Metformin attenuates hepatic insulin resistance in type-2 diabetic rats through PI3K/Akt/GLUT-4 signalling independent to bicuculline-sensitive GABA _A receptor stimulation

Abstract

Context: 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.Materials and 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.Discussion and conclusion: These results suggest that metformin ameliorated T2DM-induced hepatic insulin resistance through bicuculline-sensitive GABAA receptor-independent PI3K/Akt/GLUT-4 signalling pathway in animals.

Metformin treatment improves the spatial memory of aged mice in an APOE genotype–dependent manner

“…As an insulin sensitizer, metformin is used to treat T2DM and can attenuate IR by activating insulin signaling pathways (32,33). To investigate the effect of metformin on insulin signaling in the aged ApoE-TR mice, we examined the expression of IRb and the expression and phosphorylation of IRS1 and Akt from the hippocampus lysates by immunoblot (Fig.…”

Rapamycin improves insulin resistance and hepatic steatosis in type 2 diabetes rats through activation of autophagy

“…T2DM is due to insulin resistance (IR), characterized by a defect of the peripheral tissues, including liver, adipose tissues, and skeletal muscles, in response to insulin (Feng et al, 2014). IR is the core mechanism of T2DM and thus has become the main target of T2DM treatment at this stage (Jiang et al, 2015;Garabadu and Krishnamurthy, 2017).…”

Cucurbitacin Attenuates Hyperglycemia by Increasing Glut2 Through Pi3k-Pakt in the Hepatocytes of Streptozotocin Induced Diabetic Rats

“…This leads to stimulate IRS proteins, followed by activation of PI3K/Akt and subsequent translocation of GLUT and glucose uptake by the cells. [23] To explore the effect of cucurbitacin on insulin sensitivity in terms of the cascade proteins in the insulin signaling pathway in pancreas and liver was determined. The PI3K-Akt pathway act as a central part in insulin signal transduction, [24] which are responsible for the mainstream of metabolic actions of insulin specifically in muscle, liver, pancreas and adipose tissue [25] and is activated after IRS tyrosine phosphorylation upon stimulation by insulin.…”