Diabetes is a metabolic disorder that affects the production and use of insulin in the body. 5’-adenosine monophosphate activated protein kinase (AMPK) and subunits play an important role in co-ordinating metabolic pathways and regulating the effects of Type-2-diabetes. AMPK is a key enzymatic Protein involved in linkiing the energy sensing to the metabolic manipulation and is ubiquitously expressed in various tissues of the living system such as kidney, heart, liver, brain and skeletal muscles. We systematically searched PubMed and Google to generate narrative reviews on this topic. A systematic literature search was conducted from various electronic databases on topics evaluating Type-2-diabetes and the resulting regulation of the AMPK pathway by natural and synthetic activators. This review depicts that the AMPK pathway is activated in various organs and shows its effect by altering hepatic glucose production, glucose production, cholesterol levels and protein synthesis. AMPK activation occurs with natural or synthetic compounds; have an effect on reducing the effects of diabetes. This review summarizes the fact that natural and synthetic compounds play an important role in ameliorating the effects of diabetes through direct or indirect activation. In addition to beneficial effects, synthetic compounds have many side effects. In this review, we focus on the toxic nature of synthetic drugs and compare their effects with plant extracts to determine their glucose-lowering effects, action and safety.