Increased secretory demand rather than a defect in the proinsulin conversion mechanism causes hyperproinsulinemia in a glucose-infusion rat model of non-insulin-dependent diabetes mellitus

J Clin Invest. 1995 Mar;95(3):1032-9. doi: 10.1172/JCI117748.


Hyperproinsulinemia in non-insulin-dependent diabetes mellitus (NIDDM) is due to an increased release of proinsulin from pancreatic beta cells. This could reside in increased secretory demand placed on the beta cell by hyperglycemia or in the proinsulin conversion mechanism. In this study, biosynthesis of the proinsulin conversion enzymes (PC2, PC3, and carboxypeptidase-H [CP-H]) and proinsulin, were examined in islets isolated from 48-h infused rats with 50% (wt/vol) glucose (hyperglycemic, hyperinsulinemic, and increased pancreatic proinsulin to insulin ratio), 20% (wt/vol) glucose (normoglycemic but hyperinsulinemic), and 0.45% (wt/vol) saline (controls). A decrease in the islet content of PC2, PC3, and CP-H from hyperglycemic rats was observed. This reduction did not correlate with any deficiency in mRNA levels or biosynthesis of PC2, PC3, CP-H, or proinsulin. Furthermore, proinsulin conversion rate was comparable in islets from hyperglycemic and control rats. However, in islets from hyperglycemic rats an abnormal increased proportion of proinsulin was secreted, that was accompanied by an augmented release of PC2, PC3 and CP-H. Stimulation of the beta cell's secretory pathway by hyperglycemia, resulted in proinsulin being prematurely secreted from islets before its conversion could be completed. Thus, hyperproinsulinemia induced by chronic hyperglycemia likely results from increased beta cell secretory demand, rather than a defect in the proinsulin processing enzymes per se.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Aspartic Acid Endopeptidases / biosynthesis
  • Aspartic Acid Endopeptidases / genetics
  • Carboxypeptidase H
  • Carboxypeptidases / biosynthesis
  • Carboxypeptidases / genetics
  • Diabetes Mellitus, Type 2 / metabolism*
  • Endopeptidases / biosynthesis*
  • Glucose / metabolism
  • Islets of Langerhans / cytology
  • Islets of Langerhans / metabolism*
  • Male
  • Proinsulin / metabolism*
  • Proprotein Convertase 2
  • Proprotein Convertases
  • Protein Processing, Post-Translational*
  • Rats
  • Rats, Sprague-Dawley
  • Subtilisins / biosynthesis
  • Subtilisins / genetics


  • Proinsulin
  • Carboxypeptidases
  • Endopeptidases
  • Carboxypeptidase H
  • Proprotein Convertases
  • Subtilisins
  • Proprotein Convertase 2
  • Aspartic Acid Endopeptidases
  • Glucose