Article

Diabetologia

, Volume 50, Issue 8, pp 1743-1751

First online:

Stimulation of glycogen synthesis and inactivation of phosphorylase in hepatocytes by serotonergic mechanisms, and counter-regulation by atypical antipsychotic drugs

  • L. J. HampsonAffiliated withInstitute of Cellular Medicine, Newcastle University, The Medical School
  • , P. MackinAffiliated withSchool of Neurology, Neurobiology and Psychiatry, The Medical School
  • , L. AgiusAffiliated withInstitute of Cellular Medicine, Newcastle University, The Medical SchoolInstitute of Cellular Medicine, The Medical School (Leech, Level 4) Email author 

Abstract

Aims/hypothesis

Intraportal infusion of serotonin (5-hydroxytryptamine, 5-HT) or inhibitors of its cellular uptake stimulate hepatic glucose uptake in vivo by either direct or indirect mechanisms. The aims of this study were to determine the direct effects of 5-HT in hepatocytes and to test the hypothesis that atypical antipsychotic drugs that predispose to type 2 diabetes counter-regulate the effects of 5-HT.

Materials and methods

Rat hepatocytes were studied in short-term primary culture.

Results

Serotonin (5-HT) stimulated glycogen synthesis at nanomolar concentrations but inhibited it at micromolar concentrations. The stimulatory effect was mimicked by α-methyl-5-HT, a mixed 5-HT1/5-HT2 receptor agonist, whereas the inhibition was counteracted by a 5-HT2B/2C receptor antagonist. α-Methyl-5-HT stimulated glycogen synthesis additively with insulin, but unlike insulin, did not stimulate glucose phosphorylation and glycolysis, nor did it cause Akt (protein kinase B) phosphorylation. Stimulation of glycogen synthesis by α-methyl-5-HT correlated with depletion of phosphorylase a. This effect could not be explained by elevated levels of glucose 6-phosphate, which causes inactivation of phosphorylase, but was explained, at least in part, by decreased phosphorylase kinase activity in situ. The antipsychotic drugs clozapine and olanzapine, which bind to 5-HT receptors, counteracted the effect of α-methyl-5-HT on phosphorylase inactivation.

Conclusions/interpretation

This study provides evidence for both stimulation and inhibition of glycogen synthesis in hepatocytes by serotonergic mechanisms. The former effects are associated with the inactivation of phosphorylase and are counteracted by atypical antipsychotic drugs that cause hepatic insulin resistance. Antagonism of hepatic serotonergic mechanisms may be a component of the hepatic dysregulation caused by antipsychotic drugs that predispose to type 2 diabetes.

Keywords

5-Hydroxytryptamine Atypical antipsychotics Glycogen Liver Phosphorylase Serotonin Type 2 diabetes