Proinsulin

Proinsulin is synthesized in the pancreatic beta cells as a 9390 mw polypeptide of 86 amino acids.^1-3 Proinsulin is subsequently cleaved enzymatically, releasing insulin into the circulation along with a residual 3000 mw fragment called C-peptide, so-named because it connects the A and B chains of insulin within the proinsulin molecule.

Proinsulin, which has relatively low biological activity (approximately 10% of insulin potency), is the major storage form of insulin. Normally, only small amounts (∼3% of the amount of insulin, on a molar basis) of proinsulin enter the circulation. Because the hepatic clearance of proinsulin is only 25% of insulin clearance, the half-life of proinsulin is two- to threefold longer and concentrations in the fasting state are approximately 10% to 15% of insulin concentrations.

High proinsulin concentrations have been associated with benign or malignant β-cell tumors of the pancreas⁴ and endocrine pancreatic tumors associated with MEN-1.⁵ Elevated proinsulin levels have been observed in individuals with impaired glucose tolerance even in the absence of abnormal glucose or C-peptide levels.⁶ Elevated proinsulin levels have been found to be a positive risk factor for the development on NIDDM.^7,8 Most patients with β-cell tumors have increased insulin, C-peptide, and proinsulin concentrations, but occasionally only proinsulin is elevated. Despite its low biological activity, proinsulin may be increased sufficiently to produce hypoglycemia.⁹ In addition, a rare form of familial hyperproinsulinemia, due to impaired conversion to insulin, has been described. Increased proinsulin concentrations may also be detected in patients with chronic renal failure, cirrhosis, or hyperthyroidism.