What causes hyperglycemia in hyperosmolar syndrome?

Pathophysiology of Hyperglycemia in Hyperosmolar Syndrome

Hyperglycemia in hyperosmolar syndrome is primarily caused by a reduction in the net effective action of circulating insulin coupled with elevated counterregulatory hormones, leading to increased hepatic and renal glucose production and impaired peripheral glucose utilization. 1

Core Pathophysiological Mechanisms

Insulin Dysfunction and Counterregulatory Hormones

• Hyperosmolar hyperglycemic state (HHS) involves:
  • Relative insulin deficiency (not absolute as in DKA)
  • Elevated counterregulatory hormones (glucagon, catecholamines, cortisol, growth hormone) 1
• These hormonal alterations lead to:
  • Increased hepatic glucose production
  • Increased renal glucose production
  • Impaired glucose utilization in peripheral tissues 1

Key Distinction from Diabetic Ketoacidosis

• In HHS, plasma insulin concentrations are:
  • Inadequate to facilitate glucose utilization by insulin-sensitive tissues
  • But sufficient to prevent significant lipolysis and ketogenesis 1
• This explains why severe hyperglycemia occurs without significant ketosis 1

Progressive Decompensation Cycle

1. Initial Hyperglycemia:

   • Triggered by precipitating factors (infection, medications, undiagnosed diabetes) 1
   • Leads to glycosuria and osmotic diuresis

2. Dehydration Cascade:

   • Osmotic diuresis causes loss of water, sodium, potassium, and other electrolytes 1
   • Water losses exceed sodium losses, resulting in hyperosmolality 2
   • Dehydration further impairs renal function

3. Worsening Hyperglycemia:

   • Dehydration reduces glomerular filtration rate
   • Decreased renal clearance of glucose
   • Further increases in blood glucose levels 3

4. Self-Perpetuating Cycle:

   • Higher glucose levels → more osmotic diuresis → worse dehydration
   • Worsening dehydration → reduced insulin effectiveness → higher glucose levels

Clinical Evolution and Timeframe

• HHS typically develops over days to weeks (unlike DKA which develops within 24 hours) 1
• Patients often present with profound dehydration (average fluid deficit of 9L in adults) 3
• Mental status changes correlate with degree of hyperosmolality (stupor/coma when osmolality >320 mOsm/kg) 1

Common Precipitating Factors

• Infections (most common trigger) 1
• Medications (corticosteroids, thiazides, sympathomimetic agents) 1
• Discontinuation or inadequate insulin therapy 1
• Undiagnosed diabetes, particularly in elderly 1
• Acute medical events (stroke, myocardial infarction) 4

Clinical Implications

• Treatment must address both the hyperglycemia and hyperosmolality
• Fluid replacement is the cornerstone of therapy (more critical than in DKA) 5
• Insulin requirements are typically lower than in DKA 2
• Mortality remains high (15%) despite appropriate treatment 1

The pathophysiological understanding of HHS is critical for appropriate management, as the treatment approach differs somewhat from DKA, with greater emphasis on correcting fluid deficits while carefully managing insulin administration to avoid precipitous drops in glucose and osmolality.