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Why hypoglycaemia or hyperglycaemia seen in sepsis

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"sepsis" AND "glucose dysregulation" AND "hyperglycemia hypoglycemia"

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sepsis hyperglycemia insulin resistance mechanism pathogenesis diagram

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Glucose Dysregulation in Sepsis: Why Both Hyperglycemia AND Hypoglycemia Occur

Sepsis disrupts glucose homeostasis through two opposing but often sequential mechanisms. Both hyper- and hypoglycemia are recognized as independent predictors of mortality in septic patients.

HYPERGLYCEMIA IN SEPSIS ("Stress Hyperglycemia")

This is the more common early finding. Multiple converging pathways drive it:

1. Counter-regulatory hormone surge

The physiological stress response releases:
  • Glucagon - stimulates hepatic glycogenolysis and gluconeogenesis
  • Glucocorticoids (cortisol) - promote gluconeogenesis, inhibit peripheral glucose uptake
  • Catecholamines (epinephrine/norepinephrine) - drive glycogenolysis and gluconeogenesis, suppress insulin secretion
  • Growth hormone - reduces peripheral insulin sensitivity
Together, these hormones massively increase endogenous glucose production that is often refractory to exogenous insulin. - Robbins & Kumar Basic Pathology, p. 98

2. Pro-inflammatory cytokine effects

Cytokines TNF-α and IL-1β act directly to:
  • Suppress insulin secretion from pancreatic beta cells
  • Promote peripheral insulin resistance - by impairing the surface expression of GLUT-4 glucose transporter in liver and skeletal muscle
  • Drive further gluconeogenesis

3. Impaired insulin signaling (molecular mechanism)

In sepsis, insulin-induced tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) is impaired. This blocks downstream phosphoinositide 3-kinase (PI3K) activation, resulting in defective GLUT-4 translocation - so even with normal or elevated insulin levels, cells cannot take up glucose. - Current Surgical Therapy, p. 1636

4. Two parallel pathways of peripheral resistance

  1. Reduced insulin-mediated glucose uptake from defects in post-receptor signaling and GLUT-4 downregulation by cytokines
  2. Impaired non-oxidative glucose disposal - decreased muscle glycogen synthesis due to excess cortisol and epinephrine

5. Consequences of hyperglycemia

Hyperglycemia itself worsens the septic state by:
  • Decreasing neutrophil phagocytic activity and leukocyte oxidative bursts (impairs bactericidal function)
  • Increasing endothelial adhesion molecule expression
  • Triggering further cytokine, inflammatory, and oxidative stress responses - creating a vicious cycle

HYPOGLYCEMIA IN SEPSIS

Less common but life-threatening. Several distinct mechanisms:

1. Glycogen depletion (especially in children)

  • Septic children are particularly prone to hypoglycemia due to limited glycogen stores
  • Prolonged illness exhausts hepatic glycogen, removing the substrate for glycogenolysis
    • Rosen's Emergency Medicine, p. 899

2. Hepatic dysfunction

  • Sepsis-associated liver injury impairs gluconeogenesis - the liver cannot generate glucose from amino acids, lactate, and glycerol
  • Hepatic perfusion failure (from septic shock) further cripples glucose production

3. Adrenal insufficiency (late sepsis)

  • Although sepsis initially triggers an acute glucocorticoid surge, this may be followed by relative adrenal insufficiency (CIRCI - Critical illness-related corticosteroid insufficiency)
  • This can result from depression of adrenal synthetic capacity or frank adrenal necrosis from DIC (Waterhouse-Friderichsen syndrome)
  • Without cortisol, counter-regulatory glucose support collapses
    • Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 136

4. Insulin therapy-related hypoglycemia (iatrogenic)

  • Tight glycemic control protocols (targeting 80-110 mg/dL) can cause hypoglycemia, especially when enteral feeds are interrupted or insulin drips are not adjusted
  • The NICE-SUGAR trial (n = 6,104) showed intensive glucose control increased 90-day mortality, largely attributable to episodes of moderate-to-severe hypoglycemia, particularly in distributive shock
    • Current Surgical Therapy, p. 1636

5. Cytokine-mediated insulin hypersecretion

  • Some inflammatory mediators paradoxically stimulate residual insulin release in late/resolving sepsis, causing hypoglycemia when counter-regulatory hormones wane

Summary Table

FeatureHyperglycemiaHypoglycemia
TimingEarly, commonLate or iatrogenic
Primary driversCounter-regulatory hormones + cytokinesGlycogen depletion, liver failure, adrenal insufficiency
Key molecular eventGLUT-4 downregulation, IRS-1 impairmentLoss of gluconeogenic capacity
Who is most at riskAll septic patientsChildren, prolonged sepsis, hepatic dysfunction
Clinical significanceImpairs immune function, worsens outcomesIndependently associated with increased mortality

Current Clinical Target (2021 Surviving Sepsis Campaign)

Start insulin therapy at glucose ≥ 180 mg/dL; avoid hypoglycemia below 70 mg/dL. Tight control targeting 80-110 mg/dL is not recommended due to hypoglycemia risk. - Current Surgical Therapy (SSC 2021 guidelines)
Recent evidence note: A 2024 meta-analysis (PMID 37386859) confirmed hypoglycemia in sepsis/septic shock is independently associated with increased hospital mortality. A 2026 systematic review (PMID 41485125) highlights that glucose variability (swinging between hyper- and hypoglycemia) is itself a strong predictor of adverse outcomes - reflecting the bidirectional dysregulation described above.
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