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      Calorie Restriction Mimetics: Upstream-Type Compounds for Modulating Glucose Metabolism

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          Abstract

          Calorie restriction (CR) can prolong the human lifespan, but enforcing long-term CR is difficult. Therefore, a compound that reproduces the effect of CR without CR is needed. In this review, we summarize the current knowledge on compounds with CR mimetic (CRM) effects. More than 10 compounds have been listed as CRMs, some of which are conventionally categorized as upstream-type CRMs showing glycolytic inhibition, while the others are categorized as downstream-type CRMs that regulate or genetically modulate intracellular signaling proteins. Among these, we focus on upstream-type CRMs and propose their classification as compounds with energy metabolism inhibition effects, particularly glucose metabolism modulation effects. The upstream-type CRMs reviewed include chitosan, acarbose, sodium-glucose cotransporter 2 inhibitors, and hexose analogs such as 2-deoxy- d-glucose, d-glucosamine, and d-allulose, which show antiaging and longevity effects. Finally, we discuss the molecular definition of upstream-type CRMs.

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          Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes

          Bruce Neal, Vlado Perkovic, Kenneth Mahaffey … (2017)
          Background Canagliflozin is a sodium-glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on cardiovascular, renal, and safety outcomes. Methods The CANVAS Program integrated data from two trials involving a total of 10,142 participants with type 2 diabetes and high cardiovascular risk. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results The mean age of the participants was 63.3 years, 35.8% were women, the mean duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease. The rate of the primary outcome was lower with canagliflozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio, 0.86; 95% confidence interval [CI], 0.75 to 0.97; P<0.001 for noninferiority; P=0.02 for superiority). Although on the basis of the prespecified hypothesis testing sequence the renal outcomes are not viewed as statistically significant, the results showed a possible benefit of canagliflozin with respect to the progression of albuminuria (hazard ratio, 0.73; 95% CI, 0.67 to 0.79) and the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate, the need for renal-replacement therapy, or death from renal causes (hazard ratio, 0.60; 95% CI, 0.47 to 0.77). Adverse reactions were consistent with the previously reported risks associated with canagliflozin except for an increased risk of amputation (6.3 vs. 3.4 participants per 1000 patient-years; hazard ratio, 1.97; 95% CI, 1.41 to 2.75); amputations were primarily at the level of the toe or metatarsal. Conclusions In two trials involving patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal. (Funded by Janssen Research and Development; CANVAS and CANVAS-R ClinicalTrials.gov numbers, NCT01032629 and NCT01989754 , respectively.).
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            Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial.

            Jean-Louis Chiasson, Robert G Josse, Ramon Gomis … (2002)
            The worldwide increase in type 2 diabetes mellitus is becoming a major health concern. We aimed to assess the effect of acarbose in preventing or delaying conversion of impaired glucose tolerance to type 2 diabetes. In a multicentre, placebo-controlled randomised trial, we randomly allocated patients with impaired glucose tolerance to 100 mg acarbose or placebo three times daily. The primary endpoint was development of diabetes on the basis of a yearly oral glucose tolerance test (OGTT). Analyses were by intention to treat. We randomly allocated 714 patients with impaired glucose tolerance to acarbose and 715 to placebo. We excluded 61 (4%) patients because they did not have impaired glucose tolerance or had no postrandomisation data. 211 (31%) of 682 patients in the acarbose group and 130 (19%) of 686 on placebo discontinued treatment early. 221 (32%) patients randomised to acarbose and 285 (42%) randomised to placebo developed diabetes (relative hazard 0.75 [95% CI 0.63-0.90]; p=0.0015). Furthermore, acarbose significantly increased reversion of impaired glucose tolerance to normal glucose tolerance (p<0.0001). At the end of the study, treatment with placebo for 3 months was associated with an increase in conversion of impaired glucose tolerance to diabetes. The most frequent side-effects to acarbose treatment were flatulence and diarrhoea. Acarbose could be used, either as an alternative or in addition to changes in lifestyle, to delay development of type 2 diabetes in patients with impaired glucose tolerance.
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              Spermidine in health and disease

              Frank Madeo, Tobias Eisenberg, Federico Pietrocola … (2018)
              Article 0 comments Cited 387 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Nutrients
                Journal ID (iso-abbrev): Nutrients
                Journal ID (publisher-id): nutrients
                Title: Nutrients
                Publisher: MDPI
                ISSN (Electronic): 2072-6643
                Publication date (Electronic): 22 November 2018
                Publication date Collection: December 2018
                Volume: 10
                Issue: 12
                Electronic Location Identifier: 1821
                Affiliations
                [1 ]Department of Internal Medicine, Saiseikai Izuo Hospital, Osaka 551-0032, Japan; sntnhdy@ 123456gmail.com
                [2 ]United Graduate School of Agricultural Science, Ehime University, Matsuyama 790-8577, Japan
                [3 ]Faculty of Biology-Oriented Science and Technology, Kindai University, Wakayama 649-6493, Japan; ashida@ 123456waka.kindai.ac.jp
                [4 ]Faculty of Agriculture, Kagawa University, Kagawa 761-0701, Japan; sato@ 123456ag.kagawa-u.ac.jp
                Author notes
                [* ]Correspondence: 6742004b@ 123456stu.kagawa-u.ac.jp ; Tel.: +81-6-6621-5122
                Author information
                https://orcid.org/0000-0002-3296-3763
                https://orcid.org/0000-0002-8959-8875
                Article
                Publisher ID: nutrients-10-01821
                DOI: 10.3390/nu10121821
                PMC ID: 6316630
                PubMed ID: 30469486
                SO-VID: 3a989a73-84eb-463e-9a10-398a56616404
                Copyright © © 2018 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 06 November 2018
                Date accepted : 18 November 2018
                Categories
                Subject: Review

                ScienceOpen disciplines: Nutrition & Dietetics
                Keywords: calorie restriction mimetics,antiaging,lifespan extension,glucose metabolism modulation,chitosan,acarbose,sglt2 inhibitor,2-deoxy-d-glucose,d-allulose,d-glucosamine
                Data availability:
                ScienceOpen disciplines: Nutrition & Dietetics
                Keywords: calorie restriction mimetics, antiaging, lifespan extension, glucose metabolism modulation, chitosan, acarbose, sglt2 inhibitor, 2-deoxy-d-glucose, d-allulose, d-glucosamine

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