Premature Stimulation of Rat Sucrase-Isomaltase (SI) by Exogenous Insulin and the Analog B-Asp10 Is Regulated by a Receptor-Mediated Signal Triggering SI Gene Transcription

Abstract

The mechanism(s) by which insulin enhance prematurely the activity of brush border membrane (BBM) hydrolases in rat immature intestine is unknown. Therefore, we have compared the responses of four BBM enzymes [sucrase-isomaltase (SI), maltase, lactase-phloridzine hydrolase (LPH), and aminopeptidase] with exogenous insulin, the analog B-Asp10, IGF-I, and antireceptor MAb [insulin-receptor (IR) MAb] given to preweaning pups. Low doses of insulin caused a precocious induction of SI and of SI mRNA and stimulated maltase activity without effect on LPH nor on aminopeptidase activities. IGF-I given at the same dose as that of insulin had no detectable effect on these enzymes. Administration to sucklings of IR MAb prevented the effect of endogenous insulin by inhibiting the expression of SI and maltase without effect on LPH activity. B-Asp10, an insulin analogue that exhibits in vitro a 3.5-fold increase in receptor affinity with sustained signaling of the receptor tyrosine kinase, caused an overexpression of SI by 3.5-fold and of maltase by 1.5-fold compared with equivalent doses of normal insulin. The premature increases in SI activity, SI mRNA, and maltase activity in response to insulin were dose-dependent and were associated with dose-dependent increases in intracellular spermine and spermidine concentrations. In conclusion, these data suggest that the premature induction of SI by insulin is mediated by a dose-dependent signal initiated by binding of the hormone to its intestinal receptor, which after transduction into the cell indirectly triggers the transcription of the SI gene, possibly by changes in intracellular polyamine concentrations.

Ontogeny of MAP Kinases in Rat Small Intestine: Premature Stimulation by Insulin of BBM Hydrolases Is Regulated by ERKs but not by p-38 MAP Kinase

“…Also, SB 203580 had no effect on mucosal mass expressed by centimeter of gut length. Although several studies (6,10,11,35,36) have documented that the regulation of the genes of SI and of maltase and their responsiveness to insulin differs from that of lactase, the effect of SB 203580 remains unexplained. It is possible that the inhibition of p38 MAP kinase determines an antiapoptotic effect upgrading cell differentiation and the responsiveness of sucrase and maltase to insulin.…”

“…Likewise, in suckling and weaning rats, exogenous insulin stimulates the ontogenic expression of lactase and maltase with enzyme responses proportional to the dose of insulin given (6). These effects are mediated by the binding of the hormone to the extramembranous ␣-subunits of the insulin receptor and by the autophosphorylation of the tyrosine kinase domain of the receptor (4,7,12).…”

“…After weaning, the 2-fold decrease in IR concentration is associated with a reduction in responsiveness of mature enterocytes to the hormone (1,5). Our recent studies (6,7) suggest that the premature induction of SI is triggered by the binding of the hormone to the extracellular ␣-receptor subunit, allowing autophosphorylation of the tyrosine-kinase intrinsic to the juxtamembrane and cytoplasmic domains of the ␤-receptor subunit. Downstream transduction of the signal into the cell is assumed to occur by the activation of receptor substrates (IRS-1 and -2, and Shc) and tyrosine-phosphorylated proteins associating through SH 2 domain (8,9).…”

“…Downstream transduction of the signal into the cell is assumed to occur by the activation of receptor substrates (IRS-1 and -2, and Shc) and tyrosine-phosphorylated proteins associating through SH 2 domain (8,9). The final step of the signal leads to the activation of the SI gene promoter with a dose-dependent accumulation of SI mRNA (6), probably by the binding of a nuclear transcription factor [hepatocyte nuclear factor 1, (10,11)] to regulatory elements located upstream of the SI gene promoter (10,11). A recent study (12) has shown that the insulin signal that stimulates BBM hydrolases would be regulated by the cascade of MAP kinases and not by PI-3 kinase or protein kinase B.…”

“…Several studies conducted in vivo and in vitro (1,(5)(6)(7)33) have demonstrated that exogenous insulin is able to induce prematurely (before weaning) sucrase activity, sucrase protein, and sucrase mRNA levels. Likewise, in suckling and weaning rats, exogenous insulin stimulates the ontogenic expression of lactase and maltase with enzyme responses proportional to the dose of insulin given (6).…”