The Case for Clinical Trials with Novel GABAergic Drugs in Diabetes Mellitus and Obesity

Obesity and diabetes mellitus have become the surprising menaces of relative economic well-being worldwide. Gamma amino butyric acid (GABA) has a prominent role in the control of blood glucose, energy homeostasis as well as food intake at several levels of regulation. The effects of GABA in the body are exerted through ionotropic GABA(A) and metabotropic GABA(B) receptors. This treatise will focus on the pharmacologic targeting of GABA(A) receptors to reap beneficial therapeutic effects in diabetes mellitus and obesity. A new crop of drugs selectively targeting GABA(A) receptors has been under investigation for efficacy in stroke recovery and cognitive deficits associated with schizophrenia. Although these trials have produced mixed outcomes the compounds are safe to use in humans. Preclinical evidence is summarized here to support the rationale of testing some of these compounds in diabetic patients receiving insulin in order to achieve better control of blood glucose levels and to combat the decline of cognitive performance. Potential therapeutic benefits could be achieved (i) By resetting the hypoglycemic counter-regulatory response; (ii) Through trophic actions on pancreatic islets, (iii) By the mobilization of antioxidant defence mechanisms in the brain. Furthermore, preclinical proof-of-concept work, as well as clinical trials that apply the novel GABA(A) compounds in eating disorders, e.g., olanzapine-induced weight-gain, also appear warranted.