What is the diagnostic workup for hypoglycemia (low blood sugar)?

From the Guidelines

The workup for hypoglycemia should begin with immediate measurement of blood glucose to confirm the diagnosis, followed by a thorough history and physical examination, and laboratory testing during a hypoglycemic episode using Whipple's triad: documented low blood glucose (<70 mg/dL), symptoms of hypoglycemia, and resolution of symptoms with glucose administration. According to the most recent guidelines 1, the initial step in managing hypoglycemia is to confirm the diagnosis by measuring blood glucose levels. If the glucose test is not immediately available, treatments for hypoglycemia should be administered, as recommended in the 2019 standards of medical care for type 2 diabetes in China 1.

Initial Assessment and Treatment

The treatment plan should include monitoring the blood glucose every 15 minutes, and administering 15-20 g of glucose-containing food (glucose preferred) orally for conscious patients, or 20-40 ml of 50% glucose solution intravenously, or glucagon 0.5-1.0 mg intramuscularly for patients with cognitive impairment 1. The 2023 standards of care in diabetes recommend that glucose (approximately 15–20 g) is the preferred treatment for the conscious individual with blood glucose <70 mg/dL (3.9 mmol/L) 1.

Laboratory Tests and Diagnostic Approach

Initial laboratory tests should include a comprehensive metabolic panel, insulin level, C-peptide, proinsulin, beta-hydroxybutyrate, sulfonylurea screen, and antibodies against insulin. A 72-hour supervised fast is the gold standard diagnostic test for suspected hypoglycemia, during which blood samples are collected when glucose levels drop below 60 mg/dL or when symptoms occur. Imaging studies such as CT, MRI, or endoscopic ultrasound may be necessary if insulinoma is suspected. For reactive hypoglycemia, a mixed-meal tolerance test is more appropriate than a glucose tolerance test, as suggested in the example answer.

Additional Workup and Medication Review

Additional workup should include assessment of adrenal and pituitary function if adrenal insufficiency or hypopituitarism is suspected, particularly in patients with recurrent unexplained hypoglycemia. Careful medication review is essential as many drugs including insulin, sulfonylureas, quinine, salicylates, and beta-blockers can cause hypoglycemia, as mentioned in the example answer. The diagnostic approach should be tailored based on whether hypoglycemia occurs in the fasting or postprandial state, as this distinction helps narrow down potential causes. The 2021 standards of medical care in diabetes also recommend reviewing the occurrence and risk for hypoglycemia at every encounter and investigating as indicated 1.

Key Recommendations

• Occurrence and risk for hypoglycemia should be reviewed at every encounter and investigated as indicated 1.
• Glucose (approximately 15–20 g) is the preferred treatment for the conscious individual with blood glucose <70 mg/dL (3.9 mmol/L) 1.
• Glucagon should be prescribed for all individuals at increased risk of level 2 or 3 hypoglycemia 1.

From the FDA Drug Label

GLUCAGON for injection, for subcutaneous, intramuscular or intravenous use Initial U. S. Approval: 1960 RECENT MAJOR CHANGES INDICATIONS AND USAGE Glucagon for Injection is an antihypoglycemic agent and a gastrointestinal motility inhibitor indicated: for the treatment of severe hypoglycemia in pediatric and adult patients with diabetes

The FDA drug label does not answer the question.

From the Research

Workup for Hypoglycemia

The workup for hypoglycemia involves several steps to determine the underlying cause of the condition.

• Evaluation and management of hypoglycemia should only be done in patients who meet Whipple's triad: symptoms, signs, or both consistent with hypoglycemia, a low plasma glucose concentration, and resolution of those symptoms or signs after the plasma glucose concentration is raised 2.
• In patients with hypoglycemia without diabetes mellitus, the following strategy is recommended:
  • Pursue clinical clues to potential hypoglycemic etiologies, such as drugs, critical illnesses, hormone deficiencies, and nonislet cell tumors 2.
  • In the absence of these causes, the differential diagnosis narrows to accidental, surreptitious, or malicious hypoglycemia or endogenous hyperinsulinism 2.
• In patients suspected of having endogenous hyperinsulinism, the following measurements should be taken during an episode of hypoglycemia:
  • Plasma glucose
  • Insulin
  • C-peptide
  • Proinsulin
  • Beta-hydroxybutyrate
  • Circulating oral hypoglycemic agents
  • Insulin antibodies 2.

Hypoglycemia in Diabetes

Hypoglycemia is a common complication in patients with diabetes, mainly in those treated with insulin, sulfonylurea, or glinide 3.

• Impairments in counterregulatory responses and hypoglycemia unawareness constitute the main risk factors for severe hypoglycemia 3.
• Episodes of hypoglycemia are associated with physical and psychological morbidity, and the fear of hypoglycemia can impede a patient's ability to reach good glycemic control 3.
• To prevent hypoglycemia, patient education regarding risk factors, warning signs, and treatment of hypoglycemia at an early stage is crucial, along with setting personalized goals for glycemic control 3.

Treatment and Prevention of Hypoglycemia

Several medications can be used to treat and prevent hypoglycemia, including:

• Meglitinides, which are effective in controlling postprandial hyperglycemia with minimal risk of hypoglycemia 4.
• Sulfonylureas and glinides, which stimulate the release of insulin from pancreatic cells and have extrapanular hypoglycemic effects, such as reducing the clearance rate of insulin in the liver and enhancing the sensitivity of peripheral tissues to insulin 5.
• Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1RA), which have been shown to confer a lower risk of hypoglycemia compared to sulfonylureas and similar risk compared to dipeptidyl peptidase-4 inhibitors (DPP4i) 6.