Mirabegron and tadalafil effectiveness for treatment of prediabetes

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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.