Abstract
BackgroundGlucagon like peptide-1 (GLP-1) stimulates insulin secretion from the pancreas but also has extra-pancreatic effects. GLP-1 may stimulate glucose uptake in cultured muscle cells but the mechanism is not clearly defined. Furthermore, while the pancreatic effects of GLP-1 are glucose-dependent, the glucose-dependency of its extra-pancreatic effects has not been examined.MethodsSkeletal muscle satellite cells isolated from young (22.5±0.97 yr), lean (BMI 22.5±0.6 kg/m2), healthy males were differentiated in media containing either 22.5 mM (high) or 5 mM (normal) glucose for 7 days in the absence or presence of insulin and/or various GLP-1 concentrations. Myocellular effects of GLP-1, insulin and glucose were assessed by western-blot, glucose uptake and glycogen synthesis.ResultsWe firstly show that the GLP-1 receptor protein is expressed in differentiated human muscle satellite cells (myocytes). Secondly, we show that in 5 mM glucose media, exposure of myocytes to GLP-1 results in a dose dependent increase in glucose uptake, GLUT4 amount and subsequently glycogen synthesis in a PI3K dependent manner, independent of the insulin signaling cascade. Importantly, we provide evidence that differentiation of human satellite cells in hyperglycemic (22.5 mM glucose) conditions increases GLUT1 expression, and renders the cells insulin resistant and interestingly GLP-1 resistant in terms of glucose uptake and glycogen synthesis. Hyperglycemic conditions did not affect the ability of insulin to phosphorylate downstream targets, PKB or GSK3. Interestingly we show that at 5 mM glucose, GLP-1 increases GLUT4 protein levels and that this effect is abolished by hyperglycemia.ConclusionsGLP-1 increases glucose uptake and glycogen synthesis into fully-differentiated human satellite cells in a PI3-K dependent mechanism potentially through increased GLUT4 protein levels. The latter occurs independently of the insulin signaling pathway. Attenuation of both GLP-1 and insulin-induced glucose metabolism by hyperglycemia is likely to occur downstream of PI3K.
Highlights
Glucagon like peptide-1 (GLP-1) is a potent incretin hormone produced by L-cells in the ileum and colon
GLP-1 receptor protein is expressed in human skeletal muscle tissue and differentiated muscle satellite cells
In order to assess whether human skeletal muscle expresses the GLP-1 receptor (GLP-1R), INS-1 cells were used as a control in the immunoblot
Summary
Glucagon like peptide-1 (GLP-1) is a potent incretin hormone produced by L-cells in the ileum and colon. The evidence that GLP-1 plays a role in skeletal muscle metabolism emanates almost exclusively from the laboratory of Villanueva-Penacarillo. This group has reported that GLP-1 promotes glucose transport and glycogen synthase activity in rat and human skeletal muscle via a protein kinase C (PKC) related mechanism [9,10,11,12]. The mechanism by which GLP-1 promotes glucose metabolism in muscle is poorly defined due to the use of a number of unspecific inhibitors. In particular the PKC inhibitor, RO318220, was shown to significantly inhibit GLP-1-induced glucose metabolism. Glucagon like peptide-1 (GLP-1) stimulates insulin secretion from the pancreas and has extra-pancreatic effects. While the pancreatic effects of GLP-1 are glucose-dependent, the glucose-dependency of its extra-pancreatic effects has not been examined
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