Q&A: Investigations for Unexplained Hypoglycaemia in a Healthy Adult

Hypoglycemia is a clinical syndrome with diverse causes in which low levels of plasma glucose eventually lead to neuroglycopenia. In healthy persons, postabsorptive levels of plasma glucose stay within a narrow range (about 60 to 100 mg per deciliter [3.3 to 5.6 mmol per liter]) despite the intermittent ingestion of food. Insulin, the primary regulatory hormone that blunts postprandial hyperglycemia and maintains postabsorptive euglycemia, has its effects counterbalanced by several factors that provide a minimal level of glycemia in order to sustain the nutrition of the central nervous system. An uninterrupted flow of glucose in the blood is essential for normal metabolism in the brain.

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In this article:
Glucose Counterregulation
MCQ: clinical scenario
MCQ: answer
MCQ: explanation

Glucose Counterregulation

Studies of insulin-induced hypoglycemia in healthy volunteers suggest a hierarchy of responses among the physiologic factors that act to counterbalance declining levels of glycemia. The glycemic thresholds for the activation of these counterregulatory factors are higher than those for the development of symptoms and the impairment of cognitive function. Each factor's place in the hierarchy of counterregulatory forces represents the physiologic importance of that factor in defending against acute hypoglycemia. Glucagon provides the primary defense against hypoglycemia; without it, full recovery does not occur. Epinephrine is not necessary for counterregulation when glucagon is present. In the absence of glucagon, however, epinephrine has an important role. In contrast, hypoglycemia after an overnight fast, a 72-hour fast, or a meal cannot be generated by a deficiency of glucagon or epinephrine alone; deficiencies of both are required.

Neither growth hormone nor cortisol appears to contribute substantially to glucose counterregulation during acute insulin-induced hypoglycemia. During prolonged insulin-induced hypoglycemia — approximately 12 hours in length — deficiencies of cortisol and growth hormone in the blood result in lower plasma glucose concentrations, though they do not impair recovery from hypoglycemia. It should be pointed out that the effects of counterregulatory hormones on glucose homeostasis in studies of insulin-induced hypoglycemia may be different from those effects in clinical situations, in which hypoglycemia is caused by a deficiency of a counterregulatory hormone without insulin mediation.

MCQ: clinical scenario

A 17 year old patient has had two episodes of severe hypoglycemia. He is being investigated for a possible insulinoma but is also suspected of factitious (self-medicated) insulin-induced hypoglycemia by injection of insulin. His plasma insulin levels are elevated.

Which of the following is most likely to help in confirming self-induced hypoglycemia?

a) Weekly early morning plasma insulin levels
b) Hemoglobin level
c) Serum glucose level
d) Plasma C-peptide hormone level
e) A weekly weight chart

MCQ: answer

The correct answer is D

MCQ: explanation

Among the causes of recurrent hypoglycemic episodes in seemingly healthy patients, discriminating between sulfonylurea-induced hypoglycemia and insulinoma is of utmost importance because of the indistinguishable biochemical constellation. Inappropriately elevated serum levels of insulin and C-peptide during hypoglycemia are characteristic features of both conditions.

In contrast, hypoglycemia caused by exogenous insulin administration is associated with a high serum insulin level and a low serum C-peptide. Molar ratio of insulin to C-peptide in a hypoglycemic patient in excess of 1.0 is indicative of exogenous insulin administration. A ratio less than 1.0 is found in both insulinoma and sulfonylurea intake. Determination of insulin antibodies to prove exogenous insulin administration is not recommended because of the high degree of purity of current insulin preparations and the lack of specificity.

PHYSIOLOGY
After β-cell stimulation by carbohydrate or other secretagogues, insulin and C-peptide are secreted into the portal vein in a 1:1 molar ratio. A large fraction of endogenous insulin is cleared by the liver, whereas C-peptide, which is cleared primarily by the kidney and has a lower metabolic clearance rate than insulin, traverses the liver with essentially no extraction by hepatocytes. Hence, the molar ratio of insulin to C-peptide in peripheral venous blood (ICPR) should be less than 1.0 during fasting and feeding, unless exogenous insulin is introduced into the systemic circulation. Consequently, an ICPR in excess of 1.0 in a hypoglycemic patient argues persuasively for surreptitious or inadvertent insulin administration and against insulinoma (or sulfonylurea ingestion) as the cause of the hypoglycemia.

Reference(s)
1). Lebowitz MR, Blumenthal SA: The molar ratio of insulin to C-peptide: an aid to the diagnosis of hypoglycemia due to surreptitious (or inadvertent) insulin administration. Arch Intern Med. 1993;153(5):650-655. doi:10.1001/archinte.1993.00410050082011
2). Service FJ: Hypoglycemic disorders. N Engl J Med. 1995 Apr 27;332(17):1144-52. doi:10.1056/NEJM199504273321707.
3). Wiesli P, Lehmann R: Pitfalls in the Evaluation of Spontaneous Hyperinsulinemic Hypoglycemia. Diabetes Spectrum. Volume 13 Number , 2000, Page 56.