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      Type 2 Diabetes Is Associated with a Different Pattern of Serum Polyamines: A Case–Control Study from the PREDIMED-Plus Trial

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          Abstract

          Objective: Polyamines are naturally occurring cationic molecules present in all living cells. Dysregulation of circulating polyamines has been reported in several conditions, but little is known about the levels of serum polyamines in chronic metabolic disorders such as type 2 diabetes (T2D). Therefore, the aim of this study was to evaluate the polyamine-related metabolome in a cohort of metabolic syndrome individuals with and without T2D. Design and methods: This was a nested case–control study within the PREDIMED-Plus trial that included 44 patients with T2D and 70 patients without T2D. We measured serum levels of arginine, ornithine, polyamines, and acetyl polyamines with an ultra-high performance liquid chromatography tandem mass spectrometry platform. Results: Our results showed that serum putrescine, directly generated from ornithine by the catalytic action of the biosynthetic enzyme ornithine decarboxylase, was significantly elevated in patients with T2D compared to those without T2D, and that it significantly correlated with the levels of glycosylated hemoglobin (HbA1c). Correlation analysis revealed a significantly positive association between fasting insulin levels and spermine. Multiple logistic regression analysis (adjusted for age, gender and body weight index) revealed that serum putrescine and spermine levels were associated with a higher risk of T2D. Conclusions: Our study suggests that polyamine metabolism is dysregulated in T2D, and that serum levels of putrescine and spermine are associated with glycemic control and circulating insulin levels, respectively.

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          Spermidine in health and disease

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            Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity.

            In obesity and type 2 diabetes, Glut4 glucose transporter expression is decreased selectively in adipocytes. Adipose-specific knockout or overexpression of Glut4 alters systemic insulin sensitivity. Here we show, using DNA array analyses, that nicotinamide N-methyltransferase (Nnmt) is the most strongly reciprocally regulated gene when comparing gene expression in white adipose tissue (WAT) from adipose-specific Glut4-knockout or adipose-specific Glut4-overexpressing mice with their respective controls. NNMT methylates nicotinamide (vitamin B3) using S-adenosylmethionine (SAM) as a methyl donor. Nicotinamide is a precursor of NAD(+), an important cofactor linking cellular redox states with energy metabolism. SAM provides propylamine for polyamine biosynthesis and donates a methyl group for histone methylation. Polyamine flux including synthesis, catabolism and excretion, is controlled by the rate-limiting enzymes ornithine decarboxylase (ODC) and spermidine-spermine N(1)-acetyltransferase (SSAT; encoded by Sat1) and by polyamine oxidase (PAO), and has a major role in energy metabolism. We report that NNMT expression is increased in WAT and liver of obese and diabetic mice. Nnmt knockdown in WAT and liver protects against diet-induced obesity by augmenting cellular energy expenditure. NNMT inhibition increases adipose SAM and NAD(+) levels and upregulates ODC and SSAT activity as well as expression, owing to the effects of NNMT on histone H3 lysine 4 methylation in adipose tissue. Direct evidence for increased polyamine flux resulting from NNMT inhibition includes elevated urinary excretion and adipocyte secretion of diacetylspermine, a product of polyamine metabolism. NNMT inhibition in adipocytes increases oxygen consumption in an ODC-, SSAT- and PAO-dependent manner. Thus, NNMT is a novel regulator of histone methylation, polyamine flux and NAD(+)-dependent SIRT1 signalling, and is a unique and attractive target for treating obesity and type 2 diabetes.
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              Polyamines: Bio-Molecules with Diverse Functions in Plant and Human Health and Disease

              Biogenic amines—polyamines (PAs), particularly putrescine, spermidine and spermine are ubiquitous in all living cells. Their indispensable roles in many biochemical and physiological processes are becoming commonly known, including promoters of plant life and differential roles in human health and disease. PAs positively impact cellular functions in plants—exemplified by increasing longevity, reviving physiological memory, enhancing carbon and nitrogen resource allocation/signaling, as well as in plant development and responses to extreme environments. Thus, one or more PAs are commonly found in genomic and metabolomics studies using plants, particulary during different abiotic stresses. In humans, a general decline in PA levels with aging occurs parallel with some human health disorders. Also, high PA dose is detrimental to patients suffering from cancer, aging, innate immunity and cognitive impairment during Alzheimer and Parkinson diseases. A dichotomy exists in that while PAs may increase longevity and reduce some age-associated cardiovascular diseases, in disease conditions involving higher cellular proliferation, their intake has negative consequences. Thus, it is essential that PA levels be rigorously quantified in edible plant sources as well as in dietary meats. Such a database can be a guide for medical experts in order to recommend which foods/meats a patient may consume and which ones to avoid. Accordingly, designing both high and low polyamine diets for human consumption are in vogue, particularly in medical conditions where PA intake may be detrimental, for instance, cancer patients. In this review, literature data has been collated for the levels of the three main PAs, putrescine, spermidine and spermine, in different edible sources—vegetables, fruits, cereals, nuts, meat, sea food, cheese, milk, and eggs. Based on our analysis of vast literature, the effects of PAs in human/animal health fall into two broad, Yang and Yin, categories: beneficial for the physiological processes in healthy cells and detrimental under pathological conditions.
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                Author and article information

                Journal
                J Clin Med
                J Clin Med
                jcm
                Journal of Clinical Medicine
                MDPI
                2077-0383
                10 January 2019
                January 2019
                : 8
                : 1
                : 71
                Affiliations
                [1 ]Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), Malaga 29010, Spain; josecarlosfdezgarcia@ 123456hotmail.com (J.C.F.-G.); danie__cc@ 123456hotmail.com (D.C.-C.); aracelimugar@ 123456gmail.com (A.M.-G.); maribelqo@ 123456gmail.com (M.I.Q.-O.); fjtinahones@ 123456hotmail.com (F.J.T.)
                [2 ]CIBER Physiopathology of Obesity and Nutrition (CIBERobn), Institute of Health Carlos III, Madrid 28029, Spain; robelopajiju@ 123456yahoo.es
                [3 ]Eurecat, Centre Tecnològic de Catalunya, Centre for Omic Sciences (Joint Unit Eurecat-Universitat Rovira i Virgili), Unique Scientific and Technical Infrastructure (ICTS), Reus 43204, Spain; antoni.delpino@ 123456eurecat.org (A.D.-R.); iris.samarra@ 123456urv.cat (I.S.)
                [4 ]Department of Internal Medicine, Regional University Hospital of Malaga, Institute of Biomedical Research in Malaga (IBIMA), University of Malaga, Malaga 29010, Spain
                [5 ]Department of Medical Oncology, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Malaga (IBIMA), Malaga 29010, Spain
                Author notes
                [* ]Correspondence: fernando.cardona@ 123456ibima.eu (F.C.); bruno.ramos@ 123456ibima.eu (B.R.-M.); Tel.: +34-951-036-2647 (F.C. & B.R.-M.); Fax: +34-951-924-651 (F.C. & B.R.-M.)
                [†]

                Current address: Laboratory of Biomedical Research-IBIMA, Virgen de la Victoria University Hospital, Campus de Teatinos s/n, Malaga 29010, Spain.

                Author information
                https://orcid.org/0000-0003-2229-8488
                https://orcid.org/0000-0002-1867-1158
                https://orcid.org/0000-0002-0238-0890
                https://orcid.org/0000-0001-6804-5449
                Article
                jcm-08-00071
                10.3390/jcm8010071
                6352090
                30634588
                80084503-e876-4e5e-8653-bc6a5cc6aa81
                © 2019 by the authors.

                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
                : 17 December 2018
                : 07 January 2019
                Categories
                Article

                polyamines,diabetes,insulin,hba1c,case-control
                polyamines, diabetes, insulin, hba1c, case-control

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