## Proinsulin Processing and Maturation ### Structure of Proinsulin Proinsulin is a 86-amino acid single-chain precursor synthesized on ribosomes as preproinsulin. It contains: - A-chain (21 amino acids) - B-chain (30 amino acids) - C-peptide (35 amino acids) connecting the A and B chains ### Post-Translational Cleavage **Key Point:** Proinsulin undergoes specific enzymatic cleavage in the secretory granules of pancreatic β-cells by **proprotein convertases PC1/3 and PC2** (also called prohormone convertases). These serine proteases recognize and cleave at the dibasic amino acid residues (Lys-Arg and Arg-Arg) flanking the C-peptide. ### Products of Cleavage The cleavage yields three products that are co-secreted in equimolar amounts: 1. **Mature insulin** (51 amino acids: A-chain + B-chain linked by disulfide bonds) 2. **C-peptide** (35 amino acids) 3. **Dipeptides** (Lys-Arg or Arg-Arg fragments) ### Clinical Significance **High-Yield:** The equimolar secretion of insulin and C-peptide is exploited clinically: - C-peptide measurement is used to assess **endogenous insulin secretion** (not affected by exogenous insulin therapy) - In insulinoma diagnosis, elevated C-peptide with elevated insulin confirms endogenous hyperinsulinism - In factitious hypoglycemia (exogenous insulin injection), C-peptide is suppressed while insulin is elevated **Clinical Pearl:** Defects in proprotein convertases (rare) lead to accumulation of proinsulin and proinsulin-like molecules in circulation, causing mild hyperglycemia. ### Why Not Other Proteases? - **Trypsin** is a pancreatic digestive enzyme, not involved in hormone processing within β-cells - **Pepsin** is a gastric protease with different specificity; the secretory granule pH is not acidic enough for pepsin activity - **Direct secretion** of uncleaved proinsulin does occur minimally (~5%) but the bulk requires PC1/3 and PC2 cleavage [cite:Guyton & Hall 14e Ch 79]
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