal by the use of the gamma camera. Gut 1986;27: 300-8.

18 Troncon LEA, Oliveira RB, Romanello LMF,Rosa-e-Silva L, Pinto MCC, Iazigi N. Abnormnalprogression of a liquid meal through the stomach andsmall intestine in patients wtih Chagas' disease. Dig DisSci 1993; 38: 1511-7.

19 Tothill P, McLoughlin GP, Holt S, Heading RC. The effectof posture on errors in gastric emptying measurements.Phys Med Biol 1980; 25: 1071-7.

20 Caride VJ, Prokop EK, Troncale FJ, Buddoura W,Winchenbach K, McCallum RW. Scintigraphic deter-mination of small intestinal transit time: comparison withthe hydrogen breath technique. Gastroenterology 1984; 86:714-20.

21 Siegel S. In: Estatistica nao parametrica-para as ciencias docomportamento. Brasil: Editora McGaw-Hill, 1975.

22 Trier JS, Winter HS. Anatomy, embriology and develop-mental abnormalities of the small intestine and colon. In:Sleisenger MIH, Fordtran JS, eds. Gastrointestinal disease.Philadelphia: WB Saunders, 1989: 991-1021.

23 Phillips WT, Schwartz JG, McMahan CA. Rapid gastricemptying of an oral glucose solution in type 2 diabeticpatients. J Nucl Med 1992; 33: 1496-500.

24 Wald A, Van Thiel DH, Hoechstetter L, Gavaler JS,Egler KM, Verm R, et al. Gastrointestinal transit: theeffect of the menstrual cycle. Gastroenterology 1981; 80:1497-500.

25 Dao T, Chee B, Bouvard G, Justum AM, Verwaerde JC,Valla A. Lack of modulation of gastric emptying by acutehyperglycemia in type 2 diabetes mellitus. Gastroenterology1990; 98: A342.

26 Moore JG, Tweedy C, Christian PE, Datz FL. Effect of ageon gastric emptying of liquid-solid meals in man. Dig DisSci 1983; 28: 340-4.

27 Chang EB, Bergenstal RM, Field M. Diarrhea instreptozotocin-treated rats-loss of adrenergic regulation ofintestinal fluid and electroyle transport. J Clin Invest 1985;75: 1666-70.

28 Greydanus MP, Camilleri M, Colemont U, Phillips SF,Brown ML, Thomforde GM. Ileocolonic transfer of solidchyme in small intestinal neuropathies and myopathies.Gastroenterology 1990; 99: 158-64.

29 Camilleri M, Brown ML, Malagelada JR. Impaired transitof chyme in chronic intestinal pseudoobstruction.Gastroenterology 1986; 91: 619-26.

30 McIntyre AS, Thompson DG, Day S, Burmham WR,Walker ER. Modulation of human upper intestinalnutrient transit by a beta adrenoreceptor mediatedpathway. Gut 1992; 33: 1062-70.

31 Camilleri M, Malagelada JR. Abnormal intestinal motilityin diabetics with the gastroparesis syndrome. Eur 7 ClinInvest 1984; 14: 420-7.

32 Camilleri M, Malagelada JR, Stanghellini V, Fealey RD,Sheps SG. Gastrointestinal motility disturbances inpatients with orthostatic hypotension. Gastroenterology1985; 88: 1852-9.

33 Rosa-e-Silva L, Troncon LEA, Oliveira RB, Iazigi N,Gallo Jr L, Foss MC. Treatment of diabetic gastroparesiswith oral clonidine. Aliment Pharmacol Ther 1995; 9:179-83.

34 Chang EB, Fedorak RN, Field M. Experimental diabeticdiarrhea in rats - intestinal mucosal denervation hyper-sensitivity and treatment with clonidine. Gastroenteroloy1986; 91: 564-9.

35 Bamett JL, Owyang C. Serum glucose concentration as amodulator of interdigestive gastric motility. Gastro-enterology 1988; 94: 739-44.

36 MacGregor IL, Gueller R, Watts HD, Meyer JH. The effectof acute hyperglycemia on gatric emptying in man.Gastroenterology 1976; 70: 190-6.

37 Fraser RJ, Horowitz M, Maddox AF, Harding PE,Chatterton BE, Dent J. Hyperglycaemia slows gastricemptying in type 1 (insulin-dependent) diabetes mellitus.Diabetologia 1990; 33: 675-80.

38 De Boer SY, Masclee AAM, Lam WF, Schipper J,Jansen JBMJ, Lamers CBHW. Hyperglycemia modulatesgallbladder motility and small intestinal transit time inman. Dig Dis Sci 1993; 38: 2228-35.

39 Camilleri M, Vassalo M. Small intestinal motility and transitin disease. Baillieres Clin Gastroenterol 1991; 5: 431-51.

40 Ladas SD, Isaacs PET, Queresh Y, Sladen G. Role of thesmall intestine in postvagotomy diarrhea. Gastroenterology1983; 85: 1088-93.

41 O'Brien JD, Thompson DG, McIntyre A. Effect of codeineand loperamide on upper intestinal transit and absorptionin normal subjects and patients with post vagotomydiarrhea. Gut 1988; 29: 312-6.

42 Sellin JH, Hart R. Glucose malabsorption associated withrapid intestinal transit. Am J Gastroenterol 1992; 87:584-9.

43 Ford GA, Preece JD, Davies IH, Wilkinson SP. Use of theSeHCAT test in the investigation of diarrhoea. PostgradMedJ 1992; 68: 272-6.

44 Spiller RC, Trotman IF, Adrian TE, Bloom SR,Misiewicz JJ, Gilin DBA. Further characterization of the'ileal brake' reflex in man - effect of ileal infusion of partialdigests of fat, protein and starch on jejunal motility andrelease of neurotensin, enteroglucagon and peptide YY.Gut 1988; 29: 1042-51.

45 Kreyman B, Williams MA, Ghatei A, Bloom SR. Glucagon-like peptide 17-36: a physiological incretin in man. Lancet1987; ii: 1300-3.

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