Hypoglycemia

Hypoglycemia is characterized by a reduction in plasma glucose concentration to a level that may induce symptoms or signs such as altered mental status and/or sympathetic nervous system stimulation. This condition typically arises from abnormalities in the mechanisms involved in glucose homeostasis. The most common cause of hypoglycemia in patients with diabetes is injecting a shot of insulin and skipping a meal or overdosing insulin. ^{[1, 2]}

The image below depicts a diagnostic algorithm for hypoglycemia.

The glucose level at which an individual becomes symptomatic is highly variable, although a plasma glucose level of less than 50 mg/dL has generally been considered the threshold.

However, the 2025 Standards of Care in Diabetes, from the American Diabetes Association (ADA), lists glucose levels in hypoglycemia as follows ^[3] :

• Level 1 - Glucose level between less than 70 mg/dL (<3.9 mmol/L) and at or above 54 mg/dL (≥3.0 mmol/L)
• Level 2 - Glucose level less than 54 mg/dL (<3.0 mmol/L)
• Level 3 - “A severe event characterized by altered mental and/or physical status requiring assistance for treatment of hypoglycemia, irrespective of glucose level”

According to the ADA, a 70 mg/dL blood glucose concentration "has been recognized as a threshold for adrenergic responses to falling glucose in people without diabetes." ^[3]

Hypoglycemia typically arises from abnormalities in the mechanisms involved in glucose homeostasis.

To diagnose hypoglycemia, the Whipple triad is characteristically present. This triad includes the documentation of low blood sugar, the presence of symptoms, and the reversal of these symptoms when the blood sugar level is restored to normal.

See also Pediatric Hypoglycemia, Neonatal Hypoglycemia, and Congenital Hyperinsulinism.

Hypoglycemic symptoms are related to sympathetic activation and brain dysfunction secondary to decreased levels of glucose. Stimulation of the sympathoadrenal nervous system leads to sweating, palpitations, tremulousness, anxiety, and hunger. Reduction in cerebral glucose availability (ie, neuroglycopenia) can manifest as confusion, difficulty with concentration, irritability, hallucinations, focal impairments (eg, hemiplegia), and, eventually, coma and death.

The adrenergic symptoms often precede the neuroglycopenic symptoms and, thus, provide an early warning system for the patient. Studies have shown that the primary stimulus for the release of catecholamines is the absolute level of plasma glucose; the rate of decrease of glucose is less important. Previous blood sugar levels can influence an individual's response to a particular level of blood sugar. However, it is important to note that a patient with repeated hypoglycemia can have almost no symptoms (hypoglycemic unawareness). The threshold at which a patient feels the hypoglycemic symptoms decreases with repeated episodes of hypoglycemia.

A study by Zhong et al indicated that in patients with type 2 diabetes mellitus, a proximal hemoglobin A1c (HbA1c) level above or below the reference level of 7.0% increases the risk of a first incidence of hypoglycemia requiring hospitalization (HH). The investigators found that when the proximal HbA1c level ranges between 4.0% and 6.5%, every 0.5% level increase reduces the first HH risk, while for patients with a proximal HbA1c level of 8.0-11.5%, the risk of first HH rises with each 0.5% increase in HbA1c. The investigators also found that current sulfonylurea users in the study did not exhibit this U-shaped phenomenon but that current insulin users did. ^[4]

Causes of hypoglycemia are varied, but it is seen most often in patients with diabetes. Hypoglycemia may result from medication changes or overdoses, infection, diet changes, metabolic changes over time, or activity changes; however, no acute cause may be found. Other causes include alimentary problems, idiopathic causes, fasting, insulinoma, endocrine problems, extrapancreatic causes, hepatic disease, and bariatric surgery, along with additional miscellaneous etiologies.

Clinical practice guidelines released in 2024 by the Italian Society of Pediatric Endocrinology and Diabetology, on the prevention and treatment of hypoglycemia in children and adolescents with diabetes, state that impaired glucose awareness can be an issue in children with diabetes and can significantly increase their chance for developing severe hypoglycemia. ^[5]

In a multicenter, retrospective cohort study, Riegger et al reported that independent risk factors for intraoperative hypoglycemia in children include age under 5 years, weight for age below the fifth percentile, American Society of Anesthesiologists status of III or above, the presence of a gastric or jejunal tube, poor feeding, and abdominal surgery. Eighty percent of hypoglycemia cases were in children under age 5 years and in youngsters weighing under 20 kg. ^[6]

A study by van Furth et al indicated that both dumping syndrome and post–bariatric surgery hypoglycemia can be attributed to a common etiology, with glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) being key to the development of each. The investigators point out that L-cells, which secrete GLP-1 and PYY, are affected by bariatric surgery, with, for example, an increase in L-cells in the perianastomotic jejunum occurring after Roux-en-Y gastric bypass. ^[7]

Fasting hypoglycemia

Nesidioblastosis is a rare cause of fasting hypoglycemia in infants and an extremely rare cause in adults. This condition is characterized by a diffuse budding of insulin-secreting cells from pancreatic duct epithelium and pancreatic microadenomas of such cells. Several cases of nesidioblastosis have been reported after gastric bypass surgery.

Causes of fasting hypoglycemia usually diagnosed in infancy or childhood include inherited liver enzyme deficiencies that restrict hepatic glucose release (deficiencies of glucose-6-phosphatase, fructose-1,6-diphosphatase, phosphorylase, pyruvate carboxylase, phosphoenolpyruvate carboxykinase, or glycogen synthetase).

Inherited defects in fatty acid oxidation, including those resulting from systemic carnitine deficiency and inherited defects in ketogenesis (3-hydroxy-3-methylglutaryl-CoA lyase deficiency), cause fasting hypoglycemia by restricting the extent to which nonneural tissues can derive their energy from plasma free fatty acids (FFA) and ketones during fasting or exercise. This results in an abnormally high rate of glucose uptake by nonneural tissues under these conditions.

Drugs

Ethanol (including propranolol plus ethanol), haloperidol, pentamidine, quinine, salicylates, and sulfonamides ("sulfa drugs") have been associated with hypoglycemia. Other drugs that may be related to this condition include oral hypoglycemics, phenylbutazone, insulin, bishydroxycoumarin, p-aminobenzoic acid, propoxyphene, stanozolol, hypoglycin, carbamate insecticide, disopyramide, isoniazid, methanol, methotrexate, tricyclic antidepressants, cytotoxic agents, organophosphates, didanosine, chlorpromazine, fluoxetine, sertraline, fenfluramine, trimethoprim, 6-mercaptopurine, thiazide diuretics, thioglycolate, tremetol, ritodrine, disodium ethylenediaminetetraacetic acid (EDTA), clofibrate, angiotensin converting enzyme (ACE) inhibitors, and lithium.

A study by Fournier and colleagues indicates that treatment for pain with the opioid analgesic tramadol increases a patient’s risk of being hospitalized for hypoglycemia. Information from the United Kingdom Clinical Practice Research Datalink and the Hospital Episode Statistics database was analyzed for 28,110 patients who were newly prescribed tramadol and 305,924 individuals who were newly prescribed codeine, all for noncancer pain, with 11,019 controls also included in the study. Using case-control, cohort, and case-crossover analysis, the investigators found that tramadol increased the risk of hospitalization for hypoglycemia by more than three-fold, with the risk particularly elevated in the first 30 days of treatment. The actual risk was small, however, occurring in about 7 patients per 10,000 annually. ^{[8, 9]}

A study by Eriksson et al indicated that in patients with type 2 diabetes undergoing second-line treatment, the combination of metformin and sulfonylurea carries a greater risk for severe hypoglycemia, cardiovascular disease, and all-cause mortality than does the combination of metformin and dipeptidyl peptidase-4 inhibitor (DPP4i). ^[10]

Similarly, a study by Gautier et al found that patients with type 2 diabetes treated with metformin plus insulin secretagogues (such as sulfonylurea or glinide) were more likely to experience hypoglycemia than were those treated with metformin plus DPP4i while starting insulin. Both groups achieved similar glycemic control. ^[11]

Surreptitious sulfonylurea use/abuse

Factitious, or self-induced, hypoglycemia can occur through use/abuse of the antidiabetic sulfonylureas by healthcare workers or by relatives who care for family members with diabetes. ^[12]

Exogenous insulin

Surreptitious use of insulin may be seen, typically among those likely to have access to insulin. Measurement of insulin level along with C-peptide is very crucial in making this diagnosis.

Endogenous insulin or insulin-receptor–mediated hypoglycemia

Sources of endogenous insulin include insulin-producing tumors of the pancreas and non–beta-cell tumors.

Insulin-producing tumors of the pancreas

Islet cell adenoma or carcinoma (insulinoma) is an uncommon and usually curable cause of fasting hypoglycemia and is most often diagnosed in adults. It may occur as an isolated abnormality or as a component of the multiple endocrine neoplasia type I (MEN I) syndrome.

Carcinomas account for only 10% of insulin-secreting islet cell tumors. Hypoglycemia in patients with islet cell adenomas results from uncontrolled insulin secretion, which may be clinically determined during fasting and exercise. Approximately 60% of patients with an insulinoma are female. Insulinomas are uncommon in persons younger than 20 years and are rare in those younger than 5 years. The median age at diagnosis is about 50 years, except in patients with MEN syndrome, in which the median age is in the mid third decade of life. Ten percent of patients with an insulinoma are older than 70 years.

Non–beta-cell tumors

Hypoglycemia may also be caused by large non–insulin-secreting tumors, most commonly retroperitoneal or mediastinal malignant mesenchymal tumors. The tumor secretes abnormal insulinlike growth factor (large IGF-II), which does not bind to its plasma binding proteins. This increase in free IGF-II exerts hypoglycemia through the IGF-I or the insulin receptors. The hypoglycemia is corrected when the tumor is completely or partially removed and usually recurs when the tumor regrows.

Reactive hypoglycemia

Reactive hypoglycemia can be idiopathic, due to alimentary problems, or a result of congenital enzyme deficiencies.

The form of reactive hypoglycemia known as alimentary hypoglycemia occurs in patients who have had previous upper gastrointestinal (GI) surgical procedures (gastrectomy, gastrojejunostomy, vagotomy, pyloroplasty) and allows rapid glucose entry and absorption in the intestine, provoking excessive insulin response to a meal. This may occur within 1-3 hours after a meal. Very rare cases of idiopathic alimentary hypoglycemia occur in patients who have not had GI operations.

Congenital enzyme deficiencies include hereditary fructose intolerance, galactosemia, and leucine sensitivity of childhood. In hereditary fructose intolerance and galactosemia, an inherited deficiency of a hepatic enzyme causes acute inhibition of hepatic glucose output when fructose or galactose is ingested. Leucine provokes an exaggerated insulin secretory response to a meal and reactive hypoglycemia in patients with leucine sensitivity of childhood.

Other causes of hypoglycemia include the following, singly or in combination (eg, chronic renal failure and sulfonylurea ingestion):

• Autoimmune hypoglycemia - Insulin antibodies and insulin receptor antibodies

• Hormonal deficiencies - Hypoadrenalism (cortisol), hypopituitarism (growth hormone) (in children), glucagon deficiency (rare), and epinephrine deficiency (very rare)

• Critical illnesses - Cardiac, hepatic, and renal diseases; sepsis with multiorgan failure

• Exercise (in patients with diabetes treated with diabetes medications)

• Pregnancy

• Renal glycosuria

• Ketotic hypoglycemia of childhood

• Adrenal insufficiency

• Hypopituitarism

• Starvation

• Artifact

According to the above-mentioned Italian guidelines on the prevention and treatment of hypoglycemia in children and adolescents with diabetes, aerobic exercise carries a higher risk of hypoglycemia than does anaerobic exercise. The guidelines state that the “depletion of glucose stores, impaired counter-regulatory hormone responses during sleep, and increased insulin sensitivity due to nighttime fasting” are the primary causes of nighttime hypoglycemia following exercise. ^[5]

The incidence of hypoglycemia in a population is difficult to ascertain. Patients and physicians frequently attribute symptoms (eg, anxiety, irritability, hunger) to hypoglycemia without documenting the presence of low blood sugar. The true prevalence of hypoglycemia, with blood sugar levels below 50 mg/dL, is generally 5-10% of people presenting with symptoms suggestive of hypoglycemia.

A study by Heidenreich et al of more than 500,000 patients with type 2 diabetes who were hospitalized in the Veterans Affairs health care system found that the rate of patients who had an episode of hypoglycemia fell by 17% between 2016 and 2022 (from 7.4% to 6.3%). ^[13]

A Brazilian study, by Lamounier et al, found that during a 4-week prospective evaluation period, at least one hypoglycemic event occurred in 91.7% of study patients with type 1 diabetes and in 61.8% of those with type 2 diabetes. This included nocturnal hypoglycemia in 54.0% and 27.4% of patients, respectively; asymptomatic hypoglycemia in 20.6% and 10.6% of patients, respectively; and severe hypoglycemic events in 20.0% and 10.3% of patients, respectively. ^[14]

Hypoglycemia is a known complication of several medications, and the incidence is difficult to determine with any certainty. In addition, this condition is a known complication of many therapies for diabetes; therefore, the incidence of hypoglycemia in a population of people with diabetes is very different from that in a population of people without diabetes. ^{[15, 16, 17, 18, 19, 20]}

Insulin-producing tumors are a rare but important treatable cause of hypoglycemia, with an annual US incidence of 1-2 cases per million persons per year.

Reactive hypoglycemia is reported most frequently by women aged 25-35 years, and as stated earlier, approximately 60% of patients with an insulinoma are female. The median age at diagnosis of an insulinoma is about 50 years, but cases have been reported in patients ranging from birth to age 80 years. ^[21]

In the above-mentioned study by Heidenreich and colleagues, of hospitalized patients with type 2 diabetes, the rate of individuals experiencing an episode of hypoglycemia was found to be significantly higher in the youngest and oldest patients. The investigators also determined that the risk of hypoglycemia was higher in Black and Hispanic patients than in non-Hispanic White persons. Moreover, “women had borderline less hypoglycemia than men.” ^[13]

The prognosis of hypoglycemia depends on the cause of this condition, its severity, and its duration. If the cause of fasting hypoglycemia is identified and treated early, the prognosis is excellent.

If the cause of hypoglycemia is not curable, such as an inoperable malignant tumor, the long-term prognosis is poor. However, note that these tumors may progress rather slowly. Severe and prolonged hypoglycemia can be life threatening and may be associated with increased mortality in patients with diabetes.

If the patient has reactive hypoglycemia, symptoms often spontaneously improve over time, and the long-term prognosis is very good. Reactive hypoglycemia is often treated successfully with dietary changes and is associated with minimal morbidity. Mortality is not observed. Untreated reactive hypoglycemia may cause significant discomfort to the patient, but long-term sequelae are not likely.

A study by Boucai et al found that drug-associated hypoglycemia was not associated with increased mortality risk among patients admitted to general wards. This suggests that hypoglycemia may be a marker of disease burden and not a direct cause of death. ^[22]

Patients with diabetes who have episodes of hypoglycemia need education in nutrition, in checking glucose levels at home, and in early signs and symptoms of hypoglycemia. Recognition of early symptoms is paramount for self-treatment.