Roles of insulin signalling and p38 MAPK in the activation by lithium of glucose transport in insulin-resistant rat skeletal muscle.

We have demonstrated previously in insulin-sensitive skeletal muscle that lithium, an alkali metal and non-selective inhibitor of glycogen synthase kinase-3 (GSK-3), activates glucose transport by engaging the stress-activated p38 mitogen-activated protein kinase (p38 MAPK). However, it is presently unknown whether this same mechanism underlies lithium action on the glucose transport system in insulin-resistant skeletal muscle. We therefore assessed the effects of lithium on basal and insulin-stimulated glucose transport, glycogen synthesis, insulin signalling (insulin receptor (IR), Akt, and GSK-3), and p38 MAPK in soleus muscle from female obese Zucker rats. Lithium (10 mM LiCl) increased basal glucose transport by 49% (p < 0.05) and net glycogen synthesis by 2.4-fold (p < 0.05). In the absence of insulin, lithium did not induce IR tyrosine phosphorylation, but did enhance (p < 0.05) Akt ser(473) phosphorylation (40%) and GSK-3beta ser(9) phosphorylation (88%). Lithium potentiated (p < 0.05) the stimulatory effects of insulin on glucose transport (74%), glycogen synthesis (2.4-fold), Akt ser(473) phosphorylation (39%), and GSK-3beta ser(9) phosphorylation (36%), and elicited robust increases (p < 0.05) in p38 MAPK phosphorylation both in the absence (100%) or presence (88%) of insulin. The selective p38 MAPK inhibitor A304000 (10 muM) completely blocked basal activation of glucose transport by lithium, and significantly reduced (42%, p < 0.05) the lithium-induced enhancement of insulin-stimulated glucose transport in insulin-resistant muscle. These results indicate that lithium enhances both basal and insulin-stimulated glucose transport and glycogen synthesis in insulin-resistant skeletal muscle of female obese Zucker rats, and that these lithium-dependent effects are associated with enhanced Akt and GSK-3beta serine phosphorylation. As in insulin-sensitive muscle, the lithium-induced activation of glucose transport in insulin-resistant skeletal muscle is dependent on the engagement of p38 MAPK.

The high-fat-fed lean Zucker rat: a spontaneous isocaloric model of fat-induced insulin resistance associated with muscle GSK-3 overactivity.

High-fat feeding (HFF) is a well-accepted model for nutritionally-induced insulin resistance. The purpose of this investigation was to assess the metabolic responses of female lean Zucker rats provided regular chow (4% fat) or a high-fat chow (50% fat) for 15 wk. HFF rats spontaneously adjusted food intake so that daily caloric intake matched that of chow-fed (CF) controls. HFF animals consumed more (P < 0.05) calories from fat (31.9 +/- 1.2 vs. 2.4 +/- 0.2 kcal/day) and had significantly greater final body weights (280 +/- 10 vs. 250 +/- 5 g) and total visceral fat (24 +/- 3 vs. 10 +/- 1 g). Fasting plasma insulin was 2.3-fold elevated in HFF rats. Glucose tolerance (58%) and whole body insulin sensitivity (75%) were markedly impaired in HFF animals. In HFF plantaris muscle, in vivo insulin receptor beta-subunit (IR-beta) and insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation and phosphorylation of Akt Ser473 and glycogen synthase kinase-3beta (GSK-3beta) Ser9, relative to circulating insulin levels, were decreased by 40-59%. In vitro insulin-stimulated glucose transport in HFF soleus was decreased by 54%, as were IRS-1 tyrosine phosphorylation (26%) and phosphorylation of Akt Ser473 (38%) and GSK-3beta Ser9 (25%), the latter indicative of GSK-3 overactivity. GSK-3 inhibition in HFF soleus using CT98014 increased insulin-stimulated glucose transport (28%), IRS-1 tyrosine phosphorylation (28%) and phosphorylation of Akt Ser473 (38%) and GSK-3beta Ser9 (48%). In summary, the female lean Zucker rat fed a high-fat diet represents an isocaloric model of nutritionally-induced insulin resistance associated with moderate visceral fat gain, hyperinsulinemia, and impairments of skeletal muscle insulin-signaling functionality, including GSK-3beta overactivity.