Abstract 13045: Chronic Beta3-Adrenergic Receptor Antagonist Therapy Rescues Diabetic Cardiomyopathy in a Mouse Model With Type 2 Diabetes: Insights into Cellular Mechanism

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Jing Cao ◽  
Xiaoqiang Sun ◽  
Heng Jie Cheng ◽  
Yixi Liu ◽  
Dalane Kitzman ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Mouse Model ◽  
Diabetic Cardiomyopathy ◽  
Adrenergic Receptor ◽  
Effective Prevention ◽  
Glucose Levels ◽  
Wild Type Female ◽  
Myocyte Function ◽  
Myocyte Contractility

Background: Diabetic cardiomyopathy (DCM) leads to progressive decline in cardiac function, increasing the risk for heart failure. There are no known effective prevention approaches or therapeutic strategies. Recent evidence in diabetes mellitus (DM) human and animal hearts suggests that the up-regulation of β 3 -adrenergic receptor (AR)-mediated inhibitory pathway may be responsible for the progression of DCM. However, its precise role is still being debated. We hypothesize that β 3 -AR antagonists (β 3 -ANT) may rescue the detrimental effects of β 3 -AR activation, improve cardiomyocyte function, and preserve normal β-AR regulation, leading to the regression of DCM. Methods: We compared LV myocyte function, [Ca 2+ ] i transient ([Ca 2+ ] iT ) at baseline and responses to β-AR simulation with isoproterenol (ISO,10 -8 M) in 3 groups wild-type female mice over 14 weeks (W):1) Type 2 DM ( T2 ) (n=9), 14 W fed high-fat diet (HFD), but after HFD for 4 W receiving streptozotocin (STZ, 40 mg/kg/day, i.p. 5 days); 2) T2/β 3 -ANT (n=7), T2 mice at 10 W received L-748,337, a selective β 3 -ANT (10 -7 M/kg/day, mini-pump) for 4 W; and 3) Vehicle controls (C) (n=9). Results: Versus C, T2DM was induced in mice received HFD and low dose STZ with significantly elevated blood glucose levels (T2: 388, T2/β 3 -ANT: 369 vs C: 128 mg/dl). In T2, LV myocyte basal function and [Ca 2+ ] iT regulation were impaired measured as significantly decreased myocyte contractility (dL/dt max ) (76.8 vs 135.2 μm/s), relengthening (dR/dt max ) (62.1 vs 113.8 μ m/s) and [Ca 2+ ] iT (0.16 vs 0.21). Furthermore, versus C, in T2 myocytes, ISO-induced increases in dL/dt max (T2: 40% vs C: 58%), dR/dt max (35% vs 54%) and [Ca 2+ ] iT (19% vs 30%) were significantly reduced. By contrary, versus T2, T2/β 3 -ANT myocytes showed normal basal cell contraction (127.8 μm/s), relaxation (109.4 μm/s) and [Ca 2+ ] iT (0.21) with preserved ISO-stimulated positive inotropic effect. Versus C, in T2/β 3 -ANT, ISO caused similar increases in dL/dt max (57%), dR/dt max (52%) and [Ca 2+ ] iT (30%). Conclusion: Chronic β 3 -ANT leads to the preservation of LV myocyte function, [Ca 2+ ] iT , and β-AR responsiveness in a mouse model of type 2 diabetes. Thus, antagonizing β 3 -AR might provide a new therapeutic strategy for DM-related decline in myocardial function.

Abstract 13035: Beta3-Adrenergic-Receptor-Deficient Mice Protected From Diabetic Cardiomyopathy in Type 2 Diabetic Murine Model: Beneficial Effects on Cardiomyocyte Contractile Function, [Ca 2+ ] i Regulation and Beta-Adrenergic Modulation

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Xiaoqiang Sun ◽  
Jing Cao ◽  
Heng-Jie Cheng ◽  
Yixi Liu ◽  
Zhe Chen ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Adrenergic Receptor ◽  
Contractile Function ◽  
Progressive Decline ◽  
Beneficial Effects ◽  
Adrenergic Modulation ◽  
Myocyte Function ◽  
Mean Blood Glucose ◽  
Deficient Mice

Background: Diabetic cardiomyopathy (DCM) is the main cause of increased mortality in Diabetes mellitus (DM). There are no effective therapeutic strategies. Recently, we found that DM is associated with the upregulation of β 3 adrenergic receptor (AR) mediated cardiac inhibitory pathway. This suggests cardiac β 3 -AR activation may contribute to DCM progression and be a therapeutic target. We hypothesize that upregulation of β 3 -AR is maladaptive, and DM-caused progressive decline in cardiac function and β-adrenergic reserve will be prevented in β 3 -AR knockout (β 3 KO) mice. Methods: Studies were conducted in female mice of 2 Vehicle controls groups (n=8/group) of wild-type (CWT) and Cβ 3 KO, and 2 Type 2 DM (T2) of T2WT (n=8) and T2β 3 KO (n=6).T2 was induced by fed high-fat diet (HFD) for 14 weeks (W), but after HFD for 4 W receiving streptozotocin (STZ, 40 mg/kg/day, i.p. for 5 days). We compared LV myocyte contractile and [Ca 2+ ] iT responses to β-AR subtype stimulation by random exposure of myocytes to the superfusion of isoproterenol (ISO,10 -8 M) or a selective β 1 -, or β 3 -agonist, Norepinephrine (NE, 10 -7 M), and BRL-37,344 (BRL, 10 -8 M), respectively. Results: Mice received HFD plus STZ developed T2DM with elevated mean blood glucose from 128 mg/dl of control to 388 mg/dl and 382 mg/dl in T2WT and T2β 3 KO, respectively. However only T2WT mice developed DCM followed by significant decreases in myocyte contraction (dL/dt max , T2WT: 74.8 vs CWT:140.1 μm/s), relaxation (dR/dt max , 58.0 vs 117.9 μm/s) and [Ca 2+ ] iT (0.16 vs 0.22). ISO-stimulated increases in dL/dt max (37% vs 58%), dR/dt max (30% vs 53%), and [Ca 2+ ] iT (19% vs 30%) were attenuated accompanied by a diminished NE-caused increase in dL/dt max (28% vs 41%), but enhanced BRL-induced decrease in dL/dt max (29% vs 15%). By contrary, T2β 3 KO showed normal basal dL/dt max (137.6 μm/s), dR/dt max (111.4 μm/s) and [Ca 2+ ] iT (0.22). Importantly, T2β 3 KO myocytes showed preserved ISO-stimulated increases in dL/dt max (60%), dR/dt max (51%) and [Ca 2+ ] iT (32%) and restored normal dL/dt max responses to NE (41%). Conclusions: β 3 KO prevents T2DM-caused contrast changes in β 1 - and β 3 -AR-stimulated cardiac inotropic actions and leading to the preservation of normal myocyte function, [Ca 2+ ] iT , and β-AR responsiveness in DCM.

Abstract 12808: Mechanism of Chronic Ranolazine Caused Regression of Cardiac Dysfunction in a Murine of Diabetic Cardiomyopathy: Beneficial Effects on Cardiomyocyte Contractile Function, [Ca 2+ ] i Regulation and Beta-Adrenergic Modulation

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Xiaoqiang Sun ◽  
Jing Cao ◽  
Heng-Jie Cheng ◽  
Yixi Liu ◽  
Zhe Chen ◽  
...  
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Contractile Function ◽  
Cell Contractility ◽  
Beneficial Effects ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Therapeutic Choice ◽  
Adrenergic Modulation ◽  
Myocyte Function ◽  
Myocyte Contractility

Background: Diabetic cardiomyopathy (DCM) increases the risk of heart failure. As yet, no effective therapeutic strategies exist. Recent evidence indicates that intracellular Na + concentration ([Na + ] i ) is augmented in the myocytes from diabetic hearts, where it causes oxidative stress, augments the sarcoplasmic reticulum Ca 2+ leak and contributes to electrical, structural and functional remodeling. Ranolazine (RAN), inhibiting persistent or late inward Na + current has been proposed to be a therapeutic choice for DCM. However, the role and mechanism of chronic RAN in DCM are unclear. We assessed the hypothesis that RAN improves myocyte function, [Ca 2+ ] i regulation, and β-adrenergic receptor (AR) signaling effectiveness, thus limiting DCM. Methods: We compared LV myocyte function, [Ca 2+ ] i transient ([Ca 2+ ] iT ) and responses to the stimulation of β-AR in 3 groups wild-type (WT) female mice over 10 weeks (W):1) DM (n=8), 10 W after receiving streptozotocin (STZ, 200 mg/kg, ip); 2) DM/RAN (n=6), 6 W after STZ, RAN (10 -5 M/kg/day, mini-pump) was initiated and was given for 4 W; and 3) Sham controls (C) (n=8). Results: Versus control, STZ-treated WT mice had DM with significantly elevated blood glucose levels (410 vs 128mg/dl) followed by LV myocyte dysfunction with decreases in myocyte contractility (dL/dt max ) (75.0 vs 140.1 μm/s), relengthening (dR/dt max ) (62.5 vs 116.6 μm/s) and [Ca 2+ ] iT (0.15 vs 0.22). In DM myocytes, the ability of β-AR agonist, isoproterenol (ISO, 10 -8 M) to increase cell contractility was blunted. Versus control, in DM myocytes, ISO-induced increases in dL/dt max (31% vs 60%), dR/dt max (23% vs 50%) and [Ca 2+ ] iT (15% vs 30%) were significantly reduced. By contrary, versus DM alone, DM/RAN myocytes showed normal basal cell contraction (137.8 μm/s), relaxation (117.2 μm/s) and [Ca 2+ ] iT (0.22) with preserved ISO-stimulated positive inotropic effect. Compared control, in DM/RAN, ISO caused similar increases in dL/dt max (62% vs 60%), dR/dt max (52% vs 50%) and [Ca 2+ ] iT (32% vs 30%). Conclusion: Chronic ranolazine leads to the preservation of myocyte function, [Ca 2+ ] iT and β-AR responsiveness in DCM. Thus, antagonizing myocyte [Na + ] i dysregulation might provide a new therapeutic strategy for DM-related decline in myocardial function.

Structural analysis of tooth and jawbone in a type 2 diabetes mouse model

2014 ◽  
Author(s):  
Silvia Pabisch ◽  
Tsuguno Yamaguchi ◽  
Yasushi Koike ◽  
Kenji Egashira ◽  
Shinsuke Kataoka ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Structural Analysis ◽  
Mouse Model ◽  
Diabetes Mouse

Pharmacological Neprilysin Inhibition Improves Glucose Homeostasis in a Mouse Model of Type 2 Diabetes

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 1825-P ◽  
Author(s):  
JACQUELINE H. PARILLA ◽  
STEVE MONGOVIN ◽  
BREANNE BARROW ◽  
NATHALIE ESSER ◽  
SAKENEH ZRAIKA
Keyword(s):  
Type 2 Diabetes ◽  
Mouse Model ◽  
Glucose Homeostasis ◽  
Neprilysin Inhibition

Effect of High ß-Glucan Barley on Postprandial Plasma Glucose Levels in Subjects with Normal Glucose Tolerance and Patients with Type 2 Diabetes

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 772-P
Author(s):  
MARIKO HIGA ◽  
AYANA HASHIMOTO ◽  
MOE HAYASAKA ◽  
MAI HIJIKATA ◽  
AYAMI UEDA ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Tolerance ◽  
Plasma Glucose ◽  
Normal Glucose Tolerance ◽  
Postprandial Plasma Glucose ◽  
Glucose Levels ◽  
Normal Glucose

1734-P: High Dietary Fat Intake Exacerbates Insulin Resistance in a Type 2 Diabetes Genetic Mouse Model

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1734-P
Author(s):  
AUSTIN REILLY ◽  
SHIJUN YAN ◽  
ALEXA J. LONCHARICH ◽  
HONGXIA REN
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Mouse Model ◽  
Dietary Fat ◽  
Fat Intake ◽  
Dietary Fat Intake ◽  
Genetic Mouse Model

Efeitos dos Programas de Treinamento Aeróbio, de Força e Combinado na Glicose Sanguínea em Diabéticos do Tipo 2: uma Revisão Sistemática/ Effects of Aerobic, Strength and Combined Programs Training on Blood Glucose in Type 2 Diabetic: a Systematic Review.

1970 ◽  
Vol 5 (1) ◽  
pp. 61-74 ◽  
Author(s):  
Alexandre de Souza E Silva ◽  
Maria Paula Gonçalves Mota
Keyword(s):  
Diabetes Mellitus ◽  
Systematic Review ◽  
Type 2 Diabetes ◽  
Blood Glucose ◽  
Training Program ◽  
Aerobic Training ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Pubmed Database

O trabalho tem como objetivo analisar os estudos que avaliaram os efeitos dos programas de treinamento aeróbio, força e combinado nos níveis de glicose sanguínea em indivíduos com diabetes do tipo 2. Foi utilizado o método de revisão sistemática, sendo utilizada a base de dados PubMed. As palavras chaves utilizadas para pesquisa foram training and diabetes. Foram identificados 484 artigos originais. Apenas 17 estudos respeitaram os critérios de inclusão. Os resultados evidenciam que os programas de treinamento aeróbio diminuíram os níveis de glicose. O programa de treinamento de força também foi favorável à diminuição dos níveis de glicose sanguínea. Já o programa de treinamento combinado não demonstrou efeitos favoráveis no controle da glicose sanguínea. Conclui-se que o programa de treinamento aeróbio e de força ajudam a controlar os níveis de glicose sanguínea em indivíduos com diabetes do tipo 2. Palavras-chave: diabetes mellitus, treinamento, glicose.ABSTRACTThe study aims to analyze the studies that evaluated the effects of aerobic, strength and combined programs training in blood glucose levels in people with type 2 diabetes. We used a systematic review method and is used to PubMed database. The key words used for searching were training and diabetes. We identified 484 original articles. Only 17 studies complied with the inclusion criteria. The results show that aerobic training programs decreased glucose levels. The strength training program was also favorable to decrease in blood glucose levels. But the combined training program has not shown favorable effects on blood glucose control. We conclude that the aerobic training and strength helps control blood glucose levels in individuals with type 2 diabetes. Keywords: diabetes mellitus, training, glucose.

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