What are the causes and management of hyperglycemia?

Causes of Hyperglycemia

Hyperglycemia is primarily caused by insulin resistance, insulin deficiency, or a combination of both mechanisms, with stress response, medications, and underlying medical conditions being major contributors to elevated blood glucose levels. 1

Primary Causes of Hyperglycemia

1. Diabetes Mellitus

• Type 1 Diabetes: Autoimmune destruction of pancreatic beta cells leading to absolute insulin deficiency
• Type 2 Diabetes: Progressive insulin resistance with relative insulin deficiency
• Gestational Diabetes: Insulin resistance during pregnancy

2. Stress-Induced Hyperglycemia

• Mechanism: Peripheral insulin resistance is the main mechanism 1
• Contributing factors:
  • Release of stress hormones (glucagon, cortisol, catecholamines)
  • Inflammatory mediators (interleukin 1 and 6)
  • Increased hepatic glucose production
  • Decreased glucose clearance
  • Increased renal reabsorption of glucose

3. Medication-Induced Hyperglycemia

• Corticosteroids: Impair beta cell insulin secretion, increase insulin resistance, and enhance hepatic gluconeogenesis 1
• Antipsychotics: Especially second-generation agents (clozapine, olanzapine, quetiapine) cause insulin resistance 2
• Cardiovascular medications:
  • Thiazide diuretics
  • Beta-blockers
  • Statins (dose-dependent effect)
• Other medications:
  • Immunotherapy agents (checkpoint inhibitors) 1
  • Antiretrovirals (protease inhibitors)
  • Calcineurin inhibitors
  • Pentamidine (direct pancreatic cell dysfunction)
  • Fluoroquinolones (at high doses)

4. Immune Checkpoint Inhibitor-Associated Diabetes (CIADM)

• Typically occurs around 12 weeks after initiation of therapy but can occur years later 1
• Requires monitoring during treatment and for 12 months after completion

Pathophysiological Mechanisms

1. Insulin Resistance

• Decreased peripheral tissue response to insulin
• Can persist for days after triggering events
• Aggravated by:
  • Obesity
  • Physical inactivity
  • Prolonged fasting
  • Lipid metabolism alterations

2. Insulin Deficiency

• Absolute: Complete lack of insulin production (Type 1 diabetes)
• Relative: Insufficient insulin production to overcome resistance

3. Increased Hepatic Glucose Production

• Enhanced gluconeogenesis
• Glycogenolysis

Clinical Scenarios Associated with Hyperglycemia

1. Perioperative Hyperglycemia

• Prevalence: 30-80% depending on surgery type 1
• Highest in cardiac surgery
• Risk factors:
  • Surgical stress
  • Duration of procedure
  • Catecholamine infusion
  • Corticosteroid use
  • Obesity
  • Advanced age
  • Hypothermia
  • Hypoxia

2. Critical Illness

• Metabolic and hormonal changes with increased counterregulatory hormones 3
• Associated with increased infection risk 4
• Impaired host defenses including decreased polymorphonuclear leukocyte function

3. Checkpoint Inhibitor-Associated Diabetes Mellitus (CIADM)

• Requires monitoring during treatment and for 12 months post-completion 1
• Patients should be educated on self-monitoring and warning symptoms

Diagnostic Considerations

1. Distinguishing Stress Hyperglycemia from Undiagnosed Diabetes

• HbA1c measurement can differentiate between:
  • Stress hyperglycemia (HbA1c <6.5%)
  • Previously undiagnosed diabetes (HbA1c ≥6.5%) 1

2. Diagnostic Criteria for Diabetes

• Fasting blood glucose ≥1.26 g/L (7.0 mmol/L) on two occasions
• Plasma glucose ≥2 g/L (11.1 mmol/L) at 2 hours during OGTT
• Random plasma glucose ≥2 g/L (11.1 mmol/L) with symptoms 1

Management Approach

1. General Management Principles

• Identify and address underlying cause when possible
• Monitor blood glucose levels appropriately
• Implement lifestyle modifications
• Consider medication adjustments

2. Lifestyle Interventions

• Structured intensive lifestyle program with reduced energy intake
• Regular physical activity (150 minutes/week moderate-intensity plus resistance training)
• Weight loss of 5-7% of starting weight 3

3. Pharmacological Management

• First-line therapy: Metformin (starting dose 500mg once or twice daily) 3
• For patients with cardiovascular or renal disease: Consider SGLT2 inhibitors or GLP-1 receptor agonists 3
• Insulin therapy:
  • Initial dose of basal insulin: 0.3-0.4 units/kg/day
  • For severe hyperglycemia (A1c >10%): 10 units or 0.1-0.2 units/kg/day 3, 5

4. Specific Scenarios

• Steroid-induced hyperglycemia: Management should be tailored to steroid pharmacokinetics 1
• Immune checkpoint inhibitor-related hyperglycemia: Requires monitoring during treatment and for 12 months after completion 1

Common Pitfalls and Considerations

• Failing to identify medication-induced causes
• Not distinguishing between stress hyperglycemia and undiagnosed diabetes
• Overlooking the risk of diabetic ketoacidosis in patients on SGLT2 inhibitors 3
• Neglecting to monitor for vitamin B12 deficiency in long-term metformin users 3
• Therapeutic inertia (failing to intensify therapy despite suboptimal control) 3

Hyperglycemia management should be approached systematically with attention to the underlying cause, appropriate monitoring, and targeted interventions to prevent complications and improve outcomes.