Constitutively Active CaMKKα Stimulates Skeletal Muscle Glucose Uptake in Insulin Resistant Mice In Vivo.

TitleConstitutively Active CaMKKα Stimulates Skeletal Muscle Glucose Uptake in Insulin Resistant Mice In Vivo.
Publication TypeJournal Article
Year of Publication2013
AuthorsHinkley MJ, Ferey JL, Brault JJ, Smith CAS, Gilliam LAA, Witczak CA
Date Published2013 Oct 7

In insulin-sensitive skeletal muscle, expression of constitutively active Ca(2+)/calmodulin-dependent protein kinase kinase α (caCaMKKα) stimulates glucose uptake independent of insulin signaling (i.e. Akt and Akt-dependent TBC1D1/TBC1D4 phosphorylation). Our objectives were to determine if caCaMKKα could stimulate glucose uptake additively with insulin in insulin-sensitive muscle, in the basal state in insulin-resistant muscle, and if so to determine whether the effects were associated with altered TBC1D1/TBC1D4 phosphorylation. Mice were fed a control or high (60%kcal) fat diet for 12-wks to induce insulin resistance. Muscles were transfected with empty vector or caCaMKKα plasmids using in vivo electroporation. After 2-wks, caCaMKKα protein was robustly expressed. In insulin-sensitive muscle, caCaMKKα increased basal in vivo [(3)H]-2-deoxyglucose uptake ∼2-fold, insulin increased glucose uptake ∼2-fold, and caCaMKKα+insulin increased glucose uptake ∼4-fold. caCaMKKα did not increase basal TBC1D1 (Ser(237), Thr(590), Ser(660), pan-Thr/Ser) or TBC1D4 (Ser(588), Thr(642), pan-Thr/Ser) phosphorylation. In insulin-resistant muscle, caCaMKKα increased basal glucose uptake ∼2-fold, and attenuated high fat diet-induced basal TBC1D1 (Thr(590), pan-Thr/Ser) and TBC1D4 (Ser(588), Thr(642), pan-Thr/Ser) phosphorylation. In cell-free assays, CaMKKα increased TBC1D1 (Thr(590), pan-Thr/Ser) and TBC1D4 (Ser(588), pan-Thr/Ser) phosphorylation. Collectively, these results demonstrate that caCaMKKα stimulates glucose uptake additively with insulin, and in insulin-resistant muscle; and alters the phosphorylation of TBC1D1/TBC1D4.

Alternate JournalDiabetes