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      Current and future impact of clinical gastrointestinal research on patient care in diabetes mellitus

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          Abstract

          The worldwide rise in the prevalence of obesity supports the need for an increased interaction between ongoing clinical research in the allied fields of gastrointestinal medicine/surgery and diabetes mellitus. There have been a number of clinically-relevant advances in diabetes, obesity, and metabolic syndrome emanating from gastroenterological research. Gastric emptying is a significant factor in the development of upper gastrointestinal symptoms. However, it is not the only mechanism whereby such symptoms occur in patients with diabetes. Disorders of intrinsic pacing are involved in the control of stomach motility in patients with gastroparesis; on the other hand, there is limited impact of glycemic control on gastric emptying in patients with established diabetic gastroparesis. Upper gastrointestinal functions related to emptying and satiations are significantly associated with weight gain in obesity. Medications used in the treatment of diabetes or metabolic syndrome, particularly those related to pancreatic hormones and incretins affect upper gastrointestinal tract function and reduce hyperglycemia and facilitate weight loss. The degree of gastric emptying delay is significantly correlated with the weight loss in response to liraglutide, a glucagon-like peptide-1 analog. Network meta-analysis shows that liraglutide is one of the two most efficacious medical treatments of obesity, the other being the combination treatment phentermine-topiramate. Interventional therapies for the joint management of obesity and diabetes mellitus include newer endoscopic procedures, which require long-term follow-up and bariatric surgical procedure for which long-term follow up shows advantages for individuals with diabetes. Newer bariatric procedures are presently undergoing clinical evaluation. On the horizon, combination therapies, in part directed at gastrointestinal functions, appear promising for these indications. Ongoing and future gastroenterological research when translated to care of individuals with diabetes mellitus should provide additional options to improve their clinical outcomes.

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          Long-term follow-up after bariatric surgery: a systematic review.

          Bariatric surgery is an accepted treatment for obesity. Despite extensive literature, few studies report long-term follow-up in cohorts with adequate retention rates.
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            Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans.

            We report the discovery and translational therapeutic efficacy of a peptide with potent, balanced co-agonism at both of the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This unimolecular dual incretin is derived from an intermixed sequence of GLP-1 and GIP, and demonstrated enhanced antihyperglycemic and insulinotropic efficacy relative to selective GLP-1 agonists. Notably, this superior efficacy translated across rodent models of obesity and diabetes, including db/db mice and ZDF rats, to primates (cynomolgus monkeys and humans). Furthermore, this co-agonist exhibited synergism in reducing fat mass in obese rodents, whereas a selective GIP agonist demonstrated negligible weight-lowering efficacy. The unimolecular dual incretins corrected two causal mechanisms of diabesity, adiposity-induced insulin resistance and pancreatic insulin deficiency, more effectively than did selective mono-agonists. The duration of action of the unimolecular dual incretins was refined through site-specific lipidation or PEGylation to support less frequent administration. These peptides provide comparable pharmacology to the native peptides and enhanced efficacy relative to similarly modified selective GLP-1 agonists. The pharmacokinetic enhancement lessened peak drug exposure and, in combination with less dependence on GLP-1-mediated pharmacology, avoided the adverse gastrointestinal effects that typify selective GLP-1-based agonists. This discovery and validation of a balanced and high-potency dual incretin agonist enables a more physiological approach to management of diseases associated with impaired glucose tolerance.
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              Gastric emptying and glycaemia in health and diabetes mellitus.

              The rate of gastric emptying is a critical determinant of postprandial glycaemia and, accordingly, is fundamental to maintaining blood glucose homeostasis. Disordered gastric emptying occurs frequently in patients with longstanding type 1 diabetes mellitus and type 2 diabetes mellitus (T2DM). A complex bidirectional relationship exists between gastric emptying and glycaemia--gastric emptying accounts for ∼35% of the variance in peak postprandial blood glucose concentrations in healthy individuals and in patients with diabetes mellitus, and the rate of emptying is itself modulated by acute changes in glycaemia. Clinical implementation of incretin-based therapies for the management of T2DM, which diminish postprandial glycaemia, in part by slowing gastric emptying, is widespread. Other therapies for patients with T2DM, which specifically target gastric emptying include pramlintide and dietary-based treatment approaches. A weak association exists between upper gastrointestinal symptoms and the rate of gastric emptying. In patients with severe diabetic gastroparesis, pathological changes are highly variable and are characterized by loss of interstitial cells of Cajal and an immune infiltrate. Management options for patients with symptomatic gastroparesis remain limited in their efficacy, which probably reflects the heterogeneous nature of the underlying pathophysiology.
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                Author and article information

                Contributors
                Journal
                World J Diabetes
                WJD
                World Journal of Diabetes
                Baishideng Publishing Group Inc
                1948-9358
                15 November 2018
                15 November 2018
                : 9
                : 11
                : 180-189
                Affiliations
                Center for Advanced Laparoscopic General and Bariatric Surgery, MedStar Washington Hospital Center and Georgetown University School of Medicine, Washington, DC 20010, United States. timothy.r.koch@ 123456medstar.net
                Center for Advanced Laparoscopic General and Bariatric Surgery, MedStar Washington Hospital Center and Georgetown University School of Medicine, Washington, DC 20010, United States
                Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States
                Author notes

                Author contributions: All of the authors drafted the manuscript and approved the final version of the article.

                Supported by the grant from National Institutes of Health, No. R01-DK67071.

                Correspondence to: Timothy R Koch, MD, Doctor, Professor, Center for Advanced Laparoscopic General and Bariatric Surgery, MedStar Washington Hospital Center and Georgetown University School of Medicine, POB South, Suite 301, 106 Irving Street, NW, Washington, DC 20010, United States. timothy.r.koch@ 123456medstar.net

                Telephone: +1-202-8777788 Fax: +1-877-6808198

                Article
                jWJD.v9.i11.pg180
                10.4239/wjd.v9.i11.180
                6242723
                55d6b7e7-865d-4a5f-bccc-bb3628807c62
                ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.

                This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.

                History
                : 23 July 2018
                : 12 August 2018
                : 11 October 2018
                Categories
                Editorial

                obesity,gastric emptying,diabetes mellitus,gastric bypass,bariatric surgery,weight loss

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