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      Review: Miglitol has potential as a therapeutic drug against obesity

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          Abstract

          The number of obese patients has increased annually worldwide. Therefore, there is a strong need to develop a new effective and safe anti-obesity drug. Miglitol is an alpha-glucosidase inhibitor (αGI) that is commonly used as an anti-diabetic drug, and there is growing evidence that it also has anti-obesity effects. Miglitol has been shown to reduce body weight and ameliorate insulin resistance in both clinical trials with adult patients and in rodent models of obesity. Although the specific mechanism of action of this effect remains unclear, some mechanisms have been suggested through experimental results. Miglitol has been shown to inhibit adipogenesis of white adipocytes in vitro, activate brown adipose tissue (BAT) in mice, influence bile acid metabolism in mice, and regulate the secretion of incretin hormones in humans. Among these results, we consider that BAT activation is likely the definitive mediator of miglitol’s anti-obesity effect. A unique advantage of miglitol is that it is already used as an anti-diabetic drug with no severe side effects, whereas many of the anti-obesity drugs developed to date have been withdrawn because of their severe side effects. Miglitol is currently used clinically in a limited number of countries. In this review, we provide an overview of the state of research on miglitol for obesity treatment, emphasizing that it warrants more detailed attention. Overall, we demonstrate that miglitol shows good potential as a therapeutic for the treatment of obesity. Thus, we believe that further investigations of how it exerts its anti-obesity effect will likely contribute to the development of a new class of safe and effective drugs against obesity.

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          Long-term drug treatment for obesity: a systematic and clinical review.

          Thirty-six percent of US adults are obese, and many cannot lose sufficient weight to improve health with lifestyle interventions alone. To conduct a systematic review of medications currently approved in the United States for obesity treatment in adults. We also discuss off-label use of medications studied for obesity and provide considerations for obesity medication use in clinical practice. A PubMed search from inception through September 2013 was performed to find meta-analyses, systematic reviews, and randomized, placebo-controlled trials for currently approved obesity medications lasting at least 1 year that had a primary or secondary outcome of body weight change, included at least 50 participants per group, reported at least 50% retention, and reported results on an intention-to-treat basis. Studies of medications approved for other purposes but tested for obesity treatment were also reviewed. Obesity medications approved for long-term use, when prescribed with lifestyle interventions, produce additional weight loss relative to placebo ranging from approximately 3% of initial weight for orlistat and lorcaserin to 9% for top-dose (15/92 mg) phentermine plus topiramate-extended release at 1 year. The proportion of patients achieving clinically meaningful (at least 5%) weight loss ranges from 37% to 47% for lorcaserin, 35% to 73% for orlistat, and 67% to 70% for top-dose phentermine plus topiramate-extended release. All 3 medications produce greater improvements in many cardiometabolic risk factors than placebo, but no obesity medication has been shown to reduce cardiovascular morbidity or mortality. Most prescriptions are for noradrenergic medications, despite their approval only for short-term use and limited data for their long-term safety and efficacy. Medications approved for long-term obesity treatment, when used as an adjunct to lifestyle intervention, lead to greater mean weight loss and an increased likelihood of achieving clinically meaningful 1-year weight loss relative to placebo. By discontinuing medication in patients who do not respond with weight loss of at least 5%, clinicians can decrease their patients' exposure to the risks and costs of drug treatment when there is little prospect of long-term benefit.
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            Central administration of GLP-1-(7-36) amide inhibits food and water intake in rats.

            Glucagon-like peptide (GLP)-1-(7-36) amide and its pancreatic receptors are important for control of blood glucose levels. However, rat GLP-1 receptors are also localized in the brain, in hypothalamus, and in areas without a blood-brain barrier. When rats were kept on a food restriction schedule, intracerebroventricular injection of GLP-1 just before food was offered inhibited food intake. However, peripheral GLP-1 administration by intraperitoneal injection had little effect. GLP-1 effects on water intake and output were also investigated. Intracerebroventricular GLP-1 profoundly inhibited angiotensin II-induced drinking behavior in rats, and water intake was suppressed by exogenous GLP-1 in rats habituated to a water restriction schedule. These effects were reproduced by intraperitoneal administration of GLP-1. Furthermore, intracerebroventricular GLP-1 stimulated urinary excretion of water and sodium. The centrally elicited effects were blocked by the GLP-1 antagonist exendin-(9-39) amide, whereas the N-terminally extended and inactive GLP-1-(1-36) amide had no effect on feeding and drinking. GLP-1 had no effect in behavioral assays measuring exploratory locomotor activity and conditioned taste aversion. In conclusion, GLP-1 may play a physiological role in regulation of both ingestion and the water and salt homeostasis.
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              Indispensable role of mitochondrial UCP1 for antiobesity effect of beta3-adrenergic stimulation.

              Mitochondrial uncoupling protein-1 (UCP1) has been thought to be a key molecule for thermogenesis during cold exposure and spontaneous hyperphagia and thereby in the autonomic regulation of energy expenditure and adiposity. However, UCP1 knockout (KO) mice were reported to be cold intolerant but unexpectedly did not get obese even after hyperphagia, implying that UCP1 may not be involved in the regulation of adiposity. Treatment of obese animals with beta3-adrenergic agonists is known to increase lipid mobilization, induce UCP1, and, finally, reduce body fat content. To obtain direct evidence for the role of UCP1 in the anti-obesity effect of beta3-adrenergic stimulation, in the present study, UCP1-KO and wild-type (WT) mice were fed on cafeteria diets for 8 wk and then given a beta3-adrenergic agonist, CL-316,243 (CL), or saline for 2 wk. A single injection of CL increased whole body oxygen consumption and brown fat temperature in WT mice but not in KO mice, and it elicited almost the same plasma free fatty acid response in WT and KO mice. WT and KO mice increased similarly their body and white fat pad weights on cafeteria diets compared with those on laboratory chow. Daily treatment with CL resulted in a marked reduction of white fat pad weight and the size of adipocytes in WT mice, but not in KO mice. Compared with WT mice, KO mice expressed increased levels of UCP2 in brown fat but decreased levels in white fat and comparable levels of UCP3. It was concluded that the anti-obesity effect of beta3-adrenergic stimulation is largely attributable to UCP1, but less to UCP2 and UCP3, and thereby to UCP1-dependent degradation of fatty acids released from white adipose tissue.
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                Author and article information

                Contributors
                +81-773-43-0123 , satoru-s@koto.kpu-m.ac.jp
                hisakazu@koto.kpu-m.ac.jp
                kosak001@koto.kpu-m.ac.jp
                hhosoi@koto.kpu-m.ac.jp
                Journal
                Nutr Metab (Lond)
                Nutr Metab (Lond)
                Nutrition & Metabolism
                BioMed Central (London )
                1743-7075
                1 December 2015
                1 December 2015
                2015
                : 12
                : 51
                Affiliations
                [ ]Department of Pediatrics, Ayabe Municipal Hospital, 20-1 Otsuka, Aono-cho, Ayabe city, 623-0011 Kyoto Japan
                [ ]Department of Pediatrics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465-Kajiicho, Hirokoji-Kawaramachi, Kamikyo-ku, Kyoto, 602-8566 Kyoto Japan
                Article
                48
                10.1186/s12986-015-0048-8
                4666030
                26628904
                846ae59f-d075-418c-a461-47dee246f7a3
                © Sugimoto et al. 2015

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 31 July 2015
                : 25 November 2015
                Categories
                Review
                Custom metadata
                © The Author(s) 2015

                Nutrition & Dietetics
                miglitol,obesity,brown adipose tissue,incretin hormones,bile acid metabolism
                Nutrition & Dietetics
                miglitol, obesity, brown adipose tissue, incretin hormones, bile acid metabolism

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