Differential mitogenic signaling in insulin receptor-deficient fetal pancreatic beta-cells.
Level 5 - mechanism / opinion, no new human data
In vitro laboratory study using murine cell lines
PubMed 16396989 · doi:10.1210/en.2005-0831
What was done
Islets were isolated from fetal mice with floxed insulin receptor alleles (IRLoxP) and immortalized using an SV40 large T antigen retrovirus to generate beta-cell lines (beta-IRLoxP). An adenovirus expressing Cre recombinase was introduced to delete the insulin receptor, establishing beta-IR(-/-) cell lines. Researchers measured insulin and Pdx-1 mRNA expression in response to glucose and analyzed signaling pathways including p44/p42 MAPK, PI3K, mTOR, and p70S6K phosphorylation, as well as beta-cell proliferation in response to insulin or glucose, with or without pathway inhibitors (Wortmannin, PD98059, rapamycin).
What was found
The abstract reports no numeric values, effect sizes, or confidence intervals. In beta-IRLoxP cells, insulin stimulated p44/p42 MAPK, PI3K, mTOR/p70S6K phosphorylation, and proliferation. Single inhibition with Wortmannin or PD98059 did not block insulin-mediated mTOR/p70S6K activation or mitogenesis, but dual inhibition or rapamycin alone completely blocked these responses. In beta-IR(-/-) cells, glucose did not stimulate PI3K activity but induced p44/p42 MAPK and mTOR/p70S6K phosphorylation and proliferation. In these knockout cells, PD98059 or rapamycin blocked glucose-induced mTOR/p70S6K signaling and mitogenesis, whereas Wortmannin had no effect.
Why it matters
The study shows that insulin stimulates fetal beta-cell proliferation through redundant PI3K and MAPK pathways converging on mTOR, and that glucose can independently stimulate mitogenesis via a MAPK- and mTOR-dependent pathway when insulin receptors are absent.
Limits
The study is entirely in vitro using SV40 large T antigen-immortalized mouse cell lines, which may not accurately reflect primary beta-cell physiology or human fetal development. The abstract does not report sample sizes, replicate numbers, or quantitative measurements.
Cited by
- supports The insulin receptor is coupled to the mitogen-activated protein kinase (MAP kinase) pathway, which stimulates cell growth and division.