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

• 批准号: 10363388
• 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
• 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/10363388
• 关键词: Address; Adipocytes; Adipose tissue; Adrenergic Receptor; 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; Lead; 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; 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

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.

大约有8400万美国人患有糖尿病前期，进展为2型糖尿病的发生率 每年5％至10％，是心脏病的危险因素。尽管生活方式改变是有效的，但大多数 糖尿病人无法实现逆转糖尿病或预防糖尿病所需的变化。 在最近的研究中，我们用β-肾上腺素受体（β3AR）激动剂治疗了肥胖的胰岛素耐药性人 Mirabegron，这导致口服葡萄糖耐受性提高，HBA1C较低，胰岛素增加 灵敏度和β细胞功能。这些变化发生在没有体重减轻的情况下。虽然棕色 脂肪组织没有增加，mirabegron治疗增加了米色脂肪，脂肪炎症减少和 骨骼肌中1型纤维和毛细管密度增加。米色脂肪细胞对 葡萄糖代谢，被邮寄为葡萄糖水槽。 Mirabegron刺激β3AR刺激CAMP介导的PKA激活和激活 p38 MAP激酶，诱导UCP1和脂肪变为。最近的研究表明，CGMP激活 蛋白激酶G（PKG）以类似的方式作用，以改善葡萄糖代谢并增加白脂肪 成为。实际上，CGMP是由天然配体（ANP，BNP，一氧化氮）刺激的。磷酸二酯酶5 （PDE5）抑制剂西地那非和他达拉非抑制剂防止CGMP破坏，激活PKG，这导致 脂肪细胞中的UCP1增加。因此，我们假设与 Mirabegron或Tadalafil将改善葡萄糖代谢。我们进一步假设合并治疗 随着Mirabegron和Tadalafil的葡萄糖代谢将增加改善 刺激环状核苷酸营和CGMP以及诱导脂肪成为的动作。 具体目的1。我们假设用β3激动剂米拉贝隆进行4个月的治疗将导致 改善了肥胖，糖尿病前研究参与者的葡萄糖代谢，并改善了这种改善 通过与Mirabegron Plus Tadalafil联合疗法，葡萄糖代谢将进一步改善。 具体目的2。我们将确定改善葡萄糖稳态的基本机制。 通过表征胰岛素敏感性，胰岛素分泌，脂肪组织变为 肌肉纤维类型和肌肉毛细血管。 临床相关性：除了减肥外，我们只有有限的改善糖尿病前期的方法。毒品 靶向白脂肪变为啮齿动物和人类的葡萄糖代谢，我们提出 可以探索这可以减轻糖尿病前期。该申请解决了两种药物的有效性 被广泛规定，容忍良好，但尚未广泛研究其代谢 在患有糖尿病前的受试者中的有效性，从未结合使用过。结果 研究可能导致更大的试验，这可能会大大改变我们对糖尿病前期治疗的方法。