Journal
DIABETES
Volume 63, Issue 1, Pages 142-151Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db13-0452
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- National Institute of Arthritis and Musculoskeletal and Skin Diseases [R00 AR056298, F32 AR061946]
- East Carolina University
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R00AR056298, K99AR056298, F32AR061946] Funding Source: NIH RePORTER
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In insulin-sensitive skeletal muscle, the expression of constitutively active Ca2+/calmodulin-dependent protein kinase kinase (caCaMKK) stimulates glucose uptake independent of insulin signaling (i.e., Akt and Akt-dependent TBC1D1/TBC1D4 phosphorylation). Our objectives were to determine whether caCaMKK 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-fat diet (60% kcal) for 12 weeks to induce insulin resistance. Muscles were transfected with empty vector or caCaMKK plasmids using in vivo electroporation. After 2 weeks, caCaMKK protein was robustly expressed. In insulin-sensitive muscle, caCaMKK increased basal in vivo [H-3]-2-deoxyglucose uptake approximately twofold, insulin increased glucose uptake approximately twofold, and caCaMKK plus insulin increased glucose uptake approximately fourfold. caCaMKK 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, caCaMKK increased basal glucose uptake approximately twofold, 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, CaMKK increased TBC1D1 (Thr(590), pan-Thr/Ser) and TBC1D4 (Ser(588), pan-Thr/Ser) phosphorylation. Collectively, these results demonstrate that caCaMKK stimulates glucose uptake additively with insulin, and in insulin-resistant muscle, and alters the phosphorylation of TBC1D1/TBC1D4.
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