PKCδ Blues for the β-Cell

Very few studies have focused on the involvement of protein kinase C (PKC) in mediating β-cell dysfunction, which is surprising because there are several hundred articles addressing a corresponding role for PKC during insulin resistance. The conventional and novel subgroups of this family of serine-threonine, protein kinases are usually activated in receptor signaling cascades by lipid second messengers. Under conditions of lipid oversupply, however, it was envisioned that nutrient fatty acids or their derivatives might also activate PKC and thereby disrupt both insulin signaling and, more speculatively, β-cell function (1). Important support for this concept in β-cells is now provided in this issue of Diabetes (2).

Hennige et al. (2) generated transgenic mice that overexpress a catalytically inactive form of PKCδ specifically in β-cells. This competes functionally with endogenous PKCδ and inhibits its activity in a relatively specific manner. This strategy improved the glucose intolerance caused by feeding mice a high-fat diet; minimal effects were seen in normal chow–fed mice. The improvement was accompanied in vivo by an enhancement of glucose-stimulated insulin secretion, an increase in mean islet size, and a reduction in markers of apoptosis. This is consistent with a generally proapoptotic role of PKCδ reported in a few prior investigations of β-cells (3–5 ) and studied more extensively in several other cell types (6). The current study also demonstrates that once the alteration in β-cell mass is taken into account, PKCδ does not appear to …