GLP-1(28-36)amide, a C-terminal nonapeptide derived from the cleavage of GLP-1 by neutral endopeptidase (NEP), is an important compound that functions as an antioxidant primarily targeting the mitochondrion to inhibit mitochondrial permeability transition (MPT), displaying anti-diabetic properties and cardioprotection effects[1].

Unlike DPP-IV, the enzyme NEP cleaves GLP-1(7-36)amide or GLP-1(9-36)amide into GLP-1(28-36)amide and is prevalent in endothelial, vascular smooth muscle, cardiac, and renal epithelial cells[1]. Treatment with GLP-1(28-36)amide (100 nM) on hepatocytes for 24 hours specifically influences mitochondrial oxidative metabolism, including gluconeogenesis within hepatocyte mitochondria[1]. Moreover, the plasma half-life of GLP-1(28-36)amide in human hepatocytes (t1/2 = 24 min) surpasses its duration in mouse hepatocytes (t1/2 = 13 min)[1].

Administering GLP-1(28-36)amide at 18.5 nmol/kg body weight/day for 9 weeks significantly reduces hepatic steatosis in diet-induced obese mice. Similarly, daily intraperitoneal injections of 18 nmol/kg GLP-1(28-36)amide over 9 weeks enhance pancreatic β cell mass and proliferation, showcasing a cytoprotective effect in a β-cell injury diabetic mouse model. An in vivo study further reveals that a six-week course of GLP-1(28-36)amide at 18.5 nmol/kg in high-fat diet-fed mice significantly improves hepatic glucose metabolism, an effect linked with increased cAMP levels and PKA target phosphorylation. Moreover, a brief 20-minute administration of GLP-1(28-36)amide to male C57BL6/J mice followed by a procedure involving 30 minutes of global ischemia and 40 minutes of reperfusion results in a significantly enhanced recovery of left ventricular developed pressure (LVDP) in GLP-1(28-36)amide treated hearts compared to controls[1].