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      Circulating Cardiac Biomarkers in Diabetes Mellitus: A New Dawn for Risk Stratification—A Narrative Review

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          Abstract

          The aim of this narrative review is to update the current knowledge on the differential choice of circulating cardiac biomarkers in patients with prediabetes and established type 2 diabetes mellitus (T2DM). There are numerous circulating biomarkers with unconfirmed abilities to predict clinical outcomes in pre-DM and DM individuals; the prognostication ability of the cardiac biomarkers reported here has been established, and they are still being studied. The conventional cardiac biomarkers, such as natriuretic peptides (NPs), soluble suppressor tumorigenisity-2, high-sensitivity circulating cardiac troponins and galectin-3, were useful to ascertain cardiovascular (CV) risk. Each cardiac biomarker has its strengths and weaknesses that affect the price of usage, specificity, sensitivity, predictive value and superiority in face-to-face comparisons. Additionally, there have been confusing reports regarding their abilities to be predictably relevant among patients without known CV disease. The large spectrum of promising cardiac biomarkers (growth/differential factor-15, heart-type fatty acid-binding protein, cardiotrophin-1, carboxy-terminal telopeptide of collagen type 1, apelin and non-coding RNAs) is discussed in the context of predicting CV diseases and events in patients with known prediabetes and T2DM. Various reasons have been critically discussed related to the variable findings regarding biomarker-based prediction of CV risk among patients with metabolic disease. It was found that NPs and hs-cTnT are still the most important tools that have an affordable price as well as high sensitivity and specificity to predict clinical outcomes among patients with pre-DM and DM in routine clinical practice, but other circulating biomarkers need to be carefully investigated in large trials in the future.

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          Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes.

          The ability of mammals to resist body fat accumulation is linked to their ability to expand the number and activity of "brown adipocytes" within white fat depots. Activation of β-adrenergic receptors (β-ARs) can induce a functional "brown-like" adipocyte phenotype. As cardiac natriuretic peptides (NPs) and β-AR agonists are similarly potent at stimulating lipolysis in human adipocytes, we investigated whether NPs could induce human and mouse adipocytes to acquire brown adipocyte features, including a capacity for thermogenic energy expenditure mediated by uncoupling protein 1 (UCP1). In human adipocytes, atrial NP (ANP) and ventricular NP (BNP) activated PPARγ coactivator-1α (PGC-1α) and UCP1 expression, induced mitochondriogenesis, and increased uncoupled and total respiration. At low concentrations, ANP and β-AR agonists additively enhanced expression of brown fat and mitochondrial markers in a p38 MAPK-dependent manner. Mice exposed to cold temperatures had increased levels of circulating NPs as well as higher expression of NP signaling receptor and lower expression of the NP clearance receptor (Nprc) in brown adipose tissue (BAT) and white adipose tissue (WAT). NPR-C(-/-) mice had markedly smaller WAT and BAT depots but higher expression of thermogenic genes such as Ucp1. Infusion of BNP into mice robustly increased Ucp1 and Pgc-1α expression in WAT and BAT, with corresponding elevation of respiration and energy expenditure. These results suggest that NPs promote "browning" of white adipocytes to increase energy expenditure, defining the heart as a central regulator of adipose tissue biology.
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            MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily.

            Macrophages play a key role in both normal and pathological processes involving immune and inflammatory responses, to a large extent through their capacity to secrete a wide range of biologically active molecules. To identify some of these as yet not characterized molecules, we have used a subtraction cloning approach designed to identify genes expressed in association with macrophage activation. One of these genes, designated macrophage inhibitory cytokine 1 (MIC-1), encodes a protein that bears the structural characteristics of a transforming growth factor beta (TGF-beta) superfamily cytokine. Although it belongs to this superfamily, it has no strong homology to existing families, indicating that it is a divergent member that may represent the first of a new family within this grouping. Expression of MIC-1 mRNA in monocytoid cells is up-regulated by a variety of stimuli associated with activation, including interleukin 1beta, tumor necrosis factor alpha (TNF-alpha), interleukin 2, and macrophage colony-stimulating factor but not interferon gamma, or lipopolysaccharide (LPS). Its expression is also increased by TGF-beta. Expression of MIC-1 in CHO cells results in the proteolytic cleavage of the propeptide and secretion of a cysteine-rich dimeric protein of Mr 25 kDa. Purified recombinant MIC-1 is able to inhibit lipopolysaccharide -induced macrophage TNF-alpha production, suggesting that MIC-1 acts in macrophages as an autocrine regulatory molecule. Its production in response to secreted proinflammatory cytokines and TGF-beta may serve to limit the later phases of macrophage activation.
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              Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions.

              Natriuretic peptides are a family of structurally related but genetically distinct hormones/paracrine factors that regulate blood volume, blood pressure, ventricular hypertrophy, pulmonary hypertension, fat metabolism, and long bone growth. The mammalian members are atrial natriuretic peptide, B-type natriuretic peptide, C-type natriuretic peptide, and possibly osteocrin/musclin. Three single membrane-spanning natriuretic peptide receptors (NPRs) have been identified. Two, NPR-A/GC-A/NPR1 and NPR-B/GC-B/NPR2, are transmembrane guanylyl cyclases, enzymes that catalyze the synthesis of cGMP. One, NPR-C/NPR3, lacks intrinsic enzymatic activity and controls the local concentrations of natriuretic peptides through constitutive receptor-mediated internalization and degradation. Single allele-inactivating mutations in the promoter of human NPR-A are associated with hypertension and heart failure, whereas homozygous inactivating mutations in human NPR-B cause a form of short-limbed dwarfism known as acromesomelic dysplasia type Maroteaux. The physiological effects of natriuretic peptides are elicited through three classes of cGMP binding proteins: cGMP-dependent protein kinases, cGMP-regulated phosphodiesterases, and cyclic nucleotide-gated ion channels. In this comprehensive review, the structure, function, regulation, and biological consequences of natriuretic peptides and their associated signaling proteins are described.
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                Author and article information

                Contributors
                aeberezin@gmail.com
                Journal
                Diabetes Ther
                Diabetes Ther
                Diabetes Therapy
                Springer Healthcare (Cheshire )
                1869-6953
                1869-6961
                19 May 2020
                19 May 2020
                June 2020
                : 11
                : 6
                : 1271-1291
                Affiliations
                [1 ]Internal Medicine Department, Ministry of Health of Ukraine, State Medical University, Zaporozhye, 69035 Ukraine
                [2 ]Internal Medicine Department, Medical Academy of Post-Graduate Education, Ministry of Health of Ukraine, Zaporozhye, 69096 Ukraine
                Author information
                http://orcid.org/0000-0002-0446-3999
                Article
                835
                10.1007/s13300-020-00835-9
                7261294
                32430864
                2d76bb0f-63d6-459d-ae47-a3f263aae349
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

                History
                : 7 April 2020
                Categories
                Review
                Custom metadata
                © The Author(s) 2020

                Endocrinology & Diabetes
                cardiac biomarkers,cardiovascular risk,prediabetes,prognostication,risk factors,type 2 diabetes mellitus

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