Hypoglycemia, or low plasma glucose level can result in sympathetic nervous system stimulation and central nervous system dysfunction. In patients with diabetes who take insulin or antihyperglycemic treatment, hypoglycemia is common and is defined as a glucose level of ≤ 70 mg/dL. In contrast, hypoglycemia unrelated to exogenous insulin therapy is an uncommon clinical syndrome caused by various disorders or medications. Diagnosis requires blood tests done at the time of symptoms or during a 72-hour fast. Treatment of hypoglycemia is provision of glucose combined with treatment of the underlying disorder.
Most commonly, symptomatic hypoglycemia is a complication of medication treatment of diabetes mellitus
Symptomatic hypoglycemia unrelated to treatment of diabetes mellitus is relatively rare, in part because the body has extensive counter-regulatory mechanisms to compensate for low blood glucose levels. Glucagon and epinephrine levels surge in response to acute hypoglycemia and appear to be the first line of defense. Cortisol and growth hormone levels also increase acutely and are important in the recovery from prolonged hypoglycemia. The threshold for release of these hormones is usually above that for hypoglycemic symptoms. Hereditary or congenital syndromes that cause hypoglycemia in infancy and childhood are not discussed here.
Etiology of Hypoglycemia
Hypoglycemia in patients without diabetes is rare. It can occur in the fasting or in the postprandial state (1 to 3 hours after eating) and can be classified as insulin-mediated or non-insulin–mediated.
A helpful practical classification is based on clinical status: whether hypoglycemia occurs in patients who appear healthy or ill.
In well-appearing adults without diabetes, the differential diagnosis includes insulin-mediated and non-insulin–mediated disorders.
Insulin-mediated causes include
Exogenous insulin
Insulin
Insulinoma
Post-bariatric surgery hypoglycemia
Non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS)
Insulin autoimmune hypoglycemia
Insulinoma is a rare neuroendocrine tumor of insulin-producing beta cells. It typically causes fasting hypoglycemia although postprandial hypoglycemia can also occur.
Hypoglycemia that occurs after bariatric surgery is a hyperinsulinemic hypoglycemia that develops sometimes years after bariatric (especially roux-en-Y gastric bypass) surgery. It is rare, but the true frequency is not known, and pathology specimens show nesidioblastosis (hypertrophy of pancreatic beta cells). Hypoglycemia is typically postprandial.
NIPHS is a rare condition in which patients have hyperinsulinemic hypoglycemia with negative localizing imaging studies and no history of bariatric surgery. Hypoglycemia is usually postprandial, and surgical specimens demonstrate features of nesidioblastosis.
Insulin autoimmune hypoglycemia is a condition that most often occurs in patients with other autoimmune conditions such as systemic lupus erythematosus. Autoantibodies bind to insulin or insulin receptors on cell membranes in target tissues (eg, the liver, muscles, adipose tissue) and dissociate. Circulating insulin becomes available to bind to the receptor upon dissociation from the antibodies, causing hypoglycemia. Treatment is corticosteroids or immunosuppressants.
Non-insulin–mediated causes include
Use of medications other than insulin
In ill patients, the differential diagnosis also includes insulin-mediated and non-insulin–mediated disorders.
Insulin-mediated disorders include
Exogenous insulin
Insulin secretagogue (sulfonylurea) use
Non-insulin–mediated disorders include
Undernutrition or starvation
Heart failure, if advanced
Non-islet cell tumor hypoglycemia
Use of medications other than insulin or a sulfonylurea
In patients who are ill and hospitalized, spontaneous hypoglycemia that is not caused by medications. It can occur when poor nutrition is combined with advanced organ failure (especially liver, kidney, or heart failure) and/or sepsis. In these patients, hypoglycemia portends a poor prognosis.
Non-islet cell tumor hypoglycemia is a rare condition caused by production of large amounts of aberrant forms of insulin-like growth factor 2 (IGF-2) by a tumor. The aberrant form of IGF-2 binds to the insulin receptor and causes hypoglycemia. By the time hypoglycemia develops, the tumor is usually advanced.
Pseudohypoglycemia occurs when processing of blood specimens in untreated test tubes is delayed and cells, such as red blood cells and leukocytes (especially if increased, as in leukemia or polycythemia), consume glucose. Poor circulation to the digits can also cause erroneously low fingerstick glucose measurements.
Factitious hypoglycemia is true hypoglycemia induced by nontherapeutic administration of sulfonylureas or insulin.
Symptoms and Signs of Hypoglycemia
The surge in autonomic activity in response to low plasma glucose causes sweating, nausea, warmth, anxiety, tremulousness, palpitations, and possibly hunger and paresthesias. Insufficient glucose supply to the brain causes headache, blurred or double vision, confusion, agitation, seizures, and coma. In older patients, hypoglycemia may cause stroke-like symptoms of aphasia or hemiparesis and is more likely to precipitate stroke, myocardial infarction, and sudden death.
Patients with diabetes mellitus, especially patients with type 1 diabetes, type 2 diabetes of long duration or patients with frequent hypoglycemia may be unaware of hypoglycemic episodes because they no longer experience autonomic symptoms (hypoglycemia unawareness) (1).
In research studies under controlled conditions, autonomic symptoms begin at or beneath a plasma glucose level of about 60 mg/dL (3.3 mmol/L), whereas central nervous system symptoms occur at or below a glucose level of about 50 mg/dL (2.8 mmol/L) (2). People with glucose levels at these thresholds may have no symptoms, while people with symptoms suggestive of hypoglycemia can have normal glucose concentrations.
Symptoms and signs references
1. Martín-Timón I, Del Cañizo-Gómez FJ. Mechanisms of hypoglycemia unawareness and implications in diabetic patients. World J Diabetes 2015;6(7):912-926. doi:10.4239/wjd.v6.i7.912
2. Cryer PE. Symptoms of hypoglycemia, thresholds for their occurrence, and hypoglycemia unawareness. Endocrinol Metab Clin North Am 1999;28(3):495-vi. doi:10.1016/s0889-8529(05)70084-0
Diagnosis of Hypoglycemia
Measurement of blood glucose level
The severity of hypoglycemia in patients with diabetes is based on blood glucose levels and need for assistance
Level 1 (mild) hypoglycemia: blood glucose < 70 mg/dL (< 3.9 mmol/L) but ≥ 54 mg/dL (≥ 3 mmol/L)
Level 2 (moderate) hypoglycemia: blood glucose < 54 mg/dL (< 3 mmol/L)
Level 3 (severe) hypoglycemia: hypoglycemia requiring assistance from another person due to change in mental or physical status
In patients not receiving diabetes treatment, diagnosis of a hypoglycemic disorder requires confirmation of Whipple's triad or confirmation of low blood glucose during a fast. Whipple's triad includes
Symptoms of hypoglycemia
Low plasma glucose level (< 55 mg/dL [3.05 mmol/L]) that occurs at the time symptoms occur
If a clinician is present when symptoms occur, blood should be sent for glucose testing in a tube containing a glycolytic inhibitor. If glucose is normal, hypoglycemia is ruled out and other causes of symptoms should be considered. If glucose is abnormally low, and no cause can be identified from history (eg, medications, adrenal insufficiency, severe undernutrition, organ failure ,sepsis), serum insulin, insulin antibodies, and sulfonylurea levels should be checked. C-peptide and proinsulin measured from the same tube can distinguish insulin-mediated from non–insulin-mediated and factitious from physiologic hypoglycemia and can obviate the need for further testing.
In practice, however, it is unusual that clinicians are present when patients experience symptoms suggestive of hypoglycemia. Home glucose meters are unreliable for quantifying hypoglycemia, and there are no clear glycosylated hemoglobin (HbA1C) thresholds that distinguish long-term hypoglycemia from normoglycemia. Continuous glucose monitors are also less accurate in the hypoglycemic range. So the need for more extensive diagnostic testing is based on the probability that an underlying disorder that could cause hypoglycemia exists given a patient’s clinical appearance and coexisting illnesses.
To differentiate between insulin-mediated and non-insulin–mediated hypoglycemia and to determine the etiology of hypoglycemia, a 48- or 72-hour fast may be required. A prolonged fast can trigger hypoglycemia in a person who has a history of fasting hypoglycemia.
A 72-hour fast done in a controlled setting is the standard for diagnosis. However, in almost all patients with a hypoglycemic disorder, a 48-hour fast is adequate to detect hypoglycemia, and a full 72-hour fast may not be necessary. Patients drink only noncaloric, noncaffeinated beverages. Plasma glucose is measured at baseline, whenever symptoms occur, and every 4 to 6 hours or every 1 to 2 hours if glucose falls below 70 mg/dL (3.9 mmol/L).
Serum insulin, C-peptide, and proinsulin should be measured when a simultaneous plasma glucose measurement is < 55 mg/dL (< 3.05 mmol/L). These measurements help to distinguish endogenous from exogenous (factitious) hypoglycemia. The fast is terminated at 72 hours if the patient has experienced no symptoms and glucose remains normal, sooner if glucose decreases to ≤ 45 mg/dL (≤ 2.5 mmol/L) in the presence of symptoms of hypoglycemia.
End-of-fast measurements include beta-hydroxybutyrate (which should be low if the cause is an insulinoma), serum sulfonylurea to detect medication-induced hypoglycemia, and plasma glucose after IV glucagon injection to detect an increase characteristic of insulinoma. Sensitivity, specificity, and predictive values for detecting hypoglycemia by this protocol have not been reported.
If symptomatic hypoglycemia has not occurred by 48 to 72 hours, the patient should exercise vigorously for about 30 minutes. If hypoglycemia still does not occur, insulinoma is essentially excluded and further testing is generally not indicated.
There is no definitive lower limit of glucose that unequivocally defines pathologic hypoglycemia during a monitored fast. Females tend to have lower fasting glucose levels than males and may have glucose levels as low as 50 mg/dL (2.8 mmol/L) without symptoms.
In patients with a history of a postprandial pattern of hypoglycemia, such as in a patient with hypoglycemia after bariatric surgery, a prolonged fast may not trigger hypoglycemia. In those individuals, hypoglycemia should be assessed after a mixed meal or after eating a meal that is similar to a meal that previously triggered hypoglycemic symptoms (often high in refined carbohydrates and fat). Fingerstick glucose measurements and blood tests for glucose, insulin and C-peptide can be checked at 30-minute intervals after the meal for up to 4 hours.
Treatment of Hypoglycemia
Treatment in patients taking antihyperglycemic medications
In patients treated with glucose-lowering medications (insulin or sulfonylureas), a plasma glucose level < 70 mg/dL (< 3.9 mmol/L) is considered hypoglycemia and should be treated to avoid further decreases in blood glucose and consequences of hypoglycemia.
Patients who are able to eat or drink can drink juices, sucrose water, or glucose solutions; eat candy or other foods; or chew on glucose tablets when symptoms occur.
The rule of 15s should be followed for treatment of hypoglycemia. Typically, 15 g of glucose or sucrose should be ingested. Patients should check their glucose levels 15 minutes after glucose or sucrose ingestion and ingest an additional 15 g if their glucose level is not > 80 mg/dL (> 4.4 mmol/L). After glucose levels improve to > 80 mg/dL, a snack containing complex carbohydrates and protein may be ingested to prevent the glucose level from dropping again.
< 25 kg body weight) or 1 mg (≥≥ ≥ 6 years.
glucagon has little effect on plasma glucose in patients who have been fasting or who are hypoglycemic for long periods.
Hyperglycemia may follow hypoglycemia either because too much sugar was ingested or because hypoglycemia caused a surge in counter-regulatory hormones (glucagon, epinephrine, cortisol, growth hormone).
Treatment in patients not taking antihyperglycemic medications
Hypoglycemia in patients not taking insulin
insulininsulin secretion may be needed.
Drugs that cause hypoglycemia, including alcohol, must be stopped.
Treatment of hereditary and endocrine disorders, liver failure, renal failure, heart failure, and sepsis are described elsewhere.
Key Points
In patients taking medications for treatment of diabetes, hypoglycemia is defined as a plasma glucose level < 70 mg/dL (< 3.9 mmol/L).
Most hypoglycemia is caused by medications used to treat diabetes mellitus (including surreptitious use); insulin-secreting tumors are rare causes.
To diagnose a hypoglycemic disorder not due to diabetes treatment requires a low plasma glucose level (< 55 mg/dL [< 3 mmol/L]) plus
If the etiology of hypoglycemia is unclear, do a 48- or 72-hour fast with measurement of plasma glucose at regular intervals and whenever symptoms occur.
Measure serum insulin, C-peptide, and proinsulin at times of hypoglycemia to distinguish endogenous from exogenous (factitious) hypoglycemia.
Treat patients with hypoglycemia due to insulin
In patients with hypoglycemia not due to insulin
