Interleukin-6 acts as insulin sensitizer on glycogen synthesis in human skeletal muscle cells by phosphorylation of Ser⁴⁷³ of Akt

Abstract

Previous studies showed an insulin-"desensitizing" action of IL-6 on glycogen synthesis in hepatocytes. We recently found no inhibition of the proximal steps of the insulin signal cascade in human skeletal muscle cells. Because these data indicate a possible tissue-specific effect of IL-6, we investigated the influence of IL-6 on insulin-stimulated glycogen synthesis in these cells. At first, we found that incubation of the cells with 20 ng/ml IL-6 alone induced phosphorylation of Ser473 of Akt, but not of Thr308 time dependently and we observed that IL-6 augments insulin-induced Ser473 and Thr308 phosphorylation in the low nanomolar range of insulin. Moreover, IL-6 increased insulin-stimulated phosphorylation of glycogen synthase kinase-3. Accordingly, IL-6 enhanced glycogen synthesis in the presence of 3 and 10 nM insulin, whereas IL-6 alone had only a marginal effect. IL-6 treatment of C57Bl/6 mice readily stimulated phosphorylation of Ser473 in skeletal muscle. Our result that IL-6 did not induce Ser473 phosphorylation in the liver of these mice suggests a tissue-specific effect. Together, our data demonstrate a novel insulin-sensitizing function of IL-6 on glycogen synthesis in skeletal muscle cells and indicate that IL-6 exerts cell/tissue-specific effects on insulin action.

Interleukin-6 Increases Insulin-Stimulated Glucose Disposal in Humans and Glucose Uptake and Fatty Acid Oxidation In Vitro via AMP-Activated Protein Kinase

“…For the duration of the clamp, subjects were also infused with either rhIL-6 or sham (control) in a random, repeated-measures, single-blinded fashion. Our pilot work and data from previous studies (9,10,19) demonstrated that IL-6 delivered in 2% human albumin at a rate of 5 g/h would predict a plasma concentration of 100 -140 pg/ml, a level seen with strenuous exercise.…”

Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice

“…AMPK phosphorylation Previous studies have reported that IL-6 increases the phosphorylation of AMPK in several different cells [16][17][18][19]. Indeed, phosphorylated AMPK was markedly increased in the IL-6 mice, while gp130 was not altered (Fig.…”

“…In contrast to the effects in liver and adipose cells, positive effects have been reported in skeletal muscle in terms of increasing glucose uptake in short-term experiments [17][18][19]. However, the overall importance of these short-term experimental studies is unclear considering that IL-6 levels are chronically elevated in obesity, mainly due to increased production by the adipose tissue and the enlarged fat cells [5,42].…”

“…However, insulin-like effects in skeletal muscle cells, associated with AMP kinase (AMPK) activation, have also been shown [16][17][18][19]. Taken together, many experimental studies have shown that chronic exposure to IL-6 induces insulin resistance with the possible exception of skeletal muscle.…”

Discordant gene expression in skeletal muscle and adipose tissue of patients with type 2 diabetes: effect of interleukin-6 infusion

“…We recently showed that infusion of IL6 into patients with type 2 diabetes normalised insulin levels without affecting glucose clearance [11], raising the possibility that acute IL6 infusion may augment insulin sensitivity. In support of this notion, Weigert et al [12,13] recently demonstrated that insulin signalling and glycogen synthesis were increased by IL6 administration in L6 myotubes, while whole-body IL6 knockout renders mice obese and glucose intolerant [14]. In contrast, IL6 treatment impairs liver insulin signalling [15] and leads to impaired insulin action during an insulin tolerance test [16] and a euglycaemic-hyperinsulinaemic clamp [17] in mice.…”