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8400万美国人患有前驱糖尿病，进展为2型糖尿病的速度 每年5%到10%，是心脏病的风险因素。虽然改变生活方式是有效的，但大多数 糖尿病前期患者无法实现逆转糖尿病前期或预防糖尿病所需的变化。 在最近的研究中，我们用β肾上腺素能受体(β3AR)激动剂治疗肥胖、胰岛素抵抗的人类 米拉贝格隆，结果是改善了口服葡萄糖耐量，降低了糖化血红蛋白，增加了胰岛素 敏感度和β细胞功能。这些变化是在没有减肥的情况下发生的。虽然是棕色的 脂肪组织没有增加，米雷贝格隆治疗增加了米色脂肪，减少了脂肪炎症和 骨骼肌中I型纤维和毛细血管密度增加。米色脂肪细胞对 葡萄糖代谢，并被认为是一个葡萄糖接收器。 米雷贝格隆刺激β-3AR，从而刺激cAMP介导的蛋白激酶A活化 P38MAPK，诱导UCP1和脂肪褐变。最近的研究表明，cGMP激活 蛋白激酶G(PKG)在改善葡萄糖代谢和增加白色脂肪方面也起着类似的作用 浅色的。事实上，cGMP受到天然配体(ANP、BNP、一氧化氮)的刺激；磷酸二酯酶5 (PDE5)抑制剂药物西地那非和他达拉非可阻止cGMP的分解，激活PKG，从而导致 脂肪细胞UCP1表达增加。因此，我们假设糖尿病前期受试者使用 米拉贝格隆或他达拉非会改善葡萄糖代谢。我们进一步假设联合治疗 米拉贝格隆和他达拉非对葡萄糖代谢有相加的改善作用，这可能是因为它们是平行的。 刺激环核苷酸cAMP和cGMP，诱导脂肪褐变。 具体目标1.我们假设用β3激动剂米拉贝格隆治疗4个月将导致 改善肥胖、糖尿病前期人类研究参与者的葡萄糖代谢，这一改善 米拉贝格隆联合他达拉非治疗可进一步改善糖代谢。 具体目标2.我们将确定改善血糖稳态的潜在机制 通过对胰岛素敏感性、胰岛素分泌、脂肪组织褐变、 肌肉纤维类型和肌肉毛细血管。 临床意义：除了减肥，我们只有有限的方法来改善糖尿病前期。毒品 靶向白色脂肪褐变改善了啮齿动物和人类的葡萄糖代谢，我们建议 这可以被用来减轻糖尿病前期的症状。这项申请涉及两种药物的有效性 处方广泛，耐受性良好，但尚未对其代谢进行广泛研究 对糖尿病前期患者的有效性，从未进行过联合研究。由此产生的结果 这项研究可能会导致一项更大规模的试验，这可能会极大地改变我们治疗糖尿病前期的方法。