Exenatide administration time determines the effects on blood pressure dipping in db/db mice via modulation of food intake and sympathetic activity

Abstract

AbstractType 2 diabetics have an increased prevalence of hypertension and nondipping blood pressure (BP), which worsen cardiovascular outcomes. Exenatide, a short acting glucagon-like peptide-1 receptor agonist (GLP-1RA) used to treat type 2 diabetes, also demonstrates blood pressure (BP)-lowering effects. However, the mechanisms behind this and the impact of administration timing on BP dipping remain unclear. We investigated the effects of exenatide intraperitoneal injected at light onset (ZT0) or dark onset (ZT12) in diabetic (db/db) mice and nondiabetic controls. Using radio-telemetry and BioDAQ cages, we continuously monitored BP and food intake. Db/db mice exhibited non-dipping BP and increased food intake. ZT0 exenatide administration restored BP dipping by specifically lowering light-phase BP, while ZT12 exenatide reversed dipping by lowering dark-phase BP. These effects correlated with altered food intake patterns, and importantly, were abolished when food access was removed. Additionally, urinary norepinephrine excretion, measured by HPLC, was significantly reduced 6 hours post-exenatide at both ZT0 and ZT12, suggesting sympathetic nervous system involvement. Notably, combining exenatide with either ganglionic blocker mecamylamine or -blocker prazosin did not enhance BP reduction beyond the individual effects of each blocker. These findings reveal that exenatide, when administered at light onset, restores BP dipping in db/db mice by suppressing light-phase food intake and sympathetic activity. Importantly, the efficacy of exenatide is dependent on food availability and its timing relative to circadian rhythms, highlighting the potential for chronotherapy in optimizing GLP-1RA- based treatments for type 2 diabetes and hypertension. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=178 HEIGHT=200 SRC="FIGDIR/small/601700v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@29812dorg.highwire.dtl.DTLVardef@dfbaaborg.highwire.dtl.DTLVardef@586343org.highwire.dtl.DTLVardef@dcebe4_HPS_FORMAT_FIGEXP M_FIG C_FIG Article HighlightsO_LIMaintaining a normal blood pressure (BP) circadian rhythm is vital for cardiovascular health, but diabetes often disrupts this rhythm. The effect of exenatide, a GLP-1 receptor agonist (GLP-1RA), on BP rhythm in diabetes is uncertain. C_LIO_LIThis study investigates the impact of exenatide administration timing on BP patterns in diabetic db/db mice. C_LIO_LIFindings indicate that exenatide given at the onset of rest restores normal BP dipping, while at the start of the active phase worsens BP rhythm by modulating food intake and sympathetic activity. C_LIO_LITiming GLP-1 RA administration may optimize BP control and provide cardiovascular benefits for type 2 diabetes patients. C_LI