title: Metformin attenuates hepatic insulin resistance in type-2 diabetic rats through PI3K/Akt/GLUT-4 signalling independent to bicuculline-sensitive GABAAreceptor stimulation.
abstract: BACKGROUND
  Metformin attenuates type-2 diabetes mellitus (T2DM)-induced hepatic dysfunction and altered PI3K/Akt/GLUT-4 signalling in experimental studies. However, its effect on bicuculline-sensitive gamma amino butyric acid (GABA)-A receptor (GABAAR)-mediated calcium-dependent PI3K/Akt/GLUT-4 signalling in liver challenged to T2DM has not been established.
  
  
  OBJECTIVE
  The effectiveness of metformin on bicuculline-sensitive GABAAR-mediated hepatic insulin signalling was carried out in presence or absence of bicuculline (2.0 mg/kg, i.p.) in experimental T2DM rats.
  
  
  METHODS
  The whole experimental design was divided into three independent sets of experiments. Each set comprised seven groups of six male rats each. T2DM was induced in the animals by administering streptozotocin (45 mg/kg, i.p.) and nicotinamide (110 mg/kg, i.p.) at a time lag of 15 min except control group rats in three experiments. Metformin and/or bicuculline or wortmannin were administered once daily for one week from seventh day of streptozotocin injection in all the experimental sets.
  
  
  RESULTS
  Metformin attenuated T2DM-induced hyperglycaemia in glucose (40%) and insulin (50%) tolerance tests in rats. Metformin also attenuated T2DM-induced hyperglycaemia (40%), hyperinsulinaemia (30%), insulin resistance (50%) and β-cell dysfunction (300%) in the animals. Metformin did not attenuate T2DM-induced decrease in rat hepatic intracellular calcium. Further, metformin mitigated T2DM-induced decrease in hepatic phosphorylated Akt and GLUT-4 translocation in the animals. The anti-diabetic activity of metformin was abolished by wortmannin but not with bicuculline co-administration in T2DM animals.
  
  
  CONCLUSIONS
  These results suggest that metformin ameliorated T2DM-induced hepatic insulin resistance through bicuculline-sensitive GABAAreceptor-independent PI3K/Akt/GLUT-4 signalling pathway in animals.
authors.affiliation: a Pharmacology Laboratory, Department of Pharmaceutics , Indian Institute of Technology (Banaras Hindu University) , Varanasi , UP , India.
authors.forename: Debapriya
authors.initials: D
authors.lastname: Garabadu
authors.affiliation: a Pharmacology Laboratory, Department of Pharmaceutics , Indian Institute of Technology (Banaras Hindu University) , Varanasi , UP , India.
authors.forename: Sairam
authors.initials: S
authors.lastname: Krishnamurthy
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D051275:Glucose Transporter Type 4 / Q000502:physiology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D011963:Receptors, GABA-A; C495694:Slc2a4 protein, rat; D008687:Metformin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium; D000077191:Wortmannin; D001640:Bicuculline
keywords: Calcium; glucose transporter-4; liver; nicotinamide; phosphoinositide3-kinase (PI3K)/phosphokinase-B (Akt); streptozotocin; wortmannin