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Factitious hypoglycemia

Factitious hypoglycemia
Author:
Adrian Vella, MD
Section Editor:
Irl B Hirsch, MD
Deputy Editor:
Katya Rubinow, MD
Literature review current through: Apr 2025. | This topic last updated: Jul 29, 2024.

INTRODUCTION — 

Factitious hypoglycemia results from the surreptitious or accidental use of insulin or oral insulin secretagogues (sulfonylureas, meglitinides). The term factitious (or factitial) hypoglycemia is often used to imply covert human activity. Thus, considering this possibility can affect the patient-clinician relationship, leading the clinician to feel deceived and the patient to feel mistrusted. However, the pejorative connotation of factitious hypoglycemia is unwarranted as it does not solely result from covert actions. For example, dispensing errors in the outpatient or inpatient setting can lead to inappropriate administration of hypoglycemic agents. Factitious hypoglycemia therefore should be considered in the differential diagnosis for anyone presenting with unexplained hypoglycemia, and the possibility of factitious hypoglycemia can be evaluated without judgement or accusation.

The clinical features, diagnosis, and treatment of factitious hypoglycemia will be reviewed here. Other causes of hypoglycemia are discussed elsewhere. (See "Hypoglycemia in adults without diabetes mellitus: Clinical manifestations, causes, and diagnosis" and "Insulinoma".)

ETIOLOGY

Causal agents — Factitious hypoglycemia results from the nonprescribed use of insulin or oral insulin secretagogues (sulfonylurea, meglitinides) but generally not from the use of metformin or other drugs used for diabetes management that are not associated with hypoglycemia [1-3].

Glucose-lowering medications that are not insulin secretagogues, such as the thiazolidinediones, alpha-glucosidase inhibitors, and sodium-glucose cotransporter 2 (SGLT2) inhibitors, are generally not associated with hypoglycemia unless they are used in conjunction with insulin or an insulin secretagogue [4,5]. Glucagon-like peptide 1 (GLP-1) receptor agonists stimulate insulin secretion in a glucose-dependent fashion, and their effects on secretion are attenuated as glucose levels decrease. Nonetheless, these agents have been associated with hypoglycemia in patients both with and without underlying diabetes [6] and therefore may complicate the diagnostic evaluation of factitious hypoglycemia. Hypoglycemia has been reported with either accidental or purposeful overdose of the GLP-1 receptor agonist liraglutide, although marked gastrointestinal symptoms appear to be much more prominent than hypoglycemia after GLP-1 receptor agonist overdose [7-9].

Covert administration — Factitious hypoglycemia may be caused by covert self-administration of insulin or oral insulin secretagogues [3] or administration by someone else. Covert self-administration of these agents is considered a form of factitious disorder [10] and includes inappropriate medication use by an individual with diabetes. (See "Factitious disorder imposed on self (Munchausen syndrome)".)

Hypoglycemia also may result from covert administration of insulin or insulin secretagogues to a patient by caregivers, including health care providers. Administration of a hypoglycemic agent by a caregiver to a child is an insidious form of child abuse [11,12]. (See "Medical child abuse (Munchausen syndrome by proxy)".)

The first reported case of factitious hypoglycemia related to a sulfonylurea was due to the surreptitious self-administration of chlorpropamide by a patient without diabetes [13]. Covert insulin administration has also been used in attempted suicide [14]. A review of published cases found that completed suicide occurred in 17 of 97 attempts [15]. In most cases, those attempting suicide were patients with insulin-treated diabetes.

Accidental administration — Accidental ingestion of oral insulin secretagogues may occur due to errors in drug dispensing or administration. It also may occur due to use of contaminated herbal products or medications.

Dispensing errors – In contrast to patients who knowingly take insulin secretagogues, some patients develop hypoglycemia because a sulfonylurea was mistakenly dispensed [16]. In most instances, confusion in dispensing the drug arises from similarity in spelling between the intended medication and the sulfonylurea. The most common errors in early reports were the substitutions of Diabinese for Diamox [17,18] and of Tolinase for Tolectin; however, Diabinese (chlorpropamide) and Tolinase (tolazamide) are now rarely used [19].

Thus, as part of the initial evaluation for unexplained hypoglycemia, patients should present the containers for all their current prescription and nonprescription medications and supplements. (See 'Initial evaluation' below.)

Administration errors – Hypoglycemia in an older person whose spouse (or other household member) is treated with an oral insulin secretagogue agent is often due to a mix-up in medication administration. A medical history of the spouse/partner therefore may be an important part of the initial evaluation, as are questions about how medication is prepared for dosing (eg, use of similar versus distinct pill boxes). (See 'Initial evaluation' below.)

Herbal products or medication contamination – Hypoglycemia also may occur after ingestion of herbal products used to treat diabetes [20] or other conditions [21,22] if contaminated with sulfonylureas. As an example, hypoglycemia has been reported after ingestion of illegal sexual enhancement drugs or herbal preparations contaminated with glyburide in amounts ranging from 13 to 100 mg per tablet [21]. In a case series from Singapore, seven patients who ingested such products were comatose secondary to prolonged neuroglycopenia and four patients subsequently died [21,23].

CLINICAL CHARACTERISTICS

Sociodemographic characteristics — In older reports, factitious hypoglycemia due to covert medication administration was more common in women than men, and it occurred more often in people with health-related occupations and typically during the third or fourth decade of life [3,24,25]. These sociodemographic patterns also have been identified with factitious disorder in general, although not all studies have produced consistent findings. For example, in a case series of individuals who attempted suicide with insulin overdose, the sex distribution was equal and a wide age distribution was evident, ranging from 20 to 70 years [15]. Risk factors for factitious disorder are discussed separately. (See "Factitious disorder imposed on self (Munchausen syndrome)", section on 'Risk factors'.)

Patients without diabetes — Patients without diabetes who have factitious hypoglycemia may present with a clinical syndrome that appears similar to insulinoma; as a result, many may inappropriately undergo surgical exploration or subtotal pancreatectomy. Careful diagnostic evaluation is therefore critical before further studies or procedures are undertaken for presumed insulinoma. (See 'Diagnostic evaluation' below and "Hypoglycemia in adults without diabetes mellitus: Clinical manifestations, causes, and diagnosis", section on 'Clinical manifestations'.)

Patients with diabetes — Factitious hypoglycemia in patients with diabetes is probably more common than the incidence noted in published series [24,26-29]. In patients with factitious hypoglycemia, errors in insulin management can be difficult to distinguish from purposeful manipulation of insulin dosing. Individuals with factitious hypoglycemia typically have repeated episodes of hypoglycemia despite a reduction in insulin dose or even cessation of insulin therapy. When truly deprived of access to hypoglycemic agents, patients with diabetes and factitious hypoglycemia develop hyperglycemia. (See "Hypoglycemia in adults with diabetes mellitus", section on 'Strategies to manage hypoglycemia'.)

Alternatively, patients with diabetes and factitious hypoglycemia may appear to have brittle diabetes [30], with seemingly unexplained, large fluctuations in glycemia. As in individuals without diabetes, factitious hypoglycemia occasionally has been mistaken for insulinoma in people with diabetes, and some patients have undergone needless pancreatic exploration and resection [31,32]. (See 'Differentiating factitious hypoglycemia from other etiologies' below.)

DIAGNOSTIC EVALUATION

When to consider the diagnosis — The possibility of factitious hypoglycemia should be considered in every patient undergoing evaluation for a hypoglycemic disorder. Clinical suspicion is particularly warranted when the individual has access to insulin or oral insulin secretagogues or when the hypoglycemia occurs randomly, without any relation to meals or fasting. Factitious hypoglycemia should be suspected in people with a prior diagnosis of diabetes who have experienced diabetes remission (eg, due to body weight loss) and subsequently develop hypoglycemia.

Factitious hypoglycemia is not uncommon in individuals who present with an apparent hypoglycemic disorder. For example, in a population-based study of unexplained hypoglycemia in France, 7 (5 women, 2 men) of 56 patients had a detectable sulfonylurea in their plasma [33]. The evaluation to establish the presence of a hypoglycemic disorder is reviewed in detail separately. (See "Hypoglycemia in adults without diabetes mellitus: Clinical manifestations, causes, and diagnosis", section on 'Diagnostic evaluation'.)

Initial evaluation — The initial evaluation should include careful review of the patient's clinical and medication history.

Clinical history – A complete medical history should be obtained for all individuals undergoing evaluation for a hypoglycemic disorder. Factitious hypoglycemia is more likely in individuals who are overall healthy, whereas those with comorbid conditions have a broader differential for potential causes of hypoglycemia.

A key element of the social history is whether the person or any household or family members are health care professionals and therefore could have access to medications that can cause hypoglycemia. A detailed approach to the initial etiologic evaluation of hypoglycemic disorders is presented separately. (See "Hypoglycemia in adults without diabetes mellitus: Determining the etiology", section on 'Initial assessment to determine the etiology'.)

Medication history – All medications, including herbal preparations or other over-the-counter products, should be identified. The assistance of a pharmacist is often helpful. Patients should bring in all medication containers for visual inspection and provide a detailed account of how each medication is administered; these steps can help identify possible dispensing or administration errors.

A complete medication list for all household members also should be obtained, as this information can reveal access to insulin or insulin secretagogues. It also can help identify potential medication administration errors (eg, accidental ingestion of a household member's medication).

Non-glucose-lowering medications that can cause hypoglycemia are discussed separately (table 1). (See "Hypoglycemia in adults without diabetes mellitus: Clinical manifestations, causes, and diagnosis", section on 'Medications and alcohol'.)

Laboratory evaluation

Biochemical tests — Most of the key diagnostic laboratory tests should be obtained during an episode of hypoglycemia. In contrast, anti-insulin antibodies can be measured at any time.

Tests during hypoglycemia – The diagnosis of factitious hypoglycemia usually can be established by documenting the presence of hypoglycemia and by simultaneously measuring plasma levels of the following:

Insulin

C-peptide

Proinsulin

Insulin secretagogues (sulfonylurea and meglitinides)

For most individuals, this evaluation may be performed either during a spontaneous episode of hypoglycemia or through supervised testing (algorithm 1). Performance of a 72-hour fast, which is primarily used to diagnose insulinoma, may be required in patients with factitious hypoglycemia. Nonetheless, the fast may be negative if the patient does not take the offending agent.

In patients with diabetes who are treated with oral insulin secretagogues or insulin (including inhaled insulin), confirmation of factitious hypoglycemia can be very difficult. Diagnosis requires an assessment under controlled conditions, where individuals can be closely monitored and observed, with all blood glucose testing, food, and insulin administered by the staff. (See "Hypoglycemia in adults without diabetes mellitus: Determining the etiology", section on 'Supervised testing'.)

Anti-insulin antibodies Anti-insulin antibodies should be measured in all patients with insulin-treated diabetes and in patients not treated with insulin who have biochemical evidence of insulin-mediated hypoglycemia.

Patients on insulin therapy – In all patients with insulin-treated diabetes, insulin antibodies should be measured once, but they do not have to be measured during an episode of hypoglycemia. The detection of anti-insulin antibodies in insulin-treated patients has no diagnostic utility because the presence of such antibodies is common. However, the presence of anti-insulin antibodies can interfere with measurements of plasma insulin and C-peptide concentrations. As a result, if anti-insulin antibodies are present, free insulin and C-peptide levels should be measured when possible. The titers of anti-insulin antibodies have fallen over time with the use of human insulin formulations and insulin analogs compared with the earlier use of animal source insulins [34].

Patients not taking insulin therapy – In patients who are not treated with insulin, anti-insulin antibodies should be measured only if the laboratory evaluation suggests hypoglycemia due to endogenous hyperinsulinism (algorithm 2). Antibodies do not have to be measured during an episode of hypoglycemia. In this setting, the presence of anti-insulin antibodies helps evaluate for possible autoimmune hypoglycemia. In autoimmune hypoglycemia, insulin antibodies are spontaneously generated without prior exposure to exogenous insulin [35,36]. Patients with autoimmune hypoglycemia have high plasma titers of insulin antibodies and may have a history of autoimmune disease or exposure to sulfhydryl-containing drugs. (See "Hypoglycemia in adults without diabetes mellitus: Determining the etiology", section on 'C-peptide level ≥0.2 nmol/L'.)

Differentiating factitious hypoglycemia from other etiologies — The approach to interpreting laboratory test results during a supervised fast is shown in the algorithms and reviewed in detail elsewhere (algorithm 2 and algorithm 3). (See "Hypoglycemia in adults without diabetes mellitus: Determining the etiology", section on 'Interpretation of supervised fast results'.)

In patients with hyperinsulinemic hypoglycemia, the distinction between an endogenous or exogenous source of insulin can be made by measuring plasma C-peptide and insulin at the time of the hypoglycemic episode (and preferably in the same sample) (table 2 and algorithm 2) [37]. Interpretation of C-peptide, insulin, and glucose levels must be performed in concert; none of these tests is diagnostically useful in isolation. Key findings that differentiate factitious hypoglycemia from other etiologies of hypoglycemia depend on whether hypoglycemia appears due to endogenous or exogenous hyperinsulinism.

Hypoglycemia due to endogenous hyperinsulinism – Factitious hypoglycemia caused by insulin secretagogues (sulfonylureas or glucagon-like peptide 1 [GLP-1] receptor agonists) biochemically mimics insulinoma. Insulin and C-peptide are secreted in an equimolar fashion [38]; as a result, the plasma concentrations of these two peptides parallel each other in patients with endogenous hyperinsulinism. Patients with insulinoma, autoimmune hypoglycemia, or insulin secretagogue-induced hypoglycemia can have plasma insulin, C-peptide, and proinsulin values above or within the fasting reference range during confirmed hypoglycemia. (Values within the reference range are abnormal if the plasma glucose concentration is low.) The detection of sulfonylureas or meglitinides in the plasma or urine confirms the diagnosis of factitious hypoglycemia (table 2 and algorithm 2) [35,39].

In autoimmune hypoglycemia, both the plasma insulin and C-peptide concentrations can be very high, with plasma insulin levels often well above 1000 microU/mL (6000 pmol/L). The diagnosis is confirmed through detection of anti-insulin antibodies. Antibodies do not have to be measured during an episode of hypoglycemia. (See 'Biochemical tests' above and "Hypoglycemia in adults without diabetes mellitus: Determining the etiology", section on 'C-peptide level ≥0.2 nmol/L'.)

Hypoglycemia due to exogenous hyperinsulinism – In contrast, in patients with factitious hypoglycemia due to insulin use, plasma insulin values are typically high (often above 100 microU/mL [600 pmol/L]), whereas plasma C-peptide and proinsulin values are suppressed, usually close to the lower limit of detection for the assay (table 2 and algorithm 2). This observation applies to both patients without diabetes [24,40,41] and to those with type 2 diabetes [24,26,29]. Patients with type 1 diabetes are characteristically severely insulin deficient and have low or undetectable plasma concentrations of C-peptide. Although the C-peptide values in these patients cannot be further suppressed, confirmation that C-peptide is low during hypoglycemia eliminates any consideration of endogenous hyperinsulinism (ie, due to insulinoma) [28,42].

However, in hypoglycemia caused by synthetic insulin analogs (eg, glargine, lispro, aspart), insulin concentrations may be low, depending upon the insulin assay used. Clinical suspicion should guide subsequent testing for various insulin analogs. For example, suppressed ketogenesis despite an appropriately low insulin level may suggest the presence of an unmeasured insulin analog. The same sample obtained at the time of hypoglycemia should be used for such additional testing. (See 'Type of insulin assay' below and "Hypoglycemia in adults without diabetes mellitus: Determining the etiology", section on 'Interpretation of supervised fast results'.)

Caveats for interpretation — Misinterpretation of laboratory test results can lead to misdiagnosis of either insulinoma or factitious hypoglycemia. Misdiagnosis can deprive the patient of a potentially curative procedure (if the diagnosis of insulinoma is missed) [43], lead to unnecessary surgery (if the diagnosis of insulin secretagogue use is missed), or result in subsequent, potentially fatal hypoglycemic events. Thus, thoughtful selection of laboratory assays and careful interpretation of test results are critical (algorithm 2 and algorithm 3).

Type of insulin assay — Some insulin assays detect only human insulin, whereas others detect both human insulin and synthetic insulin analogs (glargine, detemir, lispro, aspart) [44-46]. In addition, some assays have been developed to specifically measure synthetic insulin analogs (eg, lispro, aspart) or animal insulin (porcine, beef) without any cross-reactivity with human insulin [47-49]. Assay specificity depends upon the selection of monoclonal antibody used for detection. Mass spectrometry-based assays allow rapid identification of human insulin and its synthetic or animal analogs [50-52]. It is important for the clinician to know which insulin assay is used and whether it measures human insulin, insulin analogs, or both. This helps determine whether additional testing with different assays is indicated.

Insulin secretagogue detection — During confirmed hypoglycemia, plasma should be obtained for the measurement of sulfonylureas and meglitinides (nateglinide, repaglinide). It is important to verify that the assay used can reliably identify all these compounds. The Department of Laboratory Medicine at the Mayo Clinic developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method that is highly sensitive for the detection of sulfonylureas and meglitinides. Similar assays are available in other countries [53,54]. Capillary electrophoresis (CE) and high-performance liquid chromatography (HPLC) assays are also available for detecting surreptitious use of sulfonylureas or meglitinides [55,56].

MANAGEMENT

Acute reversal of hypoglycemia — The acute management of factitious hypoglycemia is generally similar to the management of hypoglycemia during the treatment of diabetes. The treatment of hypoglycemia in individuals with diabetes is reviewed in more detail elsewhere. (See "Hypoglycemia in adults with diabetes mellitus", section on 'Reversing hypoglycemia'.)

Symptomatic hypoglycemia – Patients with symptomatic hypoglycemia should ingest carbohydrates (eg, 15 to 20 grams of oral glucose). Glucose may be ingested in the form of glucose tablets, juice, milk, or other snacks. Rapid absorption of the carbohydrate is key, so fat-rich foods (eg, ice cream) or full meals, which may delay carbohydrate absorption, are not recommended for acute management.

Severe hypoglycemia – Severe hypoglycemia is defined as hypoglycemia that impairs cognition sufficiently to require assistance from another person [57].

Outpatient setting – Treatment of severe hypoglycemia, when the patient is unconscious or unable to ingest carbohydrate, requires glucagon administration. Glucagon (0.5 to 1 mg) can be administered intranasally or by subcutaneous or intramuscular injection.

Inpatient setting – Patients brought to the hospital can be treated more quickly by giving 25 g of 50 percent glucose (dextrose) intravenously (IV). A subsequent glucose infusion (or food, if patient is able to eat) is often needed, depending upon the half-life of the drug causing the hypoglycemia.

Refractory or recurrent hypoglycemia – Refractory or recurrent hypoglycemia may evolve after ingestion of sulfonylureas with longer duration of action. In this setting, octreotide may be used, although data supporting its use are limited. As an example, in a trial of adults with sulfonylurea-induced hypoglycemia, participants who were randomly assigned to receive octreotide (a single subcutaneous dose of 75 mcg) in addition to 1 ampule of 50 percent dextrose IV had significantly higher mean glucose values during the first eight hours of therapy than those who received only IV dextrose [58]. (See "Sulfonylurea agent poisoning", section on 'Intoxication'.)

Intentional sulfonylurea overdose – In the setting of symptomatic hypoglycemia due to sulfonylurea overdose, octreotide should be administered. Management of sulfonylurea overdose is reviewed in detail separately. (See "Sulfonylurea agent poisoning", section on 'Symptomatic intentional overdose'.)

Long-term management — The long-term treatment of factitious hypoglycemia involves changing behavioral patterns to protect the patient from the consequences of hypoglycemia. Meetings held to inform patients about their diagnosis may be more effective when they are a collaborative intervention by an attending clinician and mental health specialist together. Having the support of caregivers/family members is also important for mediating behavioral change. It is important to emphasize that the patient needs help, providing assurance that medical care and support are available. (See "Factitious disorder imposed on self (Munchausen syndrome)", section on 'Specific treatment' and "Factitious disorder imposed on self (Munchausen syndrome)", section on 'Prognosis'.)

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 topic (see "Patient education: Low blood sugar in people without diabetes (The Basics)")

SUMMARY AND RECOMMENDATIONS

Etiology – Factitious hypoglycemia results from the use of insulin or insulin secretagogues (sulfonylurea, meglitinides) but not from metformin or other drugs used for diabetes management that are not associated with hypoglycemia. (See 'Etiology' above.)

Clinical characteristics – Patients without diabetes who have factitious hypoglycemia may present with a clinical syndrome that appears similar to insulinoma. Patients with diabetes and factitious hypoglycemia may have repeated episodes of hypoglycemia despite a reduction in insulin dose or even cessation of insulin therapy. (See 'Clinical characteristics' above and "Hypoglycemia in adults without diabetes mellitus: Clinical manifestations, causes, and diagnosis", section on 'Clinical manifestations'.)

Diagnostic evaluation

When to consider – The possibility of factitious hypoglycemia should be considered in every patient undergoing evaluation for a hypoglycemic disorder. Clinical suspicion is particularly warranted when the individual has access to insulin or other glucose-lowering agents or when the hypoglycemia occurs randomly, without any relation to meals or fasting. (See 'When to consider the diagnosis' above.)

Initial evaluation – A complete clinical and medication history are critical for the initial evaluation. All medications, including herbal preparations or other over-the-counter products, should be identified and visually inspected (table 1). (See 'Initial evaluation' above.)

Laboratory evaluation

Biochemical tests – The diagnosis of factitious hypoglycemia can usually be established by documenting the presence of hypoglycemia and by simultaneously measuring plasma levels of the following:

-Insulin

-C-peptide

-Proinsulin

-Insulin secretagogues (sulfonylurea and meglitinides)

For most individuals, this evaluation may be performed either during a spontaneous episode of hypoglycemia or through supervised testing (algorithm 1). (See 'Biochemical tests' above.)

In patients with diabetes who are treated with insulin or oral insulin secretagogues, confirmation of factitious hypoglycemia can be very difficult. Diagnosis requires an assessment under controlled conditions, where individuals can be closely monitored and observed. (See "Hypoglycemia in adults without diabetes mellitus: Determining the etiology", section on 'Supervised testing'.)

Test interpretation – Patients with insulinoma, autoimmune hypoglycemia, or insulin secretagogue-induced hypoglycemia can have plasma insulin, C-peptide, and proinsulin values above or within the fasting reference range during confirmed hypoglycemia. The detection of sulfonylureas or meglitinides in the plasma confirms the diagnosis of factitious hypoglycemia (table 2 and algorithm 2 and algorithm 3).

In contrast, in patients with factitious hypoglycemia due to insulin use, plasma insulin values are typically high (often above 100 microU/mL [600 pmol/L]), whereas plasma C-peptide and proinsulin values are suppressed, usually close to the lower limit of detection for the assay. However, 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 for various insulin analogs. (See 'Differentiating factitious hypoglycemia from other etiologies' above.)

Management – The acute management of factitious hypoglycemia is similar to the management of hypoglycemia during the treatment of diabetes. The long-term treatment of factitious hypoglycemia involves changing behavioral patterns. (See 'Management' above and "Hypoglycemia in adults with diabetes mellitus", section on 'Reversing hypoglycemia'.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges F John Service, MD, PhD, who contributed to earlier versions of this topic review.

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