In the healthy urinary tract, the epithelium of the urethra, bladder, ureters, and the collecting ducts express and secrete a cocktail of antimicrobial peptides and proteins (AMPs) that effectively constrain fecal uropathogenic E. coli (UPEC) bacteria from ascending into the parenchyma of the kidney. The expression of several of these AMPs, produced by the ICs of the collecting ducts, is dependent on the classical insulin signaling pathway (red arrows). In the direction of the urine flow down the collecting ducts (black arrow), the concentration of the antimicrobial cocktail increases, creating an increasingly more effective immune barrier. In the setting of type 2 diabetes, which is characterized by insulin resistance, expression of the insulin-dependent AMPs is suppressed, creating a less optimal antimicrobial environment, permitting viable microbes to ascend into the collecting ducts. Once attached to the epithelium of the collecting ducts, bacteria invade the epithelial cells, expand in number, and subsequently provoke an acute inflammatory response, clinically recognized as pyelonephritis.