Growth factor-mediated proliferation and differentiation of insulin-producing INS-1 and RINm5F cells: identification of betacellulin as a novel beta-cell mitogen

Endocrinology. 1998 Apr;139(4):1494-9. doi: 10.1210/endo.139.4.5882.


It is not clear which growth factors are crucial for the survival, proliferation, and differentiation of pancreatic beta-cells. We used the relatively differentiated rat insulinoma cell line INS-1 to elucidate this issue. Responsiveness of the DNA synthesis of serum-starved cells was studied to a wide variety of growth factors. The most potent stimulators were PRL, GH, and betacellulin, a member of the epidermal growth factor (EGF) family that has not previously been shown to be mitogenic for beta-cells. In addition to these, only vascular endothelial growth factor, insulin-like growth factor-1 and -2, had significant mitogenic activity, whereas hepatocyte growth factor, nerve growth factor-beta, platelet-derived growth factors, basic fibroblast growth factor, EGF, transforming growth factor-alpha (TGF-alpha), neu differentiation factor, and TGF-beta were inactive. None of these factors affected the insulin content of INS-1 cells. In contrast, certain differentiation factors, including nicotinamide, sodium butyrate, activin A, and 1,25-dihydroxyvitamin D3 inhibited the DNA synthesis and increased the insulin content. Also all-trans-retinoic acid had an inhibitory effect on cell DNA synthesis but no effect on insulin content. From these findings betacellulin emerges as a novel growth factor for the beta-cell. Half-maximal stimulation of INS-1 DNA synthesis was obtained with 25 pM betacellulin. Interestingly, betacellulin had no effect on RINm5F cells, whereas both EGF and TGF-alpha were slightly mitogenic. These effects may possibly be explained by differential expression of the erbB receptor tyrosine kinases. In RINm5F cells a spectrum of erbB gene expression was detected (EGF receptor/erbB-1, erbB-2/neu, and erbB-3), whereas INS-1 cells showed only expression of EGF receptor. Expression of the erbB-4 gene was undetectable in these cell lines. In summary, our results suggest that the INS-1 cell line is a suitable model for the study of beta-cell growth and differentiation because the responses to previously identified beta-cell mitogens were essentially similar to those reported in primary cells. In addition, we have identified betacellulin as a possible modulator of beta-cell growth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Betacellulin
  • Cell Differentiation / drug effects*
  • Cell Division / drug effects*
  • Cell Line
  • DNA / biosynthesis
  • ErbB Receptors / genetics
  • Gene Expression
  • Growth Substances / pharmacology*
  • Human Growth Hormone / pharmacology
  • Humans
  • Insulin / biosynthesis*
  • Insulin-Like Growth Factor I / pharmacology
  • Insulin-Like Growth Factor II / pharmacology
  • Insulinoma
  • Intercellular Signaling Peptides and Proteins*
  • Islets of Langerhans / cytology*
  • Islets of Langerhans / drug effects
  • Mitogens / pharmacology*
  • Pancreatic Neoplasms
  • Prolactin / pharmacology
  • Rats
  • Recombinant Proteins / pharmacology


  • BTC protein, human
  • Betacellulin
  • Btc protein, rat
  • Growth Substances
  • Insulin
  • Intercellular Signaling Peptides and Proteins
  • Mitogens
  • Recombinant Proteins
  • Human Growth Hormone
  • Insulin-Like Growth Factor I
  • Insulin-Like Growth Factor II
  • Prolactin
  • DNA
  • ErbB Receptors