Review

G astrointestinal Manifestations of
Diabetes Mellitus
SHELDON TAUB, ANTHONY MARIANI, AND JAMIE S. BARKIN

This review briefly outlines the gastrointestinal manifestations of diabetes mellitus. Usually, gastro-
intestinal abnormalities are asymptomatic. Severe gastrointestinal dysfunction may be quite debilitating,
however. Gastrointestinal symptoms that are a consequence of diabetes may be confused with other
primary gastrointestinal disorders. We attempt to provide a clinical approach to differentiating the basis of
symptoms and outline the therapeutic plan that we generally employ. Much additional research is
necessary to clarify our understanding of the pathophysiology of the gastrointestinal complications of
diabetes and to develop improved therapeutic strategies, DIABETES CARE 2.- 437-447, SEPTEMBER-OCTOBER 1979.

D
iabetes mellitus is a protean disease that affects
every organ in the body. Since it is a common
disorder, affecting approximately 10 million
Americans,1 one would expect to frequently
encounter complications as a result of diabetic gastro-
enteropathy.2"3 However, this is not true. It is noteworthy
that despite extensive pathologic involvement of the gut,
there are frequently no clinical manifestations indicating
diabetic involvement, with symptoms occurring in only a
small percentage of patients with gastrointestinal (GI)
involvement. As a result of patients being asymptomatic for
the most part, no definite data are available on the overall
frequency of GI manifestations in diabetes mellitus.
Five basic mechanisms have been proposed to account for
the functional and structural abnormalities associated with
the GI tract in diabetes mellitus.3 The first and most
important is the visceral neuropathy that is responsible for
motor weakness and hypotonia. Neuropathy may also affect
secretory ability of such organs as the pancreas.3 Pathologic
abnormalities are noted in the sympathetic ganglion and
visceral afferents, but there is a very poor correlation between
structural changes and the functional aberrations.4'5 Second,
although diabetic microangiopathy might be responsible for
the disordered motor activity of the intestines, microscopic
studies have failed to show microangiopathy in the mucosa
of the GI tract.6 The third possible mechanism is the
electrolyte imbalance that occasionally accompanies uncon-
trolled diabetes, such as hypokalemia and hyperkalemia,
which along with hypoglycemia and hyperglycemia have been
shown to have variable effects on the gut motility.3 These
effects are best demonstrated during diabetic ketoacidosis,
which is often accompanied by marked gastric distention
secondary to acute gastric retention. A fourth mechanism
that may be responsible for the abnormalities of the GI tract
in diabetes is the altered hormone production of insulin and
glucagon. Elevated levels of these hormones usually result in a
depression of GI motility and secretion. A fifth possible
mechanism is the increased susceptibility of diabetic subjects
to secondary infection, as demonstrated by their higher
incidence of Candida esophagitis7 and ileocecal tuberculosis.3
ESOPHAGUS
Of the GI manifestations associated with diabetes mellitus,
those involving the esophagus are the most recently de-
scribed. Katz and Spiro, in their extensive review in 1966 of
GI manifestations of diabetes,2 failed to even recognize the
effects that diabetes has on the esophagus. Mandelstam, in
1967, was the first to adequately describe the relationship
between esophageal motility problems and diabetic neurop-
athy.8 Since then, numerous studies have shown that
esophageal motor dysfunction is common in patients with
associated diabetic neuropathy.9"11 Usually, diabetic periph-
eral neuropathy precedes esophageal dysfunction.12 Cine
barium studies may reveal esophageal dilation, delayed
esophageal emptying (especially when the subject is supine),

DIABETES CARE, VOL. 2 NO. 5, SEPTEMBER-OCTOBER 1979 437

 GASTROINTESTINAL MANIFESTATIONS OF DIABETES MELLITUS/S. TAUB, A. MARIANI, AND J. S. BARKIN
and an increase in spontaneous contractions. Manometry
may indicate absence or reduction in number of primary
coordinated peristaltic waves that follow swallowing, as well
as the presence of tertiary contractions, which occur
randomly. Combinations of these manometric findings may
also be seen. In the more severe lesions, the esophageal
motor abnormality may be identical with the defect found in
patients with diffuse esophageal spasm, showing both repeti-
tive, nonperistaltic contractions during swallowing and
frequent spontaneous contractions.
The esophageal musculature seems intact as demonstrated
by the normal amplitude of esophageal contractions with a
decrease in esophageal contraction velocity. Sometimes the
lower esophageal sphincter is uninvolved, but usually a
reduced gastroesophageal sphincter pressure is noted by
manometry.9 Manometric studies have been variously
described as showing a variety of different abnormalities,
ranging from decreased frequency of peristalsis to increased
repetitive contractions.9*13
A recent study of esophageal motor function in a larger
group of unselected diabetic patients, without symptoms,
revealed that greater than half showed one or more of the
signs of motility disorder, including absent peristaltic response
to swallowing and spontaneous and/or repetitive esophageal
contractions.14 In addition, there was a highly significant
relationship between abnormal esophageal motility and the
presence of peripheral neuropathy. Only 4 of 20 diabetic
patients without neuropathy had abnormal motility studies,
whereas 24 of 30 (80%) patients with neuropathy were
found to have abnormal motility. Thus, if a diabetic patient
has peripheral neuropathy, there is an increased likelihood
of an esophageal motor abnormality.
Despite the fact that an autonomic abnormality in
esophageal motor function is common on esophageal
manometry in patients with diabetes mellitus, none of the
patients in this study had symptoms of esophageal dysfunc-
tion.14 Symptoms, when present, usually are mild and
consist of heartburn or rarely dysphagia. Many of these pa-
tients also have a decrease of gastric acid secretion, which
may account for their paucity of symptoms.14a Thus, a
diabetic patient with a complaint of dysphagia or heartburn
should be thoroughly evaluated for other causes of dysphagia.
Evaluation should include at least barium swallow with
cineradiography and possibly esophagoscopy. Motility studies
also may be considered. Since treatment of these motor
disorders is generally symptomatic, it is usually unnecessary.
Monilial esophagitis usually only appears in patients who
have an altered immune response, and thus may occur in
uncontrolled diabetes mellitus.15 The patient with monilial
esophagitis often complains of dysphagia or odynophagia,
which may be so severe that he or she is unable to swallow.
A barium swallow may show the findings of candidiasis,
including a shaggy outline of the esophageal wall or frank
ulcerations, intramucosal filling defects, and/or nodular
438 DIABETES CARE, VOL. 2 NO. 5, SEPTEMBER-OCTOBER 1979
formation.16 These findings are usually more prominent in
the middle or lower third of the esophagus. Esophagoscopy
often reveals a yellowish cheesy exudate, and a mucosa that
ranges from erythema with friability to frank ulceration.
Demonstration of yeast forms is often easier by smears of
esophageal brushing than by biopsies.17 Cultures for Candida
may be positive. Serum agglutinin titers are usually of little
value, since many normal individuals harbor the organism
without tissue invasion.
The differential diagnosis of monilial esophagitis in the
diabetic patient with odynophagia includes severe reflux
esophagitis and herpetic esophagitis. Treatment of monilial
esophagitis generally consists of a trial with nystatin suspen-
sion 250,000 U every 2 h in water for 1 wk. An alternative
is nystatin suppositories that may be given orally every 4 h for
1 wk. This regimen generally is effective in most cases.
Patients who fail with this form of therapy may be treated
systematically with flucytosine, low dose amphoterecin B,
or miconazole.
STOMACH
G
astric motor abnormalities occur in 20-30% of
diabetic patients and, like esophageal motor
abnormalities, are often without clinical mani-
festations or symptomatology.3 On occasion,
delayed gastric emptying or gastric retention may cause vague
abdominal discomfort, "heartburn," or protracted nausea,
vomiting, and halitosis. Anorexia and bloating are less
common, and weight loss is uncommon. Clinically, these
manifestations are punctuated by symptom-free intervals.
As with the esophagus, patients with gastric motility
problems usually have an associated peripheral neuropathy18
or combined peripheral and autonomic neuropathy (orthostatic
hypotension is the most common autonomic dysfunction).
Gastric neuropathy secondary to diabetes was first
recognized by Kassander in 1958, which he dubbed
"gastroparesis diabeticorum" to describe the atony with
delayed gastric emptying seen in diabetic patients.19 The
basis of this delayed gastric emptying is probably vagal
neuropathy, since the vagi are normally involved in specific
reflexes that regulate gastric motility and emptying. Support
for this hypothesis is that the normal stomach, because of its
function as a reservoir, is able to accept increasing volumes
without increasing the intragastric pressure. This receptive
relaxation, mediated through the vagal nerves, is impaired
after vagotomy as it is similarly impaired in diabetic patients.20
The motor activity of the stomach is also impaired, resulting
in absence of the usual three contractions per minute, or
reduction of the peristaltic amplitude of those waves that are
present.21 As a whole, irregularity and uncoordination
characterize the motor activity of the stomach both after
vagotomy or as a consequence of diabetes. However,
 GASTROINTESTINAL MANIFESTATIONS OF DIABETES MELLITUS/S. TAUB, A. MARIANI, AND J. S. BARKIN
morphologic confirmation of a vagal lesion is lacking. The
histology of the gastric wall in patients with gastric retention
and diabetes mellitus reveals that both the plexus of Meissner
and that of Auerbach are normal. Other possible but unlikely
factors that may induce gastric atony are hyperglycemia
induced by a rapidly rising glucose level and an elevation of
glucagon.21
Gastric stasis results in the formation of coagulums of food,
which further coalesce and form gastric bezoars.22 Their
symptoms are nausea, vomiting, and a sense of epigastric
fullness. In addition, they can cause gastric outlet obstruc-
tion. Thus, before making the "clinical" diagnosis of
gastroparesis diabeticorum, gastric bezoar function must be
excluded. Fortunately, these bezoars usually respond to
mechanical or chemical dissolutions.
Gastric stasis may also result in bacterial overgrowth, as
well as gastric candidiasis. Gastric candidiasis is usually
localized, but there may be diffuse dissemination in 10%-
15% of patients.23 The delayed emptying of the stomach may
result in the errative entry of food into the small intestine
to be absorbed. This erratic absorption may be responsible
for frequent episodes of hypoglycemia and lability of
diabetic control.
Radiologic manifestations of diabetic gastric neuropathy
have been well described.24'25 The most common radiologic
feature on upper GI series is the consistent and striking finding
of sluggish, ineffectual, and irregularly occurring gastric
peristalsis.25 This may be accompanied by a significant
amount of solid gastric residue despite a 12-h fasting period
prior to the x rays. This phenomenon is seen in up to 90% of
patients. Other features commonly noted on barium studies
include elongation of the stomach, giving it a "sausage-
shaped" configuration, significant retention of ingested
barium (defined as 50% or more of the ingested barium
present on the 30-min follow-up film), and duodenal bulb
atony and dilation without evidence of organic obstruction.
Several entities may radiographically simulate diabetic
gastric neuropathy,25 and include the following. (1) Auto-
vagotomy that is due to tumor invasion of the vagus
nerve, originating from a pulmonary, esophageal, or gastric
carcinoma. (2) Surgical vagotomy may temporarily simulate
diabetic gastroparesis. However, the intramural nervous
system of the stomach gradually takes over and furnishes
enough parasympathetic activity to make peristalsis effective
again. (3) Drug-induced motility disturbance may occur. The
drugs most commonly incriminated are tranquilizers (especially
diazepam), anticholinergics, ganglion-blocking agents, and
tricyclic antidepressants. These are probably dose-related
effects, but occasionally an idiosyncratic reaction may be
responsible. The effects are reversible upon discontinuation of
the responsible agent, and therefore a detailed drug history is
imperative before the diagnosis of diabetic gastroparesis
is made.
The prognosis of patients with gastroparesis diabeticorum
DIABETES CARE, VOL. 2 NO. 5, SEPTEMBER-OCTOBER 1979
is guarded, as these patients usually have advanced complica-
tions of diabetes mellitus.
Acute erosive gastritis, along with acute gastric dilation,
may complicate diabetic ketoacidosis.3 Bleeding in this cir-
cumstance is usually minor, and hardly ever due to duodenal
ulcer disease.3 The pathogenesis of this acute gastritis is
uncertain, but several physiologic factors may play a role.
These include marked gastric retention with stasis, which may
stimulate an increased level of detergents in the:'gastric
juices. This may facilitate back diffusion of acid and lead to
the breakdown of the gastric mucosal barrier.3
Until recently, the methods available for treating gastro-
paresis diabeticorum have been less than gratifying. Strict
diabetic control is important. Cholinergic agents such as
bethanechol and the cholinesterase-inhibitor ambenonium
chloride have met with variable success, but are often
associated with disturbing side effects.24 Operative^ drainage
of the atonic stomach, either with a gastroenteros^bmy or
pyloroplasty, has occasionally been shown to be effective.26
Predictably, the results are less than optimal, since it is a
gastric motor abnormality and not a gastric outlet defect.
Metoclopramide, a drug recently introduced into the United
States, but as yet not approved for use, stimulates contraction
of the smooth muscle of the GI tract. Metoclopramide is
thought to act by enhancing the local effect of acetylcholine
at postganglionic nerve endings.27 It has occasionally proved
to be effective in diabetic gastroparesis. 28"29a
Metoclopramide strikingly increases the rate of gastric
emptying, as evidenced by (1) decreased gastric volumes,
(2) decreased recovery of ingested solid foods, and (3)
decreased half-time^'of gastric emptying as. shown by
decreased recovery o^ fadiolabeled gastric markers.28 Unfor-
tunately, improvements with the drug have sometimes been
only temporary, and in the absence of controlled trials, the
possibility of a "placebo effect" cannot be totally excluded.29
A decrease in gastric secretion has been described in
diabetes mellitus and may explain the reported decreased
frequency of duodenal ulcer disease in diabetic patients.30'31
However, diabetic patients more commonly have complica-
tions of duodenal ulcer disease.7 Basal and augmented acid
secretion are lower than normal in diabetic patients, and in
one study, approximately 17% of diabetic patients secreted
no acid after histamine stimulation.31 This may be explained
by the fact that gastric mucosa in diabetic individuals
becomes atrophic both at an earlier age and more frequently
than in nondiabetic subjects.7 As many as 85% of diabetic
patients may have partial or complete atrophy of the gastric
mucosa, as confirmed by biopsy.18 The gastritis that is found
does not appear to be related to the severity or duration of
the diabetes per se, but rather is age-related. The older the
patient, the greater the frequency of either superficial or
atrophic gastritis.18
A recent study evaluated gastric function in diabetic
patients with symptoms of gastroparesis diabeticorum (i.e.,
439
 GASTROINTESTINAL MANIFESTATIONS OF DIABETES MELLITUS/S. TAUB, A. MARIANI, ANDJ. S. BARKIN
nausea and recurrent vomiting) in comparison with long-
standing but asymptomatic diabetic patients and nondiabetic
controls.318 Both groups of diabetic patients had reduced acid
secretory responses to sham feeding, consistent with vagal
neuropathy. On the other hand, acid secretory responses to
homogenized food infused directly into the stomach were
normal, despite an enhanced serum gastrin response in the
diabetic patients.
Antibodies to various gastric components are more
frequently found in diabetic than in nondiabetic individuals.32
Up to 25% of diabetic patients may have circulating
parietal cell antibodies compared with only about 8% of
controls. Parietal cell antibodies are especially prevalent in
young female insulin-dependent diabetic patients.32 Intrinsic-
factor antibodies are also found more commonly in diabetes,
occurring in up to 8% of those in whom it is searched for.
Both intrinsic-factor and parietal cell antibodies are more
frequent in insulin-dependent diabetic patients,3 especially in
women with complications. In addition, latent pernicious
anemia appears to be more common in middle-aged and
elderly diabetic patients, especially females, and affects up to
4%-5% of insulin-dependent diabetic patients in this group.3
It may be justifiable to do periodic Schilling tests in middle-
aged insulin-dependent diabetic patients to ascertain
potential need for parenteral vitamin B12.
Two other entities are unique to the diabetic patient. The
first is diabetic radiculopathy or diabetic plexus neuropathy,33
resulting in abdominal pain secondary to diabetic neuropathy
involving the thoracic nerve root area. This entity has been
incriminated as the cause of chronic abdominal pain
stimulating an abdominal malignancy and occasionally
resulting in unneeded exploratory laparotomy. These patients
may have anorexia and weight loss, and are often extensively
evaluated in pursuit of a malignancy, especially pancreatic
carcinoma. Patients usually have insulin-dependent diabetes
and often have diffuse peripheral neuropathies. Frequently,
the pain gradually subsides on its own over 6-20 mo. In the
interim, treatment is symptomatic. The diagnosis may be
made by electromyographic examination.
The second entity is postprandial facial sweating, which is a
manifestation of diabetic autonomic neuropathy.34 The
patient describes drenching facial sweats occurring a few
seconds after starting to chew food. The stimulus to this
gustatory sweating is the chewing of tasty food and this
symptom appears to be inhibited effectively by anti-
cholinergic agents.
SMALL INTESTINE
L
ike the esophagus and stomach, the small bowel
may be extensively involved in diabetes mellitus.
While the disorders involving the esophagus and
and stomach may often go unnoticed, the diabetic
440 DIABETES CARE, VOL. 2 NO. 5, SEPTEMBER-OCTOBER 1979
involvement of the small bowel is often symptomatic,
resulting in diarrhea and/or steatorrhea.
The incidence of diarrhea as a complication of diabetes
mellitus ranges from 0.001% to as high as 10%.35 Approxi-
mately half of those patients presenting with diarrhea have
documented steatorrhea.35 Thus, patients with diabetic
enteropathy may present with diarrhea alone or in combina-
tion with steatorrhea.
Diarrhea and/or steatorrhea in the diabetic patient may be
caused by (1) diabetic diarrhea, the pathogenesis of which is
unclear; (2) bacterial overgrowth of jejunal segments, which
is associated with a slow transit time resulting in a "blind
loop" syndrome; (3) chronic pancreatitis with exocrine
insufficiency, an uncommon cause of diarrhea and steatorrhea
in diabetes; and/or (4) superimposed adult celiac disease.3
Diabetic diarrhea is defined as the presence of chronic
diarrhea without steatorrhea.36 The diarrhea is usually brown,
watery, voluminous, and may be associated with tenesmus.37
It may occur during the day or at night, and when it occurs at
night it often presents with incontinence. Usually the
affected patient is a middle-aged male who has long-standing
diabetes, often poorly controlled on insulin. The patient may
be of normal weight or occasionally obese and often has
evidence of peripheral neuropathy, especially associated
impotence. The diarrhea is typically episodic, with bouts
lasting days to weeks. These episodes are often followed by an
interval of weeks to months of either normal bowel habits or
occasionally even constipation. Interestingly, as time passes
the diarrhea tends to become less severe.
The pathogenesis of diabetic diarrhea is still not totally
resolved. It appears that diabetic autonomic neuropathy plays
a fundamental, although poorly understood, role.36 The only
significant autonomic pathologic finding, however, is a non-
specific dendritic swelling in the sympathetic prevertebral
and paravertebral ganglia, which is often present in diabetes
whether there is diarrhea or not.38 The ganglion cells of the
plexuses of Auerbach and Meissner are normal. The intestinal
mucosa in this group is usually normal, despite significant
steatorrhea.3 Although pancreatic exocrine insufficiency has
been proposed as a cause of diabetic diarrhea, most patients
have normal exocrine pancreatic function as determined by
the secretion tests.4 Serum carotene levels may be normal
or elevated.3
In approaching the differential diagnosis of diarrhea in a
diabetic patient, differentiation should be made between
diarrhea and steatorrhea complicating diabetes. This is best
accomplished by measuring 72-h fecal fat while the patient
consumes a diet with a minimum of 75-100 g fat daily.
Radiologic features of diabetic diarrhea relate to associated
autonomic neuropathy and include delayed gastric emptying
(vide supra), variation in luminal caliber with dilated loops of
small bowel, segmentation, and mucosal swelling with
coarsening of mucosal folds. There is considerable variability
in intestinal transit time, varying from shortening to con-
 GASTROINTESTINAL MANIFESTATIONS OF DIABETES MELLITUS/S. TAUB, A. MARIAN!, AND J. S. BARKIN
siderable prolongation.39 The history of small bowel biopsy
is usually normal, although occasionally a mild lymphocytic
infiltrate is present in the lamina propria.40
Therapeutic approaches in patients with diabetic diarrhea
are somewhat limited, but include (1) strict control of the
diabetes with carefully regulated insulin dosages; (2) possibly
restriction of iced beverages; (3) use of psyllium hydrophilic
mucilloid (Metamucil) powder in conjunction with di-
phenoxylate hydrochloride (Lomotil) or codeine sulfate, a
regime that has met with variable success.
Steatorrhea may complicate diabetic enteropathy, and is
present in as many as 75% of diabetic patients with diarrhea.
Significant steatorrhea should be evaluated as to its cause. As
noted, a 72-h fecal fat collection is used to quantitate the
steatorrhea. Conventional evaluation for etiology includes
upper GI series and small bowel barium studies, malabsorption
studies (i.e., D-xylose, folate levels, Schilling test), and small
bowel biopsy. In most respects, the patient with diabetic
steatorrhea is indistinguishable from the diabetic patient with
diarrhea alone, except for the fecal fat content of the stool.4
As mentioned, earlier, patients with diabetic diarrhea and
steatorrhea usually have normal jejunal biopsies, the differ-
ence between patients with and without steatorrhea usually
being one of degree.35 The mechanism responsible for
steatorrhea in diabetes is usually unexplained, although the
following causes may be seen in patients with diabetes: (1)
pancreatic exocrine insufficiency, (2) bacterial overgrowth
secondary to motility disturbance, or (3) concomitant adult
celiac disease.41
Abnormalities of pancreatic exocrine function may occur
in 20%-70% of diabetic patients, including those with
juvenile-onset diabetes mellitus.42 The abnormalities which
may be found after secretin stimulation (secretin test) are a
low pancreatic volume and/or low exocrine secretion in
duodenal aspirates.7 Gross pancreatic exocrine insufficiency
is a rare sequel of the diabetic state, and thus pancreatic
enzyme replacement usually does not ameliorate the
steatorrhea even when abnormalities are detected in the
secretin test.
A small percentage of diabetic patients demonstrate
bacterial overgrowth in the proximal small intestine. This is
usually seen in those patients who have slow transit time.
The bacterial overgrowth may lead to a type of "blind loop"
syndrome, with resultant diarrhea and possible steatorrhea.43
Abnormal bacterial cultures include increased concentra-
tions of Escherichia coli, enterococci, aerobacter, and
staphylococci, which may be found in the small bowel in
concentrations of lOVrnl. A few patients, especially those
with gastroparesis diabeticorum, demonstrate an overgrowth
of bacteria in the stomach.35 However, abnormal bacterial
concentrations are found in less than 20% of patients in
whom such clinical suspicion precipitates investigation.
Bacterial overgrowth leads to defective micellar formation
and resultant fat malabsorption and formation of hydroxy
DIABETES CARE, VOL. 2 NO. 5, SEPTEMBER-OCTOBER 1979
long-chain fatty acids, which may also incite a secretory type
of diarrhea, similar to that seen after castor oil.43 The
diagnosis of bacterial overgowth syndrome is usually made
clinically with gastric or small bowel cultures. It is possible
to determine the magnitude of bile acid deconjugation
induced by intestinal bacterial overgrowth by means of the
14
C-glycocholate ( 14 C-GCA). test.43'4311 The test involves
demonstration of increased breath 14CO2 in patients with
bacterial overgrowth, with the response normalized after
antibiotic therapy.43a An empiric trial of antibiotics may be
warranted in the diabetic patient with diarrhea. A clinical
response reaffirms the diagnosis. Therapy should be with a
broad-spectrum antibiotic such as tetrqpycline or ampicillin.
The dosage and duration of therapy should be individualized
if the initial response is favorable. We have found that
ampicillin 250 mg four times daily for 1 wk of each month is
usually sufficient to control the diarrhea secondary to a blind
loop syndrome.
A third mechanism of steatorrhea in diabetic patients is
celiac disease. Although the association of diabetes mellitus
and celiac disease has been widely reported for many years,
the number.of patients in whom the diagnosis of celiac
disease has been fully confirmed is small.44 It is entirely
possible that diabetes mellitus and adult celiac disease do not
occur anymore frequently than they would by chance alone.44
However, in children there does appear to be a more frequent
association between these two disease entities than would
occur by chance alone, although even these conclusions are
based on very small numbers.44 If there is a common linkage
or bridge between diabetes mellitus and celiac disease, it
appears to be connected in some way with histocompatability
(HLA) antigens. This could imply some type of common
genetic predisposition to both diabetes and celiac disease. A
significantly higher incidence of HLA B8 antigens has been
demonstrated in patients with celiac disease (80%) com-
pared with controls (29.5%).45>56 Likewise, HLA B8 antigen
occurs more commonly in patients with juvenile-onset
diabetes mellitus than in controls.47
Diabetic diarrhea has many similarities to celiac disease: In
both, the diarrhea may be intermittent, preceded by
borborygmi, or associated with steatorrhea.. In addition, the
diarrhea may be most troublesome at night and associated
with incontinence.44
Diabetic diarrhea is more common in men and occurs
mostly in patients in whom diabetes was diagnosed many
years previously. These patients are usually on insulin and
often their diabetes is rather poorly controlled. Peripheral
neuropathy is found in most cases and autonomic neuropathy
is often demonstrable. The patient is often able to maintain
a remarkably good nutritional state despite frequent bowel
movements, and features of malabsorption are not usually
apparent. Also, in diabetic diarrhea, a tendency toward
hypoglycemia during episodes of diarrhea is not a feature.
In contrast, celiac disease occurs more commonly in
441
 GASTROINTESTINAL MANIFESTATIONS OF DIABETES MELLITUS/S. TAUB, A. MARIANI, AND J. S. BARKIN
women and has its onset before or coincident with the onset
of diabetes. These patients often have features of malabsorp-
tion such as bone pain and peripheral edema. If neuropathy
is present in a diabetic patient with celiac disease, it is most
likely to be a manifestation of the diabetes.44 Likewise, the
absence of a neuropathy in a diabetic patient with diarrhea
should arouse suspicion that the diarrhea is not of diabetic
origin. An important clue that diarrhea in a diabetic patient
may be due to celiac disease is a history of repeated episodes
of hypoglycemia, particularly when the diarrhea is trouble-
some.44 Adherence to a strict, gluten-free diet in patients
with celiac disease often results in a decrease of these hypo-
glycemic episodes, even though insulin requirements are
often increased. In general, it is easier to control the diabetes
following therapy of the associated celiac disease.35 Labora-
tory evaluation consistent with malabsorption such as a low
carotene, albumin, and/or a low serum folate, or an elevated
alkaline phosphatase may increase the suspicion of the
presence of celiac disease. The small bowel biopsy will
enable one to diagnose celiac disease.44 Typical jejunal biopsy
features of celiac disease are varying degrees of villous
atrophy, cellular infiltrates in the lamina propria, and hyper-
plasia of the cells in the basal portions of the crypts of
Lieberkuhn. A favorable response to a gluten-free diet, and
occasionally the addition of steroids, is reasonably specific
for the diagnosis of sprue.35 Likewise, if the small bowel
biopsy is normal or shows a mild lymphocytic infiltrate in the
lamina propria, celiac disease is unlikely, and one is probably
dealing with diabetic diarrhea.
LARGE INTESTINE
C
onstipation can be seen in as many as 20% of
diabetic patients who have neuropathy.3 Whether
this is increased above the normal population is
uncertain, since both entities have a relatively
frequent occurrence. Occasionally, a massive amount of fecal
material may be found in the huge, atonic and dilated colon.
This may simulate intestinal obstruction or fecal impaction
with the impaired mass evacuation of contents into the rectal
ampulla.3 Occasionally, stercoral ulcerations have been
reported in diabetes mellitus in association with colonic
distension and subsequent mucosal erosion.48
Like the other intestinal motor abnormalities, large bowel
motility problems are usually seen in patients with associated
peripheral neuropathies.35 Treatment is basically sympto-
matic, with administration of laxatives and/or stool softeners.
LIVER
Fatty liver. The incidence of fatty liver in diabetes mellitus
ranges from 21% to 78%. 49 Whereas biopsy-proved fatty liver
is present in up to 44% of diabetic patients over 60 yr of age,
it is found in only 4.5% of patients with juvenile diabetes.
442 DIABETES CARE, VOL. 2 NO. 5, SEPTEMBER-OCTOBER 1979
The presence of a fatty liver in juvenile diabetes usually
implies metabolic decompensation and is frequently asso-
ciated with an enlarged liver that is tender to palpation and
may be painful. These symptoms improve following better
diabetic control.45 In maturity-onset diabetes, there is no
correlation between either duration of diabetes or degree of
diabetic control and amount of fat in the liver. Fatty liver in
this group is usually asymptomatic and rarely is associated with
elevated bilirubin or transaminase activity. Obesity and
maturity-onset diabetes are closely linked in the causation of
fatty liver.50 Loss of weight in these patients is usually followed
by improvement in the fatty liver, as well as improved con-
trol of the diabetes. Tolbutamide alone has not been shown to
reduce the steatosis of diabetes.49 The histologic picture of
fatty liver in maturity-onset diabetes consists of large fat
globules having the composition of adipose tissue fat. Electron
microscopy shows abnormal mitochondria and displacement
of organelles by the fat globules.51
Glycogen content of the liver. The liver of diabetic patients
is rich in glycogen, although there is no correlation between
the hepatic glycogen content and the fasting blood glucose,
type of diabetes, degree of ketosis, or fat content of hepato-
cytes.49 Hepatomegaly due to glycogen deposition may be
seen in brittle diabetes, especially in children. At this same
time a tendency toward hypoglycemia may develop. These
features appear to be the result of chronic use of excess
insulin.49
Glycagon is found in the nuclei of hepatocytes in 60%-
75% of diabetic patients. It is present in 30% of patients
without fatty liver and is found with greater frequency in
patients with increased amounts of cytoplasmic fat. In pa-
tients with massive fatty liver, glycogenated nuclei are
invariably present.52 Glycogenated nuclei also may occur in
some normal subjects as well as in Wilson's disease, tuber-
culosis, cirrhosis, and hepatitis.49'53
Cirrhosis. It is felt that the fatty liver of diabetes does not
progress to cirrhosis, although isolated case reports have
appeared.54 On the other hand, as many as 80% of patients
with established cirrhosis develop carbohydrate intolerance,8
including overt diabetes with fasting hyperglycemia and
glucosuria in 12%-32%. 55 It would appear that there is a
correlation between severity of liver disease and degree of
impairment of glucose tolerance. In fact, lowered serum
albumin is correlated with abnormal glucose tolerance. In
addition, there is a greater frequency of glucose intolerance
in patients with portal-systemic shunting, whether the shunt-
ing be surgically induced or spontaneous.56
The hyperglycemia of hepatic cirrhosis is associated with
hyperinsulinemia and insulin resistance. The cause of
impaired glucose tolerance in cirrhosis is unclear, although
hyperglucagonemia appears to play an important role in its
development. Recent studies demonstrated increased levels
of glucagon in cirrhosis, particularly in association with
portal-systemic shunting.57'58 The hepatocellular damage
 GASTROINTESTINAL MANIFESTATIONS OF DIABETES MELLITUS/S. TAUB, A. MARIANI, AND J. S. BARKIN
resulting from cirrhosis may impair the ability of the liver to
assimilate large glucose loads, thus leading to postprandial
hyperglycemia, hyperinsulinemia, and insulin resistance.59
Other factors that have been implicated in the glucose
intolerance of cirrhosis include hypokalemia,60 chronic
pancreatitis,61 and hemosiderosis.62 Idiopathic hemochroma-
tosis affects the pancreas and the liver. Thus, it is not sur-
prising that glucose intolerance or overt diabetes is observed
in up to 80% of these patients.63 Typical diabetic complica-
tions such as retinopathy, nephropathy, and peripheral
neuropathy may occur in diabetes secondary to hemochroma-
tosis, but are not common in cirrhotic patients with
diabetes.64 The diabetes in patients with idiopathic hemo-
chromatosis is not solely due to pancreatic islet cell damage
but may be contributed to by cirrhosis and genetic influences.65
Other states. There is an increased frequency of hepatitis
in diabetic patients, which may be due to decreased resistance
to infection, but is more likely due to repeated hospital
exposure. Madalinski et al. reported a 6.5% frequency of
hepatitis B antigen.66
Glucose tolerance tests are often impaired during the acute
phase of viral hepatitis. One hundred cases of clinical diabetes
have been reported to occur during viral hepatitis, excluding
corticosteroid treatment. The pathogenesis of this glucose
intolerance remains unclear. However, most authors
postulate the existence of a viral endocrine pancreatitis or an
insulin-resistant state related either to hepatic cell insuf-
ficiency or an increase in free fatty acid concentration.67
Several oral hypoglycemic agents may cause hepato-
toxicity. The incidence of chlorpropamide-induced cholestatic
hepatitis is 0.5%, although transient but significant eleva-
tions of the serum alkaline phosphatase level have been
observed in as many as 25% of patients under treatment with
this drug.68 Tolbutamide is less likely to cause hepatic
dysfunction. Patients who recover from chlorpropamide
hepatitis generally do not relapse when given tolbutamide.
Foster et al.69 reported the occurrence of diabetes mellitus
in association with hepatic cell adenomas in four family
members. They postulated that a defect in carbohydrate
metabolism may play a role in the development of hepatic
cell adenomas.
Diabetic ketoacidosis is believed to have been the etiologic
factor in the hepatic infarction suffered by a young man with
brittle diabetes mellitus.70 Plasma norepinephrine and
epinephrine levels are usually elevated in patients with
diabetic ketoacidosis. Ng et al. suggested that this
catecholamine elevation may have caused vasoconstriction
sufficient to produce hepatic ischemia and infarction in their
patient.70
Holt et al.71 found that 5 of 14 patients with solitary
liver abscesses had diabetes, whereas none of 22 patients with
multiple liver abscesses had diabetes. Biliary tract infection
was also present in the 5 diabetic patients with liver
abscesses.
DIABETES CARE, VOL. 2 NO. 5, SEPTEMBER-OCTOBER 1979
BILIARY TRACT
T
here appears to be an increased incidence of
cholelithiasis in patients with diabetes mellitus.72
Lieber73 found gallstones in 11.6 of 29,779
autopsies; however, in a selected group of
diabetic subjects, the frequency was approximately 30%.
Warren74 and Robertson75 also reported a similar association
between cholelithiasis and diabetes. Other authors, however,
have been unable to demonstrate this increase.76'77 Studies in
Pima Indians have been contradictory, although it is note-
worthy that this population has perhaps the highest incidence
in the world of both diabetes and gallstones.78 More studies
are needed to clarify whether there is an increased incidence
of cholelithiasis in diabetic patients, but the association
appears to be more than fortuitous.
Recently, Ponz de Leon et al.79 reported that bile from
patients with maturity-onset diabetes was supersaturated with
cholesterol, and the absolute values for biliary bile acid con-
centrations were significantly reduced. Both trends would
favor cholesterol precipitation and stone formation. The
above changes were not apparent in juvenile-onset diabetes.
The size of the bile acid pool and the proportion of the
individual biliary bile acids were normal in both types of
diabetes.
The gallbladder of diabetic patients tends to be larger in
size than that of nondiabetic individuals.80 Radiologic
studies have demonstrated that the diabetic gallbladder con-
tracts less vigorously after a fatty meal than does a normal
gallbladder. These findings are not in themselves indications
for cholecystectomy.
Acute cholecystitis. Acute cholecystitis is particularly lethal
in patients with diabetes mellitus in whom a high incidence
of suppurative complications accounts for a mortality of about
20%. Thus, diabetic patients with acute cholecystitis should
undergo cholecystectomy early in the course of the latter
disease. It has been postulated that arterial ischemia of the
gallbladder wall may be an etiologic factor in the acute
cholecystitis of diabetic patients.81 Some authors also suggest
elective cholecystectomy in diabetic patients with asympto-
matic cholelithiasis in order to minimize potentially life-
threatening complications.82
Emphysematous cholecystitis is a form of acute cholecystitis
that derives its name from the occurrence of gas within the
gallbladder lumen. Twenty percent of such patients also suffer
from diabetes mellitus. The gas-forming organisms that have
been implicated in the pathogenesis of emphysematous
cholecystitis include Clostridium welchii, which has been
cultured most often, as well as anaerobic streptococci,
Escherichia coli, Staphylococcus aureus, Pseudomonas, and
Kkbsiella.83 Clinically, these patients exhibit a more toxic
course; their pain may be more severe than expected in
uncomplicated acute cholecystitis. The majority of patients
with emphysematous cholecystitis are men in their sixth or
443
 GASTROINTESTINAL MANIFESTATIONS OF DIABETES MELLITUS/S. TAUB, A. MARIANI, AND J. S. BARKIN
seventh decade of life. The initial management of these
patients consists of high doses of antibiotics (e.g., ampicillin
12 g daily) and general supportive measures to stabilize the
patient. This is followed early by laparotomy and chol-
ecystectomy. In those cases where the patient remains
unstable despite supportive therapy, cholecystostomy for
drainage may be preferable to cholecystectomy.82
PANCREAS
A
bnormalities of pancreatic exocrine secretion are
seen in 20%-70% of diabetic patients.84 These
abnormalities, usually not severe, are clinically
inapparent and may be due to vagal neuropathy,
deficient stimulating action of insulin, or glucagon
inhibition.85
The diabetic patient is at increased risk for acute pan-
creatitis86 and pancreatic carcinoma. On the other hand,
acute pancreatitis, chronic pancreatitis, and carcinoma of the
pancreas may themselves cause or exacerbate glucose
intolerance and diabetes.
Autopsy studies on patients over 20 yr of age have shown
that pancreatitis occurs twice as frequently in diabetic as in
nondiabetic patients, and the damage appears to result from
vascular lesions of the diabetic pancreas.86'87 There also
appears to be an increased incidence of acute pancreatitis in
patients with juvenile-onset diabetes mellitus.88 Patients with
acute pancreatitis complicating diabetic ketoacidosis have a
high risk of mortality because of the frequently associated
shock and precipitous hypoglycemia.85
Acute pancreatitis may induce glucose intolerance.
Johansen and Ornsholt89 reported an 18% incidence of mild
diabetes among 22 patients studied 7-48 mo after an attack of
acute pancreatitis. Those patients who developed diabetes
mellitus were less than 35 yr old, did not require insulin
therapy, and had abnormally low and delayed insulin re-
sponses after oral glucose intake. Knight and co-workers90
reported high serum glucagon levels during the 24 h
immediately following an attack of acute pancreatitis, with
such values falling rapidly thereafter. Hyperglycemia has been
found in 10%-79% of patients experiencing an episode of
acute pancreatitis. Berkowitz and Glassman suggested the
use of the intravenous tolbutamide test to aid in the earlier
diagnosis of acute pancreatitis when faced with difficult acute
abdominal presentation.91
Rarely, acute hemorrhagic pancreatitis may result in
diabetes severe enough to cause ketoacidosis and even
isolated cases of diabetic coma (both the ketotic and non-
ketotic hyperosmolar variety).92 Apart from these cases of
diabetic coma, there is no correlation between the severity of
hyperglycemia or the diabetic state and the mortality from
acute pancreatitis. Thus, the carbohydrate intolerance of
acute pancreatitis usually is asymptomatic, temporary, and
may subside rapidly. Insulin treatment is considered only in
the presence of symptoms of diabetes or if ketosis develops.
444 DIABETES CARE, VOL. 2 NO. 5, SEPTEMBER-OCTOBER 1979
When insulin is used in these patients, caution should be
taken to avoid hypoglycemia. Bank et al. suggest the use of a
glucose tolerance test and possibly insulin studies 3 mo after
an attack of acute pancreatitis to detect any deterioration
in the endocrine function of the pancreas.92
The use of phenformin therapy in the management of
maturity-onset diabetes has been associated with acute
pancreatitis.93 Discontinuation of phenformin will avoid
progression of this drug-induced pancreatitis.
Chronic pancreatitis. There is no evidence of an increased
incidence of chronic pancreatitis in patients with genetic
diabetes mellitus. However, idiopathic diabetes mellitus and
chronic pancreatitis are frequently seen in association with
many disease states, e.g., cystic fibrosis and idiopathic
hemochromatosis.
The diabetes secondary to chronic pancreatitis represents
0.3% of all cases of diabetes. In patients with chronic
pancreatitis followed from 1 to 15 yr who had no detectable
pancreatic calcifications, Bank et al. noted overt diabetes in
30% and an abnormal glucose tolerance in another 20%.92
When pancreatic calcifications were present radiologically,
overt diabetes was found in 70%, and a further 20% had an
abnormal glucose tolerance. The frequency of glucose
intolerance in patients with chronic pancreatitis progressively
increases with duration of the disease.94
Asymptomatic diabetes is most likely to occur in alcohol-
induced pancreatitis, alcohol-induced calcific pancreatitis,
and in nonalcoholic tropical pancreatitis. This last entity is
seen especially in Uganda, India, and Indonesia and appears
to result from nutritional deficiency.95'96 The occurrence of
diabetes is lower in idiopathic chronic pancreatitis and
pancreatitis due to various other causes, e.g., biliary calculi
or trauma. Alcohol is the etiologic factor in 90% of patients
with chronic calcific pancreatitis in most Western countries.
The typical patient with pancreatic diabetes gives a history of
alcohol overindulgence for 5-15 yr, followed by recurrent
mild abdominal pain, then by the appearance of diabetes
1-20 yr later. Steatorrhea occurs 10-25 yr after onset of the
disease.92
Patients with pancreatic diabetes are unusually sensitive
to insulin and therefore may be more susceptible to
hypoglycemia.
Linde et al. noted hypoglycemic episodes in 14 of 18
insulin-treated patients with chronic pancreatitis and in 3
patients in whom severe hypoglycemia was believed to be
the cause of their death.97 The hypoglycemia may be due to
the impaired glucagon and growth hormone response to
insulin-induced hypoglycemia, which is commonly seen in
patients with pancreatic diabetes. The fasting serum insulin
levels of patients with chronic calcific pancreatitis are
approximately half that of normal. The mean peak increment
in serum insulin level after oral glucose loading was only
20-25% of normal in patients with pancreatic diabetes. The
insulin response was also delayed.62 Because of the low
 GASTROINTESTINAL MANIFESTATIONS OF DIABETES MELLITUS/S. TAUB, A. MARIANI, AND J. S. BARKIN
incidence of diabetic vasculopathy and the tendency toward
hypoglycemia, most authors advocate erring on the side of
undertreatment of pancreatic diabetes.97'98 Higher caloric
intake may be required because of the frequent finding of
weight loss in these patients. This weight loss may be
secondary to malabsorption from the associated pancreatic
exocrine insufficiency. Bank et al. suggest a trial of oral
hypoglycemic agents before insulin therapy is instituted.
Glucagon may help in managing patients with pancreatic
diabetes complicated by drug-induced hypoglycemia.97
Carcinoma of the pancreas. The frequency of carcinoma of
the pancreas in patients with diabetes mellitus appears to be
about twice that in the general population.97'98 The increased
frequency appears to be less marked in men, although this
probably reflects earlier death of men from other causes. It is
unknown why there is an increased frequency of carcinoma of
the pancreas in diabetes. It has been suggested that there are
functional links between the endocrine and exocrine pancreas
and that these may explain the above association. An
alternative proposal is that animal insulin or an impurity
thereof may be carcinogenic to the pancreas.99'100
Diabetes was present before the onset of symptoms of
pancreatic carcinoma in 4.3% of patients with pancreatic
cancer, and diabetes was detected after the onset of symptoms
in a further 15.3%.101>102 Eighty percent of patients with
pancreatic cancer have their diabetes discovered within a year
of the time that the cancer becomes manifest, suggesting
that the presence of the malignancy causes the diabetes in
many of these patients.102 Therefore, when diabetes develops
in a middle-aged patient without a family history of the
disease and with unexplained systemic symptoms, pancreatic
carcinoma should be sought.
Glucagonoma. The glucagonoma syndrome results from
functioning A-cell tumors of the pancreas. Hypergluca-
gonemia is associated with an insulin level that is normal or
markedly reduced depending on how much of the pancreatic
tissue is replaced by tumor. Associated carbohydrate in-
tolerance may range from mild to severe. Relative insulin-
resistant diabetes may be present.49 Half of the patients with
these tumors have a skin disease referred to as erythema
necrolytica migrans. Oral crusting and painful glossitis may
also be present.
Verner-Morrison syndrome.103 The clinical features of this
syndrome include profuse choleralike diarrhea (usually tea-
colored), hypokalemia, basal achlorhydria in more than 50%
of patients, diabetes, hypercalcemia in 25%, and cutaneous
flushing episodes. These patients also have an increased
incidence of gallstones and large atonic gallbladders. This
syndrome is believed to result from the presence of a non-beta
islet cell tumor of the pancreas secreting vasoactive intestinal
peptide (VIP). Animal experiments have demonstrated that
the biologic actions of VIP fit closely the described features of
these patients.104 The hyperglycemic state appears to result
from an increased hepatic glucose output, which is due to a
DIABETES CARE, VOL. 2 NO. 5, SEPTEMBER-OCTOBER 1979
high circulating VIP level. U p to two-thirds of these islet cell
tumors are malignant.
From the University of Miami School of Medicine, Division of
Gastroenterology, Miami, Florida.
Address reprint requests to Jamie S. Barkin, M.D., University
of Miami School of Medicine (D-49), P.O. Box 016960, Division
of Gastroenterology, Miami, Florida 33101.
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