Date Available
12-12-2025
Year of Publication
2024
Document Type
Doctoral Dissertation
Degree Name
Doctor of Philosophy (PhD)
College
Medicine
Department/School/Program
Pharmacology and Nutritional Sciences
Advisor
Dr. Zhenheng Guo
Abstract
Although largely impacted by age, race and ethnicity, and socioeconomic factors, Type 2 Diabetes Mellitus (T2DM) is primarily driven by obesity, currently affecting ~30 million in the U.S and ~463 million globally. T2DM carries numerous complications, including high prevalence of hypertension and nondipping blood pressure (BP), sleep insufficiency and fragmentation. Nondipping BP is an inadequate drop in BP (≤ 10%) during sleeping hours compared with waking hours. Lending to this, sleep disturbance acts as both precursor and consequence of metabolic dysregulation, greatly impacting circadian rhythmicity. To model these conditions, we utilized diabetic (db/db) mice. These mice carry a point mutation in their leptin receptor gene, rendering it unresponsive to leptin – a hormone that acts on the hypothalamus to suppress appetite and increase energy expenditure. As such, db/db mice are hyperphagic which drives progressively worsening hyperglycemia, obesity, and insulin resistance. Importantly, db/db mice consume a relatively high amount of food during their light/inactive phase. In turn, this contributes to a nondipping BP phenotype and an altered sleep-wake cycle. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), a class of T2DM medication, have demonstrated diverse therapeutic benefits. While glucoselowering and food intake suppression are core characteristics of GLP-1 RAs, they are also advantageous for cardiovascular complications associated with T2DM. Whether time of administration should be a consideration in their clinical iii use, or the mechanisms by which they exert their effects, has yet to be fully elucidated. To determine if GLP-1-based therapy could improve nondipping BP in db/db mice, the short-acting GLP-1 RA, exenatide, was intraperitoneally injected at the onset of the light (zeitgeber time, [ZT] 0) or dark (ZT12) phase in male diabetic db/db mice and nondiabetic controls (db/+). BP and food intake were simultaneously monitored using radiotelemetry and BioDAQ cages, respectively. ZT0 administration of exenatide decreased light phase BP, restoring dipping BP. In contrast, ZT12 exenatide administration decreased dark phase BP, worsening BP circadian rhythm to reversed dipping – the most severe pattern of BP rhythm. Changes in BP rhythm corresponded with changes in food intake, indicating a potential role for food intake’s daily pattern in the regulation of BP’s circadian rhythm. When food accessibility was prevented, exenatide’s BP-lowering ability was abolished. Under ad libitum feeding, urinary norepinephrine content was significantly reduced for 6 hours following exenatide administration at both ZT0 and ZT12. Pharmacological blockade utilizing a nicotinic acetylcholine receptor antagonist, or an alpha-1 antagonist prevented exenatide’s BP-lowering effect. When food was made inaccessible, pharmacological blockade alone or in combination with exenatide was unable to lower BP. Thus, ZT0 exenatide administration restores BP dipping in db/db mice by inhibiting food intake and suppressing sympathetic activity during the light phase. A potential physiological mechanism for the regulation of BP dipping in db/db mice is sleep quantity and quality. To determine if ZT0 or ZT12 exenatide iv administration has a sleep-enhancing effect, the above experimental design was utilized while mice were housed in Piezoelectric cages – a noninvasive approach for measuring amount, duration, and bouts of sleep and wake states. ZT0 exenatide administration significantly increased light phase sleep quantity and lowered indices of sleep fragmentation. ZT12 exenatide administration significantly increased dark phase sleep, blunting light and dark phase differences, and offered no sleep quality benefit. Endogenous clocks are molecular timekeeping mechanisms that generate and regulate circadian rhythms, orchestrating daily physiological and behavioral processes in anticipation of and response to environmental cycles. To determine if changes in clock gene expression may, in part, explain these observed phenotypic changes, mice were sacrificed at ZT5 or ZT17, without treatment or with 5 consecutive days of ZT0 or ZT12 exenatide administration. ZT0 exenatide administration significantly altered light-to-dark phase difference of several clock genes in the brain cortex, partially or completely restoring expression to that of nondiabetic controls
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2024.433
Funding Information
This study was supported by National Institutes of Health grants HL141103, HL14297, and F31HL162463.
Recommended Citation
Chacon, Aaron, "Exenatide as chronopharmacotherapy for T2DM associated complications: targeting nondipping blood pressure and sleep insufficiency" (2024). Theses and Dissertations--Pharmacology and Nutritional Sciences. 59.
https://uknowledge.uky.edu/pharmacol_etds/59
Included in
Cardiovascular Diseases Commons, Medical Pharmacology Commons, Nutritional and Metabolic Diseases Commons
