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: 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
• 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

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，并且进展为2型糖尿病的发生率 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， 糖尿病前期个体不能实现逆转糖尿病前期或预防糖尿病所必需的改变。 在最近的研究中，我们用β-肾上腺素能受体（β3AR）激动剂治疗肥胖的胰岛素抵抗患者 米拉贝隆，这导致口服葡萄糖耐量改善，HbA 1c降低，胰岛素增加 敏感性和β细胞功能。这些变化发生在没有体重减轻的情况下。虽然布朗 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， 增加骨骼肌中的1型纤维和毛细血管密度。米色脂肪细胞对 葡萄糖代谢，并假定作为葡萄糖汇。 Mirabegron刺激β 3 AR，β 3 AR刺激cAMP介导的PKA活化， p38 map激酶的表达，其诱导UCP 1和脂肪褐变。最近的研究表明，cGMP激活 蛋白激酶G（PKG）以类似的方式起作用，以改善葡萄糖代谢并增加白色脂肪 米色。事实上，cGMP是由天然配体（ANP，BNP，一氧化氮）刺激;磷酸二酯酶5 （PDE 5）抑制剂药物西地那非和他达拉非可防止cGMP分解，激活PKG，这导致 增加脂肪细胞中的UCP 1。因此，我们假设， 米拉贝隆或他达拉非将改善葡萄糖代谢。我们进一步假设联合治疗 与米拉贝隆和他达拉非联合使用，将对葡萄糖代谢产生叠加性改善，可能是由于其平行性， 刺激环核苷酸cAMP、cGMP和诱导脂肪沉积的作用。 具体目标1.我们假设用β3激动剂米拉贝隆治疗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， 通过米拉贝隆加他达拉非的联合治疗将进一步改善葡萄糖代谢。 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、脂肪组织染色， 肌纤维类型和肌毛细血管。 临床相关性：除了减肥，我们只有有限的方法来改善前驱糖尿病。药物 靶向白色脂肪褐变改善啮齿类动物和人类的葡萄糖代谢， 这可以用来减轻前驱糖尿病。本申请涉及两种药物的有效性 这些药物被广泛使用，耐受性良好，但尚未对其代谢进行广泛研究。 在糖尿病前期受试者中的有效性，从未进行过联合研究。结果从这个 这项研究可能会导致一个更大的试验，这可能会大大改变我们对糖尿病前期治疗的方法。