Regulation of IGF-I and -II by Insulin in Primary Cultures of Fetal Rat Hepatocytes

Abstract

During perinatal development, insulin and nutrients, rather than GH, regulate the IGF system. A selective primary culture of fetal rat hepatocytes has been established in our laboratory to elucidate the molecular mechanism of action of the above regulatory factors on IGF-I and -II gene expression during the late fetal period of the rat. In this model we have previously reported a regulatory role for glucose on IGF-I and -II synthesis and secretion. In the same experimental model, we now report that doses of insulin (0.1-5 microM) within the physiological range in rat fetuses during the last stages of gestation evoke an increase of IGF-I and -II mRNA abundance. Insulin regulated in a parallel manner IGF peptide secretion, and an excellent correlation was observed between IGF-I and -II mRNA and IGF-I and -II peptide levels in the conditioned media in response to the hormone. Finally, the insulin-induced rise in IGF-I and -II mRNA was not mediated by stimulation of gene transcription but by increased transcript stability. The results support the hypothesis that insulin plays a major role in IGF regulation at immature stages of development.

Metabolic hormones regulate basal and growth hormone-dependent igf2 mRNA level in primary cultured coho salmon hepatocytes: effects of insulin, glucagon, dexamethasone, and triiodothyronine

“…The only relevant mammalian hepatocyte culture studies used fetal hepatocytes. In fetal rat hepatocytes, Igf2 gene expression was positively regulated by insulin, but it was not responsive to Gh (Goya et al 1999(Goya et al , 2001). Based on this very limited dataset, basal insulin regulation of igf2 in juvenile salmon hepatocytes is similar to insulin regulation of igf2 in fetal rat hepatocytes.…”

“…It will be necessary to confirm these findings at the level of protein secretion and circulating Igf 2 in vivo. However, as far as it is known, Igf 2 is constitutively secreted; gene expression and secreted protein levels correlate well in mammalian hepatocyte culture studies (Goya et al 1999(Goya et al , 2001, and liver igf2 gene expression and Igf 2 production drive circulating levels in vivo (Humbel 1990).…”

The relation of insulin, leptin and IGF‐1 to birthweight in offspring of women with type 1 diabetes

“…In contrast to leptin, absolute IGF‐1 concentrations are little different in ODM and controls. This is of interest as IGF‐1 concentrations are hypothesized to be modulated by nutrition in the foetus, an effect believed to reflect direct influences of glucose and insulin (Thissen et al ., 1994; Efstratiadis, 1998; Goya, et al ., 2001). It is paradoxical then that, despite marked hyperinsulinaemia and presumed exposure to excess glucose in ODM, IGF‐1 concentrations are not raised.…”

Insulin‐Like Growth Factor Replacement Therapy for Diabetic Neuropathy: Experimental Basis

“…IGF levels are reduced in the prediabetic state prior to hyperglycemia, and reduced further as a consequence of aging. It is instructive that IGF-I and IGF-II gene expression are increased in cultured hepatocytes directly in response to insulin (Phillips et al, 1991;Goya et al, 2001). Consequently, IGF gene expression may decline in diabetes partially as a consequence of the reduction in insulin activity rather than in response to hyperglycemia.…”