Glucose Counterregulation

Insulin regulates glycemia through modulation of hepatic glucose production in the postabsorptive state and glucose utilization in the postprandial state, and it is the only hormone able to physiologically reduce glycemic level. In catabolic states (fasting), insulin concentration falls and the levels of counterregulatory hormones rise; in fact, hypoglycemia is capable of inducing the release of counterregulatory hormones, including glucagon, catecholamines (epinephrine and norepinephrine – released both from adrenal medulla and the sympathetic neurons), cortisol and GH. The glucagon secretory response to hypoglycemia is largely CNS-independent whereas catecholamine, cortisol and GH responses are prevailingly CNS-dependent. Glucagon acts within minutes and is the primary hormone of glucose maintenance (by stimulating hepatic glucose production through increase in glycogenolysis and gluconeogenesis). Catecholamines also act swiftly, stimulating glucose production

and limiting glucose utilization in humans through both b 2 - and a 2 -adrenergic mechanisms. Cortisol and GH, on the contrary, act within several hours with a delayed glucoregulatory action (antagonizing insulin action, mobilizing substrate and activating hepatic gluconeogenesis through the induction of the relative gluconeogenic enzymes). All these hormones have a synergic action on the induction of hyperglycemia and on the prevention and correction of hypoglycemia. Glucagon plays the most important counterregulatory action whereas catecholamines play a minor role, that becomes important when there is glucagon deficiency, as it often happens early during the course of diabetes mellitus. Catecholamines are the warning system in hypoglycemia through the symptoms and signs of adrenergic overactivity. Cortisol and GH play no role in short-term hypoglycemia but have a substantial role in the recovery from long-term hypoglycemia. The relevance of other hormones or neurotransmit- ters in preventing and correcting hypoglycemia has been debated but it is not definitely established. In type 1 diabetic patients, counterregulation is often altered and, in some patients it may be very deficient. It has been reported that almost all diabetic patients show a deficient glucagon secretory response to hypoglycemia, perhaps as a result of the long-term hyperglycemia (glucose toxicity) or the loss of the regulating effect of insulin on glucagon secretion. In the presence of a defective glucagon secretion, type 1 diabetic patients during hypoglycemic episodes became dependent upon catecholamines to correct low glycemic level, i.e. epinephrine response compensates for deficient glucagon response. Some diabetic patients with long-standing disease have also a deficient catecholamine response to hypoglycemia and this combined disorder impairs glucose counterregulation and represents a high risk of iatrogenic hypoglycemia in these subjects. GH and cortisol responses to hypoglycemia

Table 1. Causes of hypoglycemia A. Fasting hypoglycemia

B. Postprandial or reactive hypoglycemia 1. Reduced glucose production

Alimentary hypoglycemia (gastrectomy, Liver or renal insufficiency

gastrojejunostomy, pyloroplasty Deficiency of counterregulatory hormones

or vagotomy) Childhood ketotic hypoglycemia

Hyperthyroidism (substrate or enzyme deficiency)

Obesity with hyperinsulinism Drugs (alcohol, salicylates, b-blockers)

Early stage of type 2 diabetes, prediabetes 2. Increased glucose utilization

or IGT Idiopathic reactive hypoglycemia

b -Cell tumor or insulinoma Functional hypersecretion of b-cells

Idiopathic postprandial syndrome or Autoantibodies to insulin

pseudohypoglycemia Autoantibodies to insulin receptors

Inherited disorders of carbohydrate Sepsis

metabolism in children Intake of leucine in leucine-sensitive

Insulin or insulin-releasing drugs (sulfonylureas, pentamidine, quinine)

children

Newborn hypoglycemia (first hours of life, if mother is diabetic) Extrapancreatic non-b-cell tumors Childhood nonketotic hypoglycemia

(deficit of carnitine or of enzymes of FFA utilization

Exhaustive exercise 3. Factitious or artifactual

Factitious hypoglycemia (surreptitious insulin or sulfonylurea administration) Artifactual hypoglycemia (in hemolytic anemia or in leukemia or in hyperlipemia)

in type 1 diabetes are usually not reduced, but deficiency of their secretion may occur.

Classification of Hypoglycemia (see table 1) Postabsorptive or Fasting Hypoglycemia

Fasting hypoglycemia may result from impaired hepatic glucose production (involving glycogenolysis or gluconeogenesis) or enhanced peripheral glucose utilization. It can be induced by several causes, listed below.

Reduced Glucose Production. This occurs in the following instances: (1) Chronic failure of critical organs such as liver diseases (hepatitis,

cirrhosis or hepatoma, severe heart failure with hepatic congestion) which cirrhosis or hepatoma, severe heart failure with hepatic congestion) which

(2) Deficiency of counterregulatory hormones (glucagon and epinephrine, cortisol and GH) that impairs gluconeogenesis, as occurs in hypopituitarism, in adrenal insufficiency and rarely in glucagon deficiency.

(3) Ketotic hypoglycemia of infancy and childhood, linked to substrate deficiency or due to defects in one or more of the gluconeogenic or glycogenolytic enzymes, sometimes associated to lactic acidosis.

(4) Drugs such as alcohol (which inhibits hepatic gluconeogenesis) especially when associated to fasting, salicylates (a common cause of hypoglycemia in infants) which would increase peripheral glucose utilization and reduce hepatic gluconeogenesis, b-blockers (which reduce the glycogenolytic response to epinephrine).

Increased Glucose Utilization. Several causes may lead to increased glucose utilization: (1) Endogenous hyperinsulinism (that causes glucose overutilization) produced by: (a) b-cell tumor or insulinoma (a rare, most often small and single, benign tumor occurring in 1/250,000 adult individuals) or islet cell hyperplasia (nesidioblastosis), a rare syndrome in adult subjects; (b) functional hypersecretion of b-cells; (c) autoimmune hypoglycemia (autoantibodies against insulin, with inappropriate release of antibody-bound insulin in the circulation), common in Japan; (d) rare instances of acanthosis nigricans (insulin receptor autoantibodies, which most often cause insulin resistant diabetes, can in some patients act as insulin-like factors); (e) ectopic insulin secretion.

(2) Sepsis (cytokines associated to endotoxinemia increase insulin release). (3) Insulin or drugs that stimulate insulin release, such as sulfonylurea compounds in diabetic patients, pentamidine (which exerts a toxic effect with

b -cell cytolysis), and quinine (which induces massive insulin release, although this effect is not well demonstrated).

(4) Hypoglycemia of infants born from diabetic mothers, occurring during the first hours of life (provoked by fetal hyperinsulinemia linked to hyperplasia of b-cells induced by maternal hyperglycemia and hyperglucagonemia).

(5) Non-b-cell or extrapancreatic large tumors of mesenchymal (50%) or epithelial origin (5–10%) or hepatomas (25%) or other carcinomas (5–10%) or some malignant hematologic diseases (5–10%), in which hypoglycemia is induced by production of insulin-like growth factors such as IGF-2, that interacts with insulin receptors (and may suppress endogenous insulin secretion), or by overutilization of glucose (by the tumoral tissue).

(6) Nonketotic hypoglycemia due to systemic carnitine deficiency or en- zymatic defects which limit the utilization of FFA or ketones (which entails enhanced glucose oxidation for energetic purposes).

(7) Prolonged and exhaustive exercise, especially in untrained persons (increased glucose utilization). Factitious or Artifactual Hypoglycemia. Two conditions should be distinguished: (1) Factitious hypoglycemia from deliberate and surreptitious insulin or sulfonylurea assumption (especially in medical people or family members of diabetic patients with psychiatric disturbances).

(2) Artifactual hypoglycemia as it may occur in hemolytic anemia or in leukemia and leukemic reactions (due to overutilization of glucose in the test tube by young erythrocytes or leukemic leukocytes) or in the presence of marked hyperlipemia (which may cause a 15% – or more – underestimation of glucose concentration).

Postprandial or Reactive Hypoglycemia This form of hypoglycemia occurs within 6 h after a meal, and includes

several forms, listed below: (1) Alimentary hypoglycemia (or alimentary hyperinsulinism) caused by gastrectomy, gastrojejunostomy, pyloroplasty or vagotomy, involving about 5–10% of operated patients and developing 30–120 min after ingestion of carbohydrate-containing meals (due to rapid gastric emptying and glucose absorption which stimulate excessive insulin release, and perhaps also to hypersecretion of enterohormones such as enteroglucagon, secretin, GIP, etc.); it may perhaps also occur in patients with hyperthyroidism, or in obesity with hyperinsulinism.

(2) Early stage of type 2 diabetes or prediabetes or IGT (deficient early- phase insulin release leads to higher glucose elevation with subsequent excessive stimulation of insulin secretion). However, it should be mentioned that the relationship between the early stage of type 2 diabetes or prediabetes or IGT and postprandial hypoglycemia is not well established.

(3) Idiopathic reactive hypoglycemia or true hypoglycemia (with lowered glucose levels), a rare syndrome characterized by adrenergic symptoms without symptoms of severe neuroglycopenia, probably linked to an increased insulin response or a higher affinity of insulin receptors or to a subtle dysfunction of gastrointestinal tract.

(4) Idiopathic postprandial syndrome or pseudohypoglycemia (with a near-normal glycemic value), characterized by adrenergic symptoms and light symptoms of neuroglycopenia, which develop regularly and repetitively during the patient’s life (causes are unknown and might include enhanced

Table 2. Clinical signs and symptoms of hypoglycemia Sympathetic/parasympathetic activation

Neuroglycopenia A. Clinical signs and symptoms of adrenergic

Clinical signs and symptoms of activation

neuroglycopenia Pallor, tremor, palpitations and anxiety

Headache, dizziness, fatigue, irritability or Acute sensation of hunger

apathy and lethargy Occasionally hypothermia, vomiting,

Frequent yawning and perioral numbness fever, moderate tachycardia, crises of

Disturbed vision and diplopia systolic hypertension

Paresthesias and motor dysfunction B. Clinical signs and symptoms of

Cognitive impairment, mental confusion parasympathetic activation

and inebriation Nausea and eructation

Personality changes, psychotic behavior Occasionally transient hemiparesis or

Cold sweating focal neurologic deficits Mitigation of expected tachycardia or true

bradycardia Convulsions (in children simulating true Mild hypotension

crises of epilepsy) Semi-coma, coma and even death

epinephrine release in some subjects, with stress or anxiety contributing in many subjects).

(5) Inherited disorders of carbohydrate metabolism in children (hereditary fructose intolerance from deficiency of fructose-1-P aldolase or galactosemia from deficiency of galactose-1-P uridyltransferase).

(6) Intake of leucine in leucine-sensitive children (due to increased insulin secretion).

Clinical Signs and Symptoms of Hypoglycemia (see table 2) The clinical manifestations of hypoglycemia are generally nonspecific and

varying, not only from patient to patient but also in the same subject from episode to episode. Their development can depend not only on the glycemic value but also on the rate of the fall in blood glucose. Manifestations can be distinguished into adrenergic (due to sympathetic activation) and neuroglycopenic (due to neuronal alterations secondary to glucose deprivation). When glucose drops rapidly, adrenergic symptoms are most evident while when glucose drops gradu- ally neuroglycopenic symptoms may dominate the clinical picture. During a hypoglycemic episode, the response of counterregulatory hormones begins before the symptomatic glucose threshold is reached.

Neuropenic symptoms may not occur even in the presence of glucose level as low as 25–30 mg/dl (1.4–1.7 mmol/l) due to the ability of normal persons to increase brain blood flow and therefore glucose delivery. This adaptation may be prevented in patients with cerebral atherosclerosis and inelastic vessels, in whom neuropenic symptoms may appear at relatively high glucose levels.

It should be pointed out that severe hypoglycemic reactions may occur even in the presence of near-normal or even high glycemic values (pseudohypoglycemia), especially in diabetic patients; on the other hand, there may be no clinical hypoglycemic reactions with very low concentrations of plasma glucose (25–30 mg% or 1.4–1.7 mmol/l). The most important factors probably are the rate of fall in glycemia and the fact that the glucose plasma level may not strictly reflect the glucose concentration in brain tissue. A glycemic range (55–70 mg% or 3.00–3.88 mmol/l) seems to exist in which dysfunction from neuroglycopenia and activation of counterregulatory hormones occur but symptoms are not yet manifest; therefore, the value of 3.88 mmol/l may be a cut-off value of hypoglycemia, useful and safe to consider in the treatment of diabetes mellitus.

Adrenergic Symptoms and Signs These are due to catecholamine hypersecretion that develops in response

to a blood glucose level =53 mg% or 2.95 mmol/l, and include pallor, anxiety, tremor, palpitations, tachycardia (occasionally with crises of systolic hypertension) and acute sensation of hunger. It is noteworthy that symptoms and signs induced by parasympathetic response can also occur during hypoglycemia, producing nausea, eructation, cold sweating, mitigation of expected tachycardia or true bradycardia, and mild hypotension.

Neuroglycopenic Symptoms and Signs These are due to dysfunction of CNS that develops in response to hypogly-

cemia =45 mg% or 2.50 mmol/l, and include headache, dizziness, fatigue, irritability or apathy, lethargy, frequent yawning, cognitive impairment, mental confusion, inebriation, personality changes and psychotic behavior, disturbed vision and diplopia, perioral numbness, paresthesias, motor dysfunction, convulsions, occasionally transient hemiparesis or focal neurologic deficits (especially in elderly diabetic patients), semi-coma, complete loss of consciousness until hypoglycemic coma and even death. The different neurologic manifestations have been correlated with specific sites of the brain involved in different degrees of hypoglycemia. Clinical hypoglycemic symptoms and signs sometimes suggest true mental disorders, accounting for the frequent reported mistake or delay in diagnosis.

In children, adrenergic manifestations are near-absent and neuroglycopenic symptoms can predominate with seizures simulating true crises of epilepsy. A failure to develop several adrenergic symptoms before the development of neuroglycopenic symptoms (hypoglycemia unawareness) is observed in 50% of patients with long-standing diabetes (due to the reduced response of sympathetic system to hypoglycemia, secondary to the autonomic neuropathy). However, glucose threshold may also be lowered by hypoglycemia itself which may cause subsequent hypoglycemia unawareness, as it may be observed in patients with insulinoma.

Glucose Counterregulation