Factitious Hypoglycemia


May 08, 2002

In This Article

Basis for Laboratory Diagnosis of Factitious Hypoglycemia

The biochemical aspects of insulin secretion by the pancreatic beta-cells play an important role in evaluating hypoglycemia.[9] Initially, proinsulin, a polypeptide precursor of insulin, is synthesized in the microsomal fraction of the pancreatic beta cells.[18] In the storage granule, a proteolytic process cleaves the molecule at 2 sites, which results in the formation of the insulin molecule and C-peptide (31 amino acid). Insulin, a double-stranded peptide, consists of an A-chain (21 amino acids) and a B-chain (30 amino acids), which are held together by 2 disulfide bonds.[18] Equimolar amounts of insulin and C-peptide are released from the storage granules into the circulation by means of exocytosis.[9] A small amount of proinsulin enters the bloodstream because of incomplete processing.

Equimolar amounts of endogenous insulin and C-peptide are released into circulation.[18] A large fraction of the circulating insulin is rapidly removed from the liver. The liver clears only a negligible amount of circulating C-peptide. C-peptide is cleared primarily by the kidneys at a lower metabolic clearance rate.[19] During fasting and feeding, the molar ratio of insulin to C-peptide in the peripheral venous circulation should be less than 1.

Normally, the C-peptide levels increase when pancreatic secretion of insulin increases.[8] Conversely, the C-peptide levels decrease when pancreatic secretion of insulin is low. Exogenous administration of insulin results in an increase in insulin levels without a concomitant increase in the C-peptide level.[6]

The diagnostic criteria for exogenous insulin administration include high serum insulin levels and the absence of serum C-peptide levels in the presence of hypoglycemia.[18] During the purification of commercial insulin preparations, the C-peptide is removed.[18] As a result, C-peptide cannot be detected by means of radioimmunoassay. By contrast, both insulin and C-peptide levels are elevated and detectable in patients with insulinoma.[14,18]

In the past, the identification of circulating antibodies to insulin (eg, beef, pork) was useful in diagnosing insulin-induced factitious hypoglycemia.[6] This test is less useful since the development of recombinant human insulin as exogenous administration of recombinant human insulin produces smaller titers of antibodies.[6]

Since sulfonylureas stimulate the release of endogenous insulin, the plasma levels of insulin and C-peptide are inappropriately high in patients with sulfonylurea-induced hypoglycemia.[3] These plasma levels are higher than those in patients with an insulinoma.[3]

Diagnosis of surreptitious use of sulfonylureas may be very difficult without detecting the drug by means of blood or urine analysis.[3] It is important to confirm the diagnosis by determining the level of sulfonylurea at the time of hypoglycemia.[6]

In 1946, self-induced hypoglycemia by surreptitious use of insulin in a nurse was described.[20] Although many cases have been described since this report, it is difficult to determine the frequency of the condition.[3] The medical literature suggests that the condition is more common in men than in women. However, researchers investigated 19 cases between 1994 and 1996 and reported a ratio of 11 women to 8 men. The patients' ages ranged from 15 to 40 years; patients were knowledgeable about the effects of insulin.[3]

Sulfonylureas are the most important group of drugs besides insulin that can predictably cause severe hypoglycemia when an overdose is administered.[3] Traditionally, this group of oral hypoglycemic drugs is subclassified into 2 generations of drugs.[21] The first generation includes tolbutamide, acetohexamide, tolazamide, and chlorpropamide. The second generation includes glyburide, glipizide and glimepiride.

Structurally, all sulfonylureas contain the sulfonylurea moiety (-SO2-NH-CO-NH-) but differ in terms of the chemical structure(s) attached to the sulfonylurea moiety.[22] These differences affect the potency, pharmacokinetics, and duration of action of the sulfonylureas. The oral hypoglycemic drugs are metabolized by the liver and their metabolites are excreted by the kidneys.[21]

Sulfonylureas bind to high-affinity receptors on the beta cells and stimulate the release of insulin from functional beta cells.[22] The order of potency of the different sulfonylureas in binding to the receptors parallels their potency in stimulating the release of insulin. There is no evidence suggesting that sulfonylureas increase the synthesis of insulin or increase the release of insulin in response to ingesting food.[23] This group of drugs produces a fasting type of hypoglycemia instead of a reactive type of hypoglycemia. As a result, there is a tendency for factitious sulfonylurea-induced hypoglycemia to be confused with an insulinoma.[23]

The actual incidence of sulfonylurea-induced-factitious hypoglycemia is not known.[3]

Repaglinide, an oral antidiabetic drug, belongs to a new class of drugs known as prandial glucose regulators.[24] Its primary mechanism of action is to stimulate the secretion of insulin from the beta cells. The drug is rapidly absorbed and metabolized by the liver.[25] It is eliminated primarily via the bile (~90% in feces).[26] Repaglinide has a short half-life (~0.5-1.4 hr) which results in a brief duration of activity.[25]

Recently, researchers reported the first case of repaglinide-induced factitious hypoglycemia in an 18-year-old male.[26] A series of diagnostic tests suggested an insulinoma. However, when the patient was hospitalized for 2 weeks, he was able to maintain normal glucose levels. The diagnosis of repaglinide-induced factitious hypoglycemia was made by determining the serum concentration of repaglinide during an episode of hypoglycemia.