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      Favourable effect of the sodium‐glucose co‐transporter‐2 inhibitor canagliflozin plus the dipeptidyl peptidase‐4 inhibitor teneligliptin in combination on glycaemic fluctuation: An open‐label, prospective, randomized, parallel‐group comparison trial (the CALMER study)

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          Abstract

          This multicentre, prospective, randomized, open‐label, blinded‐endpoint, parallel‐group, short‐term (4–5 weeks) controlled trial was conducted to investigate the superiority of the effect of reducing mean amplitude of glycaemic excursions (MAGE) during meal tolerance tests (MTTs) for the combination of dipeptidyl peptidase‐4 (DPP‐4) inhibitor and sodium‐glucose co‐transporter‐2 (SGLT2) inhibitor compared with SGLT2 inhibitor monotherapy. Ninety‐nine patients with type 2 diabetes who were taking teneligliptin (20 mg/d) were randomized to one of the following two groups: those who switched to 100 mg/d of canagliflozin (SWITCH group) or those who added 100 mg/d of canagliflozin (COMB group). MAGE in the COMB group was significantly decreased compared with that in the SWITCH group (COMB 117.5 ± 39.8 to 92.2 ± 28.0 mg/dL vs SWITCH 110.7 ± 29.8 to 104.2 ± 27.6 mg/dL; P<0.01). Mean blood glucose decreased significantly during MTTs in both groups, although the extent of the reduction was significantly greater in the COMB group (COMB 142.3 ± 28.7 to 119.5 ± 25.1 mg/dL vs SWITCH 146.4 ± 25.5 to 135.5 ± 22.4 mg/dL; P < 0.01). SGLT2 inhibitor combined with DPP‐4 inhibitor therapy strongly reduced glycaemic fluctuation compared with SGLT2 inhibitor monotherapy.

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          Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance

          Obesity-induced metabolic disease involves functional integration among several organs via circulating factors, but little is known about crosstalk between liver and visceral adipose tissue (VAT). In obesity, VAT becomes populated with inflammatory adipose tissue macrophages (ATMs). In obese humans, there is a close correlation between adipose tissue inflammation and insulin resistance, and in obese mice, blocking systemic or ATM inflammation improves insulin sensitivity. However, processes that promote pathological adipose tissue inflammation in obesity are incompletely understood. Here we show that obesity in mice stimulates hepatocytes to synthesize and secrete dipeptidyl peptidase 4 (DPP4), which acts with plasma factor Xa to inflame ATMs. Silencing expression of DPP4 in hepatocytes suppresses inflammation of VAT and insulin resistance; however, a similar effect is not seen with the orally administered DPP4 inhibitor sitagliptin. Inflammation and insulin resistance are also suppressed by silencing expression of caveolin-1 or PAR2 in ATMs; these proteins mediate the actions of DPP4 and factor Xa, respectively. Thus, hepatocyte DPP4 promotes VAT inflammation and insulin resistance in obesity, and targeting this pathway may have metabolic benefits that are distinct from those observed with oral DPP4 inhibitors.
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            Postprandial plasma glucose excursions and cognitive functioning in aged type 2 diabetics.

            Postprandial plasma glucose (PPG) excursion is a significant determinant of overall metabolic control as well as an increased risk for diabetic complications. Older persons with type 2 diabetes mellitus (DM2) are more likely to have moderate cognitive deficits and neurophysiologic and structural changes in brain tissue. Considering that poor metabolic control is considered a deranging factor for tissue/organ damage in diabetics, the authors hypothesized that PPG excursion is associated with a decline in cognitive functioning and that a tighter control of PPG may prevent cognitive decline. Two groups of aged diabetic patients were randomly selected to be treated with repaglinide (n = 77) or glibenclamide (n = 79). Coefficient of variation of PPG (CV-PPG) was associated with Mini-Mental State Examination (MMSE) scores (r = -0.3410; p < 0.001) and a composite score of executive and attention functioning (r = -0.3744; p < 0.001) after adjusting for multiple confounders. Both groups showed a significant decline in hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG), but only the repaglinide group demonstrated a significant decline of CV-PPG over time. In models investigating the change in cognitive functioning over time, adjusted for HbA1c and CV-FPG, a decline in cognitive functioning was observed only in the glibenclamide group (p < 0.001). After adjusting for CV-PPG, the authors no longer found a decline in executive and attention functioning composite score (p = 0.085) or the MMSE (p = 0.080) with glibenclamide. Exaggerated postprandial glucose (PPG) excursions are associated with a derangement of both global, executive, and attention functioning. A tighter control of PPG may prevent cognitive decline in older diabetic individuals.
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              Impact of dapagliflozin, an SGLT2 inhibitor, on serum levels of soluble dipeptidyl peptidase‐4 in patients with type 2 diabetes and non‐alcoholic fatty liver disease

              Soluble dipeptidyl peptidase-4 (sDPP-4) is secreted by hepatocytes and induces adipose tissue inflammation and insulin resistance. Sodium-glucose co-transporter-2 (SGLT2) inhibitors can improve hepatic steatosis by inhibiting hepatic de novo lipogenesis. We investigated the effects of dapagliflozin (an SGLT2 inhibitor) on serum levels of sDPP-4 in patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD).
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                Author and article information

                Contributors
                hmiyoshi@med.hokudai.ac.jp
                Journal
                Diabetes Obes Metab
                Diabetes Obes Metab
                10.1111/(ISSN)1463-1326
                DOM
                Diabetes, Obesity & Metabolism
                Blackwell Publishing Ltd (Oxford, UK )
                1462-8902
                1463-1326
                13 October 2019
                March 2020
                : 22
                : 3 ( doiID: 10.1111/dom.v22.3 )
                : 458-462
                Affiliations
                [ 1 ] Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine Hokkaido University Sapporo Japan
                [ 2 ] Clinical Research and Medical Innovation Centre Hokkaido University Hospital Sapporo Japan
                [ 3 ] Third Department of Internal Medicine Hokkaido P.W.F.A.C Obihiro‐Kosei General Hospital Obihiro Japan
                [ 4 ] Sapporo Diabetes and Thyroid Clinic Sapporo Japan
                [ 5 ] Division of Diabetes and Endocrinology, Department of Medicine, Sapporo Medical Centre NTT East Corporation Sapporo Japan
                [ 6 ] Department of Internal Medicine Jiyugaoka Medical Clinic Obihiro Japan
                [ 7 ] Department of Diabetes Centre Manda Memorial Hospital Sapporo Japan
                [ 8 ] Kurihara Clinic Sapporo Japan
                [ 9 ] Aoki Clinic Sapporo Japan
                [ 10 ] Division of Diabetes and Obesity, Faculty of Medicine and Graduate School of Medicine Hokkaido University Sapporo Japan
                Author notes
                [*] [* ] Correspondence

                Hideaki Miyoshi, MD, Division of Diabetes and Obesity, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, N15 W7, Kita‐ku, Sapporo 060‐8638, Japan.

                Email: hmiyoshi@ 123456med.hokudai.ac.jp

                Author information
                https://orcid.org/0000-0002-3131-0832
                https://orcid.org/0000-0002-8192-0006
                https://orcid.org/0000-0001-5766-6047
                Article
                DOM13879
                10.1111/dom.13879
                7065098
                31486230
                f97b8b5f-c5c4-4e3a-b20a-5f33162178cc
                © 2019 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 23 June 2019
                : 26 August 2019
                : 01 September 2019
                Page count
                Figures: 1, Tables: 1, Pages: 5, Words: 3670
                Funding
                Funded by: Mitsubishi Tanabe Pharma Corporation , open-funder-registry 10.13039/501100012351;
                Categories
                Brief Report
                Brief Reports
                Custom metadata
                2.0
                March 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.7 mode:remove_FC converted:11.03.2020

                Endocrinology & Diabetes
                continuous glucose monitoring,dpp‐4 inhibitor,randomized trial,sglt2 inhibitor,type 2 diabetes.

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