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

Abstract

Exendin-4 (Ex-4) mimics glucagon-like peptide-1 (GLP-1 or GCG as listed in the HUGO database), being anti-diabetic and anorectic, in stimulating glucose and lipid metabolism in extrapancreatic tissues. We studied the characteristics of Ex-4 and GLP-1 action, during prolonged treatment, on GLUTs expression (mRNA and protein), glycogen content (GC), glucose transport (GT), glycogen synthase a (GSa), and kinase (PI3K and MAPKs) activity, in liver, muscle, and fat of insulin-resistant (IR, by fructose) and type 2 diabetic (T2D, streptozotocin at birth) rats compared with normal rats. In both IR and T2D, the three tissues studied presented alterations in all measured parameters. In liver, GLP-1 and also Ex-4 normalized the lower than normal Glut2 (Slc2a2) expression and showed a trend to normalize the reduced GC in IR, and GLP-1, like Ex-4, also in T2D, effects mediated by PI3K and MAPKs. In skeletal muscle, neither GLP-1 nor Ex-4 modified Glut4 (Slc2a4) expression in either experimental model but showed normalization of reduced GT and GSa, in parallel with the normalization of reduced PI3K activity in T2D and MAPKs in both models. In adipose tissue, the altered GLUT4 expression in IR and T2D, along with reduced GT in IR and increased GT in T2D, and with hyperactivated PI3K in both, became normal after GLP-1 and Ex-4 treatment; yet, MAPKs, that were also higher, became normal only after Ex-4 treatment. The data shows that Ex-4, as well as GLP-1, exerts a normalizing effect on IR and T2D states through a distinct post-receptor mechanism, the liver being the main target for Ex-4 and GLP-1 to control glucose homeostasis.

Effects of intraportal exenatide on hepatic glucose metabolism in the conscious dog

“…Most importantly, incretins are known to stimulate insulin secretion during hyperglycemia. In addition, glucagon secretion may be reduced, and some studies have suggested that incretins may have direct effects on tissues such as the liver, increasing insulin sensitivity (1,10,26) and modifying molecular regulators of hepatic glucose metabolism (3,14,15,45,54), thereby modifying liver glucose production and uptake independently from the effects of changes in insulin secretion. On the other hand, other studies have not observed a direct effect (1,10,26), and our data support the latter conclusion.…”

“…Ex-4 has been shown to increase liver glucokinase activity in hepatocytes isolated from diabetic mice in an insulin-independent manner (14,15). In addition, GLP-1 and Ex-4 have been reported to increase glycogen accumulation in rat hepatocytes, an effect associated with increased and decreased glycogen synthase and phosphorylase activities, respectively (3,45,54), although others were unable to reproduce those results (47). In vivo, in response to physiological GLP-1 infusion in humans and dogs, some studies have identified insulin-independent increases in glucose uptake, including by the liver (11,12,22,48), whereas others have not (50,57).…”

“…For example, when rat models of insulin resistance and diabetes were treated with Ex-4 at 1.7 pmol·kg Ϫ1 ·min Ϫ1 for 3 days, there were effects on liver, skeletal muscle, and adipose tissues, including improvements in glucose transporter expression and glucose transport associated with normalization of phosphoinositide 3-kinase (PI3K) activity (45). In other studies, when tissues from normal rats were incubated with Ex-4, skeletal muscle glucose utilization and oxidation increased, as did glycogen synthase activity and glycogen content in isolated hepatocytes (3), effects associated with activation of PI3K, PKC, and protein phosphatase-1 (54).…”

Network-Based Method for Identifying Co-Regeneration Genes in Bone, Dentin, Nerve and Vessel Tissues

“…As a functional component of the nuclear pore complexes, considering that nuclear pore complexes have been reported to contribute to the generation of dentin [75], it is reasonable to summarize that NUP153 is definitely a co-regenerative gene for both dentin and vessel [84]. GCG (ENSP00000387662) has been widely reported to contribute to glucose metabolism and homeostasis [85,86]. According to recent publications, GCG has been confirmed to enhance the dentin bio modification potentials, implying its potential functions during dentin regeneration [87].…”

Apigenin Causes Biochemical Modulation, Glut4 and Cd38 Alterations to Improve Diabetes and to Protect Damages of Some Vital Organs in Experimental Diabetes

“…Membrane samples were prepared from the liver cells and muscles according to available method (Moreno et al, 2012). Membrane samples were stored at-70°C for analysis.…”