Regulation of glycemia, causes of hypoglycemia and hyperglycemia

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Introduction

Blood glucose levels must be maintained within a narrow physiological range to supply energy to tissues—especially the brain, which depends almost entirely on glucose. Glycemia is regulated by a complex interplay of hormones, metabolic pathways, and organ systems (primarily the pancreas, liver, muscles, and adipose tissue). Disturbances in these regulatory mechanisms lead to hypoglycemia or hyperglycemia, both of which can have significant pathophysiological consequences.

Definition

Glycemia refers to the concentration of glucose in the blood.

Normal fasting glycemia: 3.9–5.6 mmol/L.

• Hypoglycemia = blood glucose < 3.9 mmol/L
• Hyperglycemia = fasting glucose > 7.0 mmol/L or random > 11.1 mmol/L

Regulation depends on the balance between hormones that lower glycemia (insulin) and hormones that raise glycemia (glucagon, cortisol, epinephrine, growth hormone).

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Regulation of Glycemia

1. Role of Insulin

Insulin is the primary hormone decreasing blood glucose.

Main actions

• ↑ Glucose uptake (muscle, adipose tissue)
• ↓ Hepatic glucose production
• ↑ Glycogen synthesis
• ↑ Fat storage
• ↓ Lipolysis
• ↓ Proteolysis

Released when

• Blood glucose rises (after meals)

Purpose

Prevent excessive postprandial hyperglycemia and promote nutrient storage.

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2. Role of Glucagon

Glucagon increases blood glucose.

Main actions

• ↑ Glycogenolysis (breakdown of glycogen)
• ↑ Gluconeogenesis
• ↑ Lipolysis (provides substrates for glucose production)

Released when

• Blood glucose falls
• During fasting or stress

Purpose

Maintain adequate glucose supply during fasting or increased energy demand.

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3. Other Counterregulatory Hormones

Hormone	Effect
Epinephrine	Rapid ↑ in glucose (glycogenolysis, lipolysis)
Cortisol	Long-term ↑ glucose (gluconeogenesis, insulin resistance)
Growth hormone	Reduces glucose uptake, ↑ insulin resistance
Thyroid hormones	Increase metabolic rate and glucose turnover

These hormones prevent hypoglycemia during fasting, stress, or illness.

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4. Liver, Muscle, and Adipose Tissue

• Liver: produces glucose (gluconeogenesis + glycogen breakdown)
• Muscle: stores glycogen, uptakes glucose in response to insulin
• Adipose tissue: stores energy, releases fatty acids during fasting

Together, they regulate glucose availability.

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Causes of Hypoglycemia

Hypoglycemia occurs when glucose utilization exceeds glucose availability.

1. Excess Insulin

• Insulin therapy (most common cause in diabetics)
• Oral antidiabetic drugs (e.g., sulfonylureas)
• Insulinoma (rare pancreatic tumor)

2. Reduced Glucose Intake or Absorption

• Prolonged fasting
• Malnutrition
• Post-gastrectomy or bariatric surgery (dumping syndrome)

3. Increased Glucose Utilization

• Strenuous exercise
• Severe infections
• Pregnancy (increased fetal consumption)

4. Impaired Glucose Production

• Liver failure
• Adrenal insufficiency (low cortisol)
• Growth hormone deficiency
• Alcohol-induced inhibition of gluconeogenesis

Clinical Features

• Sweating, tremor
• Palpitations
• Hunger
• Headache, confusion
• Seizures, loss of consciousness (severe)

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Causes of Hyperglycemia

Hyperglycemia generally results from impaired insulin action or decreased insulin secretion.

1. Diabetes Mellitus

Type 1 Diabetes

• Autoimmune destruction of β-cells
• Absolute insulin deficiency
• Early onset, rapid progression
• Tendency to ketoacidosis

Type 2 Diabetes

• Insulin resistance + relative insulin deficiency
• Strong genetic and lifestyle components
• Common in adults
• Associated with obesity and metabolic syndrome

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2. Increased Counterregulatory Hormones

Seen in:

• Stress (trauma, sepsis)
• Cushing syndrome (excess cortisol)
• Acromegaly (excess growth hormone)
• Pheochromocytoma (excess catecholamines)

Mechanism: ↑ hepatic glucose output + ↑ insulin resistance.

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3. Medications

• Glucocorticoids
• Thiazide diuretics
• Beta-agonists
• Antipsychotics
• Immunosuppressants (e.g., tacrolimus)

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4. Liver Disease

• Impaired glucose storage
• Increased gluconeogenesis

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5. Other Causes

• Pancreatitis (affects insulin secretion)
• Pregnancy (gestational diabetes)
• Endocrine disorders (hyperthyroidism)

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Clinical Features of Hyperglycemia

• Polyuria (osmotic diuresis)
• Polydipsia
• Polyphagia
• Weight loss (mainly in type 1)
• Fatigue
• Blurred vision

Severe cases:

• DKA (diabetic ketoacidosis)
• HHS (hyperosmolar hyperglycemic state)

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Conclusion

Glycemia is regulated through a balance between insulin and counterregulatory hormones, coordinated actions of the liver, muscles, and adipose tissue. Hypoglycemia arises from insufficient glucose availability or excess insulin effect, while hyperglycemia results from impaired insulin action, hormonal disturbances, or metabolic dysfunction. Understanding these mechanisms is essential for recognizing the pathophysiology of common metabolic disorders.

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References

• Guyton & Hall. Textbook of Medical Physiology.
• Boron & Boulpaep. Medical Physiology.
• Alberti KG. Hormonal regulation of glucose metabolism.
• ADA Guidelines for diagnosis and classification of diabetes mellitus.