Related Experiment Videos
Fructose-1,6-bisphosphatase as a therapeutic target for type 2 diabetes: from molecular mechanisms to clinical
Pallavi Joshi1, Avijit Mazumder1, Bhavani Pentela1
1Department of Pharmacology, Noida Institute of Engineering and Technology (Pharmacy Institute), Knowledge Park-II, Greater Noida, India.
Abstract:
Type 2 diabetes mellitus (T2DM) affects over 415 million individuals globally, with excessive hepatic glucose production representing a primary contributor to hyperglycaemia. Fructose-1,6-bisphosphatase (FBP1), a rate-limiting gluconeogenic enzyme, has emerged as a promising therapeutic target. This review examines FBP1's molecular mechanisms, including its tetrameric structure and allosteric regulation by AMP. FBP1 dysregulation in diabetes involves transcriptional control by FOXO1, CREB, PGC-1α, and epigenetic modifications. Drug discovery efforts have yielded diverse inhibitor classes, including AMP-competitive inhibitors, covalent modulators targeting cysteines C128/C179, and natural products. Leading compounds demonstrate exceptional potency (IC50 0.029 μM) with favourable bioavailability and efficacy in preclinical models. Structure-based design and AI-driven approaches have accelerated optimisation. Clinical translation of FBP1 inhibitors represents a paradigm-shifting opportunity, potentially providing the first medication class specifically targeting hepatic gluconeogenesis for T2DM treatment.
Related Concept Videos
Type II Diabetes II: Pathophysiology
Glucagon-like Receptor Agonists
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by the...
Dipeptidyl Peptidase 4 Inhibitors
Type II Diabetes I: Introduction
Transducer Mechanism: Enzyme-Linked Receptors
Major types that are helpful drug targets include:
Insulin: The Receptor and Signaling Pathways