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Division of Intramural Research, National Institute of Diabetes, Digestive and Kidney Diseases (B.H., M.C.S., P.G.), and Departments of Pharmacy (F.P.) and Clinical Pathology (G.C.), W. G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland 20892; and Laurel Endocrine Associates (R.B.), Columbia, South Carolina 29204
Address correspondence and requests for reprints to: Phillip Gorden, M.D., NIDDK Director, National Institutes of Health, Building 10, Room 8S235, Bethesda, Maryland 20892.
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Introduction |
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Case Report |
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The patient denied drinking alcohol recently and admitted drinking only at holiday celebrations. The patient was admitted to a local hospital for a 72-h fast, during which the patient maintained normal plasma glucose. A computed tomography scan of the abdomen failed to reveal a pancreatic lesion. He was discharged from the hospital and remained asymptomatic for 4 weeks when he was found to be unresponsive in the middle of the night by his wife and was taken to the ER, where his plasma glucose was 10 mg/dL. A consulting endocrinologist ordered additional studies on a sample of blood with a glucose of 1.05 mmol/L (19 mg/dL) revealing a simultaneous insulin of 395 pmol/L (normal, 323–145), C-peptide of 2966 pmol/L (8.9 ng/mL; normal, 0.9–4.0), proinsulin of 81 pmol/L (normal, 2.0–2.6), and cortisol of 220.7 nmol/L. A urine screen for sulfonylureas was negative. Pancreatic ultrasound was negative. Magnetic resonance imaging of the pituitary and abdomen and pancreatic angiography failed to demonstrate a pancreatic tumor. The patient reported a weight increase of 9.5 kg over the last several weeks, and he felt hungry at all times. He was referred to the NIH for further evaluation.
The patient was a pleasant white male, well built, and in no acute distress. No pathological findings were recorded during the physical examination. His wife recounted that the patient dropped out of high school at age 15 to support her while she was pregnant. They lived together with their 2-yr-old daughter in his mother-in-law’s home. His sister-in-law, who also lived in the same dwelling, had type 2 diabetes and was prescribed repaglinide (Prandin) and metformin (Glucophage). His grandfather was an insulin-requiring type 2 diabetic. The patient was recently dismissed from his job at a major retail chain because of frequent absences related to weakness and fatigue.
The patient underwent a second supervised fast. He remained asymptomatic with normal plasma glucose concentrations and with suppressed insulin levels. However, a small increase in both glucose and insulin was measured at 24 and 48 h. The patient denied eating during the fast, and the patient and his family denied the possibility that he was ingesting hypoglycemic agents. Lacking definite proof of drug surreptitious use, the patient was discharged home after being instructed of the potentially devastating consequences of prolonged hypoglycemia.
After returning home, the patient experienced two severe episodes of hypoglycemia requiring iv glucose resuscitation, followed by prolonged infusion of glucose in the hospital to prevent nocturnal hypoglycemic. He returned to the NIH. On admission, the patient was hypoglycemic with a glucose of 2.05 mmol/L (37 mg/dL), insulin of 145 pmol/L, C- peptide of 1500 pmol /L (normal, 170–900), and proinsulin of 44 pmol/L (0.4 ng/mL; normal, 0–0.2). The patient received glucose, and a third supervised fast was begun the following morning and concluded after 6 h due to hypoglycemia.
A repeat abdominal computed tomography, magnetic resonance imaging, and ultrasound of the pancreas were negative. Calcium-stimulated arteriography demonstrated a 2-fold increased insulin secretion after injection of calcium into the gastroduodenal artery. During these 2 weeks of hospitalization, the patient maintained normal glucose levels.
Novo Nordisk Pharmaceuticals and Bristol-Myers Squibb Co. (Syracuse, NY) agreed to provide measurements of
repaglinide and metformin, respectively.
Repaglinide serum concentrations were determined with
liquid chromatography (Applied Analytical Industries, Neu-Ulm,
Germany). Repaglinide was detectable (0.2 ngmL) in six of
seven stored specimens obtained by the referring endocrinologist during
the hypoglycemic episodes at home. The serum concentrations were as
high as 4.8–20.7 ng/mL in three specimens. Metformin serum
concentrations were all reported as below limits of quantification
(0.042 mg/L) for these specimens. While at the NIH for reevaluation,
only 1 of 15 serum specimens collected over a 12-day period had
detectable (4.1 ng/mL) repaglinide. This positive specimen
was obtained during the first night of the hospitalization, taken when
the patient was hypoglycemic. As a control, two serum specimens
obtained from a hypoglycemic patient with proven insulinoma had no
detectable repaglinide. The patient fasted for 48 h
with no symptoms and complete suppression of his insulin and proinsulin
levels (Fig. 1
). Based on these results,
the patient’s clinical presentation did not fit insulinoma, and we had
evidence for repaglinide ingestion.
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Discussion |
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TopAbstractIntroductionCase ReportDiscussionReferences |
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Hypoglycemia has been reported to occur by the intentional misuse of insulin or sulfonylureas. Surreptitious administration of insulin is a serious psychiatric disturbance with a poor prognosis (1). The literature suggests that the profile of patients diagnosed with this disorder is more likely to be a female with access to insulin, commonly associated with the medical profession (1, 2). In a postmortem study of lethal hypoglycemia due to injection of insulin, the subjects were more frequently nondiabetic males, with no diabetic relatives and no association with the medical profession (9).The diagnosis of factitious hypoglycemia due to injection of insulin is based on the finding of high (often extremely high) serum insulin in combination with suppression of C-peptide and, possibly, insulin antibodies. Sulfonylurea abuse results in a clinical picture that mimics the biochemical findings observed in patients with insulinoma. Consequently, a drug screen for first- and second-generation sulfonylureas must be performed (3, 4, 5, 6). In the case of a positive screen, care must be taken to confirm the findings and to rule out interfering substances (10). Only 50% of patients confronted acknowledge self-administration of these drugs (2).
The current case is unique because this is the first reported case of
surreptitious hypoglycemia secondary to repaglinide.
Repaglinide, a carbamoylmethyl benzoic acid derivative,
belongs to the class of antidiabetic agents structurally related to
meglitinide (previously known as the nonsulfonyluria moiety of
glibenclamide). Its insulinotropic activity is believed to result from
closure of ATP-sensitive K+ channels in
pancreatic islet cells, resulting in stimulation of
Ca2+ influx. It is rapidly absorbed, metabolized
by the liver, and eliminated primarily via the bile (
90% in feces).
It has a short half-life of 
1.0–1.4 h, resulting in a brief
duration of activity and recommended to be taken immediately before
each meal (11). Because this drug is not part of the
current sulfonylurea screen, it could not have been detected, and only
because of the high level of suspicion, the use of this agent was
proved in a research setting.
Interestingly, the patient had high proinsulin levels that have been shown to be associated with insulinoma (12). In the past, we measured proinsulin as a percentage of the total plasma immunreactive insulin pool. This technique is cumbersome and not applicable outside a research setting. The percent proinsulin of the total immunreactive insulin tends to decrease following ingestion of tolbutamide. There are no data concerning direct immunoreactive measurement of proinsulin following the ingestion of other insulin secretagogues. Thus, this case clearly shows that proinsulin measured directly and not as a percentage of total insulin in plasma may be elevated in patients without insulinoma, who are ingesting insulin secretagogues. We have shown that proinsulin is usually not suppressible in patients with insulinoma but is suppressible in noninsulinoma patients at the end of the diagnostic fast. Thus, it is imperative to obtain measurements of proinsulin both at the beginning and the end of the fast (13).
It has been shown that intra-arterial calcium stimulation with venous sampling for insulin gradients is the most sensitive preoperative test for localizing insulinomas (14). Still, it must be made clear that this is only a localization test and should not be regarded as a diagnostic test geared to confirm the diagnosis of insulinoma. There are no available studies that describe the outcome of such a test in normal individuals. As seen in the current case, the patient had doubling of the insulin gradient in the area of the gastroduadenal artery, indicating a possible tumor located in the head of the pancreas. Presumably, the specificity of this test is based on the ability of calcium to stimulate insulin release from an insulinoma while the normal islets are suppressed. Under circumstances where an insulin secretagogue stimulates insulin release, the localized response is lost as all islets are influenced.
This patient was clearly faced with a life-threatening illness and was particularly challenging because it is the first reported instance of repaglanide as the etiologic agent. Thus, clinical suspicion must be our guide in the absence of definitive laboratory information. As illustrated by this case, clinical suspicion does not prescribe a remedy for this life-threatening situation. The patient was only able to admit to misusing repaglinide after he was presented with definitive proof. The inpatient environment ensures a controlled setting for diagnostic testing and observation. Whereas the approach to each patient is individualized, there are certain generalizations that are useful. Throughout the period of hospitalization, all members of the health care team should provide frequent supportive interto gain the patient’s confidence. Once the diagnostic evaluations are complete, the patient can be confronted directly with the clinical and laboratory evidence of surreptitious cause of hypoglycemia. This evidence is presented in a nonaccusatory manner, with enough technical explanation geared to the patient’s level of intellectual and educational capabilities to ensure understanding. Although this presentation is done in as nonthreatening a manner as possible, the team must persist until the patients usually acknowledge their role in the process. This process may take several days. The relationships established with the health care team before confrontation are used after confrontation to help develop a plan for follow-up and to provide an opportunity for the patients to work through their reaction to confrontation. Because of the potential severity of psychiatric disorders in these patients, suicide precaution measures must be taken at and after the time of confrontation (1). After all of these measures, the destructive behavior will hopefully cease.
In conclusion, we present the first case of repaglinide-induced factitious hypoglycemia. This case, again, demonstrates the importance of pure clinical judgment in the face of often-conflicting laboratory data in reaching a correct diagnosis and the requirement of definitive data for an appropriate therapeutic resolution.
Received June 19, 2000.
Revised September 29, 2000.
Accepted October 8, 2000.
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 S. Nakayama, T. Hirose, H. Watada, Y. Tanaka, and R. Kawamori Hypoglycemia Following a Nateglinide Overdose in a Suicide Attempt Diabetes Care, January 1, 2005; 28(1): 227 - 228. [Full Text] [PDF]
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 R Gama, J D Teale, and V Marks Best Practice No 173: Clinical and laboratory investigation of adult spontaneous hypoglycaemia J. Clin. Pathol., September 1, 2003; 56(9): 641 - 646. [Abstract] [Full Text] [PDF]
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