The Impact of Diabetes Mellitus on Antimicrobial Peptide Production and Renal Bacterial Defense
Diabetes mellitus is a systemic disorder that increases susceptibility to infection. The most common site of infection in diabetic patients is the urinary tract. Urinary tract infections (UTI) are ten times more common in diabetics. The long-term objective of this proposed research project is to improve the care of diabetic patients with UTIs by identifying novel therapeutic options. The proposed research project will test the hypothesis that antimicrobial peptides (AMP), a ubiquitous component of the innate immune response, are important in the regulation and prevention of UTI. The primary objective of this proposal is to investigate if diabetes mellitus impairs the production of AMPs, weakening innate uroepithelial defense mechanisms. Specifically, this project evaluates how insulin bioavailability and downstream PI3K/AKT signaling regulates the production of AMPs. The anticipated outcome of this work is the advancement of our understanding of the innate immune mechanisms that predispose diabetics to UTI and to identify potential regulatory targets that we may utilize to develop AMPs as UTI therapeutic options. Specific Aim 1 is designed to define how urinary AMP concentrations correlate with insulin availability. Specific Aim 2 is designed to identify if altered insulin signaling influences downstream PI3K/AKT signaling and AMP production. This will be done by intercalated cell-specific knock-out of the insulin receptor in the kidney. Successful completion of these proposed aims will help develop the needed expertise to develop AMPs as novel therapeutics in patients with diabetes mellitus

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