RGD Reference Report - 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. - Rat Genome Database

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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.

Authors: Alarcon, C  Leahy, JL  Schuppin, GT  Rhodes, CJ 
Citation: Alarcon C, etal., J Clin Invest. 1995 Mar;95(3):1032-9.
RGD ID: 2308919
Pubmed: PMID:7883951   (View Abstract at PubMed)
PMCID: PMC441437   (View Article at PubMed Central)
DOI: DOI:10.1172/JCI117748   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
hyperglycemia  ISOPcsk1 (Rattus norvegicus)2308919; 2308919associated with Diabetes Mellitus more ...RGD 
hyperglycemia  IEP 2308919associated with Diabetes Mellitus more ...RGD 

Objects Annotated

Genes (Rattus norvegicus)
Pcsk1  (proprotein convertase subtilisin/kexin type 1)

Genes (Mus musculus)
Pcsk1  (proprotein convertase subtilisin/kexin type 1)

Genes (Homo sapiens)
PCSK1  (proprotein convertase subtilisin/kexin type 1)


Additional Information