Meprin consists of two homologous isoforms, meprin�� and meprin��. We have previously shown that meprin�� cleaves and releases Regorafenib E-cadherin, which is considered to act as a tumor suppressor (49). Thus, we also considered meprin�� as a potential sheddase for EGFR ligands. In contrast to meprin��, meprin�� is not implicated in the shedding of EGFR ligands (data not shown). Although, both isoforms have related cleavage sites, different substrate specificities have been described (50, 51) (Jefferson et al., 62), which most likely is the reason for their different behavior toward EGFR ligands. Additionally, meprin�� and �� exhibit remarkable differences in their activation (46) and regulation by inhibitors (52) (Jefferson et al. 62). This certainly contributes to the different functions in cell proliferation and migration as observed previously (40).

In the large intestine, only minor amounts of meprin�� are expressed. Hence, most meprin�� is released into the gut lumen in vivo and may b
endothelial dysfunction is a feature of human obesity and type 2 diabetes mellitus, and parallel impairments in insulin’s vascular and metabolic actions are seen in proportion to insulin resistance (3, 23). This has been attributed to impaired bioavailability of nitric oxide (NO) due to reduced actions of insulin to stimulate NO production, in part supported by observations that insulin’s actions to stimulate the production of NO are mediated by insulin receptor substrate-1, phosphatidylinositol 3-kinase (PI3-kinase), and protein kinase B (17, 20, 56).

Derangements in signal transduction in these pathways contribute to impairments in insulin’s metabolic actions in states of insulin resistance and appear to also underlie impairments in this vascular action of insulin (8, 27, 34, 46, 50). We and others have shown, however, that excess endogenous action of endothelin also contributes importantly to endothelial dysfunction in human obesity and type 2 diabetes (5, 6, 29). This is presumed to reflect increased production, and observations in vitro and in vivo implicate insulin as a driver of endothelin-1 (ET-1) production (14, 18, 36). Insulin appears to modulate ET-1 production via mitogen-activated protein kinase (MAPK)/MEKK pathway systems (11, 40). Importantly, these response pathways do not seem to be affected by insulin resistance.

This has been described as ��selective�� insulin resistance (19, 33), the notion that insulin’s various actions may be differentially affected by impairments in insulin response in states of metabolic insulin resistance. In this context, the possibility arises that the compensatory hyperinsulinemia Cilengitide of the insulin-resistant state would concurrently drive the overproduction of endothelin, resulting in a net impairment of vascular function on this basis.