Modulation by a Sulfonylurea of Insulin-dependent Glycogenesis, but Not of Insulin Binding, in Cultured Rat Hepatocytes: Evidence for a Postreceptor Mechanism of Action

Fleig, Wolfgang E.; Noether-Fleig, Gaby; Fussgaenger, Rolf D.; Ditschuneit, H.

doi:10.2337/diab.33.3.285

Cited by 48 publications

(1 citation statement)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The reaction was terminated by the addition of 200 μ l potassium hydroxide (KOH) (0.5 N) at 4°C. The final glycogen extraction was carried out as previously described in the study by Fleig et al (23). …”

Section: Methodsmentioning

confidence: 99%

Effect of bombesin receptor subtype-3 and its synthetic agonist on signaling, glucose transport and metabolism in myocytes from patients with obesity and type 2 diabetes

González

Martín‐Duce

Martínez-Arrieta

et al. 2015

International Journal of Molecular Medicine

View full text Add to dashboard Cite

Bombesin receptor subtype-3 (BRS-3) is an orphan G-protein-coupled receptor (GPCR) member of the bombesin receptor family. Several studies have suggested an association between obesity, alterations in glucose metabolism, diabetes and the BRS-3 receptor. In this study, we focused on patients simultaneously diagnosed with obesity and type 2 diabetes (OB/T2D). The analysis of BRS-3 expression in the skeletal muscle of these patients revealed a marked decrease in the expression of BRS-3 at the mRNA (23.6±1.3-fold downregulation, p<0.0001) and protein level (49±7% decrease, p<0.05) compared to the normal patients (no obesity and diabetes). Moreover, in cultured primary myocytes from patients with OB/T2D, the synthetic BRS-3 agonist, [D-Try6,β-Ala11,Phe13,Nle14]bombesin6–14, significantly increased the phosphorylation levels of mitogen-activated protein kinase (MAPK), p90RSK1, protein kinase B (PKB) and p70s6K. Specifically, the ligand at 10−11 M induced the maximal phosphorylation of MAPKs (p42, 159±15% of the control; p44, 166±11% of the control; p<0.0001) and p90RSK1 (148±2% of the control, p<0.0001). The basal phosphorylation levels of all kinases were reduced (p<0.05) in the patients with OB/T2D compared to the normal patients. Furthermore, the BRS-3 agonist stimulated glucose transport, which was already detected at 10−12 M (133±9% of the control), reached maximal levels at 10−11 M (160±9%, p<0.0001) and was maintained at up to 10−8 M (overall mean, 153±7%; p<0.007). This effect was less promiment than that attained with 10−8 M insulin (202±9%, p=0.009). The effect of the agonist on glycogen synthase a activity achieved the maximum effect at 10−11 M (165±16% of the control; p<0.0001), which did not differ from that observed with higher concentrations of the agonist. These results suggest that muscle cells isolated from patients with OB/T2D have extremely high sensitivity to the synthetic ligand, and the effects are particularly observed on MAPK and p90RSK1 phosphorylation, as well as glucose uptake. Moreover, our data indicate that BRS-3 may prove to be useful as a potential therapeutic target for the treatment of patients with OB/T2D.

show abstract

Section: Methodsmentioning

confidence: 99%

Effect of bombesin receptor subtype-3 and its synthetic agonist on signaling, glucose transport and metabolism in myocytes from patients with obesity and type 2 diabetes

González

Martín‐Duce

Martínez-Arrieta

et al. 2015

International Journal of Molecular Medicine

View full text Add to dashboard Cite

show abstract

Inositolphosphoglycans and diacylglycerol are possible mediators in the glycogenic effect of GLP‐1(7‐36)amide in BC3H‐1 myocytes

Galera

Clemente

Alcántara

et al. 1996

Cell Biochemistry & Function

View full text Add to dashboard Cite

A potent glycogenic effect of GLP-1(7-36)amide has been found in rat hepatocytes and skeletal muscle, and specific receptors for this peptide, which do not seem to be associated with the adenylate cyclase-cAMP system, have been detected in these tissue membranes. On the other hand, inositolphosphoglycan molecules (IPGs) have been implicated as second messengers of the action of insulin. In this work, we have found, in differentiated BC3H-1 myocytes, specific binding of [125I]GLP-1(7-36)amide, and a stimulatory effect of the peptide on glycogen synthesis, confirming the findings in rat skeletal muscle. Also, GLP-1(7-36)amide modulates the cell content of radiolabelled glycosylphosphatidylinositols (GPIs) and increases the production of diacylglycerol (DAG), in the same manner as insulin acts, indicating hydrolysis of GPIs and an immediate and short-lived generation of IPGs. Thus, IPGs and DAG could be mediators in the glycogenic action of GLP-1(7-36)amide in skeletal muscle.

show abstract

Characterization of ionotrophic purinergic receptors in hepatocytes

et al. 2007

View full text Add to dashboard Cite

Ionotrophic purinergic (P2X) receptors function as receptor-gated cation channels, where agonist binding leads to opening of a nonselective cation pore permeable to both Na ؉ and Ca 2؉ . Based on evidence that extracellular adenosine 5-triphosphate (ATP) stimulates glucose release from liver, these studies evaluate whether P2X receptors are expressed by hepatocytes and contribute to ATP-dependent calcium signaling and glucose release. Studies were performed in isolated hepatocytes from rats and mice and hepatoma cells from humans and rats. Transcripts and protein for both P2X4 and P2X7 were detectable, and immunohistochemistry of intact liver revealed P2X4 in the basolateral and canalicular domains. H epatocytes exhibit regulated release of adenosine 5Ј-triphosphate (ATP) into the extracellular space. 1 Once outside the cell, these nucleotides function as potent autocrine/paracrine signaling molecules that modulate liver function through activation of purinergic receptors in the plasma membrane. Initially discovered in neurons, purinergic receptors are implicated in the control of a spectrum of essential physiologic mechanisms ranging from vascular tone to programmed cell death. In the liver, nanomolar concentrations of ATP, or its breakdown products, activate Cl Ϫ channels, decrease cell volume, and stimulate bile flow. 2,3 Moreover, exposure of perfused isolated livers to ATP stimulates a large release of glucose. 4 Collectively, these coordinated pathways of ATP release, receptor binding, and degradation constitute a versatile mechanism for paracrine regulation of liver function.These diverse effects of ATP are not readily explained by a single receptor type. Previous studies indicate that hepatocytes express several subtypes of G-protein coupled P2Y receptors, including P2Y1, P2Y2, P2Y4, and P2Y6. Selective stimulation of P2Y2 receptors activates plasma membrane chloride channels and stimulates ductular bile secretion. 5 P2Y receptors also appear to play a role in the activation of glycogen phosphorylase, the rate-controlling enzyme in hepatic glycogenolysis, 6 and regulate multiple signaling pathways with changes in cellular [Ca 2ϩ ], eicosanoid production, and cyclic adenosine monophosphate

show abstract

Modulation by a Sulfonylurea of Insulin-dependent Glycogenesis, but Not of Insulin Binding, in Cultured Rat Hepatocytes: Evidence for a Postreceptor Mechanism of Action

Cited by 48 publications

References 10 publications

Effect of bombesin receptor subtype-3 and its synthetic agonist on signaling, glucose transport and metabolism in myocytes from patients with obesity and type 2 diabetes

Effect of bombesin receptor subtype-3 and its synthetic agonist on signaling, glucose transport and metabolism in myocytes from patients with obesity and type 2 diabetes

Inositolphosphoglycans and diacylglycerol are possible mediators in the glycogenic effect of GLP‐1(7‐36)amide in BC3H‐1 myocytes

Characterization of ionotrophic purinergic receptors in hepatocytes

Contact Info

Product

Resources

About