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Mechanism

Normal glucose metabolism

• Plasma glucose levels are maintained within a narrow range, roughly 70–110 mg/dL (3.9–6.1 mmol/L) in the fasting state with transient higher excursions after a meal, despite wide variation of food intake and activity level.
• Plasma glucose levels are maintained by:
  • Glucose and its precursors in the diet
  • Glycogenolysis
    • Hepatic glycogen stores are sufficient to maintain plasma glucose levels during a fast for approximately 8 hours.
  • Gluconeogenesis
    • Begins as glycogen stores are depleted
    • Occurs mainly in the liver but also in the kidneys
• Glucose levels are regulated by a network of hormones, neural pathways, and metabolic signals (see Figure 1).
  • Insulin
    • In the fasting state, insulin is suppressed, allowing glucose generation through glycogenolysis in the liver and by enhancing gluconeogenesis.
    • In the fed state, insulin release from the pancreatic β cells reverses this process.
      • Glycogenolysis and gluconeogenesis are inhibited, thereby reducing hepatic and renal glucose output.
  • Other hormones, such as glucagon, epinephrine, growth hormone, and cortisol, play less important roles in the control of glucose flux during normal physiologic circumstances.
• Characteristic sequence of counterregulatory hormone responses to hypoglycemia (see Table 339-2)
  • Insulin suppression
  • Glucagon secretion
    • Promotes glycogenolysis and gluconeogenesis
  • Epinephrine secretion
    • Stimulates glycogenolysis and gluconeogenesis
    • Limits glucose utilization by insulin-sensitive tissues
  • Growth hormone and cortisol secretion (prolonged hypoglycemia)
    • Reduce glucose utilization and support its production
• The glucose thresholds at which various counterregulatory hormones respond are altered in:
  • Persons with poorly controlled diabetes
  • Recurrent hypoglycemia, which may occur in persons with diabetes or an insulinoma

Causes of hypoglycemia

Drugs (accidental or factitious use)

• Insulin and insulin secretagogues (e.g., sulfonylureas, especially chlorpropamide, repaglinide, nateglinide)
  • Suppress glucose production
  • Stimulate glucose utilization
• Other oral hypoglycemic agents (biguanides, thiazolidinediones)
  • Can augment hypoglycemia in those using sulfonylureas or insulin
  • Do not stimulate insulin secretion on their own
  • Do not cause hypoglycemia on their own
• Ethanol
  • Blocks gluconeogenesis but not glycogenolysis
  • Hypoglycemia occurs after a prolonged ethanol binge during which the person consumes little food, thereby causing glycogen depletion.
• Salicylates in large doses can cause hypoglycemia by inhibiting glucose production.
• Sulfonamides rarely cause hypoglycemia by stimulating insulin secretion.
• Pentamidine
  • Toxic to pancreatic β cells
  • Causes insulin release initially, leading to hypoglycemia in ~10%
  • Predisposes to development of diabetes mellitus later
• Quinine
  • Stimulates insulin secretion
• Quinolones
  • Moxifloxacin
  • Levofloxacin

Critical illnesses

• Hepatic failure or destruction (e.g., severe toxic hepatitis)
  • Impaired gluconeogenesis
• Renal failure
  • Reduced insulin clearance and reduced mobilization of gluconeogenic precursors
• Cardiac failure
  • Mechanism leading to hypoglycemia unknown; probably involves hepatic congestion and hypoxia
• Sepsis-multifactorial etiologies of hypoglycemia
  • Impaired gluconeogenesis (possibly from hepatic and renal hypoperfusion)
  • Increased glucose utilization (induced by cytokines in muscle, liver, spleen, and small intestine)
  • Inadequate nutrition
• Prolonged starvation
  • Loss of whole-body fat stores and depletion of gluconeogenic precursors

Endocrine deficiencies

• Hypoglycemia rare in adults
• Untreated primary (Addison’s disease) or secondary adrenocortical failure
  • Low levels of gluconeogenic precursors and substrate-limited gluconeogenesis, in the setting of glycogen depletion, causes impaired ability to tolerate fasting.
• Hypopituitarism
  • Combination of secondary adrenal failure (ACTH deficiency) and growth hormone deficiency, with impaired gluconeogenesis and enhanced insulin sensitivity due to growth hormone deficiency.
  • Two of the long-term counterregulatory hormones (cortisol and growth hormone) are deficient.

Insulinoma

• Pancreatic β-cell tumor
• Nesidioblastosis with islet hyperplasia and increased β-cell mass
  • Congenital
  • Acquired in some patients after GI bypass surgery for obesity

Non–β-cell tumors (rare)

• Some large mesenchymal or epithelial tumors can produce an incompletely processed form of IGF-II.
  • This precursor form of IGF-II does not bind normally to serum IGF-binding proteins and circulates as a highly bioactive free or loosely bound peptide.
  • Hypoglycemia results from the action of this IGF-II precursor on insulin (and/or IGF-I) receptors.
  • Propensity to hypoglycemia is further enhanced by suppression of growth hormone by this IGF-II precursor.
• Tumors
  • Fibrosarcoma, mesothelioma, rhabdomyosarcoma, liposarcoma, other sarcomas
  • Hepatoma, adrenocortical tumors, carcinoid
  • Leukemia, lymphoma, melanoma, teratoma

Other causes of endogenous hyperinsulinism (rare)

• Noninsulinoma pancreatogenous hypoglycemia syndrome (nesidioblastosis)
• Autoimmune hypoglycemia (autoantibodies to insulin, insulin receptor, β cell)
• Ectopic insulin secretion (extremely rare)

Disorders of infancy or childhood (rare)

• Transient intolerance of fasting
• Infants of diabetic mothers (hyperinsulinism)
• Congenital hyperinsulinism
• Rare enzymatic defects in carbohydrate metabolism, such as hereditary fructose intolerance and galactosemia

Postprandial hypoglycemia

• Alimentary hypoglycemia
  • After gastric or bariatric surgery that allows rapid passage of food from stomach to intestine
  • Causes a rapid postprandial increase in plasma glucose levels and release of gut incretins, which induce an exuberant insulin response and subsequent hypoglycemia
  • Pathologically characterized by pancreatic β-cell hyperplasia (nesidioblastosis)
• The existence of a clinically relevant idiopathic reactive hypoglycemia syndrome is debated.

Factitious hypoglycemia

• Malicious or self-administration of insulin, sulfonylureas, or other insulin secretagogues (e.g., repaglinide)

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