Cell signalling of glucagon-like peptide-1 action in rat skeletal muscle

Abstract

Glucagon-like peptide-1 (GLP-1), an incretin with glucose-dependent insulinotropic and insulinindependent antidiabetic properties, has insulin-like effects on glucose metabolism in extrapancreatic tissues participating in overall glucose homeostasis. These effects are exerted through specific receptors not associated with cAMP, an inositol phosphoglycan being a possible second messenger. In rat hepatocytes, activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB), protein kinase C (PKC) and protein phosphatase 1 (PP-1) has been shown to be involved in the GLP-1-induced stimulation of glycogen synthase. We have investigated the role of enzymes known or suggested to mediate the actions of insulin in the GLP-1-induced increase in glycogen synthase a activity in rat skeletal muscle strips.We first explored the effect of GLP-1, compared with that of insulin, on the activation of PI3K, PKB, p70s6 kinase (p70s6k) and p44/42 mitogen-activated protein kinases (MAPKs) and the action of specific inhibitors of these kinases on the insulin-and GLP-1-induced increment in glycogen synthase a activity.The study showed that GLP-1, like insulin, activated PI3K/PKB, p70s6k and p44/42. Wortmannin (a PI3K inhibitor) reduced the stimulatory action of insulin on glycogen synthase a activity and blocked that of GLP-1, rapamycin (a 70s6k inhibitor) did not affect the action of GLP-1 but abolished that of insulin, PD98059 (MAPK inhibitor) was ineffective on insulin but blocked the action of GLP-1, okadaic acid (a PP-2A inhibitor) and tumour necrosis factor-(a PP-1 inhibitor) were both ineffective on GLP-1 but abolished the action of insulin, and Ro 31-8220 (an inhibitor of some PKC isoforms) reduced the effect of GLP-1 while completely preventing that of insulin.It was concluded that activation of PI3K/PKB and MAPKs is required for the GLP-1-induced increment in glycogen synthase a activity, while PKC, although apparently participating, does not seem to play an essential role; unlike in insulin signaling, p70s6k, PP-1 and PP-2A do not seem to be needed in the action of GLP-1 upon glycogen synthase a activity in rat muscle.

Increased glucagon-like peptide-1 secretion may be involved in antidiabetic effects of ginsenosides

“…These factors may result in a great amelioration in IR. For instance, GLP1 increases glycogen synthesis and glucose transport in skeletal muscles and liver (Redondo et al 2003, Acitores et al 2004. The existence of GLP1 can also amplify insulin signaling in adipocytes (Gao et al 2007).…”

Normalizing action of exendin-4 and GLP-1 in the glucose metabolism of extrapancreatic tissues in insulin-resistant and type 2 diabetic states

“…Treatment of rats from the three groups was initiated at 0900 h. As respective control, rats of the three groups were treated only with saline solution. Just before and after the treatment (72 h), blood samples were collected from all rats in fed condition for plasma glucose and insulin determinations; afterwards, the animals were stunned and killed by a sharp blow to the head, and soleus muscles, epididymal fat pads, and liver of the animals, quick-frozen at K70 8C, were used to prepare solubilized membranes (Villanueva-Peñacarrillo et al 2001) for the analysis of major respective glucotransporter gene expression and the activity of cell signaling enzymes (Villanueva-Peñacarrillo et al 2001, Redondo et al 2003, Acitores et al 2004; additionally, the liver glycogen content (GC) was measured by the anthrone method (Chun and Yin 1998), the soleus muscle glycogen synthase a (GSa) activity as described previously by Luque et al (2002) and glucose transport and the isolated adipocytes glucose uptake by Sancho et al (2005).…”

“…MAP kinase activity (p-p44/p-p42) was measured by immunoblotting (Redondo et al 2003, Acitores et al 2004. PI3K activity was measured directly in p85 immunoprecipitates obtained by treating the muscle, fat, and liver lysates with anti-PI3 kinase p85 and subsequent coupling to protein A-agarose (Phung et al 1997, Redondo et al 2003, Acitores et al 2004; the immunoprecipitates were incubated for 20 min at room temperature with 20 mM [g 32 ATP]…”

“…Glucagon-like peptide-1 (GLP-1 or GCG as listed in the HUGO database), an incretin hormone with antidiabetic properties, exerts insulin-like effects upon glucose transport (GT) and metabolism in the liver, skeletal muscle, and fat of humans and rats , tissues where its effects are dependent on protein kinase (Redondo et al 2003, Acitores et al 2004. The regulatory action of GLP-1 in glucose and lipid metabolism in the liver, muscle, and fat in normal and T2D situations is, out of doubt, due to its neurotrophic and cardioprotective properties (Ossum et al 2009, Bak et al 2011.…”

“…Similar to GLP-1 (Willms et al 1996), Ex-4 lowers gastric emptying (Talsania et al 2005) due to its anorectic properties (Barrera et al 2009). The reported effects of Ex-4 on extrapancreatic tissues are dependent on an increase in the activity of several kinases (González et al 2005a, Arnés et al 2008, some of them are also involved in GLP-1 and insulin actions (Acitores et al 2004, González et al 2005a. The GLP-1-like glucoregulatory actions of Ex-4 (Nielsen et al 2004) are thought to be exerted, at least in part, not only through the pancreatic GLP-1 receptor (Tourrel et al 2002) but also by interacting with GLP-1 receptors in the liver and muscle (Delgado et al 1995, Villanueva-Peñacarrillo et al 1995, Arnés et al 2008, which seem to be structurally and/or functionally distinct from that in the pancreas (Thorens 1992).…”