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July 2007, Volume 57, Issue 7

Original Article

Poor glycaemic control is the major factor associated with increased frequency of gastrointestinal symptoms in patients with diabetes mellitus

Shahab Abidt  ( Departments of Medicine Aga Khan University )
Wasim Jafrit   ( Departments of Medicine Aga Khan University )
Amir Rizvit  ( Departments of Medicine Aga Khan University )
Firdous Jahan   ( Departments of Family Medicine 2 and Community Health Sciences, Aga Khan University )
Fauziah Rabbani   ( Department of Medicine, Civil Hospital, Karachi 3 , Pakistan. )
Najmul Islamt  ( Departments of Medicine Aga Khan University )
Masood H. Khan   ( Department of Medicine, Civil Hospital, Karachi 3 , Pakistan. )
Rana Masoo   ( Department of Medicine, Civil Hospital, Karachi 3 , Pakistan. )

Abstract

Objective:To compare the GI symptoms in diabetic patients with controls and its relationship with the complications, duration of diabetes and glycaemic control. Methods:Consecutive patients were prospectively enrolled in to two groups. Group I (diabetic patients) and Group II (non-diabetic, Controls). Patient's characteristics, demographic profiles and GI symptoms were evaluated on a questionnaire. Groups were compared for differences in various GI symptoms. Group I was further analyzed for the relationship between GI symptoms with complications, duration of diabetes andglycaemic control.Results:Atotal of 514 patients were enrolled 250 were diabetics (group I) and 264 were non-diabetics (groupII). Mean age was 51.8 +10.6 years and 50.2 +9.2 years in groups i and ii respectively. All GI symptoms;heartburn, dyspepsia, bowel related abdominal pain, diarrhea, constipation, and faecal incontinence were significantly more in diabetics than controls (P<. 05).The presence of diabetic neuropathy, retinopathy and HbA1c of >7 were significantly (P<. 05) related to GIsymptoms. Duration of diabetes (>10 years) was not found significantly linked to GI symptoms.Conclusions:GI symptoms in diabetics were more frequent then control subjects and were significantly associated with poor glycaemic control, neuropathy and retinopathy but not with duration of diabetes.  Number of GI symptoms increases with the severity of poor glycaemic control in diabetic patients (JPMA57:345:2007).

Introduction

GI symptoms are common in the general population,particularly the symptoms of dyspepsia.1 Studies have shown that GI symptoms are more frequent in diabetic patients compared to non-diabetic controls but results are still diverging.2 For instance, by using self administered,mailed questionnaires, results obtained showed no differences in the prevalence of GI symptoms when diabetic patients were compared with controls.3 On the other hand ina population based survey it was found that diabetes mellitus is associated with an increased prevalence of upperand lower GI symptoms.4 Moreover the link between duration of diabetes and development of GI symptoms were found to be confusing. Astudy done in the Chinese population showed significant link between the duration ofdiabetes and the frequency of GI symptoms5, while inanother study, duration of diabetes or type of treatment wasnot found to be associated significantly with increased frequency of GI symptoms in diabetics.4 Similarly the pathogenesis of GI symptoms in diabetic patients remains poorly defined. It has been suggested that symptoms reflectabnormal GI motility as a manifestation of irreversibleautonomic neuropathy.6However other factors are also important e.g. acute changes in blood glucose, poorglycemic control and fluctuation in insulin level7 and associated infections notably Helicobacter pylori.8 The aim of this study was therefore to examine the prevalence of GI symptoms in type II diabetic patients treated at a diabetes clinic compared to control subjects. Inaddition, the relationship between the duration of diabetes,glycaemic control and complications of diabetes with theprevalence of GI symptoms in diabetic patients was alsodetermined.

Patients and Methods

 This prospective study was performed at outpatient's clinic of two major hospitals (Aga Khan University Hospital, a private university hospital and Civil Hospital -Karachi, a major hospital in public sector) from September2002 to November 2003.  The diabetes clinics of these hospitals cater to out-patients who seek care for their diabetes control and for the management of diabetes related complications. The patients in both hospitals are fromdiverse socio-economic and ethnic backgrounds and hence represent the general diabetic population at large. Study subjects were divided into two groups. Group I (diabetic patients) attending diabetes clinic and Group II(non-diabetic, controls) who were randomly enrolled from executive check-up clinic or pre-employment medical examination and those who were attending medicalout patients clinics for some other reason. The following patients were excluded: (i) those with previous history ornewly documented organic GI lesion, including peptic ulcer(diagnosed on endoscopy), biliary stones or other pathologyin biliary system, GI tract tumor, prior GI surgery,scleroderma or other connective tissue diseases, anatomicalobstruction or stricture; (ii) those with impairment of hepatic or renal function; (iii) those with other medical disorders, e.g. heart failure, cerebro-vascular accident; (iv)Type 1 diabetic patients, defined by an acute presentationwith ketoacidosis or heavy ketonuria (>3+ ) or startinginsulin within 1 year of diagnosis, and requiring insulin continuously thereafter.9 All patients were evaluated by a questionnaire10 which contained detailed information aboutupper and lower abdominal symptoms within the last 12months. All symptoms that are not completely self-explanatory were anchored to a standard description. The following eight GI symptoms groups were used forscreening. Unless stated otherwise, a symptom was countedonly if reported to occur more than 25% of the time over the past 12 months. The questionnaire was filled by the patients themselves with the assistance of non-medical staff blinded for the diabetes status of the patient.1.Gastroesophageal reflux symptoms-heartburn or acid regurgitation at least once a week. 2.Dysmotility like Dyspepsia-epigastric pain or discomfort in combination with any upper dysmotility symptom (early satiety, postprandial fullness, bloating, abdominal swelling, nausea [at least two to three times a month], vomiting [at least once a month], and retching [at least once a month]). 3.Ulcer like dyspepsia-localized epigastric pain or discomfort combined with at least two of the following characteristics: night pain, episodic pain, pain relieved by antacids, pain relieved by food or milk, pain provoked by being hungry. 4.Bowel-related abdominal pain, abdominal pain or discomfort associated with at least two of three features (relieved with defecation, onset associated with a change in the frequency of stool, onset associated with a change in stool form). 5.Diarrhoea-very loose or watery stools more than 75% of the time and no abdominal pain. 6.Constipation-at least two of the following symptoms: <3-bowel movements/week, anal blockage, manual dis-impaction, lumpy or hard stools, incomplete evacuation, straining or patient taking fibers such asbran, cereal or ispagulla husk daily to relive constipation.7.Frequent abdominal pain-abdominal pain of at least moderate intensity occurring minimally once a week over the past 12 months. 8.Faecal incontinence-leakage of bowel movements about once a month or more frequently.The diabetic complications were classified aspresent according to the following definitions: *Nephropathy: the patient answered yes to the question"Did your doctor tell you about any kidney damage orprotein in your urine that is a result of your diabetes?" *Peripheral neuropathy: the patient answered yes to thequestion "Do you suffer from 'pins and needles' inyour feet or hands?" *Retinopathy: the patient answered yes to the question"Are you aware of any eye damage that is a result ofyour diabetes?" and had received laser therapy.Demographic profile, biochemical parameters,duration of diabetes and HbA1c levels (last level availableat the time of filling the questionnaire), were also recorded. Statistical analysis was performed using SPSS(version 11.5; SPSS, Chicago, IL). All results are expressedas mean + SD. The analysis of covariance and chi-squaretest were used for between group comparisons whereappropriate. Multivariate analysis was used to examine theindependent relationship between scoring for GI symptomsand the following; duration of diabetes, presence of variouscomplications and HbA1c. AP-value <0.05 was consideredto be significant.Institutional ethical committee's approval wasobtained from both study centers prior to the start of thestudy. Informed consent was obtained from the patientsbefore filling the questionnaire.

Results

 Atotal of 514 consecutive patients were enrolled Group I (diabetic patients) had 250 (48.64%) and Group II(non-diabetics- control) 264 (51.36%). Patients with diabetes (Group I) were slightly older (mean age 51.8+10.6 years) compared to non-diabetic patients (Group II,mean age of 50.2 +9.2 years). Both groups had predominance of females. All eight-symptom groups were reported more frequently in Group I compared to group II,p< 0.05 (Table 1). A large proportion (44%) of patients had diabetes more than 10 years and their mean HbA1c was 7.8%.Neuropathy was present in 130 (52%); retinopathy in 102(40.8%) and nephropathy in 14 (5.6%) patients with diabetes.Complications of diabetes such as peripheral

Tablel. Patient's characteristics and Comparison of Gastrointestinal symptoms between Group I (diabetics) and Group II (controls).

Patients characteristics and

Gastrointestinal Symptoms

Group I

(Diabetics)

N=250 (%)

Group II

(Controls)

N=264 (%)

P value

Age (mean t SD)

51.8 yrs t 10.6 50.2 yrs t 9.2

 

Females (%)

56

59.8

 

Smokers (%)

8

10

 

Alcohol users (%)

3

5

 

Gastroesophageal reflux symptoms

110(44)

57 (21.6)

.001

Dysmotility like dyspepsia

88(35)

27 (10.2)

<. 001

Ulcer like Dyspepsia

40(16)

18(6.8)

.05

Bowel related abdominal pain

38 (15.2)

6(2.2)

.001

Diarrhea

32 (12.8)

6(2.2)

.007

Constipation

114 (45.8)

42 (15.9)

<. 001

Frequent abdominal pain

32 (12.8)

12(4.5)

.03

Fecal Incontinence

22(8.8)

0

<. 001

Table2: Relationship between duration and complications of diabetes mellitus with Gastrointestinal symptoms.

Group I (Diabetic patients)

GI symptoms (1 or >)

Pr esent A bsent

P value

Diabetic Nephropathy n=14

8 6

NS*

Diabetic Neuropathy n=130

106 24

.045

Diabetic Rretinopathy n=102

86 16

.035

HbAlc < 7 n=74

44 30

NS*

HbAlc >=7 n=176

142 34

.015

Duration of Diabetes < 10 yrs n=140

102 38

NS*

Duration of Diabetes >10 yrs n=110

84 26

NS*

*NS = Non-significant. P 10.5

Table 3. Relationship between Number of Gastrointestinal symptoms Reported and Glycated Hb (n=250).

Symptoms

Patients (%)

Mean HbAlc

0 symptom

64 (25.6)

7.3

1 symptom

54 (21.6)

7.5

2 symptoms

54 (21.6)

8.5

3 symptoms

30(12)

7.9

4 symptoms

28 (11.2)

8.4

5 symptoms

10(4)

8.6

6 symptoms

10(4)

8

7 symptoms

0(0)

-

neuropathy and retinopathy were significantly associated (p< 0.05) with occurrence of one or more GI symptoms,where as nephropathy was not found to be associated with increase frequency of GI symptoms among diabetic patients. GI symptoms were present more frequently indiabetic patients with HbA1c level of >7 (p=0.015).However, duration of diabetes mellitus (more than 10 years) was not found significantly associated with increased frequency of GI symptoms. The relationship between duration of diabetes and its complications with the presence of GI symptoms are shown in Table 2.Almost 75 percent of diabetic patients reported atleast one or more GI symptoms. All eight GI symptom-groups were reported more frequently when the HbA1clevel was 7 or more. The frequency of gastro esophageal reflux and dyspepsia was higher. More than half of diabetic patients (52.8%) had two or more symptoms with HbA1clevel of > 7.9. The number of GI symptoms reported by 250diabetic patients and the relationship with HbA1c level is summarized in Table 3.

Discussion

It has been found that GI symptoms in diabetics are associated with significant impact on the quality of life. In one study11up to 76% of patients attending diabetes clinichad GI symptoms when specifically questioned. This study also shows that all eight GI symptom groups were more prevalent in diabetic individuals than controls. It was also observed that the number of symptoms group increased with the severity of poor glycaemic control in type IIdiabetes.Several studies have shown that acute changes inblood glucose concentration have a major effect on motor function throughout the GI tract in healthy subjects and in patients with diabetes.12,13 Variations in blood glucose concentration also have the potential to affect symptomsarising from the GI tract.14Studies have shown that the perception of nausea, occurring as a result of proximalgastric distention, is greater during hyperglycaemia.4Acute hyperglycaemia was found to be associated with delayedgastric emptying in diabetics.15It reduces lower esophagealsphincter pressure and velocity of esophageal peristalsis andalters motility of small intestine and gall bladder.16Recentlyit has been demonstrated that hyperglycaemia can triggertransient lower esophageal relaxation and contribute to theincreased esophageal acid exposure in patients withdiabetes mellitus.7 Controversy still exists as some studies showed a direct relationship between glycaemic control and GI symptoms4,17while others differ.5Based on our observations, we believe that   acute or sub-acute changes in glucose concentration (as reflected byHbA1c levels) are a key factor associated with increased frequency of GI symptoms. In our study it has been observed that the upper GI symptoms were significantly more in patients with glycated HbA1c of 7 or more. This might be due to the direct effect of  hyperglycaemia over thevagus nerve, causing delayed gastric emptying, increased degree of relaxation of proximal stomach or a central action of hyperglycaemia over the brain vagal nuclei.  These possible mechanisms suggest hyperglycaemia associated significant increase in upper GI symptoms in diabetics.7 There are several other factors, which may beresponsible for increased GI symptoms in diabetics such asautonomic neuropathy and concurrent infections. Despite its significant negative impact on survival and quality of life,diabetic autonomic neuropathy is among the leastrecognized and understood complication of diabetes.Several hypotheses concerning the multiple etiologies ofdiabetic neuropathy include a metabolic insult to nerve fibres, neurovascular insufficiency, autoimmune damageand neuro-hormonal growth factor deficiency.Hyperglycaemic activation of the polyol pathway leading to accumulation of sorbitol and potential changes in the NAD:NADH ratio may also cause direct neuronal damage. GImanifestations of autonomic neuropathy are diverse andsymptoms and pathogenic mechanisms have beencategorized according to the specific part of the affected GItract.  Esophageal dysfunction results at least in part fromvagal neuropathy. Delayed gastric emptying largelydepends on vagus nerve function, which can be severelydisrupted in diabetes. Auto antibodies to autonomic nerveshave been demonstrated, associated with the developmentof autonomic neuropathy in type 1 diabetics.18 Diarrhoea,which is typically intermittent and faecal incontinence dueto poor sphincter tone, may be related to auto nomicneuropathy. The present study has shown a significant association between diabetic neuropathy and retinopathyand GI symptoms in diabetics.Despite significant association of increase frequency of GI symptoms in diabetics with neuropathy in our study,we cannot conclude that neuropathy alone was responsiblefor GI symptoms. This is because of the fact that noassociation was found between duration of diabetes (thatusually correlates with the development of neuropathy) andGI symptoms in our study. Alarge population based surveyconcluded that neither poor glycaemic control norautonomic neuropathy alone is enough to explain thepathogenesis of GI symptoms in all diabetic patients.4 However as evident from our study, poor gylcaemic controlplays an important role in generation of at least upper GIsymptoms in diabetics. Certain GI infections may also play an importantrole in causation of GI symptoms; at least in a subset ofdiabetic patients. It might be interesting to note that a high prevalence of Helicobacter pylori was found among diabetics compared to controls in a recently published study associated with dyspeptic symptoms.8 Moreover concurrentuse of certain drugs may be important in causing GIsymptoms in diabetics. However a study has recently reported that troublesome GI symptoms in patients with diabetes do not appear to be caused by use of oralhypoglycaemic medications or other drugs, except fordiarrhea which is strongly and independently associated with metformin use.19In summary, this study has provided further evidencethat both upper and lower GI symptoms were significantly more common in type II diabetic patients compared tocontrols. Poorer glycaemic control was associated with significant increase in upper GI symptoms.  Moreover long-term complications such as neuropathy and retinopathy were found to be associated with increased frequency of GIsymptoms. However the duration of diabetes was not found to be associated with increase in the frequency of GIsymptom in our study. It is therefore important that Gastro enterologistsstart seeking support from other disciplines such asdieticians, public health physicians and family medicine practitioners. Attention should be directed towards health promotion (e.g. smoking cessation and weight reduction)and secondary diabetes prevention methods in order to better manage diabetes and thus bring down case load related to GI symptoms amongst diabetic patients.

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