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Recurrent nocturnal hypoglycemia in a patient with type 1 diabetes mellitus.


A 39-year-old man with type 1 diabetes mellitus (DM) was admitted with diabetic ketoacidosis precipitated by an upper respiratory tract infection. His admitting biochemistry showed venous plasma glucose concentration of 933 mg/dL (51.8 mmol/L) [reference: 72-140 mg/dL (4.0-7.8 mmol/L)], bicarbonate of 14.7 mmol/L (22-31 mmol/L), [beta]-hydroxybutyrate of >6 mmol/L (<0.6 mmol/L), and arterial pH of 7.28 (7.35-7.45). He was treated with intravenous hydration and intravenous insulin infusion, and made a rapid recovery.

The patient had been diagnosed with type 1 DM at the age of 33 years when he presented with diabetic ketoacidosis. Glutamic acid decarboxylase antibody was increased at the time of diagnosis [10.6 U/mL (reference: <1 U/mL)] and postprandial C-peptide concentrations were undetectable. His subsequent glycemic control was poor [glycated hemoglobin (Hb [A.sub.1c]) ranged from 8.9% to 15.6%], which resulted in peripheral and autonomic neuropathy manifesting as painful sensory neuropathy and erectile dysfunction, respectively. His other medical history included mitral valve prolapse, hypertension, and dyslipidemia. He was prescribed a basal-bolus insulin regimen consisting of twice-daily insulin detemir (10 U before breakfast and 7 U before dinner) and insulin aspart (5 U before breakfast, 3 U before lunch, and 4 U before dinner), simvastatin, sildenafil, pregabalin, and omeprazole. He was not prescribed sulfonylurea and denied alcohol consumption.

After resolution of diabetic ketoacidosis, the patient was restarted on his preadmission basal-bolus insulin regimen. His insulin regimen was titrated during this hospital admission, and he had wide fluctuations in blood glucose and recurrent nocturnal hypoglycemia. Typically, there was severe hyperglycemia during daytime [capillary glucose: 205-553 mg/dL (11.4-30.7 mmol/L)], particularly after meals, and symptomatic hypoglycemia that consistently occurred between 2400 and 0230 daily [capillary glucose: 34-58 mg/dL (1.93.2 mmol/L)], accompanied by symptoms of adrenergic response such as diaphoresis, palpitations, and anxiety.

Physical examination revealed stable vital signs and low body mass index (16.4 kg/[m.sup.2]). There was no abnormal hyperpigmentation typical of Addison's disease. The thyroid gland was not enlarged, and he was clinically euthyroid. Cardiovascular and respiratory examinations were unremarkable. There was mild lipohypertrophy at the insulin injection sites.

Other relevant serum biochemistry results were albumin 4.0 g/dL (3.8-4.8 g/dL), aspartate aminotransferase 10 U/L (14-50 U/L), alanine aminotransferase 10 U/L (10-55 U/L), [gamma]-glutamyl transferase 30 U/L (10-70 U/L), and creatinine 0.6 mg/dL (53 [micro]mol/L) [0.7-1.4 mg/dL (65-125 [micro]mol/L)]. Insulin and C-peptide concentrations measured at the time of 1 of the hypoglycemic episodes (venous glucose: 2.8 mmol/L) during this admission were 83.6 mU/L (0.0-25.0 mU/L) and 36 pmol/L (364-1655 pmol/L), respectively. He was biochemically euthyroid.


Hypoglycemia is a common complication of insulin therapy in patients with DM, and is a barrier to the achievement of glycemic control. It causes significant physical and psychological morbidity and occasionally, mortality. The underlying cause of hypoglycemia should be evaluated and addressed to prevent recurrent episodes.

Hypoglycemia in a patient with DM is most commonly caused by an absolute or relative therapeutic insulin excess. Causes of absolute insulin excess include excessive or ill-timed insulin secretagogue or insulin, or decreased insulin clearance as in renal failure; relative insulin excess occurs when the prevailing insulin is not matched by glucose delivery (exogenous), utilization, or production (1). Relative or absolute insulin excess is usually apparent from the history of events before the hypoglycemic episodes. A detailed history did not suggest insulin excess as a cause of the hypoglycemic episodes. The dose of insulin prescribed in this patient was matched to his calorie intake, and he was able to administer the prescribed dose accurately. He denied any surreptitious use of insulin. Lipohypertrophy at insulin injection sites can impair absorption and is another common cause of glucose fluctuations. This patient had only mild lipohypertrophy, and change of insulin injection site in this patient did not alleviate the recurrent hypoglycemic episodes.

Hepatic and renal failure were excluded by clinical examination and aminotransferase activities and albumin and creatinine concentrations that were within reference intervals. Adrenal insufficiency, particularly coexisting Addison's disease in a patient with type 1 DM, can cause hypoglycemia. A short cosyntropin test produced a peak cortisol concentration of 34.8 [micro]g/dL (960 mmol/L) [adequate response: >20.0 [micro]g/dL (>550 mmol/L)] and excluded that diagnosis. The patient did not drink alcohol, and he was not on any other medications (apart from insulin) that could cause hypoglycemia.

Diabetic gastroparesis (prevalence: 30-40% of DM patients) is a condition characterized by delayed gastric emptying in the absence of mechanical obstruction of the stomach owing to autonomic neuropathy (2). This condition may precipitate hypoglycemia, as delayed food transit causes a mismatch between insulin delivery and carbohydrate absorption. In view of the history of autonomic neuropathy and a history of recurrent sensation of bloating after meals, a gastric emptying study was performed on this patient and showed delayed emptying. However, the pattern of hyperglycemia 2-3 h after meals (particularly postdinner) followed by hypoglycemia after midnight was not consistent with the pattern usually observed in gastroparesis.

Having excluded the more common causes of hypoglycemia in a patient with DM on insulin therapy, further investigations were undertaken to investigate other etiologies of the recurrent hypoglycemia. Insulin and C-peptide concentrations were measured during the episodes of hypoglycemia. Undetectable C-peptide concentrations during 3 separate episodes of hypoglycemia excluded endogenous hyperinsulinism, such as caused by insulinoma, as the etiology of recurrent hypoglycemia (3).

After excluding the above causes, antiinsulin antibodies (IAs) were considered, in view of the raised insulin concentration during episodes of hypoglycemia. Chronic use of exogenous insulin may give rise to IAs that may sequester insulin. Consequently, a larger dose of insulin analog may be required to overcome the binding capacity and allow sufficient free insulin to act peripherally. The free and bound insulin exist in equilibrium. As free insulin is metabolized, bound insulin will be released from IAs. This has an effect of retarding initial insulin action causing daytime hyperglycemia; conversely, the subsequent release of insulin from IA may cause nocturnal hypoglycemia, if the released insulin is not countered with calorie intake (4).

The IAs can be characterized by their binding capacity and affinity. Patients with low-capacity, high-affinity IAs typically do not develop hypoglycemia. In contrast, patients with moderate-capacity, low-affinity IAs may suffer from moderate nocturnal hypoglycemia. Patients with high-capacity, low-affinity IAs may suffer severe daytime hyperglycemia and nighttime hypoglycemia and may require treatment with immunosuppressants (5).

The IAs can be thought of as macroinsulin interference. However, unlike other macrohormone interference, evaluation of nonlinearity by dilution of patient samples or retesting of insulin on an alternate assay is not useful for investigating IAs in patients with DM on insulin therapy. This is because most insulin assays do not show linear recovery with insulin analog and have different cross-reactivity with insulin analogs (6). For this reason, assessment of underrecovery after adding insulin to the sample is probably also unreliable.

Gel chromatography can be used to confirm the diagnosis of macroinsulin, and therefore presence of IAs, by showing an insulin peak in the immunoglobulin mass area (7). IAs also can be directly measured. These assays are not routinely available in most laboratories. When IAs are suspected, measurement of free, direct, and total insulin concentrations are helpful. Direct insulin is the insulin concentration measured from the native patient sample. Free insulin is obtained by measurement of the supernatant after polyethylene glycol (PEG) precipitation. Total insulin is obtained by first adding acid to the patient sample to dissociate the antibody-bound insulin, followed by PEG precipitation and pH neutralization (8, 9).

In health, the total, direct, and free insulin concentrations exist in ratios close to 1, as circulating insulin is not significantly bound by protein (8, 9). A raised direct:free insulin or total:direct insulin ratio is suggestive of IAs. These ratios are assay specific (8, 9). For this patient, the direct:free and total:direct insulin ratios were 1.03 and 0.98, respectively, using the Advia Centaur assay (Siemens Healthcare Diagnostics). Direct measurement of the IA concentration was 0.01 nmol/L (reference: [less than or equal to] 0.02 nmol/L, Mayo Medical Laboratories). These results excluded the diagnosis of IAs.

As the cause of recurrent hypoglycemia remained unexplained, we measured 24-h insulin and glucose profiles of the patient. The 24-h insulin profile showed an unexpected peak between 2400 and 0230 that coincided with severe hypoglycemia (1.9 mmol/L). This peak could not be explained by the prescribed insulin regimen of the patient (Fig. 1). We suspected that the peak represented surreptitious administration of a short-acting insulin analog. After the results of the 24-h insulin profile were explained to the patient, there were no further occurrences of nocturnal hypoglycemia. He was subsequently referred for psychiatric care and eventually disclosed several significant social stressors.

We concluded that this patient had factitious hypoglycemia, a syndrome where patients self-induce hypoglycemia to seek medical attention or assume a sick role. It represents a significant diagnostic challenge and often goes undiagnosed for years in patients previously labeled with brittle diabetes (10). The clinical presentation often closely mimics genuine clinical conditions and patients often show concern about their condition and are keen for investigation and interventions. They often have a history of multiple admissions and visits to different institutions. This patient had been admitted to multiple local hospitals on 18 occasions over the last 2 years for recurrent hypoglycemia and noncrisis hyperglycemia.

It is important to recognize that this condition is a diagnosis of exclusion and should be made only after careful exclusion of potential organic causes to avoid inappropriately labeling the patient, which carries significant social, legal, and clinical implications. However, this should also be balanced against the need for early recognition to avoid unnecessary diagnostic and therapeutic interventions that are wasteful of resources and may bring harm to the patient. Fig. 2 shows a suggested diagnostic approach to patients with recurrent hypoglycemia.


1. What are the etiologies of recurrent hypoglycemia in patients on insulin therapy?

2. What is the suggested approach to recurrent hypoglycemia?

3. Can insulin antibodies cause hypoglycemia?


* Hypoglycemia in patients with DM is a common occurrence and is most commonly caused by an absolute or relative therapeutic insulin excess. Lipohypertrophy at the insulin injection site can impair insulin absorption and can cause glucose fluctuations. Delayed gastric emptying, caused by diabetic gastroparesis (30%-40% DM patients), can also cause hypoglycemia.

* Insulin antibodies and surreptitious use of exogenous insulin can produce inappropriately high concentrations of insulin during hypoglycemia.

* Factitious hypoglycemia is highly challenging to diagnose and manage. It should be considered as a differential diagnosis in unexplained hypoglycemia and is a diagnosis of exclusion.

* Measurement of C-peptide and free and direct insulin can help differentiate factitious hypoglycemia from other organic causes.

* A high insulin concentration with raised direct: free insulin ratio recorded during an episode of hypoglycemia suggests insulin misuse as the likely cause. or revising the article for intellectual content; and (c) final approval of the published article.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, oranalysis and interpretation of data; (b) drafting

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.


(1.) Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes 2008; 57:3169-76.

(2.) Parkman HP, Fass R, Foxx-Orenstein AE. Treatment of patients with diabetic gastroparesis. Gastroenterol Hepatol (NY) 2010; 6:1-16.

(3.) Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2009; 94:709-28.

(4.) Radermecker RP, Renard E, Scheen AJ. Circulating insulin antibodies: influence of continuous subcutaneous or intraperitoneal insulin infusion, and impact on glucose control. Diabetes Metab Res Rev 2009; 25:491-501.

(5.) Ogawa S, Kou Y, Nako K, Okamura M, Senda M, Mori T, et al. Diagnosis and treatment of diabetic patients requiring insulin who repeatedly manifest hyperglycemia and hypoglycemia due to anti-insulin antibodies. Clin Diabetes 2011; 29:148-50.

(6.) Owen WE, Roberts WL. Cross-reactivity of three recombinant insulin analogs with five commercial insulin immunoassays. Clin Chem 2004; 50:257-9.

(7.) Halsall DJ, Mangi M, Soos M, Fahie-Wilson MN, Wark G, Mainwaring-Burton R, et al. Hypoglycemia due to an insulin binding antibody in a patient with an IgA-kappa myeloma. J Clin Endocrinol Metab 2007; 92:2013-6.

(8.) Sapin R. The interference of insulin antibodies in insulin immunometric assays. Clin Chem Lab Med 2002; 40:705-8.

(9.) Kim S, Yun YM, Hur M, Moon HW, Kim JQ. The effects of anti-insulin antibodies and cross-reactivity with human recombinant insulin analogues in the E170 insulin immunometric assay. Korean J Lab Med 2011; 31:22-9.

(10.) Williams G. What goes around, comes around. Lancet 2012; 379:2235-6.

Received August 13, 2013; accepted December 16, 2013.

DOI: 10.1373/clinchem.2013.214676

Tze Ping Loh, [1] * Shao Feng Mok, [2] Shih Ling Kao, [2] Eric Khoo, [2] and Ah Chuan Thai [2]

* Address correspondence to this author at: National University Hospital, 5 Lower Kent Ridge Road, Singapore 119074. Fax +65-67771613; e-mail tploh@

[1] Department of Laboratory Medicine and 2 Department of Medicine, National University Hospital, Singapore.

[3] Nonstandard abbreviations: DM, diabetes mellitus; Hb A1c, glycated hemoglobin; IA, antiinsulin antibodies; PEG, polyethylene glycol.
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Title Annotation:Clinical Case Study
Author:Loh, Tze Ping; Mok, Shao Feng; Kao, Shih Ling; Khoo, Eric; Thai, Ah Chuan
Publication:Clinical Chemistry
Article Type:Clinical report
Date:Oct 1, 2014
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