A randomized controlled trial to compare the effects of time-restricted eating versus Mediterranean diet on symptoms and quality of life in bipolar disorder.

BACKGROUND: The primary objective of this randomized controlled trial (RCT) is to establish the effectiveness of time-restricted eating (TRE) compared with the Mediterranean diet for people with bipolar disorder (BD) who have symptoms of sleep disorders or circadian rhythm sleep-wake disruption. This work builds on the growing evidence that TRE has benefits for improving circadian rhythms. TRE and Mediterranean diet guidance will be offered remotely using self-help materials and an app, with coaching support. METHODS: This study is an international RCT to compare the effectiveness of TRE and the Mediterranean diet. Three hundred participants will be recruited primarily via social media. Main inclusion criteria are: receiving treatment for a diagnosis of BD I or II (confirmed via DIAMOND structured diagnostic interview), endorsement of sleep or circadian problems, self-reported eating window of ≥ 12 h, and no current mood episode, acute suicidality, eating disorder, psychosis, alcohol or substance use disorder, or other health conditions that would interfere with or limit the safety of following the dietary guidance. Participants will be asked to complete baseline daily food logging for two weeks and then will be randomly allocated to follow TRE or the Mediterranean diet for 8 weeks, during which time, they will continue to complete daily food logging. Intervention content will be delivered via an app. Symptom severity interviews will be conducted at baseline; mid-intervention (4 weeks after the intervention begins); end of intervention; and at 6, 9, and 15 months post-baseline by phone or videoconference. Self-rated symptom severity and quality of life data will be gathered at those timepoints, as well as at 16 weeks post baseline. To provide a more refined index of whether TRE successfully decreases emotional lability and improves sleep, participants will be asked to complete a sleep diary (core CSD) each morning and complete six mood assessments per day for eight days at baseline and again at mid-intervention. DISCUSSION: The planned research will provide novel and important information on whether TRE is more beneficial than the Mediterranean diet for reducing mood symptoms and improving quality of life in individuals with BD who also experience sleep or circadian problems. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT06188754.

Hypothalamic Overexpression of Neurosecretory Protein GL Leads to Obesity in Male C57BL/6J Mice.

INTRODUCTION: The mechanisms underlying obesity are not fully understood, necessitating the creation of novel animal models for the investigation of metabolic disorders. We have previously found that neurosecretory protein GL (NPGL), a newly identified hypothalamic neuropeptide, is involved in feeding behavior and fat accumulation in rats. However, the impact of NPGL on obesity remains unclear in any animal model. The present investigation sought to elucidate whether NPGL causes obesity in the obesity-prone mouse strain C57BL/6J. METHODS: We overexpressed the NPGL-precursor gene (Npgl) in the hypothalamus using adeno-associated virus in male C57BL/6J mice fed normal chow (NC) or a high-calorie diet (HCD). After 9 weeks of Npgl overexpression, we measured adipose tissues, muscle, and several organ masses in addition to food intake and body mass. To assess the effects of Npgl overexpression on peripheral tissues, we analyzed mRNA expression of lipid metabolism-related genes by quantitative RT-PCR. Whole body energy consumption was assessed using an O2/CO2 metabolism measurement before an apparent increase in body mass. RESULTS: Npgl overexpression increased food intake, body mass, adipose tissues and liver masses, and food efficiency under both NC and HCD, resulting in obesity observable within 8 weeks. Furthermore, we observed fat accumulation in adipose tissues and liver. Additionally, mRNA expression of lipid metabolism-related factors was increased in white adipose tissue and the liver after Npgl overexpression. Npgl overexpression inhibited energy expenditure during a dark period. CONCLUSION: Taken together, the present study suggests that NPGL can act as an obesogenic factor that acts within a short period of time in mice. As a result, this Npgl overexpression-induced obesity can be widely applied to study the etiology of obesity from genes to behavior.

Pregnancy stage determines the effect of chronic stress on ovarian progesterone synthesis.

Although stress-induced glucocorticoid release is thought to be a primary driver by which maternal stress negatively impacts pregnancy outcomes, the downstream neuroendocrine targets mediating these adverse outcomes are less well understood. We hypothesized that stress-induced glucocorticoid secretion inhibits pituitary hormone secretion, resulting in decreased ovarian progesterone synthesis. Using a chronic restraint model of stress in mice, we quantified steroid hormone production, pituitary hormones, and expression of ovarian genes that support progesterone production at both early ( day 5) and midpregnancy ( day 10). Females subjected to daily restraint had elevated baseline glucocorticoids during both early and midpregnancy; however, lower circulating progesterone was observed only during early pregnancy. Lower progesterone production was associated with lower expression of steroidogenic enzymes in the ovary of restrained females during early pregnancy. There were no stress-related changes to luteinizing hormone (LH) or prolactin (PRL). By midpregnancy, circulating LH decreased regardless of treatment, and this was associated with downregulation of ovarian steroidogenic gene expression. Our results are consistent with a role for LH in maintaining steroidogenic enzyme expression in the ovary, but neither circulating PRL nor LH were associated with the stress-induced inhibition of ovarian progesterone production during early pregnancy. We conclude that chronic stress impacts endocrine networks differently in pregnant and nonpregnant mammals. These findings underscore the need for further studies exploring dynamic changes in endocrine networks participating in pregnancy initiation and progression to elucidate the physiological mechanisms that connect stress exposure to adverse pregnancy outcomes.

A System for In Vivo Imaging of Hepatic Free Fatty Acid Uptake.

Alterations in hepatic free fatty acid (FFA) uptake and metabolism contribute to the development of prevalent liver disorders such as hepatosteatosis. However, detecting dynamic changes in FFA uptake by the liver in live model organisms has proven difficult. To enable noninvasive real-time imaging of FFA flux in the liver, we generated transgenic mice with liver-specific expression of luciferase and performed bioluminescence imaging with an FFA probe. Our approach enabled us to observe the changes in FFA hepatic uptake under different physiological conditions in live animals. By using this method, we detected a decrease in FFA accumulation in the liver after mice were given injections of deoxycholic acid and an increase after they were fed fenofibrate. In addition, we observed diurnal regulation of FFA hepatic uptake in living mice. Our imaging system appears to be a useful and reliable tool for studying the dynamic changes in hepatic FFA flux in models of liver disease.

Chronic subcutaneous infusion of neurosecretory protein GM increases body mass gain in chicks.

Recently we discovered a small hypothalamic protein in the chicken, named neurosecretory protein GL (NPGL), which is associated with body growth and energy metabolism in birds and rodents. Genome database analysis suggested that the NPGL gene has a paralogous gene in vertebrates, named neurosecretory protein GM (NPGM). However, the biological action of NPGM remains unclear. In this study, we investigated whether NPGM affects body growth in chicks. We found that subcutaneous infusion of NPGM for six days increased body mass gain in a dose-dependent manner. Despite the observed increase in body mass, infusion of NPGM did not alter food and water intake. Of note, we observed tendency of mass increase of several peripheral tissues, specifically. When we compared several tissue types, NPGM seemed to induce the largest growth increase in white adipose tissue mass. These results suggest that NPGM may accelerate fat accumulation and body growth. In addition, we analyzed whether NPGM increases body growth through the action of pituitary hormones. However, we observed no significant changes in mRNA expression of pituitary hormones or plasma levels of growth hormone in NPGM-treated chicks. This is the first report describing the biological action of NPGM in vertebrates.

Effects of chronic intracerebroventricular infusion of neurosecretory protein GL on body mass and food and water intake in chicks.

Recently, we discovered a novel cDNA encoding the precursor of a small secretory protein, neurosecretory protein GL (NPGL), in the chicken mediobasal hypothalamus. In this study, immunohistochemical analysis revealed that NPGL was produced in the infundibular and medial mammillary nuclei of the mediobasal hypothalamus, with immunoreactive fibers also detected in the hypothalamus and the median eminence. As it is known that these regions are involved in feeding behavior in chicks, we surveyed the effects of chronic intracerebroventricular infusion of NPGL on feeding behavior and body mass for a period of two weeks. NPGL stimulated food and water intake, with a concomitant increase in body mass. However, NPGL did not influence mRNA expression of several hypothalamic ingestion-related neuropeptides. Our data suggest that NPGL may be a novel neuronal regulator involved in growth processes in chicks.

Seasonal control of gonadotropin-inhibitory hormone (GnIH) in birds and mammals.

Animals inhabiting temperate and boreal latitudes experience marked seasonal changes in the quality of their environments and maximize reproductive success by phasing breeding activities with the most favorable time of year. Whereas the specific mechanisms driving seasonal changes in reproductive function vary across species, converging lines of evidence suggest gonadotropin-inhibitory hormone (GnIH) serves as a key component of the neuroendocrine circuitry driving seasonal changes in reproduction and sexual motivation in some species. In addition to anticipating environmental change through transduction of photoperiodic information and modifying reproductive state accordingly, GnIH is also positioned to regulate acute changes in reproductive status should unpredictable conditions manifest throughout the year. The present overview summarizes the role of GnIH in avian and mammalian seasonal breeding while considering the similarities and disparities that have emerged from broad investigations across reproductively photoperiodic species.

Aggressive interactions are associated with reductions in RFamide-related peptide, but not kisspeptin, neuronal activation in mice.

Aggressive interactions lead to changes in both future behavior and circulating testosterone (T) concentrations in animals across taxa. The specific neural circuitry and neurochemical systems by which these encounters alter neuroendocrine functioning are not well understood. Neurons expressing the inhibitory and stimulatory neuropeptides, RFamide-related peptide (RFRP) and kisspeptin, respectively, project to neural loci regulating aggression in addition to neuroendocrine cells controlling sex steroid production. Given these connections to both the reproductive axis and aggression circuitry, RFRP and kisspeptin are in unique positions to mediate post-encounter changes in both T and behavior. The present study examined the activational state of RFRP and kisspeptin neurons of male C57BL/6 mice following an aggressive encounter. Both winners and losers exhibited reduced RFRP/FOS co-localization relative to handling stress controls. Social exposure controls did not display reduced RFRP neuronal activation, indicating that this effect is due to aggressive interaction specifically rather than social interaction generally. RFRP neuronal activation positively correlated with latencies to display several offensive behaviors within winners. These effects were not observed in the anteroventral periventricular (AVPV) nucleus kisspeptin cell population. Together, these findings point to potential neuromodulatory role for RFRP in aggressive behavior and in disinhibiting the reproductive axis to facilitate an increase in T in response to social challenge.

Circadian rhythms have broad implications for understanding brain and behavior.

Circadian rhythms are generated by an endogenously organized timing system that drives daily rhythms in behavior, physiology and metabolism. In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus is the locus of a master circadian clock. The SCN is synchronized to environmental changes in the light:dark cycle by direct, monosynaptic innervation via the retino-hypothalamic tract. In turn, the SCN coordinates the rhythmic activities of innumerable subordinate clocks in virtually all bodily tissues and organs. The core molecular clockwork is composed of a transcriptional/post-translational feedback loop in which clock genes and their protein products periodically suppress their own transcription. This primary loop connects to downstream output genes by additional, interlocked transcriptional feedback loops to create tissue-specific 'circadian transcriptomes'. Signals from peripheral tissues inform the SCN of the internal state of the organism and the brain's master clock is modified accordingly. A consequence of this hierarchical, multilevel feedback system is that there are ubiquitous effects of circadian timing on genetic and metabolic responses throughout the body. This overview examines landmark studies in the history of the study of circadian timing system, and highlights our current understanding of the operation of circadian clocks with a focus on topics of interest to the neuroscience community.

Dorsomedial hypothalamic lesions block Syrian hamster testicular regression in short day lengths without diminishing increased testosterone negative-feedback sensitivity.

The dorsomedial nucleus (DMN) of the hypothalamus, the only site within the mediobasal hypothalamus of Syrian hamsters that both binds melatonin and has abundant concentrations of androgen receptors, has been proposed as a target tissue for induction of seasonal changes in brain sensitivity to steroid negative feedback. We tested whether DMN ablation, which does not interfere with pineal gland secretion of melatonin in short day lengths, prevents testicular regression by altering sensitivity to steroid negative feedback. Hamsters with DMN lesions, unlike control hamsters, failed to undergo testicular regression after transfer from a long (14 h light/day) to a short day length (8 h light/day); however, increased negative-feedback inhibition of follicle-stimulating hormone by testosterone was not compromised by ablation of the DMN, indicating that this tissue is not an essential mediator of seasonal changes in feedback sensitivity. We propose a redundant neural network comprised of multiple structures, each of which contributes to neuroendocrine mechanisms, that determines the effect of short days on gonadal function.

Effects of social environment on baseline glucocorticoid levels in a communally breeding rodent, the colonial tuco-tuco (Ctenomys sociabilis).

The social environment in which an animal lives can profoundly impact its physiology, including glucocorticoid (GC) responses to external stressors. In social, group-living species, individuals may face stressors arising from regular interactions with conspecifics as well as those associated with basic life history needs such as acquiring food or shelter. To explore the relative contributions of these two types of stressors on glucocorticoid physiology in a communally breeding mammal, we characterized baseline GC levels in female colonial tuco-tucos (Ctenomys sociabilis), which are subterranean rodents endemic to southwestern Argentina. Long-term field studies have revealed that while about half of all yearling female C. sociabilis live and breed alone, the remainder live and breed within their natal group. We assessed the effects of this intraspecific variation in social environment on GC physiology by comparing concentrations of baseline fecal corticosterone metabolite (fCM) for (1) lone and group-living yearling females in a free-living population of C. sociabilis and (2) captive yearling female C. sociabilis that had been experimentally assigned to live alone or with conspecifics. In both cases, lone females displayed significantly higher mean baseline fCM concentrations. Data from free-living animals indicated that this outcome arose from differences in circadian patterns of GC production. fCM concentrations for group-living animals declined in the afternoon while fCM in lone individuals did not. These findings suggest that for C. sociabilis, stressors associated with basic life history functions present greater challenges than those arising from interactions with conspecifics. Our study is one of the first to examine GC levels in a plural-breeding mammal in which the effects of group-living are not confounded by differences in reproductive or dominance status, thereby generating important insights into the endocrine consequences of group-living.

Gonadotropin-inhibitory hormone reduces sexual motivation but not lordosis behavior in female Syrian hamsters (Mesocricetus auratus).

Reproductive success is maximized when female sexual motivation and behavior coincide with the time of optimal fertility. Both processes depend upon coordinated hormonal events, beginning with signaling by the gonadotropin-releasing hormone (GnRH) neuronal system. Two neuropeptidergic systems that lie upstream of GnRH, gonadotropin-inhibitory hormone (GnIH; also known as RFamide related peptide-3) and kisspeptin, are potent inhibitory and excitatory modulators of GnRH, respectively, that participate in the timing of the preovulatory luteinizing hormone (LH) surge and ovulation. Whether these neuropeptides serve as neuromodulators to coordinate female sexual behavior with the limited window of fertility has not been thoroughly explored. In the present study, either intact or ovariectomized, hormone-treated female hamsters were implanted for fifteen days with chronic release osmotic pumps filled with GnIH or saline. The effect of GnIH on sexual motivation, vaginal scent marking, and lordosis was examined. Following mating, FOS activation was quantified in brain regions implicated in the regulation of female sexual behavior. Intracerebroventricular administration of GnIH reduced sexual motivation and vaginal scent marking, but not lordosis behavior. GnIH administration altered FOS expression in key neural loci implicated in female reproductive behavior, including the medial preoptic area, medial amygdala and bed nucleus of the stria terminalis, independent of changes in circulating gonadal steroids and kisspeptin cell activation. Together, these data point to GnIH as an important modulator of female proceptive sexual behavior and motivation, independent of downstream alterations in sex steroid production.

Circadian regulation of kisspeptin in female reproductive functioning.

Female reproductive functioning requires the precise temporal -organization of numerous neuroendocrine events by a master circadian brain clock located in the suprachiasmatic nucleus. Across species, including humans, disruptions to circadian timing result in pronounced deficits in ovulation and fecundity. The present chapter provides an overview of the circadian control of female reproduction, underscoring the significance of kisspeptin as a key locus of integration for circadian and steroidal signaling necessary for the initiation of ovulation.

Continuous body temperature as a window into adolescent development.

Continuous body temperature is a rich source of information on hormonal status, biological rhythms, and metabolism, all of which undergo stereotyped change across adolescence. Due to the direct actions of these dynamic systems on body temperature regulation, continuous temperature may be uniquely suited to monitoring adolescent development and the impacts of exogenous reproductive hormones or peptides (e.g., hormonal contraception, puberty blockers, gender affirming hormone treatment). This mini-review outlines how traditional methods for monitoring the timing and tempo of puberty may be augmented by markers derived from continuous body temperature. These features may provide greater temporal precision, scalability, and reduce reliance on self-report, particularly in females. Continuous body temperature data can now be gathered with ease across a variety of wearable form factors, providing the opportunity to develop tools that aid in individual, parental, clinical, and researcher awareness and education.

Neural substrates underlying rhythmic coupling of female reproductive and thermoregulatory circuits.

Coordinated fluctuations in female reproductive physiology and thermoregulatory output have been reported for over a century. These changes occur rhythmically at the hourly (ultradian), daily (circadian), and multi-day (ovulatory) timescales, are critical for reproductive function, and have led to the use of temperature patterns as a proxy for female reproductive state. The mechanisms underlying coupling between reproductive and thermoregulatory systems are not fully established, hindering the expansion of inferences that body temperature can provide about female reproductive status. At present, numerous digital tools rely on temperature to infer the timing of ovulation and additional applications (e.g., monitoring ovulatory irregularities and progression of puberty, pregnancy, and menopause are developed based on the assumption that reproductive-thermoregulatory coupling occurs across timescales and life stages. However, without clear understanding of the mechanisms and degree of coupling among the neural substrates regulating temperature and the reproductive axis, whether such approaches will bear fruit in particular domains is uncertain. In this overview, we present evidence supporting broad coupling among the central circuits governing reproduction, thermoregulation, and broader systemic physiology, focusing on timing at ultradian frequencies. Future work characterizing the dynamics of reproductive-thermoregulatory coupling across the lifespan, and of conditions that may decouple these circuits (e.g., circadian disruption, metabolic disease) and compromise female reproductive health, will aid in the development of strategies for early detection of reproductive irregularities and monitoring the efficacy of fertility treatments.

S-Cone Photoreceptors Regulate Daily Rhythms and Light-Induced Arousal/Wakefulness in Diurnal Grass Rats (Arvicanthis niloticus).

Beyond visual perception, light has non-image-forming effects mediated by melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs). The present study first used multielectrode array recordings to show that in a diurnal rodent, Nile grass rats (Arvicanthis niloticus), ipRGCs generate rod/cone-driven and melanopsin-based photoresponses that stably encode irradiance. Subsequently, two ipRGC-mediated non-image-forming effects, namely entrainment of daily rhythms and light-induced arousal, were examined. Animals were first housed under a 12:12 h light/dark cycle (lights-on at 0600 h) with the light phase generated by a low-irradiance fluorescent light (F12), a daylight spectrum (D65) stimulating all photoreceptors, or a narrowband 480 nm spectrum (480) that maximized melanopsin stimulation and minimized S-cone stimulation (λmax 360 nm) compared to D65. Daily rhythms of locomotor activities showed onset and offset closer to lights-on and lights-off, respectively, in D65 and 480 than in F12, and higher day/night activity ratio under D65 versus 480 and F12, suggesting the importance of S-cone stimulation. To assess light-induced arousal, 3-h light exposures using 4 spectra that stimulated melanopsin equally but S-cones differentially were superimposed on F12 background lighting: D65, 480, 480 + 365 (narrowband 365 nm), and D65 - 365. Compared to the F12-only condition, all four pulses increased in-cage activity and promoted wakefulness, with 480 + 365 having the greatest and longest-lasting wakefulness-promoting effects, again indicating the importance of stimulating S-cones as well as melanopsin. These findings provide insights into the temporal dynamics of photoreceptor contributions to non-image-forming photoresponses in a diurnal rodent that may help guide future studies of lighting environments and phototherapy protocols that promote human health and productivity.

Gonadotropin-inhibitory hormone (GnIH): discovery, progress and prospect.

A hypothalamic neuropeptide, gonadotropin-releasing hormone (GnRH), is the primary factor regulating gonadotropin secretion. An inhibitory hypothalamic neuropeptide for gonadotropin secretion was, until recently, unknown, although gonadal sex steroids and inhibin can modulate gonadotropin secretion. Findings from the last decade, however, indicate that GnRH is not the sole hypothalamic regulatory neuropeptide of vertebrate reproduction, with gonadotropin-inhibitory hormone (GnIH) playing a key role in the inhibition of reproduction. GnIH was originally identified in birds and subsequently in mammals and other vertebrates. GnIH acts on the pituitary and on GnRH neurons in the hypothalamus via a novel G protein-coupled receptor (GPR147). GnIH decreases gonadotropin synthesis and release, inhibiting gonadal development and maintenance. Such a down-regulation of the hypothalamo-pituitary-gonadal (HPG) axis may be conserved across vertebrates. Recent evidence further indicates that GnIH operates at the level of the gonads as an autocrine/paracrine regulator of steroidogenesis and gametogenesis. More recent evidence suggests that GnIH also acts both upstream of the GnRH system and at the level of the gonads to appropriately regulate reproductive activity across the seasons and during times of stress. The discovery of GnIH has fundamentally changed our understanding of hypothalamic control of reproduction. This review summarizes the discovery, progress and prospect of GnIH, a key regulator of vertebrate reproduction.

Female mice exhibit less overall variance, with a higher proportion of structured variance, than males at multiple timescales of continuous body temperature and locomotive activity records.

Despite recent work demonstrating that female rodents and humans do not show greater variance in behavior and physiology than males due to ovulatory cycles, many researchers still default to using males in their investigations. Although government funding agencies now require inclusion of female subjects where applicable, the erroneous belief that the study of males reduces overall data variance continues to result in male subject bias. Recently, we reported the first direct experimental refutation of this belief by examining continuous body temperature and locomotor activity in male and female mice. These findings revealed that males exceeded female variance within and across individuals over time, showing greater variance within a day than females do across an entire estrous cycle. However, the possibility remains that male variance within a day is impacted by ultradian rhythms, analogous to the influence of infradian estrous cycles on female variance, and both sexes show predictable, structured variance across the day. If structures underlying variance can be predicted, then the variance can be statistically accounted for, reducing experimental error and increasing precision of measurements. Here we assess these continuous body temperature and activity data for the contributions of structured and unstructured variance to overall variance within and across individuals at ultradian, circadian, and infradian timescales. In no instance do females exceed male variance, and in most instances male variance exceeds female variance. Additionally, more female variance is accounted for by temporal structure. In conclusion, even when estrous cycles are not controlled for, females show less variability than males, and this advantage can be further capitalized upon by inclusion of known temporal patterns to control for previously unknown but structured sources of variance.

Sex Differences in Pubertal Circadian and Ultradian Rhythmic Development Under Semi-naturalistic Conditions.

Biological rhythms in core body temperature (CBT) provide informative markers of adolescent development under controlled laboratory conditions. However, it is unknown whether these markers are preserved under more variable, semi-naturalistic conditions, and whether CBT may therefore prove useful in a real-world setting. To evaluate this possibility, we examined fecal steroid concentrations and CBT rhythms from pre-adolescence (p26) through early adulthood (p76) in intact male and female Wistar rats under natural light and climate at the Stephen Glickman Field Station for the Study of Behavior, Ecology and Reproduction. Despite greater environmental variability, CBT markers of pubertal onset and its rhythmic progression were comparable with those previously reported in laboratory conditions in female rats and extend actigraphy-based findings in males. Specifically, sex differences emerged in CBT circadian rhythm (CR) power and amplitude prior to pubertal onset and persisted into early adulthood, with females exhibiting elevated CBT and decreased CR power compared with males. Within-day (ultradian rhythm [UR]) patterns also exhibited a pronounced sex difference associated with estrous cyclicity. Pubertal onset, defined by vaginal opening, preputial separation, and sex steroid concentrations, occurred later than previously reported under lab conditions for both sexes. Vaginal opening and increased fecal estradiol concentrations were closely tied to the commencement of 4-day oscillations in CBT and UR power. By contrast, preputial separation and the first rise in testosterone concentration were not associated with adolescent changes to CBT rhythms in male rats. Together, males and females exhibited unique temporal patterning of CBT and sex steroids across pubertal development, with tractable associations between hormonal concentrations, external development, and temporal structure in females. The preservation of these features outside the laboratory supports CBT as a strong candidate for translational pubertal monitoring under semi-naturalistic conditions in females.

Multi-Timescale Rhythmicity of Blood Glucose and Insulin Delivery Reveals Key Advantages of Hybrid Closed Loop Therapy.

BACKGROUND: Blood glucose and insulin exhibit coordinated daily and hourly rhythms in people without diabetes (nonT1D). Although the presence and stability of these rhythms are associated with euglycemia, it is unknown if they (1) are preserved in individuals with type 1 diabetes (T1D) and (2) vary by therapy type. In particular, Hybrid Closed Loop (HCL) systems improve glycemia in T1D compared to Sensor Augmented Pump (SAP) therapies, but the extent to which either recapitulates coupled glucose and insulin rhythmicity is not well described. In HCL systems, more rapid modulation of glucose via automated insulin delivery may result in greater rhythmic coordination and euglycemia. Such precision may not be possible in SAP systems. We hypothesized that HCL users would exhibit fewer hyperglycemic event, superior rhythmicity, and coordination relative to SAP users. METHODS: Wavelet and coherence analyses were used to compare glucose and insulin delivery rate (IDR) within-day and daily rhythms, and their coordination, in 3 datasets: HCL (n = 150), SAP (n = 89), and nonT1D glucose (n = 16). RESULTS: Glycemia, correlation between normalized glucose and IDR, daily coherence of glucose and IDR, and amplitude of glucose oscillations differed significantly between SAP and HCL users. Daily glucose rhythms differed significantly between SAP, but not HCL, users and nonT1D individuals. CONCLUSIONS: SAP use is associated with greater hyperglycemia, higher amplitude glucose fluctuations, and a less stably coordinated rhythmic phenotype compared to HCL use. Improvements in glucose and IDR rhythmicity may contribute to the overall effectiveness of HCL systems.