PROJECT SUMMARY Type 2 diabetes is one of the most prevalent and costly chronic diseases worldwide. Hypertension and nondipping blood pressure (BP) are prevalent comorbidities of type 2 diabetes and significant risk factors for detrimental cardiovascular outcomes. While up to 75% of diabetic patients are nondippers, no effective therapy targets nondipping BP in diabetes. Glucagon-like-peptide-1 receptor agonists (GLP-1RA) are a class of recently FDA-approved anti-diabetic drugs that provide exciting new means for the critical but challenging task of managing cardiovascular risk in diabetic patients. The use of GLP-1RAs increased rapidly due to their recently recognized cardiovascular benefits, including lowering BP in addition to effectively reducing HbA1C and body weight. However, whether GLP-1RA influences nondipping BP in diabetes is scarcely studied, and the mechanisms via which GLP-1RA lowers BP remain to be defined. Our preliminary data demonstrate for the first time that a short-acting GLP-1RA, exenatide (Ex), when injected i.p. into type 2 diabetic db/db mice at the beginning of the inactive phase (ZT0, light on time), effectively restored nondipping BP to normal dipping BP. In contrast, when administered at the beginning of the active dark phase (ZT12, light off time), Ex worsened nondipping BP to reversed dipping (most harmful disruption). Our preliminary data also show for the first time that GLP-1 receptor (GLP-1R) mRNA varies with the time of day and is regulated by clock gene BMAL1. Interestingly, we also found that Ex administrated at ZT0 or ZT12 restored or inverted food intake rhythm in db/db mice in parallel with its effects on BP. Together with our recent publication that demonstrated time- restricted feeding effectively prevents and treats nondipping BP via the sympathetic nervous system (SNS) in diabetic db/db mice and literature evidence that the vagus nerve links food intake to modulation of BP, we hypothesize that GLP-1RA administered at ZT0 inhibits food intake, vagus nerve, and SNS via the GLP-1 receptor and its cross-talk with clock BMAL1, thus protecting BP circadian rhythm in type 2 diabetes. Two specific aims are Aim 1. Investigate GLP-1RA as a novel chronomedicine to protect BP circadian rhythm via inhibiting food intake in type 2 diabetes. Aim 2. Define the mechanism by which GLP-1RA protects BP circadian rhythm in type 2 diabetes. To achieve these goals, we will determine the effects of short-acting GLP- 1RA Ex and long-acting GLP-1RA liraglutide administered at ZT0 or ZT12 on the circadian rhythms of metabolism, food intake, clock genes, SNS, and BP in diabetic db/db, db/db-Per2Luc, Bmal1-iKO, Glp1r-KO, brain-specific Glp1r-KO, and vagal neuron-specific Glp1r-KO mice under various feeding regimens. The proposed studies will provide novel pre-clinical evidence suggesting GLP-1RA serves as a novel chronomedicine targeting the nondipping BP in type 2 diabetes, thus improving prognoses and outcomes of diabetic patien...