Type II diabetes mellitus and obesity: Common links, existing therapeutics and future developments

ABSTRACT

Type II diabetes mellitus (T2DM) and obesity are two common pathophysiological conditions of metabolic syndrome(MetS), a collection of similar metabolic dysfunctions due to sedentary lifestyle and overnutrition. Obesity arises fromimproper adipogenesis which otherwise has a crucial role in maintaining proper metabolic functions. Downstream eventsarising from obesity have been linked to T2DM. The nuclear receptor peroxisome proliferator activator gamma (PPAR-c),responsible for maintaining lipid and glucose homeostasis, is down-regulated under obesity leading to a weakened insulinsensitivity of the human body. In course of our review we will outline details of the down-regulation mechanism, provide anoverview of the current clinical therapeutics and their shortcomings. Toxicity studies on the seminal drug troglitazone,belonging to the most effective glitazone anti-diabetic category, is also discussed. This will lead to an overview aboutstructural adaptations on the existing glitazones to alleviate their side effects and toxicity. Finally, we forward a concept ofnovel therapeutics mimicking the glitazone framework, based on some design concepts and preliminary in silico studies.These could be later developed into dual acting drugs towards alleviating the deleterious effects of obesity on normalglucose metabolism, and address obesity in itself.