Comprehensive Review and Perspective on Fructose 1,6-Bisphosphatase Inhibitors for the Management of Type 2 Diabetes Mellitus

Abstract

The worldwide increasing prevalence of type 2 diabetes emphasizes the need to explore safer and more effective anti-hyperglycemic agents. Type 2 diabetes mellitus (T2DM) is characterized by excessive gluconeogenesis and the resulting endogenous glucose production. Currently used hypoglycemic agents do not act through direct inhibition of gluconeogenesis-mediated glucose production. Recently, fructose 1,6-bisphosphatase (FBPase) has emerged as a promising target to control the overproduction of glucose from gluconeogenesis, as it is a key enzyme in the middle cycle of gluconeogenesis. Several studies on FBPase inhibitors for the management of T2DM have notably shown no severe hypoglycemia, weight gain, or other serious side effects. In the present article, the authors summarize recent developments in the field of FBPase inhibitors with insights into glucose homeostasis, gluconeogenesis, mechanisms of currently available drugs, and emerging targets for the management of T2DM. Further, some strategies and structure-activity relationships (SARs) of FBPase inhibitors are discussed. This review is expected to be useful for researchers working in this area. FBPase inhibitors represent an attractive target for developing more effective and safer therapies for the treatment of T2DM and cancer. AMP mimetic inhibitors have been shown to possess an unfavorable pharmacokinetic profile; hence, efforts are required to develop covalent-allosteric, non-phosphorous-based, or natural FBPase inhibitors in the future.