A 52-year-old man with chronic obstructive pulmonary disease (COPD) exacerbation is prescribed oral prednisolone 40 mg daily for 7 days. He has a past medical history of well-controlled type 2 diabetes mellitus (HbA1c 6.8%) and hypertension. After 5 days of prednisolone therapy, his fasting blood glucose rises to 240 mg/dL and his blood pressure increases to 155/95 mmHg. He also reports new-onset insomnia and mood changes. Which of the following best describes the pharmacologic basis for the glucose elevation in this patient?

Explanation

## Glucocorticoid-Induced Hyperglycemia: Hepatic Mechanisms **Key Point:** Glucocorticoids increase blood glucose primarily through **hepatic overproduction** via two mechanisms: glycogenolysis (acute) and gluconeogenesis (sustained). ### Acute Phase: Glycogenolysis Glucocorticoids activate: - **Phosphorylase kinase** → phosphorylates glycogen phosphorylase → breaks down glycogen to glucose-1-phosphate - Occurs within hours of corticosteroid administration - Explains the rapid rise in fasting glucose (seen in this patient by day 5) ### Sustained Phase: Gluconeogenesis Glucocorticoids induce hepatic enzymes: 1. **PEPCK** (Phosphoenolpyruvate carboxykinase) — rate-limiting step 2. **G6Pase** (Glucose-6-phosphatase) — final step of both gluconeogenesis and glycogenolysis 3. **FBPase** (Fructose-1,6-bisphosphatase) Substrates for gluconeogenesis: - Amino acids (from protein catabolism — glucocorticoids are catabolic) - Lactate (from Cori cycle) - Glycerol (from lipolysis) **High-Yield:** Glucocorticoids are **anti-insulin** — they: - Decrease insulin secretion - Increase insulin resistance in muscle and adipose tissue - Suppress GLUT4 translocation (opposite of insulin effect) ### Mechanism Diagram ```mermaid flowchart TD A[Glucocorticoid administration]:::action --> B[Hepatic gene induction]:::action B --> C[↑ PEPCK, G6Pase, FBPase]:::outcome B --> D[↑ Phosphorylase kinase]:::outcome C --> E[↑ Gluconeogenesis]:::action D --> F[↑ Glycogenolysis]:::action E --> G[↑ Fasting glucose]:::outcome F --> G A --> H[↓ Insulin secretion]:::action A --> I[↑ Insulin resistance]:::action H --> G I --> G ``` ### Table: Glucocorticoid Effects on Glucose Metabolism | Process | Effect | Mechanism | Timeline | | --- | --- | --- | --- | | Glycogenolysis | ↑↑ | Phosphorylase kinase activation | Minutes to hours | | Gluconeogenesis | ↑↑ | PEPCK/G6Pase induction | Hours to days | | Insulin secretion | ↓ | Direct beta-cell suppression | Hours | | Insulin sensitivity | ↓ | GLUT4 downregulation, IRS-1 inhibition | Hours to days | | Lipolysis | ↑ | Beta-adrenergic sensitization | Hours | | Protein catabolism | ↑ | Amino acid substrate provision | Days | **Clinical Pearl:** Patients with pre-existing diabetes or impaired fasting glucose are at highest risk for steroid-induced hyperglycemia. Glucose monitoring and temporary insulin therapy are often needed during high-dose corticosteroid courses. **Mnemonic:** **PEPCK** = **P**hospho**E**nol**P**yruvate **C**arboxykinase — the master regulator of gluconeogenesis induced by glucocorticoids. [cite:KD Tripathi 8e Ch 57; Harrison 21e Ch 377]