Julio Libman, Astrid L. Libman

There is no general consensus regarding the biochemical definition of hypoglycemia. The problem arises from studies of glycemic values ​​in normal individuals during fasting and in the course of glucose tolerance tests. The results of these evaluations indicate that during a 72-hour fast, circulating glucose levels can decrease dramatically, mainly in young women, without the presence of concomitant symptoms. In this situation, blood glucose figures as low as 25 to 30 mg% have been found. Investigations carried out during oral glucid tolerance tests show that blood glucose levels lower than 55 mg% occur in 25% of normal asymptomatic people, decreasing to less than 10% if a limit figure of 50 mg% is considered. Studies of insulin-induced hypoglycemia in normal persons indicate that the greatest release of counter-regulating hormones (somatotrophin, cortisol, glucagon, and catecholamines) usually occurs with plasma glucose levels less than 50 mg%. In contrast, similar tests in diabetics with persistent hyperglycemia reveal that rapid decreases in blood glucose can result in the release of these hormones at considerably higher blood glucose levels than in normal individuals. Taken together, these studies provide a rationale for defining fasting or postprandial hypoglycemia as the existence of glucose levels equal to or less than 50mg%. glucagon and catecholamines) is usually produced with plasma glucose levels less than 50 mg%. In contrast, similar tests in diabetics with persistent hyperglycemia reveal that rapid decreases in blood glucose can result in the release of these hormones at considerably higher blood glucose levels than in normal individuals. Taken together, these studies provide a rationale for defining fasting or postprandial hypoglycemia as the existence of glucose levels equal to or less than 50mg%. glucagon and catecholamines) is usually produced with plasma glucose levels less than 50 mg%. In contrast, similar tests in diabetics with persistent hyperglycemia reveal that rapid decreases in blood glucose can result in the release of these hormones at considerably higher blood glucose levels than in normal individuals. Taken together, these studies provide a rationale for defining fasting or postprandial hypoglycemia as the existence of glucose levels equal to or less than 50mg%.


In normal persons, the plasma glucose level is closely controlled, and rarely varies by more than 40-50 mg% within 24 hours. This aspect of glucose homeostasis is the consequence of the interaction of a number of hormones, enzymes and substrates in different organs, mainly the liver and muscle. An imbalance between the use of glucose and its intake and / or its hepatic production can cause hyperglycemia, as in diabetes mellitus, or hypoglycemia.

Hypoglycemias can be grouped in various ways according to alterations in glucose utilization and production, hormonal changes, or enzyme and / or substrate deficiencies. A useful classification is one that combines physiological mechanisms with the presenting clinical picture. Based on this point of view, hypoglycemia can be classified into three fundamental categories: a) fasting, b) postprandial, and c) induced.

Fasting hypoglycemia

They are produced solely or mainly when food is not ingested. Since glucose uptake by the brain persists during prolonged fasting, in order for blood glucose to remain above 50 mg%, it is essential that the glucose production mechanisms are intact. Liver glycogen stores, which reach approximately 70 grams after fasting from one day to the next, are depleted within 24 to 48 hours of not eating, which forces a progressive increase in gluconeogenesis; This requires for its development a hormonal environment characterized by a decrease in insulin and an increase in somatotropin, cortisol, glucagon and adrenaline, intact hepatic glucogenolytic and gluconeogenic enzymes, and adequate mobilization of the precursor gluconeogenic substrate (alanine from proteins) and energy-producing substrate (free fatty acids from adipose tissue). Thus, fasting hypoglycemia can be caused by an excess of insulin or insulin-like substances, by deficiency of counter-regulation hormones, by congenital or acquired liver disease, and by substrate deficiency.

Insulinoma . Insulinomas are tumors of the beta cells of the pancreas that produce insulin autonomously, excessively, or inadequately in relation to circulating glucose levels. Hypoglycemia is the result of the excessive use of glucose together with a decrease in glycogenolysis and gluconeogenesis. In infants and children, hyperinsulinemic hypoglycemia can occur due to nesidioblastosis, an increase in the mass of islet cells, with continuous formation of these cells from the duct epithelium, in the absence of an identifiable adenoma.

Extrapancreatic tumors . Certain tumors that originate outside the pancreas, mainly large retroperitoneal mesenchymal tumors, can cause hypoglycemia due to production in some cases of insulin-like substances, by accelerated use of glucose, or by inhibition of glycogenolysis or hepatic gluconeogenesis.

Counter-regulatory hormone deficiency. The maintenance of glucose homeostasis requires, in addition to an adequate insulin secretion to plasma glucose levels, the normal production of somatotropin, glucagon, cortisol and catecholamines, all of them hyperglycemic hormones through various mechanisms: increase in 1st resistance peripheral to insulin, glycogenolysis and gluconeogenesis, and inhibition of insulin secretion, mediated by islet cell adrenergic receptors. Clinical hypoglycemia can be seen in conditions characterized by deficiency of counterregulatory hormones, such as hypopituitarism, adrenal cortical insufficiency, or isolated somatotropin or ACTH deficiency. Under these circumstances plasma insulin levels are reduced.

Liver diseases . The main source of glucose in a fasting person is the liver. In severe liver disease with destruction of 80% of the liver parenchyma, such as in the terminal phase of liver necrosis, fulminant hepatitis, metastatic infiltration or the action of toxins, hypoglycemia may occur due to decreased gluconeogenesis, increased demand for glucose and probable loss of insulin-inactivating hepatic mechanisms.

Hypoglycemia can also occur from inborn errors of metabolism characterized by deficiencies of hepatic glycogenolytic or gluconeogenic enzymes. In von Gierke disease due to accumulation of glycogen, type I, excessive accumulation of hepatic glycogen and hypoglycemia occur due to a deficiency of glucose-6-phosphatase. Fructose-1,6-diphosphatase deficiency produces fasting hypoglycemia due to alterations in gluconeogenesis.

Hypoglycemia due to substrate deficiency . Fasting glucose production requires the provision of precursor substrate, primarily alanine. During normal pregnancy, a physiological reduction in alanine and an accentuation of fasting hypoglycemia are observed. Alanine deficiency has been implicated in the pathogenesis of ketotic hypoglycemia of infancy and childhood.

Autoimmune hypoglycemia . Some patients have been described with fasting and / or postprandial hypoglycemic episodes that are accompanied by the presence of circulating anti-insulin antibodies, however, they have never received this hormone.

Hypoglycemia is attributable to the sudden release of insulin from antibodies, with an increase in the concentration of free, biologically active insulin. Anti-insulin antibodies are also observed in patients, generally paramedical personnel or with personality disorders, who develop hypoglycemia due to the surreptitious administration of insulin.

Hypoglycemia has been observed in some people with anti-insulin receptor antibodies. Anti-receptor antibodies can produce insulin resistance in certain patients by inhibiting the binding of insulin to its receptor, and in others they can produce hypoglycemia by mimicking the effect of insulin, due to the existence of different populations of insulin-like anti-receptor antibodies that recognize different antigenic sites.

Postprandial hypoglycemia

There are a considerable number of syndromes in which hypoglycemia occurs in response to a stimulus, usually the ingestion of food, such as carbohydrates or proteins.

Food hypoglycemia . Following a partial gastrectomy or gastrojejunostomy, patients present with a marked peak of hyperglycemia after ingestion of food; This determines a rapid secretory insulin response by a normal pancreas and is the cause of the hypoglycemic condition that appears later.

Hypoglycemia from carbohydrate intolerance . The onset of hypoglycaemia, generally mild, three to four hours after ingestion of glucose or simple carbohydrates in patients with carbohydrate intolerance or early adult diabetes, non-insulin dependent, reveals the loss of initial phase of insulin secretion, with the production of early hyperglycemia, which causes a delayed, but exaggerated, response of the second phase of insulin secretion.

Spontaneous reactive hypoglycemia . It constitutes a picture that is probably overly dignified. Its pathogenesis is unclear. It consists of the hypersecretion of insulin with the appearance of symptoms and signs of hypoglycemia two to four hours after the ingestion of carbohydrates. It is not possible to demonstrate any alteration suggestive of diabetes or carbohydrate intolerance.

Fructose intolerance . Inborn errors in fructose metabolism can lead to hypoglycemia when fructose is ingested. In hereditary fructosemia, fructose-1-phosphate-aldolase deficiency causes accumulation of fructose-1-phosphate. This compound appears to interfere with the action of the enzyme fructose-1,6-diphosphate aldolase, which is a necessary step in gluconeogenesis and glycolysis.

In patients with fructose-1,6-diphosphatase deficiency, hypoglycemia occurs in the fasting state or after ingestion of foods containing fructose.

Induced hypoglycemia

Insulin and oral hypoglycemic drugs from the group of sulfonylureas . The administration of insulin, used in the treatment of diabetes, is the most common cause of hypoglycemia. In patients receiving insulin, hypoglycemia can be caused by decreased food intake, intense exercise not accompanied by dose reduction or carbohydrate supplementation, renal failure with less insulin inactivation, and visceral neuropathy at the level of the apparatus. digestive system with delayed gastric evacuation. Obviously, hypoglycemia can occur in patients treated with insulin without any apparent cause, probably due to spontaneous variations in the absorption of insulin, or due to an error in the dose administered.

Oral hypoglycemic agents from the group of sulfonylureas can produce hypoglycemia with intense exercise, lack of food intake, or when there is liver or kidney failure that prevents their metabolization and / or excretion.

Alcohol . Prolonged ingestion of alcohol can cause hypoglycemia due to inhibition of gluconeogenesis.

Symptoms and signs

The symptoms and signs of hypoglycemia correspond to two groups of manifestations, those produced by alterations in the function of the central nervous system due to neuroglycopenia, and those due to the secretion of catecholamines, as an integral part of the homeostatic mechanisms aimed at returning blood glucose values. to physiological limits.

The former include reduced intellectual capacity, headaches, confusion, amnesia, irritability, abnormal behavior, seizures, and coma. Among the latter, profuse perspiration, trembling, anxiety, tachycardia with palpitations, asthenia and feeling of hunger.

Patients with insulinoma frequently have rapid weight gain, due to the lipogenic action of insulin and the fact that they soon learn that they can alleviate its clinical manifestations by increasing food intake.

Confirmation of hypoglycemia requires the existence of Whipple's triad: symptoms of hypoglycemia with low plasma glucose levels that remit with glucose administration.

Study methodology

The assessment of probable fasting hypoglycemia is different from that of postprandial or reactive hypoglycemia.

Fasting hypoglycemia . In patients suspected of having fasting hypoglycemia, the first step in the evaluation is to measure fasting blood glucose and insulinemia. An insulin / glucose ratio greater than 0.3 is suspicious for insulinoma.

Other conditions associated with an elevated insulin / glucose ratio include the surreptitious administration of exogenous insulin, the use of oral hypoglycemic agents from the group of sulfonylureas, and the rare syndrome of the existence of anti-insulin autoantibodies without prior administration of the hormone.

The proportion of proinsulin in normal individuals is less than 22% of total insulinemia. In most patients with insulinoma, the proportion of proinsulin is greater than 25% of what is measured as total insulinemia.

The quantification of peptide C distinguishes endogenous hyperinsulinemia from surreptitious administration of exogenous insulin. Peptide C is secreted in equimolar concentrations with insulin, being elevated in insulinoma and in the ingestion of sulfonylureas. The quantification of sulfonylureas or their metabolites in urine allows detecting the ingestion of oral hypoglycemic agents.

For the diagnosis of insulinoma, the best test is prolonged fasting combined with 15-minute periods of exercise, with periodic tests of blood glucose and insulin levels. 85% of patients will develop hypoglycemia with hyperinsulinemia within 24 hours of fasting.

Once the biochemical diagnosis of insulinoma has been made, it is important to locate the tumor by one or more of the following methods: pancreatic arteriography, ultrasound, computed tomography and magnetic resonance imaging. In some centers, transhepatic percutaneous catheterization of the portal and splenic veins has been used with measurement of insulinemia at different levels to determine the location of the insulinoma.

When the insulin / glucose ratio is less than 0.3, the existence of other causes of hypoglycemia, other than insulinoma, should be considered. These etiologies include pituitary or adrenal hypofunction, severe liver disease, alcohol ingestion, or the existence of an extrapancreatic tumor. Appropriate evaluation includes studies of hypophysoadrenal functional reserve, liver function, and careful evaluation of the chest and abdomen.

Postprandial hypoglycemia . Since postprandial hypoglycemia is not apparent during fasting, a careful history of dietary habits often reveals that hypoglycemic symptoms are associated with a diet rich in carbohydrates. This leads to the use of the oral glucid tolerance test for diagnostic purposes. Symptoms can appear between one and five hours after a meal, so the test should be extended for five hours when evaluating reactive hypoglycemia.

75 grams of glucose are administered in 350 ml of water and blood is drawn to measure blood glucose at 30-minute intervals. Simultaneous measurement of insulinemia adds nothing to the diagnostic utility of the test. In postgastrectomy food-reactive hypoglycemia, a high blood glucose peak occurs at 30 or 60 minutes, with values ​​of 300 or more mg%, followed by a nadir in blood glucose between 90 and 180 minutes, accompanied by symptoms of hypoglycemia.

In the cases of reactive hypoglycemia that accompanies early diabetes, the first part of the curve is pathological with blood glucose levels greater than 200 and 140 mg% at 60 and 120 minutes, respectively, and apparent hypoglycemia between 180 and 300 minutes.

In spontaneous reactive hypoglycemia, the oral glucose tolerance test is normal during the first 180 minutes, while glucose concentrations decrease dramatically between 240 and 300 minutes.