Endocrinology

Feb. 07, 2023

Hypoglycemia is a clinical syndrome confirmed by documenting Whipple's triad. It can be challenging to characterize and treat hypoglycemia when it occurs in the absence of diabetes mellitus. One established cause is factitious hypoglycemia, which results from surreptitious use of insulin secretagogues or insulin. The biochemical picture associated with insulin secretagogues such as sulfonylureas is identical to that of insulinoma, but assays have been available for many years to detect these compounds in the patient's circulation at the time of hypoglycemia and confirm the diagnosis.

Aoife M. Egan, M.B., B.Ch., Ph.D., an endocrinologist at Mayo Clinic's campus in Rochester, Minnesota, explains: "The situation can be more difficult when an individual is surreptitiously injecting insulin. In this latter scenario, we would anticipate very low or undetectable C-peptide concentrations, due to suppression of endogenous insulin secretion, and elevated insulin concentrations at the time of hypoglycemia.

"While commonly available insulin immunoassays generally have 100% cross-reactivity with human insulin — regular or isophane — their ability to detect analog insulin can be very variable depending on the type of insulin and specific assay used. Therefore, if analog insulin is present in the circulation, the immunoassay can give a result anywhere along a spectrum of undetectable to significantly elevated. This could lead to the incorrect assumption that the hypoglycemia is not mediated by insulin.

"Furthermore, standard immunoassays cannot determine the precise insulin subtype, which can add uncertainty when attempting to discuss this difficult diagnosis with the patient and/or caregiver."

Given the widespread availability and use of analog insulin in recent years, this immunoassay limitation has become a significant barrier in the work-up of hypoglycemia.

Collaboration at Mayo Clinic

Clinicians and scientists from the Division of Endocrinology, Diabetes and Metabolism and the Department of Pathology and Laboratory Medicine at Mayo Clinic recognized this gap in the diagnostic pathway and performed analytical validation of a liquid chromatography high resolution accurate mass (LC-HRAM) immunoassay to detect the following insulin analogs: lispro, glulisine, aspart, glargine metabolites and detemir.

Ravinder J. Singh, Ph.D., of the Division of Clinical Biochemistry and Immunology and the Department of Laboratory Medicine and Pathology at Mayo Clinic's campus in Rochester, Minnesota, notes: "The assay also detects and identifies human insulin. This process involved several steps which are outlined in detail in the publication cited below and included identifying the lower limit of quantification for each analog.

"Residual samples were then collected from 75 patients with insulin-requiring type 1 or type 2 diabetes, and the ability of the assay to detect analog insulin in human subject samples was confirmed."

Finally, the study team identified five clinical cases of factitious hypoglycemia due to self-injection of insulin analogs. In each case, insulin, drawn at the time of hypoglycemia, was analyzed on two or three commercially available immunoassays. This highlighted the discrepant results observed with insulin immunoassays. The samples were then tested on the new mass spectrometry assay for insulin analogs, and in each case the assay confirmed the presence of a specific analog insulin.

Impact on clinical approach to hypoglycemia

Adrian Vella, M.D., an endocrinologist at Mayo Clinic's campus in Rochester, Minnesota, concludes: "Mayo Clinic has a long tradition of evaluating and treating patients with hypoglycemic disorders with an expert multidisciplinary team and state-of-the-art endocrine testing unit. We continuously strive to ensure patients have access to the best diagnostic tests and treatment approaches.

"Factitious hypoglycemia is an uncommon, yet serious, disorder, which is often associated with a diagnosis of Munchausen syndrome or Munchausen syndrome by proxy. To achieve long-term remission from this disorder, it is important to identify the underlying behavior and ensure supported behavioral change."

The mass spectrometry immunoassay for analog insulin is now available for use in clinical practice and has facilitated patient care discussions and removed lingering concerns about misdiagnosis in several cases of factitious hypoglycemia. With increasing awareness of the availability of this assay for detection of analog insulin, it will become a key component in the work-up of hypoglycemia.

For more information

Egan AM, et al. Pitfalls in diagnosing hypoglycemia due to exogenous insulin: Validation and utility of an insulin analog assay. Mayo Clinic Proceedings. 2022;97:11.

Refer a patient to Mayo Clinic.