Abstract
The purpose of this study was to investigate the effect of lithium on glucose disposal in a high-fat diet-induced type 2 diabetes mellitus (T2DM) and streptozotocin-induced type 1 diabetes mellitus (T1DM) animal model along with low-volume exercise and low-dose insulin. Lithium decreased body weight, fasting plasma glucose, and insulin levels when to treat with low-volume exercise training; however, there were no adaptive responses like an increase in GLUT4 content and translocation factor levels. We discovered that lithium enhanced glucose uptake by acute low-volume exercise-induced glycogen breakdown, which was facilitated by the dephosphorylation of serine 473-AKT (Ser473-AKT) and serine 9-GSK3β. In streptozotocin-induced T1DM mice, Li/low-dose insulin facilitates glucose uptake through increase the level of exocyst complex component 7 (Exoc7) and Ser473-AKT. Thus, lithium enhances acute exercise-induced glycogen breakdown and insulin-induced AKT activation and could serve as a candidate therapeutic target to regulate glucose level of DM patients.
Highlights
50 years ago, lithium, an alkali metal element was found to increase glucose uptake and glycogen synthesis in rat diaphragm muscle [12, 21], similar to the effects of insulin and contraction on skeletal muscle and adipose tissue; lithium chloride (Li) has become the most commonly administered medicine for mania patients [5, 8, 13, 21]
A previous study has only determined Li effect in vitro [24]; in the current study, we investigated the significance of Li effect on glucose disposal in a high-fat diet (HFD)-induced type 2 diabetes mellitus (T2DM) and streptozotocin-induced type 1 diabetes mellitus (T1DM) animal model along with low-volume exercise and low-dosage insulin, which were not sufficient to stimulate glucose uptake
We speculated that long-term treatment of Li with lowvolume exercise for 12 weeks would increase the levels of various glucose transporter 4 (GLUT4) translocation factors; we found that Li and/or low-volume exercise for 12 weeks did not change GLUT4 content (Fig. 2a)
Summary
50 years ago, lithium, an alkali metal element was found to increase glucose uptake and glycogen synthesis in rat diaphragm muscle [12, 21], similar to the effects of insulin and contraction on skeletal muscle and adipose tissue; lithium chloride (Li) has become the most commonly administered medicine for mania patients [5, 8, 13, 21]. Signaling due to muscle contraction and insulin mediates the translocation of GLUT4 to the plasma membrane and activates GLUT4-induced glucose uptake. A previous study indicated that Li induces GLUT4 translocation to the plasma membrane, but GLUT4 is not much activated to take up glucose into the cellular than insulin and exercise [24], and the amount is only 30–40% of the rate of glucose uptake induced by insulin or tetanic contraction. This result is due to the distinct mechanisms underlying translocation and activation of GLUT4 [15, 22]; Li is known to mediate GLUT4 translocation to the plasma membrane; the other effects of Li on glucose uptake induced by muscle contraction and insulin remain unknown
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