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Introduction of Diabetes

Diabetes is recognized as a complex and heterogeneous disease that can affect people at different life stages. Modern appreciation of the heterogeneity of diabetes is not simply a product of a deeper understanding of the genetics, risk factors, and pathophysiology of the disease. In the human body, several systems and pathways function in synchrony to bring about and maintain a healthy physiological state. At the core of these processes lies the ability of the organism to maintain a constant stable state or homeostasis. An aberration of homeostasis leads to the development of an injury or a pathological state in various organs. Diabetes reduces the ability of an individual to regulate the level of glucose in the bloodstream resulting in several major and some minor complications. A constellation of changing lifestyles, technology, and societal development has spurred an unprecedented global epidemic of diabetes over the past 40 years. This epidemic has also driven the emergence of new phenotypes, for type 2 diabetes, and a disturbing shift in the demographics of affected populations. The number of people diagnosed with diabetes has increased fourfold since 1980, counting 422 million in 2014, and is expected to rise to 590 million by 2035 (World Health Organisation, 2016).

Fig.1 Scheme of regulation of blood glucose. (Skyler, 2004)

Application of Half-life Extended Drug in Diabetes

According to investigations, 80%-90% of patients with Type 2 diabetes mellitus (T2DM) are coupled with obesity. Therefore, an agent with the properties of promoting weight loss and lowering blood glucose is an ideal treatment route for T2DM. Glucagon-like peptide-1 (GLP-1) is a promising peptide for T2DM treatment due to its multi-functionality through GLP-1 receptor (GLP-1R) binding, with effects such as glucose-dependent insulin secretion, inhibition of gastric emptying, and decreasing appetite. However, the half-life of GLP-1 in circulation is very short, typically about 1-2 min, due to rapid inactivation by dipeptidyl peptidase 4 (DPP-4) and clearance by the kidneys, thus limiting its therapeutic utility. To improve their pharmacological properties, GLP-1R agonists have been extensively developed through chemical or genetic modifications. To date, seven GLP-1 agonists have been approved for the treatment of T2DM by the FDA or EMA. These GLP-1 agonists are developed through three key half-life extension strategies: (i) sequence modification; (ii) fusion to a large protein to increase the hydrodynamic volume; and (iii) exploitation of the recycling mechanism of neonatal Fc receptor (FcRn) by binding to the human serum albumin (HSA) or IgG-Fc.

Fig.2 Schematic representation of GLP-1 genetically fused to albumin-binding domain (ABD) via a linker. (Tan, 2021)

The importance of half-life extended drugs in diabetes is undoubted. Half-life extended drugs also have broad prospects in diabetes research and drug development in the future. Creative Biolabs briefly introduces these and provides comprehensive half-life extension services to global customers. If you are interested in our services or have any questions, please don't hesitate to contact us for more information.

References

1. Skyler, J. S. Diabetes mellitus: pathogenesis and treatment strategies. J Med Chem. 2004, 47(17): 4113-7.
2. Tan, H.; et al. Albumin-binding domain extends half-life of glucagon-like peptide-1. Eur J Pharmacol. 2021, 890: 173650.