Hypoglycemia is a condition characterized by a decrease in plasma glucose concentration below 2.8 mmol/L. The causes include failure to follow insulin therapy regimens in diabetes (skipping meals, physical exertion, alcohol consumption), various endocrine and metabolic disorders, and oncological diseases. The clinical symptom complex consists of autonomic and neuropsychiatric disorders of varying severity. The diagnosis is based on the detection of low plasma glucose levels either on an empty stomach or after eating. To relieve hypoglycemia, rapidly absorbable oral carbohydrates, glucose administration, or glucagon injection are used.

Hypoglycemia as a clinical syndrome

Hypoglycemia is not an independent disease but rather a clinical-laboratory syndrome. In diabetes, this condition occurs in approximately 40–60% of patients.

Among individuals with type 1 diabetes, the percentage of hypoglycemia cases is somewhat higher. However, due to the greater prevalence of type 2 diabetes, the majority of hypoglycemic episodes occur in patients with this form of the disease.

In diabetic patients with prolonged hyperglycemia (decompensation), symptoms may begin to appear even at glucose levels of 5–6 mmol/L. In children, especially newborns, the developing nervous system consumes more glucose, making them more sensitive to hypoglycemia.

What are the causes?

Hypoglycemia can have multiple etiological factors. In healthy individuals, a drop in blood glucose below normal levels can occur due to pregnancy, intense physical activity, or prolonged fasting, though these cases are rare. More commonly, hypoglycemia develops due to various diseases and pathological conditions, such as:

1. Errors in Insulin Therapy for Diabetes
   • The most common cause of hypoglycemia.
   • Occurs when a patient skips meals, consumes alcohol, or engages in physical activity while regularly injecting insulin.
   • Sometimes caused by incorrect injection techniques, accidental or intentional insulin overdose.
2. Hyperinsulinism (Excess Insulin Production)
   • The excessive secretion of insulin by pancreatic beta cells occurs in conditions such as:
     • Insulinoma (a tumor producing insulin).
     • Langerhans islet hyperplasia (nesidioblastosis).
   • Some malignant tumors (carcinomas, mesotheliomas) also stimulate excess production of insulin or insulin-like growth factors.
   • Hypoglycemia can result from autoantibodies against insulin, which bind to insulin receptors (Hirata disease).
3. Endocrine Disorders
   • Deficiency of counter-regulatory hormones (which oppose insulin) can cause hypoglycemia. These include:
     • Cortisol (adrenal insufficiency).
     • Thyroxine (hypothyroidism).
     • Growth hormone (pituitary dwarfism).
4. Medication-Induced Hypoglycemia
   • Apart from insulin, other drugs can lower glucose levels, primarily those used to treat type 2 diabetes:
     • Sulfonylureas (e.g., Glibenclamide).
     • Glinides (e.g., Repaglinide), which stimulate insulin release from the pancreas.
5. Gastrointestinal Surgeries
   • Operations on digestive organs, such as gastric or small intestine resection, can lead to dumping syndrome.
   • In this condition, undigested food enters the intestine too quickly, causing inadequate carbohydrate breakdown and absorption.
6. Hereditary Metabolic Disorders
   • Severe genetic metabolic diseases that affect carbohydrate metabolism, including:
     • Glycogen storage diseases (Glycogenoses).
     • Galactosemia.
     • Fructose intolerance (Fructosemia).
   • These disorders involve enzyme deficiencies, leading to impaired glucose production from carbohydrates or difficulty releasing glucose from glycogen stores, ultimately causing hypoglycemia.

Predisposing factors for the development of hypoglycemia include chronic diseases that slow the clearance of glucose-lowering drugs regulating blood glucose levels – renal and hepatic insufficiency. The hypoglycemic effect of sulfonylurea derivatives is enhanced when taken simultaneously with sulfonamides, salicylates, and synthetic antimalarial drugs. Delayed gastric emptying (diabetic gastroparesis) also contributes to hypoglycemia.

Pathogenesis

The central nervous system primarily relies on glucose as its main source of energy. Therefore, the CNS is highly sensitive to hypoglycemia. Initially, as a compensatory reaction, counter-regulatory hormones, including catecholamines (adrenaline, noradrenaline), are released into the bloodstream, causing autonomic symptoms. If glucose levels remain low, neuroglycopenia occurs.

Brain cells (mainly the cerebral cortex and diencephalic structures) begin to experience energy starvation, leading to inhibition of all metabolic processes, redox reactions, etc.

Persistent hypoglycemia affects the medulla oblongata and upper sections of the spinal cord, resulting in suppression of reflexes, increased seizure readiness of the brain, impaired consciousness, and coma.

Pathomorphological changes include edema and necrosis of certain areas of the brain.

Classification

Detection of hypoglycemia in blood tests does not always reflect reality. False or pseudohypoglycemia can occur in leukocytosis and erythrocytosis.

Transient hypoglycemia in newborns born to mothers with diabetes is classified separately. By severity, hypoglycemia is divided into mild, moderate, and severe; by course, it is classified as acute, subacute, or chronic. Based on etiopathogenesis, the following types of hypoglycemia are distinguished:

• Fasting (spontaneous). Develops with excessive secretion of insulin, insulin-like factors, and diseases associated with a deficiency of counter-regulatory hormones.
• Reactive (postprandial). Occurs 2–4 hours after eating. Causes include the early stage of diabetes, hereditary metabolic disorders, post-resection syndromes, and autoimmune insulin syndrome.
• Induced. Develops in diabetes and is triggered by alcohol consumption or medication use.

Symptoms of hypoglycemia

The presence and severity of symptoms may not correlate with blood glucose levels.

• The first symptoms are caused by the activation of the sympathoadrenal system (release of adrenaline, noradrenaline). A sudden and intense feeling of hunger, muscle tremors, and sweating occur.
• The cardiovascular system responds with an increased heart rate, elevated blood pressure, and angina-like chest pain.
• Neuropsychiatric symptoms also appear, including anxiety, motor agitation, a depressed mood, or, conversely, a feeling of euphoria.
• Paresthesias (tingling sensations in the lips, tongue, and fingertips) are characteristic. This is known as the adrenergic or autonomic syndrome. If hypoglycemia persists, neuroglycopenia develops.
• Concentration deteriorates, motor coordination is impaired (ataxia), and speech becomes slurred and indistinct.
• The patient becomes drowsy, responds poorly to external stimuli, and may experience photopsia (flashes of lightning before the eyes) or visual hallucinations.
• Tonic-clonic seizures, resembling epilepsy, indicate severe nervous system suppression and a critically serious condition. The onset of seizures precedes hypoglycemic coma.
• In individuals with chronic hypoglycemia (such as in insulinoma), the only clinical manifestation may be periodic headaches that quickly resolve after consuming carbohydrate-rich food.
• A decrease in nighttime glucose levels may cause some patients to experience restless sleep or nightmares. There are also atypical hypoglycemic symptoms, including nausea, vomiting, and bradycardia.

Complications

Severe hypoglycemia is characterized by a wide range of adverse consequences, often with a high fatality rate. The most common complications include cardiovascular issues (hypertensive crisis, myocardial infarction, stroke) due to a large release of catecholamines into the bloodstream. Hypoglycemia can also cause life-threatening cardiac rhythm disturbances, such as paroxysmal ventricular tachycardia, which results from a prolonged QT interval. Complications of profound hypoglycemia include brain edema, coma, respiratory arrest, and cardiac arrest.

Diagnosis

Patients with hypoglycemia are managed by endocrinologists. At the initial consultation, the doctor asks about medications the patient takes and any past surgeries.

During the general examination, attention is given to skin moisture, pupil dilation (mydriasis), suppression of physiological reflexes (tendon, skin), and the appearance of pathological reflexes (Babinski reflex).

For organic hyperinsulinism (such as insulinoma or nesidioblastosis), Whipple’s triad is characteristic: spontaneous hypoglycemic episodes, blood glucose levels below 2.8 mmol/L during an episode, and rapid symptom resolution after glucose administration or carbohydrate intake. Identifying the cause of hypoglycemia is often the most challenging task. Additional examinations include:

• Laboratory tests.

Blood tests measure C-peptide and the glucose-to-insulin ratio. In diabetes, a glucose tolerance test and glycated hemoglobin analysis are conducted. The presence of anti-insulin antibodies and insulin receptor antibodies is checked. The concentration of counter-regulatory hormones (thyroid-stimulating hormone, free thyroxine, growth hormone) is analyzed, along with an ACTH stimulation test. The activity of carbohydrate metabolism enzymes (glucose-6-phosphatase, phosphofructokinase, glycogen synthase) is also assessed.

• Provocative tests.

Diagnosing insulinomas is extremely difficult, so various provocative tests are frequently performed. The most informative is the 72-hour fasting test. Stimulation tests are also conducted to assess C-peptide suppression after the administration of glucagon, leucine, or tolbutamide.

• ECG.

Electrocardiography may reveal sinus tachycardia, atrial and ventricular extrasystoles, and prolonged QT intervals. Paroxysmal ventricular tachycardia may also be recorded. In cases of myocardial ischemia due to excess catecholamines, ST-segment depression and a negative T wave may be observed.

• Imaging of insulinomas.

Insulinomas can be visualized using ultrasound and CT of the abdominal organs in approximately 50% of cases. More sensitive techniques include multislice CT and intraoperative ultrasound. A highly effective diagnostic method is selective pancreatic arteriography with calcium gluconate injection, followed by blood sampling to measure insulin and glucose levels.

Hypoglycemia should be differentiated from alcohol intoxication, epilepsy, and autonomic crisis (panic attacks). It is also necessary to rule out acute cerebrovascular accident (stroke). An agitated mental state and pronounced motor restlessness should be distinguished from mental disorders (hysteria, psychosis). In diabetes, based on clinical signs, it can be quite difficult to differentiate hypoglycemic coma from hyperglycemic coma.

Treatment

Conservative therapy

For the treatment of mild hypoglycemia, it is sufficient to consume easily digestible carbohydrates—fruit juice, sweet tea, or a few pieces of refined sugar. In cases of moderate to severe hypoglycemia, hospitalization in the endocrinology department is necessary, and if the patient has impaired consciousness or is in a coma, admission to the intensive care and resuscitation unit is required, where the following measures are carried out:

• Stopping hypoglycemia.

An intravenous glucose solution is administered. If the patient does not regain consciousness, continuous intravenous infusion is maintained. Intramuscular administration of glucagon is also effective (except in cases of hypoglycemia caused by alcohol or sulfonylurea derivatives). Ascorbic acid is used to improve glucose utilization by neurons. To prevent cerebral edema in severe cases, magnesium sulfate, dexamethasone, and diuretics (mannitol or furosemide) are used.

• Treatment of the underlying disease.

If hypoglycemia is caused by a deficiency of counter-regulatory hormones, hormone replacement therapy is administered (hydrocortisone, fludrocortisone, L-thyroxine). In autoimmune insulin syndrome, glucocorticosteroids, immunosuppressants, and plasmapheresis sessions are used. In the treatment of malignant insulinomas, if surgery is contraindicated, the drug streptozocin is prescribed, which causes the destruction of pancreatic beta cells. Prokinetics (itopride) are used to improve gastric motility and evacuation function in diabetes.

Surgical treatment

The most effective method for treating insulinomas and nesidioblastosis is surgical intervention. In 90% of cases, surgery leads to a complete cure of the disease.

The preferred method is enucleation of the tumor. In some cases, resection of the head, body, or tail of the pancreas is performed. As part of preoperative preparation, a powerful insulin secretion inhibitor, diazoxide, is prescribed.

Within 72 hours after surgery, hyperglycemia may develop, which is managed by administering short-acting insulin. After the removal of extrapulmonary tumors, blood glucose levels quickly normalize.

Prognosis and prevention

Despite a significant number of complications, in most cases, hypoglycemia has a mild to moderate course. In diabetes, it accounts for only 3-4% of mortality cases. The main cause of fatal outcomes is cardiovascular catastrophes (heart attack, stroke).

To prevent hypoglycemia in diabetes, the patient must strictly follow the dosage, technique, and frequency of insulin administration, not skip meals, and avoid alcohol consumption.

During insulin therapy, it is necessary to regularly monitor blood glucose levels using a glucometer and always have fast-absorbing carbohydrates on hand for self-treatment of hypoglycemia. Proper selection of antidiabetic drug doses is also required, taking into account the patient’s liver and kidney function as well as possible drug interactions.

Patients with metabolic disorders (glycogen storage diseases, galactosemia) are recommended to follow frequent, small meals with a high carbohydrate content.

Sources:

1. American Diabetes Association – Hypoglycemia, (https://www.diabetes.org/healthy-living/medication-treatments/blood-glucose-testing-and-control/hypoglycemia)

2. Mayo Clinic – Hypoglycemia, (https://www.mayoclinic.org/diseases-conditions/hypoglycemia/symptoms-causes/syc-20373685)

3. National Institute of Diabetes and Digestive and Kidney Diseases – Low Blood Glucose (Hypoglycemia), (https://www.niddk.nih.gov/health-information/diabetes/overview/preventing-problems/low-blood-glucose-hypoglycemia)

4. Endocrine Society – Hypoglycemia, (https://www.endocrine.org/patient-engagement/endocrine-library/hypoglycemia)

5. World Health Organization – Diabetes, (https://www.who.int/health-topics/diabetes)

6. Journal of Clinical Endocrinology & Metabolism, (https://academic.oup.com/jcem)

7. UpToDate – Hypoglycemia in adults without diabetes mellitus, (https://www.uptodate.com/contents/hypoglycemia-in-adults-without-diabetes-mellitus-clinical-manifestations-diagnosis-and-causes)