Evaluation of Gamma Amino Butyric Acid (GABA) and Glibenclamide Combination Therapy in Streptozotocin Induced Diabetes

Abstract

Background: Type 1-diabetes (T1D) is characterized by autoimmune destruction of β-cells and loss of endogenous insulin. Lifelong dependency on exogenous supply of insulin presents a great challenge in pharmacotherapy of T1D that elicits quest for alternative therapies, which can protect β-cells and revive their insulinogenic functions. GABA (γaminobutyric acid) has immuno-protective and β-cell regenerative capabilities. Co-administration of an insulin secretagogue such as glibenclamide (Glib) along with GABA may enhance the pancreatic insulin output in T1D. Objective: The present study evaluated the possible mechanism of GABA in improvement of glucose tolerance and its effects in streptozotocin (STZ) induced T1D along with Glib. Methods: Wistar rats (180-220 g) were administered a single dose of STZ (55 mg/kg, i.p.). GABA (100 mg/kg, i.p.) and Glib (5 or 10 mg/kg, i.p.) alone or in combination were administered for 28 days. Body weight (b.w.), water consumption, fasting blood glucose (FBG), oral glucose tolerance, plasma lipids, insulin and muscle GLUT-4 (glucose transporters) protein level were assessed. Results: T1D significantly decreased b.w. and increased water-intake in rats. An increase in FBG, and decrease in plasma insulin and muscle GLUT-4 indicated STZ-triggered destruction of β-cells in diabetic rats accompanied with dyslipidaemia. GABA or Glib (10 mg/kg) significantly improved b.w., plasma insulin and GLUT-4 levels, and ameliorated FBG and blood lipid profile in diabetic rats. GABA and Glib (5 mg/kg) combination therapy achieved far better control over hyperglycaemia and related pathogenic conditions (b.w., water-intake, insulin, GLUT-4, lipids). The anti-diabetic effect of combination therapy was significantly more pronounced in comparison to individual drug treatments. Histopathological analysis revealed an increase in number of functional pancreatic-islets by combination therapy. Conclusion: GABA revitalized β-cells against STZ-toxicity. GABA and Glib synergistically augmented insulin secretion that can be used to manage T1D and its complications. GABA has the potential to remarkably enhance the therapeutic outcome in diabetic patients and reduce the dose of existing anti-diabetic drugs such as Glib.