Modulation of insulin receptor signalling by pancreastatin in HTC hepatoma cells.

Abstract

Pancreastatin, a neuropeptide derived from chromogranin A, has a glycogenolytic and counterregulatory effect to insulin in the rat liver. This effect is mediated by calcium and protein kinase C activity. Our aim was to study the possible cross-talk between pancreastatin and the insulin signalling system, by using the well-studied insulin sensitive rat hepatoma HTC cells. First, we checked the counterregulatory effect of pancreastatin on insulin action. Pancreastatin dose-dependently inhibited insulin stimulated glycogen synthesis. This effect was not due to competition for insulin receptors. Moreover, when protein kinase C activation was blocked with staurosporine, this effect of pancreastatin was not observed. Next, we found a dose-dependent inhibition of insulin receptor autophosphorylation by pancreastatin. In addition, phosphorylation of the major substrates of insulin receptor in HTC, i. e. insulin-receptor substrate (IRS)-1/IRS-2 and p62 was also blunted and so was its association with p85 regulatory subunit of phosphatidylinositol-3-kinase. Moreover, the insulin activation of S6 kinase was also blocked by pancreastatin. Again, all these inhibitory effects of pancreastatin were prevented by staurosporine. Furthermore, pancreastatin produced Ser/Thr phosphorylation of insulin receptor by a staurosporine-sensitive mechanism. Finally, we checked the pancreastatin activation of protein kinase C in HTC cells and found that a "classical" isoform of this protein is translocated to the plasma membrane. These findings suggest that pancreastatin could exert its anti-insulin effect in the hepatocyte by interrupting the stimulation of early insulin receptor signalling as a result of phosphorylation. This interaction might have a role in the mechanisms of insulin resistance.

• Authors: V Sánchez-Margalet
• Journal: Diabetologia (Diabetologia) Vol. 42 Issue 3 Pg. 317-25 (Mar 1999) ISSN: 0012-186X [Print] Germany
• PMID: 10096784 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chromogranin A
• Insulin
• Pancreatic Hormones
• insulin, iodo-
• pancreastatin
• Receptor, Insulin
• Protein Kinase C
• Staurosporine
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Chromogranin A
• Insulin (analogs & derivatives, metabolism, pharmacokinetics, pharmacology)
• Kinetics
• Liver Neoplasms, Experimental
• Pancreatic Hormones (pharmacology)
• Phosphorylation
• Protein Kinase C (metabolism)
• Rats
• Receptor, Insulin (drug effects, physiology)
• Signal Transduction (drug effects, physiology)
• Staurosporine (pharmacology)