Mirabegron and tadalafil effectiveness for treatment of prediabetes

米拉贝隆和他达拉非治疗糖尿病前期的有效性

基本信息

批准号：
10532229
负责人：
Philip A Kern
金额：
$ 30.6万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10532229
关键词：
Address Adipocytes Adipose tissue Adrenergic Agonists Adrenergic beta-Agonists Agonist American Attenuated Beta Cell Bladder Blood capillaries Body Weight decreased Brown Fat Cell physiology Clinical Trials Combined Modality Therapy Consumption Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic GMP Cyclic GMP-Dependent Protein Kinases Cyclic Nucleotides Data Diabetes Mellitus Disease Drug Combinations Drug Targeting Effectiveness Exercise FDA approved Fatty acid glycerol esters Fiber Glucose Glycosylated hemoglobin A Goals Heart Diseases Human Individual Inflammation Insulin Resistance Life Style Ligands Link Lipids Lipolysis Mediating Metabolic Methods Mission Multicenter Trials Muscle Muscle Fibers National Institute of Diabetes and Digestive and Kidney Diseases Nitric Oxide Non-Insulin-Dependent Diabetes Mellitus Obesity Oral Overactive Bladder Participant Pathway interactions Pharmaceutical Preparations Prediabetes syndrome Recommendation Research Research Project Grants Risk Factors Rodent Skeletal Muscle Smooth Muscle Thinness Treatment Effectiveness Woman beta-adrenergic receptor blood glucose regulation clinical efficacy clinically relevant comorbidity density design diabetes prevention program effectiveness evaluation glucose metabolism glucose tolerance heart disease risk improved inhibitor inhibitor therapy insulin secretion insulin sensitivity oral glucose tolerance p38 Mitogen Activated Protein Kinase phosphodiesterase V placebo controlled trial prevent protein activation response side effect sildenafil subcutaneous tadalafil uncoupling protein 1

项目摘要

Approximately 84 million Americans have prediabetes, and progression to type 2 diabetes occurs at a rate of 5% to 10% per year and is a risk factor for heart disease. Although lifestyle change is effective, most prediabetic individuals cannot achieve the changes necessary to reverse prediabetes or prevent diabetes. In recent studies, we treated obese, insulin-resistant humans with the β-adrenergic receptor (β3AR) agonist mirabegron, and this resulted in improved oral glucose tolerance, lower HbA1c, and increased insulin sensitivity and β-cell function. These changes occurred in the absence of weight loss. Although brown adipose tissue did not increase, mirabegron treatment increased beige fat, reduced adipose inflammation and increased type 1 fibers and capillary density in skeletal muscle. Beige adipocytes have beneficial effects on glucose metabolism and are postulated to act as a glucose sink. Mirabegron stimulates the β3AR which stimulates the cAMP-mediated activation of PKA and the activation of p38 map kinase, which induces UCP1 and adipose beiging. Recent studies showed that cGMP activation of protein kinase G (PKG) acted in a similar fashion to improve glucose metabolism and increase white adipose beiging. Indeed, cGMP is stimulated by natural ligands (ANP, BNP, nitric oxide); the phosphodiesterase 5 (PDE5) inhibitor drugs sildenafil and tadalafil prevent breakdown of cGMP, activating PKG and this results in increased UCP1 in adipocytes. Therefore, we hypothesize that treatment of prediabetic subjects with mirabegron or tadalafil will improve glucose metabolism. We further hypothesize that the combined treatment with mirabegron and tadalafil will have additive improvements in glucose metabolism, likely due to their parallel actions of stimulating the cyclic nucleotides cAMP and cGMP and inducing adipose beiging. Specific Aim 1. We hypothesize that a 4 month treatment with the β3 agonist mirabegron will result in improved glucose metabolism in obese, prediabetic human research participants, and this improvement in glucose metabolism will be further improved by combination therapy with mirabegron plus tadalafil. Specific Aim 2. We will identify underlying mechanisms of the improved glucose homeostasis in response to mirabegron and tadalafil by characterizing insulin sensitivity, insulin secretion, adipose tissue beiging, muscle fiber type, and muscle capillaries. Clinical relevance: Other than weight loss, we have only limited methods for improving prediabetes. Drugs that target white adipose beiging improve glucose metabolism in both rodents and humans, and we propose that this can be exploited to attenuate prediabetes. This application addresses the effectiveness of two drugs that are widely prescribed, well tolerated, but which have not been extensively studied for their metabolic effectiveness in subjects with prediabetes and have never been studied in combination. Results from this study could lead to a larger trial which could considerably alter our approach to the treatment of prediabetes.

大约 8400 万美国人患有糖尿病前期，并且以一定的速度进展为 2 型糖尿病每年 5% 至 10%，是心脏病的危险因素虽然生活方式的改变是有效的，但大多数情况下。糖尿病前期个体无法实现逆转糖尿病前期或预防糖尿病所需的改变。在最近的研究中，我们用 β-肾上腺素能受体 (β3AR) 激动剂治疗肥胖、胰岛素抵抗的人类米拉贝隆，这导致口服葡萄糖耐量改善、糖化血红蛋白降低和胰岛素增加这些变化发生在体重没有减轻的情况下。脂肪组织没有增加，米拉贝隆治疗增加了米色脂肪，减少了脂肪炎症和骨骼肌中 1 型纤维和毛细血管密度的增加对米色脂肪细胞有有益的影响。葡萄糖代谢并被假定充当葡萄糖汇。米拉贝隆刺激 β3AR，从而刺激 cAMP 介导的 PKA 激活和激活 p38 图激酶，它诱导 UCP1 和脂肪的开始。蛋白激酶 G (PKG) 以类似的方式发挥作用，改善葡萄糖代谢并增加白色脂肪事实上，cGMP 受到天然配体（ANP、BNP、一氧化氮）的刺激； (PDE5) 抑制剂药物西地那非和他达拉非可防止 cGMP 分解，激活 PKG，从而导致脂肪细胞中 UCP1 增加，因此，我们对糖尿病前期受试者进行了这种治疗。我们进一步认为联合治疗会改善米拉贝隆或他达拉非。米拉贝隆和他达拉非对葡萄糖代谢有额外的改善，可能是由于它们的并行性刺激环核苷酸cAMP和cGMP并诱导脂肪开始的作用。具体目标 1. 我们勇敢地说，使用 β3 激动剂米拉贝隆进行 4 个月的治疗将导致改善肥胖、糖尿病前期人类研究中的葡萄糖代谢，并且这种改善米拉贝隆联合他达拉非联合治疗可进一步改善糖代谢。具体目标 2. 我们将确定改善葡萄糖稳态的潜在机制通过表征胰岛素敏感性、胰岛素分泌、脂肪组织开始，来研究米拉贝隆和他达拉非，肌纤维类型和肌肉毛细血管。临床意义：除了减肥之外，我们只有有限的方法来改善糖尿病前期的药物。以白色脂肪为目标的药物开始改善啮齿动物和人类的葡萄糖代谢，我们建议可以利用这一点来减轻糖尿病前期。该应用解决了两种药物的有效性。被广泛使用，耐受性良好，但尚未对其代谢进行广泛研究从未对糖尿病前期受试者的有效性进行过联合研究。研究可能会导致更大规模的试验，这可能会大大改变我们治疗前驱糖尿病的方法。