Practice Essentials

Insulinomas are the most common cause of hypoglycemia

resulting from endogenous hyperinsulinism. Approximately 9095% of insulinomas are benign, and long-term cure with total
resolution of preoperative symptoms is expected after complete
resection. See the image below.

CT scan image with oral and

intravenous contrast in a patient with biochemical evidence of insulinoma. The
3-cm contrast-enhancing neoplasm (arrow) is seen in the tail of the pancreas
(P) posterior to the stomach (S) (Yeo, 1993).

Signs and symptoms

Insulinomas are characterized clinically by the Whipple triad, as
follows:

Presence of symptoms of hypoglycemia (about 85% of

patients)

Documented low blood sugar at the time of symptoms

Reversal of symptoms by glucose administration

About 85% of patients with insulinoma present with one of the
following symptoms of hypoglycemia:

Diplopia


Blurred vision

Palpitations

Weakness
Hypoglycemia can also result in the following:

Confusion
Abnormal behavior
Unconsciousness
Amnesia
Adrenergic symptoms (from hypoglycemia-related adrenalin
release): Weakness, sweating, tachycardia, palpitations, and
hunger

Seizures
See Clinical Presentation for more detail.

Diagnosis
Lab studies
Failure of endogenous insulin secretion to be suppressed by
hypoglycemia is the hallmark of an insulinoma. Thus, the finding
of inappropriately elevated levels of insulin in the face of
hypoglycemia is the key to diagnosis.
The biochemical diagnosis of insulinoma is established in 95% of
patients during prolonged fasting (up to 72 h) when the following
results are found:

Serum insulin levels of 10 U/mL or more (normal < 6

U/mL)

Glucose levels of less than 40 mg/dL

C-peptide levels exceeding 2.5 ng/mL (normal < 2 ng/mL)

Proinsulin levels greater than 25% (or up to 90%) of

immunoreactive insulin levels


Screening for sulfonylurea negative
Imaging studies
Insulinomas can be located with the following imaging modalities:

Endoscopic ultrasonography: Detects 77% of insulinomas in

the pancreas [1, 2, 3]

Real-time transabdominal high-resolution ultrasonography:

50% sensitivity

Intraoperative transabdominal high-resolution

ultrasonography with the transducer wrapped in a sterile rubber
glove and passed over the exposed pancreatic surface: Detects
more than 90% of insulinomas

Helical or multislice computed tomography (CT) scanning:

82-94% sensitivity

Magnetic resonance imaging (MRI) with gadolinium: Can aid

tumor detection in 85% of cases

Arteriography: Selective arteriography has 82% accuracy,

with a 5% false-positive rate; arteriography with catheterization
of small arterial branches of the celiac system combined with
calcium injections and simultaneous measurements of hepatic
vein insulin during each selective calcium injection localizes
tumors in 47% of patients

Somatostatin receptor scintigraphy: 60% sensitivity

See Workup for more detail.

Management
Pharmacologic therapy
Pharmacologic treatment is designed to prevent hypoglycemia
and, in patients with malignant tumors, to reduce the tumor
burden. Agents used in this therapy include the following:

Diazoxide: Reduces insulin secretion

Hydrochlorothiazide: Counteracts edema and hyperkalemia

secondary to diazoxide and potentiates its hyperglycemic effect

Octreotide: Prevents hypoglycemia

Surgery

Laparoscopic surgery: A large study from Spain showed

laparoscopic surgery to be safe and effective in benign and
malignant tumor resection [4]

Enucleation: Because of the small likelihood that a tumor

that presents without metastatic spread is malignant,
insulinomas may be removed by enucleation

Pancreaticoduodenectomy: If enucleation is not possible, a

larger pancreatic resection, including
pancreaticoduodenectomy, may be necessary

Whipple procedure: Major resections, such as the Whipple

procedure, may become necessary when the tumor is found in
the pancreatic head and local excision is not possible

Subtotal pancreatectomy with enucleation: If insulinoma is

associated with multiple endocrine neoplasia type 1 (MEN1),
subtotal pancreatectomy with enucleation of tumors from the
pancreatic head and uncinate processus often is recommended
over simple enucleation, because of frequent multiple tumors in
MEN1
Even when metastases are found, surgical excision is often
feasible before any medical, chemotherapeutic, or other
interventional therapy is considered. Resect all gross disease; this
would include performing wedge resections of hepatic metastases
See Treatment and Medication for more detail.

Background
Insulinomas are the most common cause
of hypoglycemia resulting from endogenous hyperinsulinism. In a
large single-center series of 125 patients with neuroendocrine

tumors, insulinomas constituted the majority of cases (55%),

followed by gastrinomas (36%), VIPomas (vasoactive intestinal
polypeptide tumor) (5%), and glucagonomas (3%).[5]

CT scan image with oral and

intravenous contrast in a patient with biochemical evidence of insulinoma. The
3-cm contrast-enhancing neoplasm (arrow) is seen in the tail of the pancreas
(P) posterior to the stomach (S) (Yeo, 1993).

Endoscopic ultrasonography
in a patient with an insulinoma. The hypoechoic neoplasm (arrows) is seen in
the body of the pancreas anterior to the splenic vein (SV) (Rosch, 1992).

In 1927, Wilder established the association between

hyperinsulinism and a functional islet cell tumor.[6] In 1929,
Graham achieved the first surgical cure of an islet cell adenoma.
Insulinomas can be difficult to diagnose. It was not uncommon for
patients to have been misdiagnosed with psychiatric illnesses or
seizure disorders before insulinoma was recognized.

Pathophysiology
An insulinoma is a neuroendocrine tumor, deriving mainly from
pancreatic islet cells, that secretes insulin. Some insulinomas also
secrete other hormones, such as gastrin, 5-hydroxyindolic acid,
adrenocorticotropic hormone (ACTH), glucagon, human chorionic
gonadotropin, and somatostatin. The tumor may secrete insulin in
short bursts, causing wide fluctuations in blood levels.
About 90% of insulinomas are benign. Approximately 10% of
insulinomas are malignant (metastases are present).
Approximately 10% of patients have multiple insulinomas; of
patients with multiple insulinomas, 50% have multiple endocrine
neoplasia type 1 (MEN 1). Insulinomas are associated with MEN
1 in 5% of patients. On the other hand, 21% of patients with MEN
1 develop insulinomas. Because of the association of insulinomas
with MEN 1, consideration should be given to screening family
members of insulinoma patients for MEN 1.
Increased expression of the phosphorylated mechanistic target of
rapamycin (p-mTOR) signaling pathway and itsdownstream
serine/threonine kinase p70S6k has been observed in insulinoma
tumor specimens.[7] This discovery has led to studies exploring
new therapeutic options.

Epidemiology
United States

Insulinomas are the most common pancreatic endocrine tumors.

The incidence is 3-10 cases per million people per year.[8] These
make up 55% of neuroendocrine tumors.

International
Exact data for international incidence of insulinomas are not
available. One source from Northern Ireland reported an annual
incidence of 1 case per million persons. A study from Iran found
68 cases in a time span of 20 years in a university in Tehran.[9] A
10-year single-institution study from Spain of 49 consecutive
patients who underwent laparoscopic surgery for neuroendocrine
pancreatic tumors included 23 cases of insulinoma.[4] These
reports may be an underestimate.

Mortality/Morbidity
The postoperative morbidity rate in one published series was 14%
and consisted mainly of local complications, such as fistula
formation after pancreatic resection. The postoperative mortality
rate in another series of 117 insulinoma patients was 7.7%. The
median survival in metastatic disease to the liver ranges from 1626 months.

Race-, Sex-, and Age-related Demographics

Insulinomas have been reported in persons of all races. No racial
predilection appears to exist.
The male-to-female ratio for insulinomas is 2:3.
The median age at diagnosis is about 47 years, except in
insulinoma patients with MEN 1, in whom the median age is the
mid 20s. In one series, patients with benign disease were younger
(mean age of 38 y) than those with metastases (mean age of 52
y). The age range for peak incidence of insulinoma is between 30
and 60 years.

History

See the list below:

About 85% of patients present with symptoms

of hypoglycemia that includediplopia, blurred vision, palpitations,
or weakness.
Other symptoms include confusion, abnormal behavior,
unconsciousness, or amnesia.
About 12% of patients have grand mal seizures.
Adrenergic symptoms (hypoglycemia causes adrenalin
release) include weakness, sweating, tachycardia, palpitations,
and hunger.
Symptoms may be present from 1 week to as long as
several decades prior to the diagnosis (1 mo to 30 y, median 24
mo, as found in a large series of 59 patients).[10] Symptoms may
occur most frequently at night or in the early morning hours.
Hypoglycemia usually occurs several hours after a meal.
In severe cases, symptoms may develop in the postprandial
period. Symptoms can be aggravated by exercise, alcohol,
hypocaloric diet, and treatment with sulfonylureas.
Weight gain occurs in 20-40% of patients. Because of
hyperinsulinism, many patients may be overweight.
A case report of a patient with type 2 diabetes who
developed recurrent hypoglycemia was published from France.
[11]

Symptoms caused by effects of local tumor mass are very

rare in insulinoma.

Physical

Insulinomas are characterized clinically by the Whipple triad

(which occurred in 75% of 67 insulinoma patients in one report).

Presence of symptoms of hypoglycemia

Documented low blood sugar at the time symptoms are

present

Reversal of symptoms by glucose administration.

Most patients with insulinoma have normal physical examination
findings.
Causes

The genetic changes in neuroendocrine tumors are under

investigation.[12] The gene of multiple endocrine neoplasia type 1,
an autosomal dominant disease, is called MEN1 and maps to
band 11q13. MEN1 is thought to function as a tumor suppressor
gene. Data suggest that the MEN1 gene also is involved in the
pathogenesis of at least one third of sporadic neuroendocrine
tumors. Researchers were able to detect loss of heterozygosity in
band 11q13 in DNA samples from resected insulinoma tissue by
using fluorescent microsatellite analysis.
In a study of 12 children with insulinoma, four cases showed
heterozygous mutations of MEN1 on 11q. Aneuploidy of
chromosome 11 and other chromosomes was common in both
MEN1 and non-MEN1 insulinomas.[13]
One study showed k -ras mutation to be present in 23% of
insulinomas.
Diagnostic Considerations

Factitious hypoglycemia can occur in patients who have

psychiatric disturbances or a need for attention and access to
insulin or sulfonylurea drugs (eg, medical staff).[14] The triad of
hypoglycemia, high immunoreactive insulin levels, and
suppressed plasma C-peptide immunoreactivity is pathognomonic

of exogenous origin. Insulin-induced hypoglycemia can be

detected by a ratio of insulin to C-peptide that is greater than 1.0.
Hypoglycemia can occur after inadvertent ingestion of
sulfonylurea due to patient or pharmacist error.
Autoimmune hypoglycemia is a rare disorder caused by the
interaction of endogenous antibodies with insulin or the insulin
receptor.[15] The condition is more common in Japan than in the
United States or Europe. The syndrome may produce severe
neuroglycopenic symptoms, making immunosuppressive therapy
occasionally necessary.[10]
Nesidioblastosis is defined as hyperplasia of the islet cells
causing hyperinsulinemic hypoglycemia. It is a predominantly
neonatal disorder, although cases in adults have been reported
recently.[16]
Noninsulinoma pancreatogenic hypoglycemia syndrome (NIPHS)
is a condition in which pancreatic islet hyperplasia is present.
[17]
This is manifested with postprandial neuroglycopenia, a
negative normal fasting test, negative pancreatic imaging results,
and positive intra-arterial calcium stimulation of serum insulin.
Familial persistent hyperinsulinemia is manifested with
inappropriately high insulin secretions seen in families with
mutations in the glucokinase enzymes, glutamate dehydrogenase
and short-chain3-hydroxyacyl1-CoA dehydrogenase.
Other causes for hypoglycemia include liver disease, endocrine
deficiencies, extrapancreatic insulin-producing tumors (an insulin-

secreting small-cell carcinoma of the cervix recently has been

described), and pentamidine-induced hypoglycemia.
Laboratory Studies

Failure of endogenous insulin secretion to be suppressed by

hypoglycemia is the hallmark of an insulinoma. Thus, the finding
of inappropriately elevated levels of insulin in the face of
hypoglycemia is the key to diagnosis. Considering the reference
range, the fasting plasma levels of insulin, C-peptide, and, to a
lesser degree, proinsulin need not be elevated in insulinoma
patients in absolute terms.
Prolonged (ie, 72 h) supervised fast in hospitalized patients
provides the most reliable results. The calculation of ratios of
insulin (U/mL) to plasma glucose (mg/dL) is diagnostic: Healthy
patients maintain a ratio of less than 0.25 (obese patients may
have a slightly higher rate), whereas in patients with insulinoma,
the ratio rises during fasting.
In a study from the Netherlands, a positive Whipple triad on a
prolonged fasting test, in combination with an insulin/C-peptide
ratio <1, had a sensitivity of 88.9% and a specificity of 100% for
the diagnosis of insulinoma.[18]
The biochemical diagnosis is established in 95% of patients
during prolonged fasting (up to 72 h) when the following
parameters are found:

Serum insulin levels of 10 U/mL or more (normal <6 U/mL)

Glucose levels of less than 40 mg/dL
C-peptide levels exceeding 2.5 ng/mL (normal <2 ng/mL)
Proinsulin levels 22 pmol/L, [19] or greater than 25% (or up to
90%) that of immunoreactive insulin

Screening for sulfonylurea negative

Stimulation tests no longer are recommended. The intravenous

application of tolbutamide, glucagon, or calcium can be
hazardous, as they may induce prolonged and refractory
hypoglycemia.
The presence of MEN 1 must be evaluated by excluding the
following:

Hyperprolactinemia due to a pituitary adenoma

Hyperparathyroidism due to parathyroid hyperplasia

Hypergastrinemia due to a gastrinoma

maging Studies
Start imaging studies only after the diagnosis has been confirmed
biochemically, because 80% of insulinomas are less than 2 cm in
size and may not be visible by CT scan or transabdominal
ultrasonography.
Successful preoperative tumor localization is achieved in about
60% of patients.[20]Some experienced surgeons perform only
transabdominal ultrasound preoperatively. Other surgeons argue
that the preoperative localization of insulinomas is not necessary
at all because surgical exploration and intraoperative
ultrasonography identify more than 90% of tumors.[21] Thus, the
extent to which one attempts to define the anatomy of the beta
cell lesion before surgery is a matter of judgment.
Helical or multislice CT scan has 82-94% sensitivity. In one study,
dual-phase helical CT proved more sensitive than single-phase
for detection of insulinoma; in addition, image acquisition in the
arterial phase proved more helpful than acquisition during the
portal-venous phase.[22]
MRI with gadolinium can be helpful in detecting a tumor in 85% of
cases. One case report suggests that diffusion-weighted MRI can

be useful for detecting and localizing small insulinomas,

especially for those with no hypervascular pattern.[23]
The accuracy of selective arteriography is 82%, although affected
by a false-positive rate of 5%. Many experts see it as the best
overall preoperative localization procedure.
Arteriography with catheterization of small arterial branches of the
celiac system combined with calcium injections (which stimulate
insulin release from neoplastic tissue but not from normal islets),
and simultaneous measurements of hepatic vein insulin during
each selective calcium injection localizes tumors in 47% of
patients.
A study by Wiesli et al found that proinsulin, C-peptide, and insulin
are all released by insulinoma cells in response to arterial calcium
stimulation; however, chromogranin A (CgA) and neuron-specific
enolase (NSE) are not released. The study also concluded that
pancreatic polypeptide may be released by healthy islet cells after
calcium stimulation.[24]
The sensitivity of somatostatin receptor scintigraphy is 60%,
although many insulinomas lack somatostatin receptor subtype 2
for successful identification.
Endoscopic ultrasonography detects 77% of insulinomas in the
pancreas.[1, 2, 3] The yield can be higher if it is done in combination
with CT scan. A majority of sporadic insulinomas will be detected
and localized by a combination of these two investigative means.
Note the following:

Real-time transabdominal high-resolution ultrasonography

has 50% sensitivity.

Intraoperative transabdominal high-resolution

ultrasonography with the transducer wrapped in a sterile rubber

glove and passed over the exposed pancreatic surface detects

more than 90% of insulinomas.

Performing a preoperative study to localize the tumor

followed by intraoperative ultrasonography and a physical
examination is not unreasonable.
Insulinomas have been shown to have a very high density of
glucagon-like peptide-1 receptors (GLP-1R), and radiolabeling
with an111 In-labeled GLP-1R agonist (111In-DOTA-exendin-4) has
successfully been used to localize small insulinomas both
preoperatively and, with the use of a gamma probe,
intraoperatively.[25] Luo et al reported that positron-emission
tomography/CT scanning with 68Ga-NOTA-exendin-4 correctly
detected insulinomas in 42 of 43 patients.[26]
Somatostatin receptor target imaging can diagnosis malignant
insulinomas missed by GLP-1 target imaging because these
malignancies often lack GLP-1 receptors.
Other tests used in the localization of insulinoma are as follows:

Preoperative portal venous sampling is obsolete as a routine

investigation because of a high complication rate (10%), but it
may be used when all other imaging procedures fail and
surgical exploration findings are negative.

Localization with anti-insulin labeled with iodine-131 was

achieved in 50% of patients, with a 37.5% false-positive rate;
therefore, it is not recommended.

Endoscopic ultrasound-guided fine-needle aspiration biopsy

of insulinoma has been described; the technique combines
endoscopic ultrasonography with local tumor biopsy and may be
indicated when the tissue diagnosis must be established
preoperatively.

Laparoscopic ultrasonography with eventual tumor biopsy

may be used in rare cases when other localization techniques
failed.

 Insulinomas are solitary tumors in 90% of patients. In MEN 1

syndrome, multiple microinsulinomas and macroinsulinomas
are found, although hypoglycemia may be caused by a
single tumor. The tumors are distributed evenly throughout
the pancreas. Tumor size does not relate to the severity of
clinical symptoms. Ectopic insulinomas may be found in the
ligament of Treitz.
No histologic criteria are available to distinguish benign from
malignant insulinomas. Malignant tumors are usually larger
(average size 6.2 cm), and a third of them have
metastasized to the liver. Insulinoma tumor cells contain less
insulin and secretory granules than normal B cells but higher
levels of proinsulin. Atypical granules, or even agranular
cells, are frequent. The clinical response to diazoxide and
somatostatin correlates with the frequency and type of
granules.
Medical Care

Medical therapy is indicated in patients with malignant

insulinomas and in those who will not or cannot undergo surgery.
These measures are designed to prevent hypoglycemia and, in
patients with malignant tumors, to reduce the tumor burden. In
malignant insulinomas, dietary therapy with frequent oral feedings
or enteral feedings may control mild symptoms of hypoglycemia.
A trial of glucagon may be attempted to control hypoglycemia.
Diazoxide is related to the thiazide diuretics and reduces insulin
secretion. Adverse effects include sodium retention, a tendency
to congestive cardiac failure, andhirsutism. Prescribe

hydrochlorothiazide to counteract the edema

and hyperkalemiasecondary to diazoxide and to potentiate its
hyperglycemic effect.
Of patients with insulinoma, 50% may benefit from the
somatostatin analogue octreotide to prevent hypoglycemia.[28] The
effect of the therapy depends on the presence of somatostatin
receptor subtype 2 on insulinoma tumor cells. As studies have
shown, an OctreoScan is not a prerequisite before starting
octreotide treatment. In patients with insulinoma and a negative
scan finding, somatostatin decreased insulin levels significantly
and lowered the incidence of hypoglycemic events.[29]
CT-guided radiofrequency ablation has been used successfully to
treat insulinoma in an elderly patient whose hypoglycemia that
was refractory to diazoxide, and who was not a candidate for
surgery because of comorbidities and poor physical condition.[30]
Everolimus has been used to treat insulinoma. In a French study,
everolimus therapy normalized blood glucose levels in 11 of 12
patients with metastatic insulinoma and refractory hypoglycemia,
with the therapeutic effect maintained for a median duration of 6.5
months (range 1-35+ months). However, three patients
discontinued everolimus because of cardiac and/or pulmonary
adverse events, which led to two deaths.[31]

Medication Summary
Diazoxide is the drug of choice because it inhibits insulin release
from the tumor. Adverse effects must be treated with
hydrochlorothiazide. In patients not responsive to or intolerant of
diazoxide (10%), somatostatin may be indicated to prevent
hypoglycemia.

Hyperglycemic agents
Class Summary
Inhibit insulin release from the tumor.
View full drug information

Diazoxide (Proglycem, Hyperstat)

Produces an increase in blood glucose within 1 h by inhibition of
insulin release from the insulinoma.

Diuretics
Class Summary
Used to counteract edema and hyperkalemia secondary to
diazoxide and to potentiate its hyperglycemic effect.
View full drug information

Hydrochlorothiazide (Microzide, HydroDIURIL, Esidrix)

Inhibits reabsorption of sodium in distal tubules, causing
increased excretion of sodium and water as well as potassium
and hydrogen ions.

Somatostatin analogs
Class Summary
May control symptoms by suppressing secretion of
gastroenteropancreatic peptides including insulin. High-dose
treatment also may lead to additional antiproliferative effects.
However, long-term application of somatostatin may downregulate receptor expression levels, resulting in decreased
efficiency despite increasing doses. Both short- and long-acting
depot preparations are available.

View full drug information

Octreotide acetate (Sandostatin)

Acts similarly to the natural hormone somatostatin and can
suppress secretion of gastroenteropancreatic peptides including
insulin.

Antineoplastic Agents
Class Summary
These agents inhibit cell growth and proliferation.
View full drug information

Streptozocin (Zanosar)
Used in fasting hypoglycemia caused by tumor. Has high affinity
for neuroendocrine cells, inhibits cell proliferation, and is cytolytic.
Interferes with normal function of DNA by alkylation and protein
modification.

Antineoplastic, Mtor Kinase Inhibitor

View full drug information

Everolimus
mTOR inhibitor