On 2014 Aug 13, Jim Woodgett commented:

From the Discussion: "Finally, although numerous specific inhibitors for GSK3β were tested, we cannot entirely rule out that nonspecific GSK3α inhibition may have partly contributed to the observed biological effect. However, the relative contribution of GSK3α in DM-induced EPC dysfunction is unlikely to be significant but remains to be elucidated."

None of the tested inhibitors (AR-A014418, CHIR98014, 6-bromoindirubin-3-oxime, GSK peptide inhibitor or LiCl) are specific for GSK-3beta (over GSK-3alpha), these inhibitors fail to show any degree of isoform specificity and are essentially equipotent in blocking each. GSK-3alpha has been implicated in insulin signalling (e.g. PMID 18781825). It isn't clear whether GSK-3alpha activity is increased in diabetic patients but the mechanisms by which the beta isoform are activated (reduced serine 9 phosphorylation) also act on the alpha isoform (serine 21). It would be interesting to test this directly. As it stands, the conclusions of this current analysis are entirely consistent with combined roles for both isoforms - especially given that the two kinases are entirely redundant with respect to Wnt signalling and are expressed at similar levels in endothelium.

It's also worth noting that GSK-3 is known to regulate protein translation as well as transcription (via eiF2B, TSC1 and other mechanisms).

On 2014 Aug 13, Jim Woodgett commented:

From the Discussion: "Finally, although numerous specific inhibitors for GSK3β were tested, we cannot entirely rule out that nonspecific GSK3α inhibition may have partly contributed to the observed biological effect. However, the relative contribution of GSK3α in DM-induced EPC dysfunction is unlikely to be significant but remains to be elucidated."

None of the tested inhibitors (AR-A014418, CHIR98014, 6-bromoindirubin-3-oxime, GSK peptide inhibitor or LiCl) are specific for GSK-3beta (over GSK-3alpha), these inhibitors fail to show any degree of isoform specificity and are essentially equipotent in blocking each. GSK-3alpha has been implicated in insulin signalling (e.g. PMID 18781825). It isn't clear whether GSK-3alpha activity is increased in diabetic patients but the mechanisms by which the beta isoform are activated (reduced serine 9 phosphorylation) also act on the alpha isoform (serine 21). It would be interesting to test this directly. As it stands, the conclusions of this current analysis are entirely consistent with combined roles for both isoforms - especially given that the two kinases are entirely redundant with respect to Wnt signalling and are expressed at similar levels in endothelium.

It's also worth noting that GSK-3 is known to regulate protein translation as well as transcription (via eiF2B, TSC1 and other mechanisms).