Metabolic memory phenomenon in diabetes mellitus: Achieving and perspectives

Accepted Manuscript Title: Metabolic memory phenomenon in diabetes mellitus: Achieving and perspectives Author: Alexander Berezin PII: DOI: Reference:

S1871-4021(16)30005-4 http://dx.doi.org/doi:10.1016/j.dsx.2016.03.016 DSX 589

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Diabetes & Metabolic Syndrome: Clinical Research & Reviews

Received date: Accepted date:

11-1-2016 5-3-2016

Please cite this article as: Berezin A, Metabolic memory phenomenon in diabetes mellitus: achieving and perspectives, Diabetes and Metabolic Syndrome: Clinical Research and Reviews (2016), http://dx.doi.org/10.1016/j.dsx.2016.03.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Title page Metabolic memory phenomenon in diabetes mellitus: achieving and perspectives Alexander Berezin* Short title of the article: Metabolic memory phenomenon in diabetes mellitus *Corresponding author: Alexander Berezin, Professor, MD, PhD, Consultant of Therapeutic

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Unit, Internal Medicine Department, State Medical University of Zaporozhye, 26, Mayakovsky Av., Zaporozhye, Postcode 69035, Ukraine.

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Tel.: +38 061 2894585 Fax: +38 0612894585 E-mail: [email protected]

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Manuscript Type: review

Conflict of interests: not declared

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Total word counts: 8010

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public, commercial, or not-for-profit sectors.

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Funding and grants: This research received no specific grant from any funding agency in the

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Abstract Diabetes mellitus (DM) exhibits raised prevalence worldwide. There is a large body of evidence regarding the incidence of DM closely associates with cardiovascular (CV) complications. In this context, hyperglycaemia, oxidant stress, and inflammation are key factors that contribute in CV events and disease in type1 and type 2 DM, even when metabolic control was optimal and / or intensive glycemic control was implemented. It has been suggested that the effect of poor metabolic control or even transient episodes of hyperglycemia in DM associates in particularly

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with worsening ability of endogenous vasoreparative systems that are mediated epigenetic changes in several cells (progenitor cells, stem cells, mononuclears, immune cells), and thereby

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lead to so called “vascular glycemic memory” or “metabolic memory”. Both terms are emphasized the fact that prior glucose control has sustained effects that persist even after return

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to more usual glycemic control. The mechanisms underlying the cellular “metabolic memory” induced by high glucose remain unclear. The review is discussed pathophysiology and clinical

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relevance of “metabolic” memory phenomenon in DM. The role of oxidative stress, inflammation, and epigenetics in DM and its vascular complications are highlighted. The effects

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of several therapeutic approaches are discussed.

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epigenetic modulation.

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Key words: diabetes mellitus; metabolic memory phenomenon; oxidative stress; inflammation;

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Introduction Despite increase prevalence of diabetes mellitus (DM) worldwide [1-3] and well developed diagnostic approaches and contemporary medical care [4-6], relatively little is known about disease progression at early stage [7]. Under diagnosis of DM is a critical problem affected prevention of acute and chronic cardiovascular (CV) complications and target-organ damage including diabetes-related nephropathy and retinopathy [8-10]. However, recent clinical and observational studies have revealed that DM complications were highly prevalent among

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subjects with both diagnosed and undiagnosed DM, even when metabolic control was optimal and / or intensive glycemic control was implemented [11-13]. Taking into consideration that CV

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complications of DM may significantly impact the CV and all cause mortality, well being, and quality of life, the risk stratification of the DM individuals at early stage of the disease appears to

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be essential for further medical approches. On the one hand, the period of poor metabolic control within evolution of the disease leads to negative consequences, such as an increase in the

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development of endothelial dysfunction, atherosclerosis, cardiomyopathies, heart failure, kidney disease, and progression of CV complications. On the other hand, CV complications may seriously limit the efficacy of glucose-lowering therapy because of full glucose control has

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usually not achieved. Overall, it has been resumed that DM patients with the high levels of CV co-morbidity may receive diminished CV benefit from intensive blood glucose control [14, 15].

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Moreover, CV co-morbidity should be considered when tailoring glucose-lowering therapy in

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patients with type 1 and type 2 DM [16]. Unfortunately, after period of poor glycemic control in DM individuals it was not possible to completely prevent a manifestation of CV complications or achieve a reverse of disease progression [17]. Indeed, type 1 DM have been exhibited a close link between hyperglycemia existed prior to glucose-lowering therapy and both micro- and macrovascular DM complications [11]. Large randomized studies have established that optimize glycemic control in type 1 DM may reduce DM-related target-organs’ damage, whereas the risk of disease progression has not minimized completely. The results of The Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) have been shown intensive glycemic control added to multi factorial intervention might reduce the CV incidence and improve clinical outcomes. Contrary, results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, and Veterans Affairs Diabetes Trial (VADT) have shown that intensive glycemic control to near normoglycemia might have potentially detrimental effect on CV outcomes in type 2 DM individuals [18-23]. It has been suggested that the effect of poor metabolic control or even transient episodes of hyperglycemia in DM associates in particularly with worsening ability of

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endogenous vasoreparative systems that are mediated epigenetic changes in several cells (progenitor cells, stem cells, mononuclears, immune cells), and thereby lead to so called “vascular glycemic memory” or “metabolic memory”. This phenomenon is induced via inflammatory, metabolic, and oxidative stimuli, direct cell-to-cell cooperation, microvesicles’ secretion, and plays a pivotal role in DM-related CV complications irrespective tight metabolic control. The aim of the mini review is summary knowledge about pathophysiology and clinical

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relevance of “metabolic memory” phenomenon in DM. Definition of glycemic memory

Glycemic memory phenomenon defined as the persistence of DM complications even after

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glycemic control has been pharmacologically achieved [24]. Glycemic memory is considered a part of generally term “metabolic memory” that is mostly wide and usually use as definition of

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systemic metabolic dysregulation in DM [25]. Both terms “metabolic memory” and “glycemic memory” are emphasized the fact that prior glucose control has sustained effects that persist

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even after return to more usual glycemic control. Consequently, glycemic memory phenomenon is clinical term, which describes tissue dysfunctions associated with DM unless glucose control, whereas metabolic memory is pathophysiologic term expanded to all molecular mechanisms and

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biochemical pathways underlying development of DM complications. Although both terms “metabolic memory” and “glycemic memory” are widely used as synonyms, obviously

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“metabolic memory” appears to be more than just tight glucose control necessary to prevent DM

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complications [26, 27]. Indeed, clinically, the emergence of this "metabolic memory" suggests the need for a very early aggressive treatment aiming to "normalize" the metabolic control and the addition of agents which reduce cellular reactive species and glycation in addition to normalizing glucose levels in DM in order to minimize long-term complications [25-27]. Pathophysiology of “glycemic memory phenomenon” The exact molecular mechanisms of “glycemic memory phenomenon” remain unexplained [28]. There is paradigm that has been postulated being of causality link between hyperglycemia and this "memory phenomenon" [29]. This paradigm has suggested that hyperglycemia exert longlasting detrimental effects on the CV system through several mechanisms, i.e. over production of free reactive species and accumulation of advanced glycation end products (AGE), which lead to glycation of mitochondrial proteins, lipids and nucleic acids. AGEs not only inhibit DNA synthesis in target cells, but also elicit vascular hyper permeability, pathological angiogenesis, and thrombogenic reactions by inducing vascular endothelial growth factor (VEGF) and plasminogen activator inhibitor-1 (PAI-1) through the interaction with the receptor for AGEs (RAGE). Thus, biochemical products of the advanced enzymatic and non-enzymatic glycation pathways are considered an integral clue implicated in metabolic memory, tissue damage and

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DM-related CV complications. However, the production of reactive species unrelated to the presence of hyperglycemia may associate with the previous production of AGEs, which maintains RAGE over-expression, level of glycation of mitochondrial proteins and the amount of mitochondrial DNA produced [29]. Indeed, AGEs have correlated with retinopathy progression, independently of HbA1c level [30]. Interestingly, that risk progression of retinopathy and neuropathy but not nephropathy has associated well with AGEs [30]. Moreover, hyperglycemia induces directly polyol pathway activity, which evidently contributes in accumulation of

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superoxide and nitric oxide (NO) levels leaded to forming peroxynitrite. Peroxynitrite may induce lipid and protein oxidation, nitration of proteins and via impaired viability and increased

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cell death may contribute to the microangiopathy development [31]. Hyperglycemia-induced superoxide production, primarily from mitochondria, is able to increase protein kinase C activity

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and through activation of a redox-sensitive nuclear transcriptional factor and NF-kappa B to induce NO and lipid peroxides production in several types of cells (i.e. endothelial cells,

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cardiomycites, smoth muscle cells, adipocites, and pericytes) leaded to persisted low-grading inflammation. Furthermore, systemic oxidative stress activates poly (ADP-ribose) polymerase fiber dysfunction [32].

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and leads to 4-hydoxynonenal adduct accumulation that correlated with large and small nerve Thus, AGE and ROS generation via molecular glucose-induced epigenetic changes might up

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regulate various genes, including the p65 subunit of NF-κB, monocyte chemoattractant protein-1

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(MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) in target cells that lead to lowgrading inflammation, direct tissue injury, pro-thrombotic state. Therefore, accumulation of AGE and free radicals might induce an altered gene expression even when hyperglycemia is resolved.

Figure 1 is reported a principal scheme explained interrelation between hyperglycemia, genetic predisposition, environmental factors, inflammation, with target organs’ damage through “metabolic memory” phenomenon. This hypothesis appears to be attractive for better understanding of the changes in the corresponding molecular pathways leaded to functional changes in metabolism via epigenetic modulation. The strength of the hypothesis bases on several evidences received from animal, pre-clinical and clinical trials. By now, "memory phenomenon" has been replicated in several animal models. Furthermore, a molecular basis in the role of oxidative stress, accumulation of end reactive products, advanced glycation processes, and epigenetic mechanisms accounting for self-perpetuating modifications of gene expression has well recognized in animal investigations [33]. Epigenetics is described as changes in gene activity and expression independent of modulation in nucleotide sequence. The epigenetic changes may lead to stable modification of gene expression,

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participating in “metabolic memory” phenomenon. Although the exact molecular mechanisms regulated transcription of mitochondrial DNA are not fully clear, it has been suggested that mitochondrial transcription factor A (TFAM) might be one of the key player in posttranslational modification of mitochondrial DNA. By now, mitochondrial homeostasis is considered a clue of the development and progression of diabetic-related target organs’ damage and TFAM could be relating chair between cytosolic chaperone, Hsp70, and oxidative genes over expressed in DM. Moreover, TFAM was ubiquitinated in the retina endothelial cells, and it continued to be

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modified after reinstitution of normal glycemia [34]. These findings might explain that role of oxidative stress in worsening mitochondrial homeostasis and “metabolic memory” development.

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Thus, proteins encoded by mitochondrial DNA become subnormal contributing to dysfunctional cell electron transport system that are important in mitochondrial DNA biogenesis and function

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[35].

The epigenetic modifications in histones and DNAs in response to cells changing environmental

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stimuli in DM are also facilitated. In this context, loci specific changes in DNA methylation patterns appear to contribute to tissue dysfunctions associated with DM via microRNA (miRNA) dysfunctions of cells’ precursors involved in endogenous repair systems [36]. Indeed,

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hyperglycemia associated with decreased ability of progenitor mononuclear / endothelial cells to promote vascular repair. This effect contributes to impaired response to chemotactic stimuli and

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reduced potential to homing, proliferation and differentiation activity. In fact, epigenetic-

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modifiyed damage of intracellular PI3K/Akt signaling system implicated inflammation stimuli sufficiently limits basic function of progenitor cells and suppresses their reparation potency. Importantly, the epigenetic regulation, including changes in DNA methylation leading to modifications in chromatin structure and deterioration in miRNA signature, is behind metabolic alterations and become irreversible over time. Indeed, glucose induced changes in miRNA-125b, miRNA-126, miRNA-146a-5p, miRNA-23b-3p are related to the long-lasting activation of nuclear factor κB (NF-κB) pathway and contribute to follow-up metabolic memory [36-38]. Zhong et al (2015) [36] using luciferase reporter assays have confirmed the biochemical relationship for miR-125b targeting on tumor necrosis factor (TNF)-α-induced protein 3 and miR-146a-5p targeting on TNF receptor-associated factor 6 and interleukin (IL)-1 receptorassociated kinase 1 during the activation of NF-κB pathway. Therefore, hyperglicemia is able to increase miR-23b-3p expression, even after the return to normal glucose [37]. As a result, over expressed miR-23b-3p increases acetylated-NF-κB expression by sirtuin 1 expression and thereby regulates high-glucose-induced cellular metabolic memory in DM. Probably, this effect might mediate decreased repair capacity of cell’ precursors, including progenitor cells different origin, stem cells, and worsening cell-to-cell cooperation via microvesicular exchange [38]. On

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the other hand, excessive formation of AGEs, which induces intracellular damage via several mechanisms (activation of the RAGE signaling axis that leads to elevation of cytosolic reactive oxygen species, NF-κB activation, increased expression of adhesion molecules and cytokines, induction of oxidative and endoplasmic reticulum stress) is under control of miRNAs [39]. However, the emerging role of miRNAs on AGE/RAGE pathway in DM-related worsening of endogenous repair system is not completely understood. Because immune cells, endothelial cells, and cells’ precursors originated from bone-narrow stem cells are primarily involved in the

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vascular complications of DM, their relative contribution to circulating miRNA signatures needs to be elucidated [40].

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Clinical relevance of “metabolic memory” phenomenon

There is evidence regarding hyperglycemia may induce an abnormal action of post-translational

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histone modifications and DNA methyltransferases as well as alter the levels of numerous miRNAs in endothelial cells, vascular smooth muscle cells, cardiomyocytes, retina, and renal

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cells. All these cells may be functionally impaired and contribute CV and non-CV complications in DM. Rajasekar et al [41] emphasizes that oxidative stress and accumulation of advanced glycation end products are key factors driving glycemic memory in endothelial cells’ precursors.

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Therefore, epigenetic changes of DNA / histone complexes are emerging as important modulators of oxidant / antioxidant and inflammatory genes that may lead to persistent low-

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grading inflammation and supporting cells’ alteration as a component of CV remodeling [42,

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43]. However, there is wide discussion regarding reprogramming of epigenetic signatures due to adverse miRNA signatures, DNA methylation, histone alterations (methylation/ acetylation) as a key driver of "memory phenomenon" and CV complications in DM, i.e. atherosclerosis, retinopathy, nephropathy [44, 45]. Indeed recent studies have been shown that DNA methylation is associated with human islet insulin secretion and insulin resistance [46, 47]. Therefore, the level of DNA methylation was found a predictive biomarker of DM susceptibility [48], disease diagnosis [49] and progression [50]. In fact, a comprehensive genomic DNA methylation profiling of type 2 DM islets revealed that CpG loci displayed a significant hypomethylation phenotype and might provide new insight on DM pathogenesis [51]. Accordingly, measure β cell-derived insulin demethylated DNA in human tissues and serum is considered a powerful tool for early identification of type 1 DM [50] and dysregulation in pancreatic islets in type 2 DM [51]. Consequently, providing detailed map of the global DNA methylation pattern in human islets, β- and α-cells that contribute to perturbed insulin and glucagon secretion may improve in assay of DM susceptibility [52, 53]. Taking into consideration several complications of DM, i.e. vascular

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impairments,

dementia

due

to

Alzheimer's

disease,

and

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neurodegenerative disorders might mediate via “metabolic memory” phenomenon [54, 55], the

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biomarker discovery with highly sensitivity and specificity for early stage of “metabolic memory” appears to be priority in future. The role of "memory phenomenon" in efficacy of clinical intervention Recent clinical studies in both type 1 and type 2 DM have proven that good glycemic control with multi factorial intervention may reduce the CV risk and the risk of development and progression of DM-related complications beyond the duration of near-normoglycemia and despite achievement of target HbA1c levels [55]. These findings have brought up the concept of

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"metabolic legacy" as early effective implementation of treatments to safely reduce blood glucose with CV multi factorial approach [56].

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The results of recent studies confirmed persistence of “metabolic memory” through 10 years of follow-up. The reduced the risk of development and progression of retinopathy by as much as

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76% compared with conventional therapy was results exhibited in DCCT (Diabetes Control and Complications Trial) that has conducted a mean of 6.5 years of intensive therapy aimed at near-

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normal glucose levels [57]. The Epidemiology of Diabetes Interventions and Complications study (EDIC) observational follow-up showed that the risk of further progression of retinopathy 4 years after the DCCT ended was also greatly reduced in the former intensive group. However,

Insulin

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the role of glucose-lowering drug in reversal of “metabolic memory” remains yet inconclusive.

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The role of insulin (insulin glargine) in “metabolic memory” recovery is controversial.

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Theoretically, glycemic variation due to closed loop insulin delivery and post-prandial glycemic excursions in DM individuals with long anamnesis of disease development, co-existing CV risk factors and genetic predisposition might contribute in transcription-regulating actions of glucose [58]. Chen et al (2016) [59] reported that insulin glargine or glibenclamide, but not metformin, restored hippocampal synaptic plasticity characterized by enhancing in vivo long-term potentiation insulin-deficient mice. Authors found that these three drugs significantly restrained NF-κB, but only insulin glargine enhanced peroxisome proliferator-activated receptor γ (PPARγ) activity at the blood-brain barrier in mice. In clinical setting, continuous subcutaneous insulin infusion with pump has associated with lower blood glucose variability in children as well as diminished poor glycemic control and dawn phenomenon [60]. Because last two factors contribute in CV complications of DM, insulin pump therapy allow us to expect that “metabolic memory” reversal is attribute good glycemia control, but not choosing of insulin type (eg, basal insulin analogues as well as rapid-acting insulin analogues, the insulin pump, or inhaled insulin). Interesting, the average glycemic control when insulin pump was used was not very different from those on multiple daily injections; fewer patients were seen higher variability of HbA1c. Thus, advance system for insulin dosage

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might improve the glycemic control in type 1 DM individuals; however, the role of early initiation of insulin therapy in type 2 DM is not fully clear [60]. Meta-analysis of 12 clinical trials (including a total of 2230 patients, the mean follow-up duration across studies varied between one and 6.5 years) in type 1 DM patients has exhibited that the risk of developing microvascular complications (retinopathy, nephropathy, neuropathy) under intensive glucose control was reduced significantly compared to conventional treatment [61]. Regarding the progression of these complications after manifestation, the effect was weaker

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(retinopathy) or possibly not existent (nephropathy) [61]. Major macrovascular outcomes (stroke and myocardial infarction) occurred very rarely, and no evidence could be established regarding

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these outcome measures. Overall the intensive glucose control related an increased risk for severe hypoglycaemia, whereas the results were heterogeneous and only the DCCT (Diabetes

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Complications Clinical Trial) showed a sufficient increase in severe hypoglycaemic episodes under intensive treatment regime. Hypoglycaemia was possibly increased for type 1 DM patients

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who started with HbA1c < 9.0%. Furthermore, there was no evidence regarding the effects of tight glycemia control in older patients or subjects with pre-existing macrovascular disease. Finally, insulin therapy in various individualized regimes (intensive / conventional glucose

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control) appears to be more effective in younger persons without known micro- and macrovascular diseases. However, insulin might probably have insufficient effect for prevention

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and reversal “metabolic memory” phenomenon due to a greater impact of age, pretreatment

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period, risk of hypoglicemia, ketoacydosis, the patient's lifestyle, CV disease and DM management capabilities. Metformin

Metformin is a commonly used anti-diabetic drug with clinically evident beneficial effects outside of its therapeutic regulation of glucose metabolism and insulin sensitivity. Metformin as potent activator of Sirtuin-1 and LKB1/AMP kinase / ROS (reactive oxygen species) pathways may attenuate high glucose-induced endothelial senescence and might prevent the development and progression of "metabolic memory" [62]. This effect is probably mediated by modulating SIRT1/p300/p53/p21 pathway and by balance between acetyltransferases and deacetylases that could be particularly important for sustained acetylation and activation of non-histone proteins (i.e. p53) [63]. Overall, metformin could enhance sirtuin-1-mediated signaling and thus protect against senescent "memory" independent of glucose lowering mechanisms. Contrary, sirtuin-1 over expression or activation by metformin inhibites the increase of mitochondrial ROSmediated glyceraldehyde-3-phosphate dehydrogenase by poly (ADP-ribose) polymerase (PARP) activity through the up-regulation of liver kinase B1/AMP-activated protein kinase

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(LKB1/AMPK), ultimately suppressing NF-κB and Bax expression [62-64]. Thus, metformin may suppress the "metabolic memory" of hyperglycemia stress in DM. It has been suggested that metformin use in DM affects brain metabolism, neuroinflammation, and regeneration via significantly attenuation of the insulin resistant condition by improving metabolic parameters, decreasing peripheral and brain oxidative stress levels [65]. However, there are some results received from the animal studies that have been supported hypothesis for metformin as a neuroprotective agent while there is a large of body evidences that metformin

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may be deleterious to neuronal survival [66- 68]. Indeed, metformin treatment may decrease an expression of the antioxidant pathway regulator Nrf2, and also suppress transcription of

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neurotrophic factors [67]. Taken together these findings do not confirm the hypothesis regarding

Incretin-based therapies of DM and glycemic memory

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reversion of “metabolic memory” in nervous tissue.

Incretins are gut-derived peptides with a variety of glucose regulatory functions. Incretin

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dysfunction can be treated with glucagon-like peptide 1 (GLP-1) receptor agonists (eg, exenatide and liraglutide) or inhibitors of dipeptidyl peptidase 4 (DPP-4) (eg, sitagliptin and saxagliptin), the enzyme that degrades GLP-1. The GLP-1 receptor agonists and DPP-4 inhibitors both

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elevate GLP-1 activity and substantially improve glycemic control [69]. The GLP-1 receptor agonists are more effective in lowering blood glucose and result in substantial weight loss,

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whereas therapy with DPP-4 inhibitors lowers blood glucose levels to a lesser degree, and they

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are weight neutral [70]. Treatment with GLP-1 receptor agonists has demonstrated durable glycemic control and improvement in multiple CV risk factors. Additionally, unlike insulin or sulfonylureas, treatment with a GLP-1 receptor agonist or a DPP-4 inhibitors have not been associated with substantial hypoglycemia [71]. In animal model, pre-clinical and clinical studies, GLP-1 receptor agonists and DPP-4 inhibitors have been exhibited a suppression of AGE / ROS production, over-expression of inflammatory cytokines, ameliorated insulin sensitivity, remarkable prevented apoptosis and tissue injury [7274]. Ishibashi et al (2013) reported that AGE-RAGE-induced generation of ROS may stimulate the release of DPP-4 from endothelial cells, which could in turn act on endothelial cells directly via the interaction with mannose 6-phosphate / /insulin-like growth factor II receptor [75]. As result, deleterious effects of AGEs on endothelium are potentiated and prolonged. It has been found that inhibition of DPP-4 by linagliptin may significantly inhibit the AGE-induced ROS generation, RAGE, intercellular adhesion molecule-1 and PAI-1 gene expression in endothelial cells [75, 76]. Theoretically, inhibition of DPP-4 itself could enhance bone marrow stem cells, mobilize peripheral blood hematopoietic cells, and restore endothelial cells’ function [77, 78]. Aso et al (2015) [79] have shown that treatment with DPP-4 inhibitor sitagliptin has increased

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the number of circulating angiopoetic CD34(+)CXCR4(+) cells by approximately 2-fold in T2DM patients. Although ability of both anti-diabetic drugs (GLP-1 receptor agonists and DPP-4 inhibitors) block the intracellular signal pathways of AGEs and NF-kB is defined [77, 78, 80, 81], whether these remedies improve “metabolic memory” phenomenon is not yet confirmed, but the expectation regarding this effect is very high. Sulfonylurea antidiabetic drugs The data regarding ability of sulfonylurea antidiabetic drugs to attenuate “metabolic memory”

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via epigenetic mechanisms or intracellular signaling pathways are very limited. The recent animal and clinical studies have revealed that sulfonylurea drugs (glipizide, glimepiride, other

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medium to long-acting sulfonylurea derivates) may suppress endothelial cell migration via block of sulfonylurea receptor 1-regulated NC(Ca-ATP) channels. In resulting it is appeared

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antiproliferative effect that is mediated through suppression of intracellular tube formation [82, 83]. Several studies showed that gliclazide and glimepiride may ameliorate the endothelial

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dysfunction through the suppression of von Willebrand factor production and the reduction of the over expression of ICAM-1, antioxidant properties, displayed its potential in alleviating DMrelated vascular complications [84, 85]. Both drugs have antioxidant properties, reduce markers of

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endothelial inflammation, and prevent glucose-induced apoptosis of endothelial cells [85]. These properties may be potentially important for slowing the CV and neuropathic complications.

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Recent clinical studies have shown that a strategy of intensive glucose control, involving

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gliclazide (modified release) and other drugs as required that lowered the glycated hemoglobin value to 6.5% does not completely prevents important complications in DM [86-88]. Although these results were associated with at least twice the risk for serious hypoglycaemia in intensive glucose control versus conventional glucose control, they were later considered as confirmation of “metabolic memory” phenomenon negatively affected on CV complications. However, based on the trials and meta-analyses (included more than 30,000 patients), it can be concluded that intensive glucose control has a beneficial effect on microvascular complications (retinopathy, nephropathy, neuropathy) in both type 1 and type 2 DM [88, 89], whereas this effect would be more comprehensive. Thus, the role of sulfonylurea antidiabetic drugs in “metabolic memory” phenomenon requires more investigations in future. Thiazolidinediones PPARγ regulates multiple pathways involved in the expression of target genes in the various cells that exerts in pathogenesis of obesity and atherosclerosis. Thiazolidinediones as PPARγ agonists are orally effective anti-diabetic medicines with co-existed ability to selective inhibition of insulin-like growth factor-1 (IGF-1) receptor signaling that is important for anti-proliferative effect [90]. Therefore, these drugs show direct actions on liver by reducing hepatic de novo

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lipogenesis, increasing hepatic insulin clearance, and modulating NO levels [91]. Obviously, all this kinds might be useful for minimizing impact of “metabolic memory” phenomenon in type 2 DM, whereas discussion the benefits and limitations of thiazolidinediones regarding predominantly CV complications remains to be continued [92]. Sodium-glucose linked transporters Sodium-glucose linked transporters (SGLT) inhibitors of both types 2 (SGLT2) and 1 (SGLT1) are novel class of antidiabetes agents with an insulin-independent mechanism of action and

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reduced risk of hypoglycemia [92, 93]. Absence of weight gain, renoprotection, and demonstrated CV risk reduction support consideration of SGLT2 inhibitors (especially

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empagliflozin) as a first line medication in addition to metformin for patients with T2DM and CV disease [94, 95]. There are evidences than SGLT2 inhibitor empagliflozin and the dual

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SGLT1 and SGLT2 inhibitor sotagliflozin, which acts in the gut and the kidney, have demonstrated reductions in HbA1c, weight, and glucose variability [96]. Moreover,

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empagliflozin treatment enhances β-cell proliferation and improves pancreatic β-cell function in type 2 DM [97]. Taking together, these findings show that SGLT inhibitors induce beneficial changes in a number of CV risk factors and improve glycaemic control, although information on

Fibrates

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clinical utility in “metabolic memory” phenomenon is currently limited.

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Fibrates are a lipid lowering therapeutic agents belong to PPAR-α agonist family. Recent

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clinical studies have revealed that treatment with fenofibrate in dyslipidemic patients with DM not only increased HDL-cholesterol levels but also improved the endothelial protective effects of HDL [98, 99]. Co-existing potential activity on AMPK/Akt/eNOS and PI3K/Akt/eNOS signaling cascades that is suitable for fenofibrate allows increasing the maturation and differentiation of progenitor cells and exerts anti inflammatory capacity. This effect is considered an important mechanism of endothelium reparation via involvement of endothelial progenitor cells, improving endothelial dysfunction and increase bioavailability of NO [100]. Indeed, fenofibrate may enhance of Akt phosphorylation, which is accompanied by increased eNO syntase phosphorylation and NO production [101] that leads to improving angiogenesis. Moreover, recent studies have shown that fenofibrate might have the inhibitory effect on metabolic memory mediated by sirtuin 1 in endothelial cells [102]. Forthcoming data on the long-term efficacy of fibrates could help to explain the role of these drugs in the “metabolic memory” reversal. Future perspectives Lipid-lowering drugs (statins, ezetimibe, niacin, PCSK9 inhibitors), cell replacement therapy and genetic approaches are considered a clue to reverse of “metabolic memory” pnenomenon in DM. Page 12 of 22

However, there are not still irrefutable clinical evidences of the strategies of choice in such patients. In conclusion, microvascular and macrovascular complications may persist after the maintenance of near-normal / normal glucose levels and achieving target HbAc1 in both types of DM. This phenomenon is named “metabolic memory” and appears to be a serious clinical problem with potential fatal consequences. Although the exact molecular mechanisms’ development regarding of this phenomenon is not fully clear, however, inflammation, oxidative stress, and epigenetic

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modulation are clue of “metabolic memory” in DM. There are old and novel antidiabetic drugs that allow preventing and even reversing of the progression of the phenomenon. However,

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modern medical care including lipid-lowering drugs, cell replacement therapy and genetic approaches is being explored in this context. Forthcoming clinical trials are required to receiving

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more information for optimal choosing drugs and their combinations for initial and maintenance

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therapy of DM to prevent and / or minimize “metabolic memory” effects.

List of abbreviations DM – diabetes mellitus

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CV – cardiovascular IL – interleukin

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miRNA – micro RNA

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IGF-1 - insulin-like growth factor-1 NF-κB - nuclear factor κB

PPARγ - peroxisome proliferator-activated receptor γ PAI-1 - plasminogen activator inhibitor-1 ROS - reactive oxygen species

SGLT2 - sodium-glucose linked transporters TNF - tumor necrosis factor

VEGF - vascular endothelial growth factor

Legend of figure Figure 1: Molecular mechanisms underlying “metabolic memory” phenomenon References 1. Engelgau MM, Geiss LS, Saaddine JB, Boyle JP, Benjamin SM, Gregg EW, Tierney et al. The evolving diabetes burden in the United States. Ann Intern Med. 2004; 140(11): 945-50.

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2. Saadi H, Carruthers SG, Nagelkerke N, Al-Maskari F, Afandi B, Reed R, et al. Prevalence of diabetes mellitus and its complications in a population-based sample in Al Ain, United Arab Emirates. Diabetes Res Clin Pract. 2007; 78(3):369-77. 3. Deshpande A, Harris-Hayes M, Schootman M. Epidemiology of Diabetes and DiabetesRelated Complications. Phys Ther. 2008; 88:1254–1264 4. Dall TM, Storm MV, Semilla AP, Wintfeld N, O'Grady M, Narayan KM. Value of lifestyle intervention to prevent diabetes and sequelae. Am J Prev Med. 2015; 48(3): 271-

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80.

5. Williamson C, Glauser TA, Burton BS, Schneider D, Dubois AM, Patel D. Health care

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provider management of patients with type 2 diabetes mellitus: analysis of trends in attitudes and practices. Postgrad Med. 2014; 126(3): 145-60.

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6. Dall TM, Narayan KM, Gillespie KB, Gallo PD, Blanchard TD, Solcan M, O'Grady M, Quick WW. Detecting type 2 diabetes and prediabetes among asymptomatic adults in the

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United States: modeling American Diabetes Association versus US Preventive Services Task Force diabetes screening guidelines. Popul Health Metr. 2014; 12: 12. 7. Smith J, Nazare JA, Borel AL, Aschner P, Barter PJ, Van Gaal L, et al. Assessment of

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cardiometabolic risk and prevalence of meeting treatment guidelines among patients with type 2 diabetes stratified according to their use of insulin and/or other diabetic

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medications: results from INSPIRE ME IAA. Diabetes Obes Metab. 2013; 15(7): 629-41.

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