Inositolphosphoglycans possibly mediate the effects of glucagon-like peptide-1(7-36)amide on rat liver and adipose tissue

Increased fat mass contributes to bone deterioration. Glucagon-like peptide 1 (GLP-1) and its related peptide exendin 1-39 amide (Ex-4), two lipid-lowering peptides, exert osteogenic effects in diabetic states. We examined the actions of 3-day administration of GLP-1 or Ex-4 on bone remodeling markers and on bone mass and structure in hyperlipidic (HL) and hypercaloric rats. Wistar rats on a hyperlipidemic diet for 35 days were subcutaneously administered GLP-1 (0 . 86 nmol/kg per h), Ex-4 (0 . 1 nmol/kg per h), or saline (control) by continuous infusion for 3 days. After killing, tibiae were removed for total RNA and protein isolation, as well as femurs and L1-L4 vertebrae for bone mass and quality assessment. Body weight and plasma insulin were unaltered in HL rats, which showed osteopenia (by dual-energy X-ray absorptiometry), associated with hyperglycemia, hypertriglyceridemia, and hypercholesterolemia. GLP-1 or Ex-4 administration decreased the levels of glucose, triglycerides, and total cholesterol in plasma but increased osteocalcin (OC) gene expression and the osteoprotegerin (OPG)/receptor activator of NF-kB ligand (RANKL) ratio -at the expense of an augmented OPG -above corresponding control values in the tibia. Each tested peptide similarly reversed the decreased femoral and vertebral bone mass in these rats, whereas the deteriorated trabecular structure in the vertebrae improved associated with normalization of bone remodeling. These findings demonstrate that GLP-1 and Ex-4 are similarly efficient in reversing the bone alterations in this HL rat model, which has proven to be useful for studying the fat-bone relationships.

Section: Introductionsupporting

confidence: 68%

GLP-1 and exendin-4 can reverse hyperlipidic-related osteopenia

Nuche-Berenguer¹,

Lozano²,

Gutiérrez‐Rojas³

et al. 2011

“…In these cells, GLP-1, like insulin, induced the immediate hydrolysis of GPIsindicating the generation of IPGs -with a global dynamic similar to that previously detected not only in BC3H-1 myocytes (Galera et al 1996) but also in a hepatoma cell line (Trapote et al 1996) and in rat hepatocytes and adipocytes (Márquez et al 1998), suggesting a role for IPGs in the immediate post-receptor mechanism leading to the GLP-1 actions.…”

Section: Discussionmentioning

confidence: 99%

“…Primary culture myocytes (2 10 4 cells per well) from each subject were pre-labeled, for 60 min at 37 C, with 0·2 µCi myo-[ 3 H]inositol in 0·75 ml -MEM with added 0·1% BSA, 1% glutamine and 1% antibiotics; the radioactive medium was then removed and cells were incubated in fresh -MEM for different time periods (0·5-10 min) in the absence (control) and presence of peptides. Incubation was interrupted by addition of 10% TCA at 4 C, and the radioactive GPI content was extracted and determined in the respective precipitates, as previously described in detail (Márquez et al 1998).…”

Section: Ipgsmentioning

confidence: 99%

See 1 more Smart Citation

Glucagon-like peptide-1 (GLP-1) and glucose metabolism in human myocytes

Luque¹,

González²,

Márquez³

et al. 2002

117

Glucagon-like peptide-1 (GLP-1) has been shown to have insulin-like effects upon the metabolism of glucose in rat liver, muscle and fat, and on that of lipids in rat and human adipocytes. These actions seem to be exerted through specific receptors which, unlike that of the pancreas, are not -at least in liver and muscle -cAMP-associated. Here we have investigated the effect, its characteristics, and possible second messengers of GLP-1 on the glucose metabolism of human skeletal muscle, in tissue strips and primary cultured myocytes. In muscle strips, GLP-1, like insulin, stimulated glycogen synthesis, glycogen synthase a activity, and glucose oxidation and utilization, and inhibited glycogen phosphorylase a activity, all of this at physiological concentrations of the peptide. In cultured myotubes, GLP-1 exerted, from 10 13 mol/l, a doserelated increase of the -[U-14 C]glucose incorporation into glycogen, with the same potency as insulin, together with an activation of glycogen synthase a; the effect of 10 11 mol/l GLP-1 on both parameters was additive to that induced by the equimolar amount of insulin. Synthase a was still activated in cells after 2 days of exposure to GLP-1, as compared with myotubes maintained in the absence of peptide. In human muscle cells, exendin-4 and its truncated form 9-39 amide (Ex-9) are both agonists of the GLP-1 effect on glycogen synthesis and synthase a activity; but while neither GLP-1 nor exendin-4 affected the cellular cAMP content after 5-min incubation in the absence of 3-isobutyl-1-methylxantine (IBMX), an increase was detected with Ex-9. GLP-1, exendin-4, Ex-9 and insulin all induced the prompt hydrolysis of glycosylphosphatidylinositols (GPIs). This work shows a potent stimulatory effect of GLP-1 on the glucose metabolism of human skeletal muscle, and supports the long-term therapeutic value of the peptide. Further evidence for a GLP-1 receptor in this tissue, different from that of the pancreas, is also illustrated, suggesting a role for an inositolphosphoglycan (IPG) as at least one of the possible second messengers of the GLP-1 action in human muscle.

“…In these extrapancreatic tissues, GLP-1 seems to act through specific receptors (Mérida et al 1993, Valverde et al 1993, Delgado et al 1995, Villanueva-Peñacarrillo et al 1995a,b, Yang et al 1998 which, unlike the pancreatic one (Thorens 1992), are not associated with an activation of adenylate cyclase , Yang et al 1998. It has been proposed that an inositol phosphoglycan (IPG) could be one of the possible second messengers in the actions of this peptide (Galera et al 1996, Trapote et al 1996, Márquez et al 1998. In fact, a recent report has shown that GLP-1 stimulates glycogen synthase a activity and glycogen synthesis in human skeletal muscle strips and primary culture myotubes, as does insulin, and that it fails to modify the cellular cAMP content while stimulating IPG generation (Luque et al 2002).…”

Section: Introductionmentioning

confidence: 99%

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

Acitores

González²,

Sancho³

et al. 2004

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.