Metabolic stress (e.g., hyperglycemia, hyperlipidemia or both ) promotes functional activation of PKCδ, which, in turn, has been shown to phosphorylate CARD9 (Thr 231) culminating in functional activation of CARD9 [62]. Activation of CARD9 leads to sustained activation of several metabolic axes (NADPH oxidase, p38MAPK) culminating in the demise of the effete β-cell. More recent studies from our laboratory have also demonstrated increased S536 phosphorylation of RelA mediated via the CARD9-Rac1 signaling module in pancreatic β-cells exposed to hyperglycemic milieu; a signaling step implicated in cellular apoptosis [57]. Potential upstream regulatory roles of BCL10 and MALT1 in functional activation of NADPH oxidase, p38MAPK and NFkB in β-cells exposed to diabetogenic conditions remains to be determined.