Hypoglycemia in Adults Without Diabetes Mellitus - Diagnostic Approach - UpToDate

10/1/2020 Hypoglycemia in adults without diabetes mellitus: Diagnostic approach - UpToDate
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Hypoglycemia in adults without diabetes mellitus: Diagnostic approach

Author: Adrian Vella, MD
Section Editor: Irl B Hirsch, MD
Deputy Editor: Jean E Mulder, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2020. | This topic last updated: Jul 23, 2020.
INTRODUCTION
Hypoglycemia is an uncommon clinical problem in patients not being treated for diabetes mellitus. It can occur in the fasting or postprandial
state. In any case of hypoglycemia, regardless of the cause, the diagnosis can usually be established by appropriate blood tests at the time of the
spontaneous occurrence of hypoglycemia, if such an event occurs in the presence of medical personnel (table 1).
If the patient is not symptomatic when seen, the diagnostic strategy is to replicate conditions in which hypoglycemia would be expected if a
hypoglycemic disorder exists. A prolonged supervised fast, which can last as long as 72 hours, has been the best established and probably most
reliable test for the evaluation of hypoglycemia occurring in the food-deprived state. For patients with postprandial hypoglycemia, however, a
mixed-meal test is the preferred provocative procedure.
This topic will review the approach to the nondiabetic patient with hypoglycemia. The clinical manifestations, diagnosis, and causes of
hypoglycemia, in general, are discussed separately (table 2 and table 3). The evaluation and management of hypoglycemia in patients with drug-
treated diabetes mellitus is also reviewed separately. (See "Hypoglycemia in adults without diabetes mellitus: Clinical manifestations, diagnosis,
and causes" and "Diagnostic dilemmas in hypoglycemia: Illustrative cases" and "Hypoglycemia in adults with diabetes mellitus".)
CANDIDATES FOR EVALUATION
The presence of a hypoglycemic disorder in a person without diabetes should not be suspected solely on the basis of a low plasma glucose
concentration [1], as this observation is necessary but insufficient for a diagnosis and, in some cases, may be misleading. Only those patients in
whom Whipple's triad is documented require evaluation and management of hypoglycemia.
Whipple's triad includes the following:
● Symptoms consistent with hypoglycemia

● A low plasma glucose concentration measured with a precise method (not a home glucose monitor) when symptoms are present
● Relief of those symptoms after the plasma glucose level is raised
Given documentation of Whipple's triad, detailed laboratory evaluation is usually required in a healthy-appearing patient, whereas hypoglycemia
may be readily recognized as part of the underlying illness or its treatment (or prescribing/dispensing error) in an ill or medicated patient (table
2). (See "Hypoglycemia in adults without diabetes mellitus: Clinical manifestations, diagnosis, and causes", section on 'Clinical manifestations'.)
It is important to confirm the presence of a hypoglycemic disorder before performing various tests to determine the etiology of hypoglycemia.
The association of symptoms reinforces the biologic significance of the low blood glucose. Healthy individuals may have low glucose
concentrations without symptoms after prolonged fasting. In addition, sympathoadrenal and neuroglycopenic symptoms may be highly
suggestive of hypoglycemia, but they cannot be ascribed to hypoglycemia with confidence unless the glucose concentration is low at the same
time. Normal glucose concentrations measured when the patient is free of those symptoms does not exclude the possibility of hypoglycemia at
the time of those earlier symptoms. Documentation of Whipple's triad helps to establish the existence of a hypoglycemic disorder [2].
Hypoglycemia is sometimes detected serendipitously. A low plasma glucose concentration in the absence of symptoms of hypoglycemia suggests
the possibility of artifactual hypoglycemia. However, a distinctly low plasma glucose concentration measured in a reliable laboratory cannot be
ignored. The measurement should be repeated using a collection tube that contains an inhibitor of glycolysis, and processing should not be
delayed. (See "Hypoglycemia in adults without diabetes mellitus: Clinical manifestations, diagnosis, and causes", section on 'Differential
diagnosis'.)
Although low blood glucose values measured using reflectance meters suggest the presence of hypoglycemia, these methods are not reliable to
diagnose hypoglycemia in the absence of diabetes treated with a medication such as insulin or a sulfonylurea that can cause hypoglycemia. Thus,
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a patient who has a single low blood glucose value measured by a meter but no symptoms of hypoglycemia probably does not need further
evaluation; on the other hand, evaluation is indicated in a patient who has repeated low values.
Patients who have only sympathoadrenal symptoms but normal concurrent plasma glucose concentrations have a low probability of having a
hypoglycemic disorder and do not require a comprehensive evaluation for a hypoglycemic disorder. This combination is most common in
patients with postprandial symptoms. (See "Postprandial (reactive) hypoglycemia".)
APPROACH TO TESTING
Our approach to the evaluation and management of hypoglycemia in nondiabetic adults is outlined below. Because hypoglycemic disorders are
uncommon in persons without diabetes, this approach is largely based upon clinical experience [1]. This approach was endorsed by the 2009
Endocrine Society guidelines for the evaluation and management of hypoglycemic disorders in adults [2].
Clinical evaluation — The first step is to review the patient's history in detail, including the nature and timing of symptoms (particularly in
relationship to meals), existence of underlying illnesses or conditions, medications taken by the individual and by family members, and social
history. Clinical evidence for adrenal insufficiency or nonislet cell tumor should be considered. In a patient with documented hypoglycemia, the
cause may be apparent from the history and physical examination (table 2). In a seemingly well individual, the cause is less apparent and may be
due to hyperinsulinism or factitious hypoglycemia. When the cause of hypoglycemia is not evident, detailed laboratory evaluation is needed.
Laboratory testing — The presence of a hypoglycemic disorder in a person without diabetes should not be inferred solely on the basis of a low
plasma glucose concentration, unless the value is severely depressed (<40 mg/dL [2.2 mmol/L]). To rule out artifactual hypoglycemia in such
cases, the measurement should be repeated using a collection tube that contains an inhibitor of glycolysis, and processing should not be
delayed.
The purpose of the initial laboratory evaluation is to document Whipple's triad [1]. Should Whipple's triad have been demonstrated previously, the
goal of testing is to assess the role of insulin in the genesis of the hypoglycemia.
If the patient is not symptomatic when seen, the diagnostic strategy is to seek Whipple's triad under conditions in which hypoglycemia would be
expected if a hypoglycemic disorder exists. In a patient who presents with a self-diagnosis of hypoglycemia, one strategy is to measure plasma
glucose concentrations at the time of symptoms, and then decide if the glucose values and the history are sufficiently suggestive to warrant
additional evaluation. This strategy is reasonable if the patient has infrequent symptoms and the suspicion is not high enough to embark
immediately on provocative testing.
If the symptoms occur primarily in the fasting state, the initial evaluation should be performed during a fast (see 'Fasting evaluation' below).
However, if there is a compelling history of postprandial symptoms, it is reasonable to seek Whipple's triad with frequent, timed plasma glucose
measurements and recording of any symptoms after a mixed meal. (See 'Postprandial evaluation' below.)
Patients who are fortuitously observed during an episode of symptoms and are found to have hypoglycemia at that time should have the
following blood tests (table 1) :
● Glucose
● Insulin
● C-peptide
● Beta-hydroxybutyrate (BHOB)
● Proinsulin
● Sulfonylurea and meglitinide screen
The interpretation of these results is shown in the table (table 4) and described below. (See 'Interpretation of data' below and 'Determining the
cause of hypoglycemia' below.)
In patients with endogenous hyperinsulinism, insulin antibodies should be measured to distinguish insulin autoimmune hypoglycemia from
other causes of hyperinsulinism (table 2 and table 4). Insulin antibodies do not need to be drawn during hypoglycemia.
Fasting evaluation — There are patients in whom symptoms occur after only a short period of food withdrawal. In such patients, continued
observation in the office or clinic, especially if they have fasted overnight, may result in an episode of symptomatic hypoglycemia [1]. Plasma
glucose should be measured repeatedly during the period of observation. If symptoms occur and hypoglycemia is documented (plasma glucose
<55 mg/dL [3 mmol/L]), the other tests described above should be performed (table 4). The results may obviate the need for a provocative test,
such as the 72-hour fast.
If this approach causes neither symptoms nor hypoglycemia and if clinical suspicion remains high, the patient should undergo a 72-hour fast.
(See '72-hour fast' below.)

Postprandial evaluation — If symptoms of hypoglycemia typically occur within five hours after eating, patients should be evaluated in the
postprandial state (mixed-meal test).
For a mixed-meal diagnostic test, the patient consumes a non-liquid meal that usually leads to symptoms and is then observed for up to five
hours [1]. Samples are collected for plasma glucose, insulin, C-peptide, and proinsulin prior to ingestion of the meal and every 30 minutes
thereafter for five hours. If severe symptoms occur prior to five hours, samples for the above lab tests should be collected before the
administration of carbohydrates (to assess for correction of symptoms). All glucose samples are sent for analysis. The samples for insulin, C-
peptide, and proinsulin should be analyzed only in those samples in which plasma glucose is <60 mg/dL (3.3 mmol/L). If Whipple's triad is
demonstrated, sulfonylureas, meglitinides, and antibodies to insulin should also be measured.
Standards for the interpretation of the mixed-meal test are not established. Thus, the interpretation of these test results is similar to when tests
are done during a spontaneous episode of hypoglycemia or during a 72-hour fast (table 4). However, proinsulin has a much longer half-life in the
circulation than insulin and accumulates for >2 hours after a meal [3,4]. (See 'Interpretation of data' below.)
An oral glucose tolerance test (OGTT) or a meal that is solely in liquid form (eg, Ensure) done in an effort to replicate postprandial symptoms
should not be performed, because misleading results may be obtained, particularly in patients with prior upper gastrointestinal surgery and
disordered gastric emptying in whom a liquid meal may precipitate dumping syndrome [5]. (See "Postprandial (reactive) hypoglycemia", section
on 'Postprandial syndrome'.)
72-hour fast — The purpose of the 72-hour fast is to provoke the homeostatic responses that keep blood glucose concentrations from falling
to concentrations that cause symptoms in the absence of food. Increased release of glucagon, epinephrine, and, to a lesser degree, growth
hormone and cortisol are the most important components of this response. All the hormonal responses begin well before the onset of
symptomatic hypoglycemia. (See "Physiologic response to hypoglycemia in normal subjects and patients with diabetes mellitus".)
Normal individuals do not have symptomatic hypoglycemia after a prolonged fast, because of a hormonally mediated increase in glucose
production and/or lipolysis and ketone body production. Gluconeogenesis accounts for approximately 50 percent of glucose production after an
overnight fast and for almost all glucose production after 42 hours or more of fasting [6].
The prolonged fast will result in hypoglycemia only if there is a defect in the ability to maintain normoglycemia due, for example, to an excess of
insulin, which inhibits endogenous glucose production, as well as the transition to alternate sources of fuel and subsequent ketone production.
The defect should be identifiable if appropriate testing is performed (table 4). (See 'Interpretation of data' below.)
Protocol — The 72-hour fast can be initiated at home, usually after the evening meal, and continued the next day in an outpatient setting or
a hospital.
The following protocol is used at our institution (Mayo Clinic, Rochester, MN) [7], whether the fast is initiated in the outpatient setting or in the
hospital. A careful record should be kept of exactly what was done, what blood samples were taken, what was to be measured in each blood
sample, and what symptoms occurred. It is equally important that the blood samples and laboratory slips be carefully labeled, particularly with
the exact time, and that the labeling information be recorded on a flow sheet. Later interpretation of the results is possible only with this detail.
● Date the onset of the fast at the time of the last intake of calories. Discontinue all nonessential medications.
● Allow the patient to drink beverages that are calorie and caffeine free.
● Ensure that the patient is active during waking hours.
● Collect blood specimens for measurement of plasma glucose, insulin, C-peptide, proinsulin, and BHOB every six hours until the glucose
concentration is below 60 mg/dL (3.3 mmol/L); at this point, the frequency of sampling should be increased to every one to two hours.
Because of possible delays in the availability of the results of plasma glucose testing, a bedside reflectance meter may have to be used to
measure blood glucose when frequent samples are obtained. However, the decision to end the fast should not be made on the basis of a
fingerstick blood glucose value. It is essential that the clinician determine in advance the correct tubes to use for the blood samples and the
correct procedures for handling and processing the samples.
Although blood is collected repeatedly, we measure insulin, C-peptide, and proinsulin only in those specimens in which the plasma glucose
concentration is ≤60 mg/dL (3.3 mmol/L).
Insulin antibodies should be measured, but they do not have to be measured during hypoglycemia.
Test endpoints and duration — The fast is ended when the plasma glucose concentration is ≤45 mg/dL (2.5 mmol/L), the patient has
symptoms or signs of hypoglycemia, 72 hours have elapsed, or when the plasma glucose concentration is less than 55 mg/dL (3 mmol/L) if
Whipple's triad was documented on a prior occasion [1,2].

Fasting for a maximum of 72 hours has been the standard test for the diagnosis of insulinoma. A 48-hour maximum has been proposed as a
simpler alternative based upon a report of 127 patients with insulinoma in which adequate information was obtained for diagnosis in all patients
[8]. The fast was terminated because of hypoglycemia (plasma glucose ≤45 mg/dL [2.5 mmol/L]) in 43 percent by 12 hours, 67 percent by 24
hours, and 95 percent by 48 hours.
However, in our series of 205 patients with insulinoma, 14 percent did not develop Whipple's triad until after 48 hours of fasting [9]. Thus, to
avoid misdiagnosis, we recommend the standard 72-hour fast.
The decision to end the fast may not be easy. Some patients have slightly low plasma glucose values but no symptoms or signs of hypoglycemia,
while others have the same symptoms during fasting that they have in ordinary life at a time when plasma glucose values are normal. In the
latter patients, the symptoms cannot be attributed to hypoglycemia. To complicate matters further, young, lean, healthy women may have
plasma glucose concentrations in the range of 40 mg/dL (2.2 mmol/L) or even lower after prolonged periods of fasting [10].
Careful questioning and testing for subtle symptoms or signs of hypoglycemia should be conducted repeatedly when the patient's plasma
glucose is near or in the hypoglycemic range. Simple tests of cognitive function may be indicated. To end the fast solely on the basis of a low
plasma glucose value (except in those patients who have had Whipple's triad documented previously), in the absence of symptoms or signs of
hypoglycemia, jeopardizes the possibility of discriminating between normal persons and those with hypoglycemia not mediated by insulin. A low
plasma glucose value is a necessary, but not sufficient, finding for the diagnosis of hypoglycemia.
The absence of symptoms or signs of hypoglycemia and lack of a low plasma glucose concentration during a 72-hour fast indicates a normal 72-
hour fast but does not preclude the existence of a hypoglycemic disorder that causes only postprandial symptoms.
Ending the fast — Three steps are performed at the end of the fast:
● Collect samples for plasma glucose, insulin, C-peptide, proinsulin, BHOB, and oral hypoglycemic agents
● 1 mg of glucagon is given intravenously and the plasma glucose measured 10, 20, and 30 minutes later
● The patient is fed
Interpretation of data — Interpretation of the data obtained at the end of the 72-hour fast is the same as that performed during the occurrence
of a spontaneous hypoglycemic episode (table 4) [7,11]. These data will help distinguish hyperinsulinemia (endogenous or exogenous) from other
causes of hypoglycemia. The normal overnight fasting reference ranges usually supplied by the laboratory for plasma insulin, C-peptide,
proinsulin, and BHOB, as well as the response of plasma glucose to intravenous glucagon, cannot be applied when the plasma glucose is in the
hypoglycemic range. New criteria are required.
In addition, ratios of insulin-to-glucose or of glucose-to-insulin are not helpful in the establishment of hyperinsulinemia; absolute values for
insulin are preferable [12].
The distribution of simultaneously measured plasma glucose and insulin concentrations in patients with surgically confirmed insulinomas and in
normal subjects studied during 72-hour fasts is shown in the figure (figure 1) [7]. The recommended diagnostic criteria for plasma insulin, C-
peptide, proinsulin, and BHOB, described below, have sensitivities and specificities of >90 and >70 percent, respectively, for the diagnosis of
insulinoma [13].
Plasma insulin — A plasma insulin concentration of 3 microU/mL (20.8 pmol/L) by immunochemiluminometric assay (ICMA) when the plasma
glucose concentration is below 55 mg/dL (3.0 mmol/L) indicates an excess of insulin and is consistent with hyperinsulinemia (eg, insulinoma)
(figure 1). Unfortunately, plasma glucose concentrations fall below 50 mg/dL (2.8 mmol/L) in some normal subjects and remain above 50 mg/dL
in an occasional patient with an insulinoma. This slight overlap can occur despite best efforts to require a plasma glucose of less than 45 mg/dL
(2.5 mmol/L) at the end of the fast because of the variation in plasma glucose in the hypoglycemic range.
Plasma insulin by ICMA may be lowered in a hemolyzed blood sample. Some insulin assays detect only human insulin, whereas others detect
both human insulin and synthetic insulin analogs. It is important that the clinician knows which insulin assay is used and whether it measures
human insulin, insulin analogs, or both. (See "Factitious hypoglycemia", section on 'Insulin measurements'.)
Plasma C-peptide — It is essential to measure plasma C-peptide at the end of the fast; measurement of plasma proinsulin can also be helpful
(figure 2) [14-16]. Plasma C-peptide distinguishes endogenous from exogenous hyperinsulinemia. In patients in whom plasma glucose
concentrations fell below 45 mg/dL (2.5 mmol/L), there was no overlap in the values in insulinoma patients and normal subjects at a plasma C-
peptide concentration of 0.2 nmol/L (200 pmol/L or 0.6 ng/mL). All insulinoma patients had higher values, and all normal subjects who were
hypoglycemic had lower values. For plasma proinsulin, the diagnostic criterion for insulinoma is 5 pmol/L or greater (figure 3).
Plasma beta-hydroxybutyrate — Because of the antiketogenic effect of insulin, plasma BHOB concentrations are lower in insulinoma
patients than in normal subjects. All patients with insulinoma had plasma BHOB values of 2.7 mmol/L or less at the end of the fast, whereas

normal subjects had higher values (figure 4). A progressive rise in the concentration of BHOB after the 18-hour point of the fast is indicative of a
negative fast [17].
The plasma BHOB value, as well as the glucose response to glucagon, can be used to confirm the diagnosis in patients in whom the insulin and C-
peptide values are in the borderline range (eg, plasma insulin concentration of <3 microU/mL [20.8 pmol/L], C-peptide <0.2 nmol/L [0.6 ng/mL]) or
to indicate the action of an insulin-like factor.
Glycemic response to glucagon — Insulin inhibits glycogenolysis and hyperinsulinemia permits retention of glycogen within the liver. As a
result, patients with insulin-mediated hypoglycemia respond to 1 mg of intravenous glucagon (a potent glycogenolytic agent) by releasing
glucose. Normal individuals will have released virtually all glucose from the liver at the end of the 72-hour fast and cannot therefore respond as
vigorously to intravenous glucagon as a patient with an insulinoma. At the end of the fast, patients with an insulinoma have an increase in
plasma glucose of 25 mg/dL (1.4 mmol/L) or more in 20 to 30 minutes, whereas normal individuals have a smaller increment (figure 5).
Determining the cause of hypoglycemia — By observing the presence of symptoms and signs of hypoglycemia and by making the above
biochemical measurements, it is usually possible to distinguish among the various causes of hypoglycemia (table 2) [7].
A lower plasma BHOB value and a vigorous plasma glucose response to intravenous glucagon point to hypoglycemia mediated by insulin or an
insulin-like factor (table 4).
● Plasma insulin, C-peptide, and proinsulin values are elevated in patients with insulinoma, oral hypoglycemia agent-induced hypoglycemia,
and insulin autoimmune hypoglycemia.
Sulfonylurea or meglitinides are present in the plasma only in oral hypoglycemic agent-induced hypoglycemia [18]. (See "Factitious
hypoglycemia".)
The presence of insulin or insulin receptor antibodies can distinguish insulin autoimmune hypoglycemia from insulinoma [19]. Insulin
autoimmune hypoglycemia occurs in patients who have antibodies directed to endogenous insulin or to the insulin receptor. Symptoms can
occur postprandially, fasting, or in both states. In patients with insulin autoantibodies, it is presumed that insulin secreted in response to a
meal binds to the antibody and then disassociates in an unregulated fashion causing hyperinsulinemia and hypoglycemia. In patients with
antibodies to the insulin receptor, hypoglycemia occurs as a result of antibody activation of the receptor.
● Plasma insulin, C-peptide, and proinsulin values are also elevated in patients with noninsulinoma pancreatogenous hypoglycemia syndrome
(NIPHS). NIPHS is endogenous hyperinsulinemia due to islet hypertrophy and nesidioblastosis, a form of primary islet cell hypertrophy with
neodifferentiation of islet of Langerhans cells from pancreatic duct epithelium. An unusual feature of this disorder is that hypoglycemia
occurs postprandially, two to four hours after a meal. Fasting hypoglycemia, characteristic of insulinoma, is rare in this disorder.
Nesidioblastosis has also been described in patients with post-gastric bypass hypoglycemia. (See "Noninsulinoma pancreatogenous
hypoglycemia syndrome".)
● Plasma insulin values are high in patients with exogenous insulin administration, whereas plasma C-peptide and proinsulin values are low. In
hypoglycemia caused by synthetic insulin analogs (eg, glargine, detemir, lispro, aspart), insulin concentrations may be low, depending upon
the insulin assay used. Clinical suspicion should guide subsequent testing of the sample obtained at the time of hypoglycemia against a
panel of antibodies to insulin capable of detecting various analogs. (See "Factitious hypoglycemia", section on 'Diagnosis'.)
● Plasma insulin, C-peptide, and proinsulin concentrations are not elevated in patients with nonislet cell tumors. Nonislet cell tumors can cause
hypoglycemia via a number of mechanisms not related to hypersecretion of insulin, including tumor production of insulin-like growth factor-
2 or more often its precursor, and tumor burden in which the tumor cell's high metabolic needs and reduced hepatic glycogen stores are
thought to be responsible for hypoglycemia. (See "Nonislet cell tumor hypoglycemia" and "Clinical features and diagnosis of hepatocellular
carcinoma", section on 'Paraneoplastic syndromes'.)
LOCALIZING STUDIES
Localizing studies should not be performed until endogenous insulin-mediated hypoglycemia has been demonstrated. In patients with
endogenous insulin-mediated hypoglycemia, the differential diagnosis includes insulinoma, nesidioblastosis/islet-cell hypertrophy, oral
hypoglycemic agent-induced hypoglycemia, and insulin autoimmune hypoglycemia (table 2). Negative results for circulating oral hypoglycemic
agents and insulin antibodies effectively rule out oral hypoglycemic agent-induced hypoglycemia and insulin autoimmune hypoglycemia,
respectively. A localizing study is required in all patients with insulin-mediated hypoglycemia, except those with positive results for insulin
antibodies or circulating oral hypoglycemic agents.
Radiologic studies — Computed tomography (CT), magnetic resonance imaging (MRI), and transabdominal ultrasonography can detect most
insulinomas [20,21]. The choice of procedure depends upon which tests are available and local radiologic skill. Transabdominal ultrasonography
is our preferred initial test. (See "Insulinoma", section on 'Tumor localization'.)

A negative imaging study does not exclude insulinoma. If an insulinoma is not visible with initial imaging, additional studies, such as endoscopic
ultrasonography (sometimes with fine-needle aspiration biopsy of detected tumors) or selective arterial calcium stimulation, are required.
Selective arterial calcium stimulation — A selective arterial calcium stimulation test with hepatic venous sampling can be performed to
distinguish between a focal abnormality (insulinoma) and a diffuse process (islet-cell hypertrophy/nesidioblastosis). We reserve this test for
complex cases of endogenous hyperinsulinemic hypoglycemia and negative radiologic localization studies.
This test involves selective injection of calcium gluconate into the gastroduodenal, splenic, and superior mesenteric arteries with subsequent
sampling of the hepatic venous effluent for insulin. A positive result is at least a doubling or tripling of basal insulin concentrations [22]. The
increase in insulin occurs in samples from the artery supplying the region with hyperfunctioning islets, either an insulinoma or islet hypertrophy,
which facilitates operative localization [23]. Understanding the local variation in pancreatic arterial anatomy is important for appropriate
regionalization.
In patients with insulinoma, the response is positive in one artery alone unless the tumor resides in a "watershed" area fed by two arteries or the
patient has multiple insulinomas scattered throughout the pancreas (table 5). A few patients have aberrant arterial anatomy that may explain
multiple areas of response [23]. This arterial variant should be identifiable by the interventional radiologist performing the procedure. In patients
with islet-cell hypertrophy, positive responses are usually but not always observed after injection of multiple arteries. (See "Insulinoma", section
on 'Selective arterial calcium stimulation' and "Noninsulinoma pancreatogenous hypoglycemia syndrome", section on 'Localization studies' and
"Diagnostic dilemmas in hypoglycemia: Illustrative cases".)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See
"Society guideline links: Hypoglycemia in adults".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written
in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics
patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and
are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can
also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topics (see "Patient education: Low blood sugar in people without diabetes (The Basics)")
SUMMARY AND RECOMMENDATIONS
● Who should be evaluated?
• Only those patients in whom Whipple's triad is documented require evaluation and management of hypoglycemia. (See 'Candidates for
evaluation' above.)
• In patients with symptoms of hypoglycemia, but normal plasma glucose concentrations at the same time, no further evaluation is
needed.
• Although low blood glucose values measured using reflectance meters suggest the presence of hypoglycemia, these methods are not
sufficiently reliable in the low range.
● Evaluation
• The first step is to review the patient's history in detail, including the nature and timing of symptoms (particularly in relationship to
meals), existence of underlying illnesses or conditions, medications taken by the individual and by family members, and social history. In
a patient with documented hypoglycemia, the cause may be apparent from the history and physical examination (table 2). When the
cause of hypoglycemia is not evident, laboratory evaluation is needed. (See 'Clinical evaluation' above.)
• In patients who are fortuitously observed during an episode of symptoms and are found to have simultaneous hypoglycemia (fasting or
postprandial), additional measurements should be performed (plasma glucose, insulin, C-peptide, proinsulin, beta-hydroxybutyrate

[BHOB], and an oral hypoglycemic agent screen) (table 1). Studies at this time may obviate the need for further testing (table 4). (See
'Laboratory testing' above.)
• If the patient is not symptomatic when seen, the diagnostic strategy is to seek Whipple's triad under conditions in which hypoglycemia
would be expected if a hypoglycemic disorder exists (either fasting or during a mixed-meal test). (See 'Fasting evaluation' above and
'Postprandial evaluation' above.)
• If neither symptoms nor hypoglycemia have been observed and if clinical suspicion remains high, the patient should undergo a 72-hour
fast, which is described in detail above. (See '72-hour fast' above.)
• An oral glucose tolerance test (OGTT) done in an effort to replicate postprandial symptoms should not be performed, because
misleading results may be obtained. (See "Postprandial (reactive) hypoglycemia".)
● Interpretation of test results
• Interpretation of the data obtained at the end of the 72-hour fast or a mixed-meal test is the same as that performed during the
occurrence of a spontaneous hypoglycemic episode (table 4).
• A lower plasma BHOB value and a vigorous plasma glucose response to intravenous glucagon point to hypoglycemia mediated by insulin
or an insulin-like factor (table 4). (See 'Interpretation of data' above.)
• Plasma insulin, C-peptide, and proinsulin values are elevated in patients with insulinomas, oral hypoglycemic agent-induced
hypoglycemia, and insulin autoimmune hypoglycemia. Sulfonylurea or meglitinides are present in the plasma only in oral hypoglycemia
agent-induced hypoglycemia. The presence of insulin or insulin receptor antibodies can distinguish insulin autoimmune hypoglycemia
from insulinoma. (See 'Determining the cause of hypoglycemia' above and "Factitious hypoglycemia".)
• In patients with exogenous insulin administration, plasma insulin values are higher than levels observed in insulinoma, but plasma C-
peptide and proinsulin values are low or undetectable. (See 'Determining the cause of hypoglycemia' above.)
• Hypoglycemia that is not mediated by insulin or an insulin-like factor is characterized by low plasma concentrations of insulin, C-peptide,
and proinsulin. (See 'Determining the cause of hypoglycemia' above.)
Illustrative cases of hypoglycemia are found elsewhere. (See "Diagnostic dilemmas in hypoglycemia: Illustrative cases".)
ACKNOWLEDGMENT
The editorial staff at UpToDate would like to acknowledge F John Service, MD, PhD, who contributed to an earlier version of this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
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Clinic, 1987-2007. J Clin Endocrinol Metab 2009; 94:1069.
14. Service FJ, O'Brien PC, McMahon MM, Kao PC. C-peptide during the prolonged fast in insulinoma. J Clin Endocrinol Metab 1993; 76:655.
15. O'Brien T, O'Brien PC, Service FJ. Insulin surrogates in insulinoma. J Clin Endocrinol Metab 1993; 77:448.
16. Kao PC, Taylor RL, Service FJ. Proinsulin by immunochemiluminometric assay for the diagnosis of insulinoma. J Clin Endocrinol Metab 1994;
78:1048.
17. Service FJ, O'Brien PC. Increasing serum betahydroxybutyrate concentrations during the 72-hour fast: evidence against hyperinsulinemic
hypoglycemia. J Clin Endocrinol Metab 2005; 90:4555.
18. Perros P, Henderson AK, Carter DC, Toft AD. Lesson of the week. Are spontaneous hypoglycaemia, raised plasma insulin and C peptide
concentrations, and abnormal pancreatic images enough to diagnose insulinoma? BMJ 1997; 314:496.
19. Lupsa BC, Chong AY, Cochran EK, et al. Autoimmune forms of hypoglycemia. Medicine (Baltimore) 2009; 88:141.
20. Grossman AB, Reznek RH. Commentary: imaging of islet-cell tumours. Best Pract Res Clin Endocrinol Metab 2005; 19:241.
21. Noone TC, Hosey J, Firat Z, Semelka RC. Imaging and localization of islet-cell tumours of the pancreas on CT and MRI. Best Pract Res Clin
Endocrinol Metab 2005; 19:195.
22. Thompson SM, Vella A, Thompson GB, et al. Selective Arterial Calcium Stimulation With Hepatic Venous Sampling Differentiates Insulinoma
From Nesidioblastosis. J Clin Endocrinol Metab 2015; 100:4189.
23. Thompson SM, Vella A, Service FJ, et al. Impact of variant pancreatic arterial anatomy and overlap in regional perfusion on the interpretation
of selective arterial calcium stimulation with hepatic venous sampling for preoperative localization of occult insulinoma. Surgery 2015;
158:162.
Topic 1798 Version 25.0

GRAPHICS
Rapid overview for hypoglycemia in adults, other than significant sulfonylurea overdose
Clinical features
Any patient with acute change in mental status or coma should undergo rapid assessment of blood glucose as a possible cause.
All findings of hypoglycemia are nonspecific, including the following:
• Autonomic response (tends to occur with blood glucose below 65 mg/dL)

- Sweating
- Weakness
- Tachycardia
- Palpitations
- Tremor
- Nervousness
- Hunger
- Paresthesias
• Neuroglycopenia
- Irritability
- Confusion
- Uncharacteristic behavior
- Seizure
- Occasionally, transient focal neurologic deficits
- Loss of consciousness
- Visual disturbance
Diagnostic evaluation
Obtain blood glucose concentration as soon as possible (usually with a meter and strips, if available):
For symptomatic patient known to have diabetes and with a low glucose value, <70 mg/dL [3.89 mmol/L], administer treatment. If a glucose test cannot be performed, do not delay. Treat as if
hypoglycemia has been confirmed.
If the glucose is low (<55 mg/dL) and the patient is a not a diabetic, draw blood for glucose, insulin, C-peptide, and an oral hypoglycemic agent screen and then treat,
Do not delay treatment if symptomatic hypoglycemia is suspected but rapid blood glucose measurement is not available or blood for diagnostic studies cannot be collected.
Treatment
If the patient is conscious and able to drink and swallow safely (ie, alert enough to do so and with gag reflex intact), administer a rapidly-absorbed carbohydrate (eg, 3 to 4 glucose tablets or a tube of
gel with 15 grams, 4 to 6 oz. fruit juice or non-diet soda, or a teaspoon of honey or table sugar).*
If the patient has altered mental status, is unable to swallow, or does not respond to oral glucose administration within 15 minutes, give an IV bolus of 12.5 to 25 gm of glucose (25 to 50 mL of 50
percent dextrose).
Measure a blood glucose 10 to 15 minutes after the IV bolus. Readminister 12.5 to 25 grams of glucose as needed to maintain the blood glucose above 80 mg/dL.
If glucose cannot be given by parenteral or oral routes, give glucagon 1 mg IM or subcutaneously. Response may be transient and should be followed by careful glucose monitoring and oral or
intravenous glucose administration.
Give additional maintenance glucose by mouth or IV. IV dextrose infusion should ensure delivery of 6 to 9 mg/kg per minute of glucose. Amounts needed vary depending upon the cause and severity
of the symptomatic hypoglycemia. Once the patient is able to ingest carbohydrate safely, providing a mixed meal (including carbohydrates, such as a sandwich) is the preferred means of maintaining
glucose levels.
Measure a blood glucose 10 to 15 minutes after the initial IV bolus and monitor every 30 to 60 minutes thereafter until stable (minimum of four hours). The measurement method should provide rapid
turnaround, preferably at the point of care.
Admit patients with ingestion of a long-acting hypoglycemic agent, recurrent hypoglycemia during observation, and those unable to eat.
IM: intramuscular; IV: intravenous.

* Patients taking an alpha-glucosidase inhibitor (eg, acarbose, miglitol, voglibose) with symptomatic hypoglycemia should only receive pure glucose (dextrose) orally because digestion and absorption of other
carbohydrates (eg, table sugar [sucrose]) will be delayed by these medications and will be less effective in raising blood glucose levels.
Graphic 73797 Version 5.0

Causes of hypoglycemia in adults
Ill or medicated individual

1. Drugs
Insulin or insulin secretagogue
Alcohol
Others (refer to UpToDate table on drugs that cause hypoglycemia)
2. Critical illnesses
Hepatic, renal, or cardiac failure
Sepsis (including malaria)
Inanition
3. Hormone deficiency
Cortisol
Glucagon and epinephrine (in insulin-deficient diabetes mellitus)
4. Nonislet cell tumor
Seemingly well individual

5. Endogenous hyperinsulinism
Insulinoma
Functional beta cell disorders (nesidioblastosis)
Noninsulinoma pancreatogenous hypoglycemia
Post-gastric bypass hypoglycemia
Insulin autoimmune hypoglycemia
Antibody to insulin
Antibody to insulin receptor
Insulin secretagogue
Other
6. Accidental, surreptitious, or malicious hypoglycemia
Reproduced with permission from: Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2009;
94:709. Copyright © 2009 The Endocrine Society.
https://www.uptodate.com/contents/hypoglycemia-in-adults-without-diabetes-mellitus-diagnostic-approach/print?search=recurrent hypoglycemia&source=search_r… 10/19

Drugs other than antihyperglycemic agents and alcohol reported to cause hypoglycemia
Moderate quality of evidence

Cibenzoline
Gatifloxacin
Pentamidine
Quinine
Indomethacin
Glucagon (during endoscopy)
Low quality of evidence

Chloroquineoxaline sulfonamide
Artesunate/artemisin/artemether
IGF-1
Lithium
Propoxyphene/dextropropoxyphene
Very low quality of evidence

Drugs with >25 cases of hypoglycemia identified
Angiotensin-converting enzyme inhibitors
Angiotensin receptor antagonists
Beta-adrenergic receptor antagonists
Levofloxacin
Mifepristone
Disopyramide
Trimethoprim-sulfamethoxazole
Heparin
6-mercaptopurine
IGF-1: insulin-like growth factor-1.
Reproduced with permission from: Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2009;
94:709. Copyright © 2009 The Endocrine Society.

Hypoglycemia: Interpretation of laboratory tests*
Circulating
Symptoms, Beta- Glucose increase Antibody
Glucose Insulin C-peptide Proinsulin oral Diag
signs, or hydroxybutyrate after glucagon to
(mg/dL)/(mmol/L) (microU/mL)/(pmol/L) (nmol/L)/(ng/mL) (pmol/L) hypoglycemic interp
both (mmol/L) (mg/dL)/(mmol/L) insulin
agent
No <55/3 <3/20.8 <0.2/0.6 <5 >2.7 <25/1.4 No No Normal
Yes <55 >>3 <0.2 <5 ≤2.7 >25 No Neg (Pos) Exogeno
Yes <55 ≥3 ≥0.2 ≥5 ≤2.7 >25 No Neg Insulinom

NIPHS, P
Yes <55 ≥3 ≥0.2 ≥5 ≤2.7 >25 Yes Neg Oral hyp

agent
Yes <55 >>3 >>0.2 ¶ >>5 ¶ ≤2.7 >25 No Pos Insulin

autoimm
Yes <55 <3 <0.2 <5 ≤2.7 >25 No Neg IGF Δ
Yes <55 <3 <0.2 <5 >2.7 <25 No Neg Not insu
IGF)-med
Neg: negative; Pos: positive; NIPHS: noninsulinoma pancreatogenous hypoglycemia syndrome; PGBH: post-gastric bypass hypoglycemia; IGF: insulin-like growth factor.
* Patterns of findings during fasting or after a mixed meal in normal individuals with no symptoms or signs despite relatively low plasma glucose concentrations (ie, Whipple's triad not documented) and in
individuals with hyperinsulinemic (or IGF-mediated) hypoglycemia or hypoglycemia caused by other mechanisms.
¶ Free C-peptide and proinsulin concentrations are low.
Δ Increased pro-IGF-2, free IGF-2, IGF-2/IGF-1 ratio.
Original table modiﬁed for this publication to include mmol/L equivalent data. Reproduced with permission from: Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult hypoglycemic disorders: an
Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2009; 94:709. Copyright © 2009 The Endocrine Society.

Plasma glucose and insulin concentrations after a prolonged

fast
Relation between plasma glucose and insulin concentrations in normal subjects and
patients with insulinoma after a prolonged fast.
Data from: Service FJ. Diagnostic approach to adults with hypoglycemic disorders. Endocrinol
Metab Clin North Am 1999; 28:519.

Plasma C-peptide concentrations after a prolonged fast
Relation between plasma glucose and C-peptide concentrations in normal subjects

and patients with an insulinoma after a prolonged fast. In patients who become
hypoglycemic, a plasma C-peptide concentration above 0.2 nmol/L is suggestive of an
insulinoma. To convert plasma glucose values to mmol/L, multiply by 0.056.
Redrawn from Service FJ. Hypoglycemic disorders. N Engl J Med 1995; 332:1144.

Plasma proinsulin concentrations after a prolonged fast
Relation between plasma glucose and proinsulin concentrations in normal subjects

and patients with an insulinoma after a prolonged fast. In patients who become
hypoglycemic, a plasma proinsulin concentration above 5 pmol/L is suggestive of an
insulinoma. To convert plasma glucose values to mmol/L, multiply by 0.056.

Plasma beta-hydroxybutyrate concentrations after a prolonged

fast
Relation between plasma glucose and beta-hydroxybutyrate concentrations in normal

subjects and patients with an insulinoma after a prolonged fast. In patients who
become hypoglycemic, a plasma beta-hydroxybutyrate concentration below 2.7
mmol/L is suggestive of an insulinoma. To convert plasma glucose values to mmol/L,
multiply by 0.056.

Plasma glucose responses to glucagon after a prolonged fast
Relationship between the plasma glucose concentration after a prolonged fast and the
increase in plasma glucose after the administration of 1 mg of intravenous glucagon in
normal subjects and patients with an insulinoma. In patients who become
hypoglycemic, an increase in plasma glucose of ≥25 mg/dL (1.4 mmol/L) after
glucagon is suggestive of an insulinoma. To convert plasma glucose values to mmol/L,
multiply by 0.056.

Arterial calcium stimulation with hepatic venous sampling for insulinoma
Artery Time, seconds Serum hepatic vein insulin, microU/mL (pmol/L)
Superior mesenteric 0 41 (284)
20 65 (451)
40 333 (2313)
60 441 (3063)
Gastroduodenal 0 30 (208)
20 42 (292)
40 38 (264)
60 36 (250)
Splenic 0 31 (215)
20 26 (180)
40 26 (180)
60 31 (215)
Intraarterial injection of calcium, an insulin secretagogue in insulinoma patients but not normal subjects, and changes in hepatic venous serum insulin concentrations in a patient with suspected insulinoma. The
hepatic venous serum insulin concentration increased 10-fold after superior mesenteric artery injection, 1.4-fold after the gastroduodenal artery injection, and did not change after the splenic artery injection. An
insulinoma was removed from the uncinate process.

Contributor Disclosures
Adrian Vella, MD Grant/Research Support: Novo Nordisk [Diabetes]. Consultant/Advisory board: vTv Therapeutics [Diabetes]; Zealand Pharmaceuticals
[Hypoglycemia]. Irl B Hirsch, MD Grant/Research/Clinical Trial Support: Medtronic [Diabetes]. Consultant/Advisory Boards: Abbott [Diabetes]; Roche [Diabetes];
Bigfoot Biomedical [Diabetes]. Jean E Mulder, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review
process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

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Hypoglycemia in adults without diabetes mellitus: Diagnostic approach

CANDIDATES FOR EVALUATION

Whipple's triad includes the following:

● Symptoms consistent with hypoglycemia

https://www.uptodate.com/contents/hypoglycemia-in-adults-without-diabetes-mellitus-diagnostic-approach/print?search=recurrent hypoglycemia&source=search_re… 1/19

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● Ensure that the patient is active during waking hours.

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● The patient is fed

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SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

● Who should be evaluated?

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● Interpretation of test results

Use of UpToDate is subject to the Subscription and License Agreement.

7. Service FJ. Hypoglycemic disorders. N Engl J Med 1995; 332:1144.

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Topic 1798 Version 25.0

https://www.uptodate.com/contents/hypoglycemia-in-adults-without-diabetes-mellitus-diagnostic-approach/print?search=recurrent hypoglycemia&source=search_re… 8/19

All findings of hypoglycemia are nonspecific, including the following:

• Autonomic response (tends to occur with blood glucose below 65 mg/dL)

IM: intramuscular; IV: intravenous.

Graphic 73797 Version 5.0

https://www.uptodate.com/contents/hypoglycemia-in-adults-without-diabetes-mellitus-diagnostic-approach/print?search=recurrent hypoglycemia&source=search_re… 9/19

Causes of hypoglycemia in adults

Ill or medicated individual

Insulin or insulin secretagogue

Others (refer to UpToDate table on drugs that cause hypoglycemia)

Hepatic, renal, or cardiac failure

Sepsis (including malaria)

Glucagon and epinephrine (in insulin-deficient diabetes mellitus)

4. Nonislet cell tumor

Seemingly well individual

Functional beta cell disorders (nesidioblastosis)

Noninsulinoma pancreatogenous hypoglycemia

Post-gastric bypass hypoglycemia

Insulin autoimmune hypoglycemia

Antibody to insulin receptor

6. Accidental, surreptitious, or malicious hypoglycemia

Graphic 78919 Version 9.0

https://www.uptodate.com/contents/hypoglycemia-in-adults-without-diabetes-mellitus-diagnostic-approach/print?search=recurrent hypoglycemia&source=search_r… 10/19

Moderate quality of evidence

Glucagon (during endoscopy)

Low quality of evidence

Very low quality of evidence

Angiotensin-converting enzyme inhibitors

Angiotensin receptor antagonists

Beta-adrenergic receptor antagonists

IGF-1: insulin-like growth factor-1.

Graphic 52892 Version 10.0

https://www.uptodate.com/contents/hypoglycemia-in-adults-without-diabetes-mellitus-diagnostic-approach/print?search=recurrent hypoglycemia&source=search_r… 11/19

Hypoglycemia: Interpretation of laboratory tests*

No <55/3 <3/20.8 <0.2/0.6 <5 >2.7 <25/1.4 No No Normal

Yes <55 ≥3 ≥0.2 ≥5 ≤2.7 >25 No Neg Insulinom

Yes <55 ≥3 ≥0.2 ≥5 ≤2.7 >25 Yes Neg Oral hyp

Yes <55 >>3 >>0.2 ¶ >>5 ¶ ≤2.7 >25 No Pos Insulin

Yes <55 <3 <0.2 <5 ≤2.7 >25 No Neg IGF Δ

Graphic 56314 Version 16.0