The incretin effect mediated by GIP and GLP-1 account for 50–70% of total postprandial insulin release in healthy subjects.1
In addition to its physiological role in regulating endocrine pancreatic secretion, GIP also acts on the adipose tissue by regulating lipid metabolism. Notably the incretin effect in type 2 diabetes is markedly reduced with greater reduction in GIP's insulinotropic effect on the pancreatic beta cells compared with GLP-1.9, 39
The homeostasis between anti-incretin factor(s) and incretins has been postulated to be disrupted most likely in the proximal foregut of diabetics.27
GIP is synthesized and released from K cells of the duodenum and is known to act as a principal mediator of the enteroinsular axis.11
GIP is also reported to possess insulin-mimetic properties and induce the activation of the AKT pathway40
resulting in the uptake of glucose by adipocytes. Inhibition of GIP signaling may also prevent obesity and metabolic syndrome.40
Although menin has recently been shown to inhibit AKT activation among its already known functions of interacting with transcriptional regulators such as NF-kB, JunD and Smad 3, little is known about factors that directly regulate this protein.18, 19, 20
Refeeding after fasting is known to increase serum GIP levels41
and leads to an increase in serum insulin that downregulates the expression of menin.29
We previously reported that menin is expressed in the duodenum22
and Ratineau et al.24
described higher menin expression in the duodenum of fasted animals compared with that in ad libitum
-fed mice. The authors determined that MEN1 transcripts are expressed in the crypts of the intestine and dispersed on cells of the villi, but did not identify the specific cell-type that expressed menin. Since menin is a metabolic protein modulated by fasting and refeeding, and regulated by insulin,29
we hypothesized that menin is a regulator of GIP expressed in K cells. Although menin may has an antiproliferative role within the crypts of the intestine, this is the first report that identifies its expression in K cells and describes the negative regulation of GIP by menin.
In this study, we demonstrate that menin is expressed in K cells of the proximal duodenum by colocalizing with GIP. We also present evidence that food intake and HF diet downregulate menin expression in the proximal duodenum and is inversely correlated with changes in GIP expression. We show for the first time that menin is a negative regulator of GIP at the promoter level and GIP has a negative feedback effect on menin by directly downregulating menin protein levels via a phosphatidylinositol-3-kinase/protein kinase B (AKT) (PI3K-AKT)-dependent pathway.
STC-1 cells have been used as a model for studies on GIP expression secretion and K cell function.28
Using STC-1 cells, we describe a functional interplay between menin and GIP to explain how diet and feeding regulate menin and GIP expression in the proximal duodenum through the PI3K-AKT signaling cascades. However, MAPK signaling may be partially implicated in GIP regulation of menin, albeit independent of phospho-p38, as UO126 abrogated GIP-induced reduction of menin expression without a change in phospho-p38 levels. As a feedback mechanism, we propose that GIP downregulates menin levels to relieve its repression. Additionally, since insulin is a direct transcriptional regulator of menin expression, changes in serum insulin as a result of fasting and refeeding or diet may also contribute to the modulation of menin levels in the proximal duodenum. The physiological response to this cascade of events is a decrease in serum insulin as a result of the fasted state, which causes an increase in menin levels. Refeeding again decreases menin expression and increases GIP.
This study is the first to correlate physiologically induced changes in menin levels as a result of fasting and refeeding and diet with GIP. Indeed, menin is expressed in other cells of the duodenum such as in the crypts along with K cells; therefore, changes in expression as shown in , , cannot be attributed to levels in K cells alone. However, it is intriguing that the overall levels of menin and GIP are inversely modulated by physiological events in the proximal duodenum, as menin is also expressed in K cells (). The inverse role of these proteins have also been described in the pancreas, where menin has an anti-proliferative effect on beta cells,42
while GIP expression is associated with increased cell proliferation and insulin secretion.43, 44
In summary, we show that food intake and diet modulate menin in the proximal duodenum in an inverse correlation with GIP expression. We demonstrate that menin is a negative regulator of GIP expression and inhibition of PI3K-AKT signaling by LY294002 causes a decrease in GIP expression and is reversed with menin siRNA. Furthermore, GIP downregulates menin protein via the PI3K-AKT pathway, where activation of AKT appears to be a key component in maintaining the expression of menin levels. Our findings provide evidence of an anti-incretin effect exerted by menin in response to food intake and diet involving the PI3-AKT signaling cascade.