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Differential impact of type-1 and type-2 diabetes on control of heart rate in mice.

ABSTRACT: AIMS:Cardiac autonomic dysfunction is a serious complication of diabetes. One consequence is disruption of the normal beat-to-beat regulation of heart rate (HR), i.e. HR variability (HRV). However, our understanding of the disease process has been limited by inconsistent HR/HRV data from previous animal studies. We hypothesized that differences in the method of measurement, time of day, and level of stress account for the differing results across studies. Thus, our aim was to systematically assess HR and HRV in two common diabetic mouse models. METHODS:ECG radiotelemetry devices were implanted into db/db (type-2 diabetic), STZ-treated db/+ (type-1 diabetic), and control db/+ mice (n=4 per group). HR and HRV were analyzed over 24 h and during treadmill testing. RESULTS:24 h analysis revealed that db/db mice had an altered pattern of circadian HR changes, and STZ-treated mice had reduced HR throughout. HRV measures linked to sympathetic control were reduced in db/db mice in the early morning and early afternoon, and partially reduced in STZ-treated mice. HR response to treadmill testing was blunted in both models. CONCLUSIONS:It is important to consider both time of day and level of stress when assessing HR and HRV in diabetic mice. db/db mice may have altered circadian rhythm of sympathetic control of HR, whereas STZ-treated mice have a relative reduction. This study provides baseline data and a framework for HR analysis that may guide future investigations.

SUBMITTER: Stables CL

PROVIDER: S-EPMC4724221 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Differential impact of type-1 and type-2 diabetes on control of heart rate in mice.

Stables Catherine L CL Auerbach David S DS Whitesall Steven E SE D'Alecy Louis G LG Feldman Eva L EL

Autonomic neuroscience : basic & clinical 20151217

<h4>Aims</h4>Cardiac autonomic dysfunction is a serious complication of diabetes. One consequence is disruption of the normal beat-to-beat regulation of heart rate (HR), i.e. HR variability (HRV). However, our understanding of the disease process has been limited by inconsistent HR/HRV data from previous animal studies. We hypothesized that differences in the method of measurement, time of day, and level of stress account for the differing results across studies. Thus, our aim was to systematica ...[more]

PMID: 26725752

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Project description:BackgroundVeterans with evidence of homelessness have high rates of mental health and substance abuse disorders, but chronic medical conditions such as diabetes are also prevalent.ObjectiveWe aimed to determine the impact of homelessness on glycemic control in patients with type 2 diabetes mellitus.DesignLongitudinal analysis of a retrospective cohort.SubjectsA national cohort of 1,263,906 Veterans with type 2 diabetes. Subjects with evidence of homelessness were identified using a combination of diagnostic and administrative codes.Main measuresOdds for poor glycemic control using hemoglobin A1C (HbA1C) cutoff values of 8 % and 9 %. Homeless defined as a score based on the number of indicator variables for homelessness within a veterans chart.Key resultsVeterans with evidence of homelessness had a significantly greater annual mean HbA1C?? 8 (32.6 % vs. 20.43 %) and HbA1C?? 9 (21.4 % vs. 9.9 %), tended to be younger (58 vs. 67 years), were more likely to be non-Hispanic black (39.1 %), divorced (43 %) or never married (34 %), to be urban dwelling (88.8 %), and to have comorbid substance abuse (46.7 %), depression (42.3 %), psychoses (39.7 %), liver disease (18.8 %), and fluid/electrolyte disorders (20.4 %), relative to non-homeless veterans (all p?<?0.0001). Homelessness was modeled as an ordinal variable that scored the number of times a homelessness indicator was found in the Veterans medical record. We observed a significant interaction between homelessness and race/ethnicity on the odds of poor glycemic control. Homelessness, across all racial-ethnic groups, was associated with increased odds of uncontrolled diabetes at a cut-point of 8 % and 9 % for hemoglobin A1C ; however, the magnitude of the association was greater in non-Hispanic whites [8 %, OR 1.55 (1.47;1.63)] and Hispanics [8 %, OR 2.11 (1.78;2.51)] than in non-Hispanic blacks [8 %, OR 1.22 (1.15;1.28)].ConclusionsHomelessness is a significant risk factor for uncontrolled diabetes in Veterans, especially among non-Hispanic white and Hispanic patients. While efforts to engage homeless patients in primary care services have had some success in recent years, these data suggest that broader efforts targeting management of diabetes and other chronic medical conditions remain warranted.

Project description:We investigated the association between the heart rate-corrected QT interval (QTc interval) measured by standard electrocardiography and heart rate variability (HRV) in patients with type 2 diabetes mellitus (T2DM). From March 1, 2009, to December 12, 2009, 411 patients with T2DM who underwent resting 12-lead electrocardiography and cardiovascular autonomic function testing concurrently without the exclusion criteria were consecutively recruited in this cross-sectional study. Time- and frequency-domain HRV variables were assessed for 5 minutes by beat-to-beat HRV recording. The QT interval was corrected for the heart rate using Bazett's formula. QTc interval measurements of >440 ms were considered abnormally prolonged. The mean age and diabetes duration were 56.3 ± 10.6 years and 9.6 ± 7.3 years, respectively. A total of 90 patients had QTc interval prolongation (21.9%). The participants with a prolonged QTc interval were older (59.4 ± 10.1 years vs 55.5 ± 10.6 years, P = .002), were more likely to be a woman (72.2% vs 51.7%, P = .001), had a higher prevalence of hypertension (46.7% vs 33.4%, P = .022), had a higher hemoglobin A1c level (8.8% ± 2.2% vs 8.2% ± 1.8%, P = .045), and had decreased values for the variables measuring HRV, except for the low frequency (LF)/high frequency (HF) ratio (total power [TP], 147.7 [74.1-335.9] ms vs 328.7 [185.7-721.7] ms, P = .002). After adjusting for multiple confounders, QTc interval prolongation was associated with the lowest quartile of the HRV parameters of TP (odds ratio [OR] = 3.99; 95% confidence interval [CI]: 2.29-6.96), HF (OR = 3.20; 95% CI: 1.84-5.58), LF (OR = 3.68; 95% CI: 2.10-6.43), standard deviation of the normal-to-normal interval (OR = 3.31; 95% CI: 1.89-5.77), and root-mean-square of the successive differences (OR = 1.98; 95% CI: 1.13-3.47) in patients with T2DM. Decreased values for the variables measuring HRV, except for the LF/HF ratio, might be associated with QTc interval prolongation in patients with T2DM.

Project description:Background: Food insecurity (FI), diabetes prevalence, and poor diabetes outcomes all disproportionately affect Latinos in the United States. Heart rate variability (HRV) reflects autonomic tone, is associated with glycemic control, and predicts mortality in type 2 diabetes. It is unknown whether FI is related to HRV and, if so, whether glycemic control accounts for this association. Objective: This exploratory cross-sectional study examined FI and HRV among US Latinos with type 2 diabetes. Methods: Participants reported demographic characteristics, socioeconomic status, and FI, including the 6-item USDA food security module and a 1-item measure of diabetes-specific food security. Participants wore an ambulatory electrocardiogram monitor for 24 h. In the time domain, HRV was assessed with the SD of the R-R interval (SDNN). In the frequency domain, the power spectrum was integrated over 3 frequency bands-very low frequency (VLF), low frequency (LF), and high frequency (HF)-and then natural log transformed. Unadjusted ANOVA and ANCOVA adjusted for age, sex, glycated hemoglobin (HbA1c), and indicators of socioeconomic status compared food security groups on HRV. Results: Participants' mean ± SD age was 59.7 ± 10.9 y, and 73% were women. Of the 94 participants, 63 reported FI according to the USDA food security module and 46 reported FI according to the diabetes-specific measure. Mean ± SD HbA1c was 8.6% ± 1.7% and was marginally higher among those reporting diabetes-specific FI than those reporting diabetes-specific food security. Participants who reported diabetes-specific FI had lower SDNN, VLF, LF, and HF HRV with effect sizes in the small-to-medium range. Differences remained significant even after controlling for age, sex, socioeconomic hardship, and HbA1c. The 6-item USDA food security module was not associated with HRV. Conclusions: Diabetes-specific FI may be a unique risk factor for poor health outcomes among US Latinos. Efforts to address FI could benefit diabetes outcomes.

Project description:OBJECTIVES:Glucagon-like peptide-1 (GLP-1) is secreted from enteroendocrine cells and exerts a broad number of metabolic actions through activation of a single GLP-1 receptor (GLP-1R). The cardiovascular actions of GLP-1 have garnered increasing attention as GLP-1R agonists are used to treat human subjects with diabetes and obesity that may be at increased risk for development of heart disease. Here we studied mechanisms linking GLP-1R activation to control of heart rate (HR) in mice. METHODS:The actions of GLP-1R agonists were examined on the control of HR in wild type mice (WT) and in mice with cardiomyocyte-selective disruption of the GLP-1R (Glp1rCM-/-). Complimentary studies examined the effects of GLP-1R agonists in mice co-administered propranolol or atropine. The direct effects of GLP-1R agonism on HR and ventricular developed pressure were examined in isolated perfused mouse hearts ex vivo, and atrial depolarization was quantified in mouse hearts following direct application of liraglutide to perfused atrial preparations ex vivo. RESULTS:Doses of liraglutide and lixisenatide that were equipotent for acute glucose control rapidly increased HR in WT and Glp1rCM-/- mice in vivo. The actions of liraglutide to increase HR were more sustained relative to lixisenatide, and diminished in Glp1rCM-/- mice. The acute chronotropic actions of GLP-1R agonists were attenuated by propranolol but not atropine. Neither native GLP-1 nor lixisenatide increased HR or developed pressure in perfused hearts ex vivo. Moreover, liraglutide had no direct effect on sinoatrial node firing rate in mouse atrial preparations ex vivo. Despite co-localization of HCN4 and GLP-1R in primate hearts, HCN4-directed Cre expression did not attenuate levels of Glp1r mRNA transcripts, but did reduce atrial Gcgr expression in the mouse heart. CONCLUSIONS:GLP-1R agonists increase HR through multiple mechanisms, including regulation of autonomic nervous system function, and activation of the atrial GLP-1R. Surprisingly, the isolated atrial GLP-1R does not transduce a direct chronotropic effect following exposure to GLP-1R agonists in the intact heart, or isolated atrium, ex vivo. Hence, cardiac GLP-1R circuits controlling HR require neural inputs and do not function in a heart-autonomous manner.

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Differential impact of type-1 and type-2 diabetes on control of heart rate in mice.

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Differential impact of type-1 and type-2 diabetes on control of heart rate in mice.

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