Diabetes: Restoring erectile function lost to diabetes A protein that initiates multiple tissue repair processes could offer effective treatment for erectile dysfunction arising from diabetes mellitus. High blood sugar levels can lead to serious damage to nerves and blood vessels, with impaired male sexual function one potential consequence. Guo Nan Yinof the Inha University School of Medicine, Incheon, South Korea, and colleagues have identified a molecular pathway that can be targeted to reverse such damage. They determined that a protein called LRG1 acts on a receptor called LPHN2 to stimulate blood vessel and nerve growth. LPHN2 is highly expressed in the penile tissue of diabetic humans and rodents, and direct injection of LRG1 effectively restored erectile function in mice. The authors hypothesize that this same pathway could also be used for treatments for other diabetic complications, such as chronic wounds. Diabetes mellitus (DM) is a chronic metabolic disorder characterized by inappropriate hyperglycemia, which causes endothelial dysfunction and peripheral neuropathy, ultimately leading to multiple complications. One prevalent complication is diabetic erectile dysfunction (ED), which is more severe and more resistant to treatment than nondiabetic ED. The serum glycoprotein leucine-rich alpha-2-glycoprotein 1 (LRG1) is a modulator of TGF-beta-mediated angiogenesis and has been proposed as a biomarker for a variety of diseases, including DM. Here, we found that the adhesion GPCR latrophilin-2 (LPHN2) is a TGF-beta-independent receptor of LRG1. By interacting with LPHN2, LRG1 promotes both angiogenic and neurotrophic processes in mouse tissue explants under hyperglycemic conditions. Preclinical studies in a diabetic ED mouse model showed that LRG1 administration into the penile tissue, which exhibits significantly increased LPHN2 expression, fully restores erectile function by rescuing vascular and neurological abnormalities. Further investigations revealed that PI3K, AKT, and NF-kappa B p65 constitute the key intracellular signaling pathway of the LRG1/LPHN2 axis, providing important mechanistic insights into LRG1-mediated angiogenesis and nerve regeneration in DM. Our findings suggest that LRG1 can be a potential new therapeutic option for treating aberrant peripheral blood vessels and neuropathy associated with diabetic complications, such as diabetic ED.