Metabolic Memory in Diabetes – Mechanistic Insights and the Impact of Cardiovascular Medication
Article Category: Review
Data publikacji: 05 maj 2022
Zakres stron: 511 - 516
DOI: https://doi.org/10.47803/rjc.2021.31.3.511
Słowa kluczowe
© 2021 Raluca Sosdean et al., published by Sciendo
This work is licensed under the Creative Commons Attribution 4.0 International License.
Diabetes mellitus (DM) is a major and developing public health concern that is associated with decreased life expectancy and increased morbidity as a consequence of the related complications. DM induces micro- and macrovascular complications that may become evident even after a good glycemic control has been accomplished. This happens mostly through the „metabolic memory” phenomenon. Potential mechanisms responsible for this „memory” include nonenzymatic glycation of cellular proteins and lipids and the increased generation of cellular reactive oxygen and nitrogen species, particularly those originating at the level of glycated mitochondrial proteins, which may act in concert to maintain stress signaling1. Intensive glycemia lowering treatment may not be sufficient to prevent these complications especially in patients with diabetes type 2 and severe insulin resistance. Diabetes Control and Complications Trial (DCCT) showed that in type 1 diabetes, where insulin resistance is not dominant, early and intensive insulin treatment led to a significant cardiovascular risk and major cardiac events reduction during the trial and even years after. These results were sustained in the
Several clinical and epidemiological studies in diabetic patients have shown a close relationship between hyperglycemia and vascular oxidative stress, which contributes to a significant reduction in the bioavailability of nitric oxide (NO)2. Chronic hyperglycemia triggers immediate direct biochemical changes in endothelial function and indirect effects via the synthesis of growth factors and vasoactive agents, resulting in vascular permeability alteration.
Furthermore, its deleterious effect is mediated through the activation of a couple of metabolic pathways. The main pathways that have been classically shown to mediate hyperglycemia-induced tissue damage are as follows: increased intracellular formation of the advanced glycation end products (AGEs), increased expression for AGEs’ receptors and their activating ligands, activation of protein kinase C (PKC) and overactivity of the hexosamine pathway3. In addition, several lines of evidence have indicated that all these mechanisms are triggered by a single upstream event, namely the mitochondrial overproduction of reactive oxygen species (ROS) and the subsequent augmented intracellular oxidative stress4 (Figure 1).
One of the mechanisms that is responsible for the accelerated atherosclerosis in diabetes is the nonenzymatic reaction between glucose and proteins or lipoproteins in the arterial wall, with the subsequent formation of advanced glycation endproducts (AGEs)5.
AGEs are a broad and heterogenous group of compounds generated when a sugar reactive carbonyl group interacts with an amino acid nucleophilic amino group during the classic Maillard reaction. The degree of non- enzymatic glycation is mainly determined by the glucose concentration and the time the tissues are exposed to it6. Structures lose some of their properties, such as structural proteins, enzymes and nucleic acids7. Also, AGEs have specific membrane receptors (RAGE) on certain types of cells. There are specific types of receptors on the surface of endothelial cells, that binds AGEs. One of the best studied AGE receptor is RAGE8tumor necrosis factor-α (TNF-α. RAGE activation promotes inflammatory responses, apoptosis, expression of adhesion molecules such as VCAM-1, which enhances monocyte attachment and transendothelial migration across the endothelial cell layer, oxidative stress. Evidence suggests that AGEs and the receptor called „RAGE” may be involved in the metabolic memory fenomenon. The interaction between AGE and RAGE causes an increased production of ROS, cytokines such as (interleukin-6) IL-6, (tumor necrosis factor-α) TNF-alfa, growth factors- IGF-1, transforming growth factor beta (TGF b).
Furthermore, Rosca et al demonstrated that glycated mitochondrial respiratory chain complexes were more likely to produce superoxide, regardless of the degree of hyperglycemia9.
The production of mitochondrial AGE can be an irreversible process and may be responsible for the long-term development of metabolic memory. Importantly, the reversal of hyperglycemia does not reverse the inflammatory process and oxidative stress (which remain high). In the EDIC study, Genuth et al observed that AGEs are long-term indicators of microvascular disease progression with the subsequent progression of diabetic retinopathy9.
Another significant change caused by hyperglycemia is the activation of the protein kinase C (PKC) system. Elevated glucose levels induce diacylglycerol de novo synthesis leading to PKC activation, which is considered a major pathway in diabetes mellitus induced vascular remodeling11.
PKC belongs to the serine-threonine kinase family and is an important cell signal transduction player for various cytokines. Evidence shows that enhanced PKC isoform activity can also result from interactions between AGEs and their cell-surface receptors12.
Ganz et al demonstrated that overactivity of PKC has been associated with decreased NO production in smooth muscle cells. Furthermore, it has been shown to inhibit insulin-stimulated expression of endothelial NO synthase (eNOS) in cultured endothelial cells13.
Several lines of evidence have also supported that PKC activation increases the expression of transforming growth factor beta (TGF-beta), which promotes thickening of the capillary basement membrane, reported to occur in early stages of diabetes. In addition, it promotes vascular endothelial growth factor excess, increasing the production of thromboxane and endothelin-1 (ET-1) and decreases production of prostacyclin14.
Takagi et al. reported that the expression of endothelin-1 is increased in the retina of diabetic rats and that intravitreous injection of endothelin-1 receptor antagonist prevented the decrease in retinal blood flow in diabetic rats15. Moreover, Shiba et al demonstrated that the decrease in retinal blood flow in diabetic rats was normalized by PKC inhibitors16.
A study of aortic rings in rats with diabetes by Koya et al showed that acetylcholine-dependent relaxation was restored by the addition of PKC inhibitors17,18.
Normally, most glucose is metabolized by glycolytic and pentose shunt pathways. Under hyperglycemia conditions, the pathways of polyol and hexosamine are activated19. In the polyol pathway, sorbitol is formed by aldose reductase, the first and rate-limiting step leading to the conversion of NADPH to NADP+. NADPH is a crucial cofactor in the synthesis of glutathione that is impaired by the polyol pathway. The conversion of sorbitol to fructose (via the activity of sorbitol dehydrogenase) results in an increased NADH/NAD+ ratio that drives the production of advanced glycation end products as well as the de novo production of diacyglycerol (DAG)20.
Several mechanisms related to the hyperglycemia-induced polyol pathway have been proposed, with the most representative being an increase in redox stress due to the consumption of NADPH. Because NADPH is a cofactor needed to regenerate reduced glutathione (GSH) and GSH is an essential scavenger of reactive oxygen species (ROS), this could induce intracellular oxidative stress.
Vikramadithyan et al demonstrated that the over-expression of human aldose reductase increased atherosclerosis in diabetic mice and decreased the expression of genes that control glutathione regeneration. It has been also demonstrated that decreased glutathionylation of cellular proteins is related to decreased NO availability in diabetic rats. Restoration of NO levels in diabetic animals improves the glutathionylation of cellular proteins, inhibits the activity of aldose reductase and prevents the accumulation of sorbitol20.
Recent studies have shown that the hexosamine pathway, previously known exclusively as a biosynthetic pathway for amino sugars, has regulatory functions. These include induction of gene expression such as growth factors in smooth muscle cells or renal mesangial cells and also of insulin resistance. Several lines of evidence suggest that the activation of TGF-b is regulated by the hexosamine pathway21. High glucose levels in cultured mesangial cells induced the production of TGF-b. During intracellular glucose metabolism, the redirection of fructose-6-phosphate from the glycolytic pathway to the hexosamine pathway (HSP) can ultimately induce increased transcription of proinflammatory cytokines, insulin desensitizationand oxidative stress— all of which are prominent features contributing to retinal neuronal apoptosis22.
Given the reported role of the hexosamine pathway in the regulation of genes related to injury and fibrosis, Leighton et al. hypothesized that the hexosamine pathway is important in inflammation and may regulate the expression of nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) dependent genes such as vascular cell adhesion molecule 1 (VCAM-1), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)23.
Glycation of mitochondrial proteins may contribute to the „metabolic memory” phenomenon. Independent of actual glycemia, glycated mitochondria can initiate a vicious cycle of mitochondrial DNA (mtDNA) damage, functional decline, increased ROS generation, and cellular injury, thereby maintaining activation of the pathways involved in the pathogenesis of diabetic complications. Mitochondrial dysfunction has been linked to retinal vascular cell loss, a common complication of diabetic retinopathy. Hyperglycemia has been shown to elicit mitochondrial fragmentation and dysfunction in retinal endothelial cells, which may lead to apoptosis. In this respect, Wang et al. conducted a study using rat retinal endothelial cells to investigate the effect of metabolic memory on mitochondrial oxidative damage-induced diabetic retinopathy. They demonstrated that high glucose triggered mitochondrial damage, increased apoptosis, and ROS generation even after cells were returned to normal glucose conditions, indicating that retinal cells possess metabolic memory24.
Brownlee has recently pointed to an excess of superoxide anion, a reactive species, in the mitochondria of endothelial cells in response to hyperglycemia with the subsequent diabetic complications25. Superoxide is the major oxygen free radical generated by the mitochondria, which is eventually transformed to more reactive species that may cause various degree of cellular damage.
Besides the antidiabetic drugs, several classes of cardiovascular drugs are used to control cardiovascular disease and the associated cardiovascular risk factors: hypertension, dyslipidemia, and thus are preferred in diabetic patients26. Drugs with multiple targets, including metabolic memory are very useful in diabetes and its complications management, where early intensive glycemic control plus hypertension and hyperlipemia management are needed27.
RAAS upregulation and imbalance is evident in diabetic patients and exert deleterious effects on the cardiovascular system by promoting accelerated atherosclerosis, cardiac remodeling (hypertrophy, fibrosis, apoptosis), inflammation, increased oxidative stress, defective angiogenesis mostly through angiotensin II and aldosterone. Reversal of these effects is therefore warranted26. Besides the beneficial effect of a substantial blood pressure lowering, and cardiac remodeling, the studies proved that both angiotensin-converting enzyme inhibitors (ACE inhibitors) and angiotensin-I (AT-1) receptor blockers target the metabolic memory pathways and work as antioxidants, having a protective effect in patients with diabetes3.
Yoshida et al. demonstrated that the AT-1 receptor blocker, telmisartan downregulates RAGE mRNA levels through activation of the peroxisome proliferator activated receptor-gamma in the liver and reduces AGE-induced C-reactive protein production, in a dose-dependent manner. This may have a protective vascular effect in diabetic patients. This effect was not observed in their study with the AT-1 receptor blocker candersartan1,28. In the same manner, the studies also showed beneficial effects of RAAS blockade for diabetic retinopathy by targeting metabolic memory. In the
Simão et al. investigated the effects of the direct renin inhibitor, aliskiren in retinal pigment epithelial cells treated with high glucose concentrations. Exposure to angiotensin II induced hyperproduction of proangiogenic factors (VEGF) and increased the production of reactive oxygen species. Aliskiren reduced the levels of oxidative stress and promoted the production of anti-angiogenic factors, thus protecting retinal cells from the undesired effects of high glucose concentrations and angiotensin II34. In a recent review, Alshahrani summarized the antioxidant, anti-inflammatory and antiatherosclerotic properties of aliskiren in several organ damage including the kidney, heart and brain, that are independent of its blood pressure lowering properties. There are several preclinical studies that demonstrated the renal protective effect of aliskiren, alone or combined with other drugs, in diabetic rats. The described mechanisms included the decrease in aldosterone levels, thus inhibiting its oxidative and profibrotic actions and increasing renal NO and cyclic guanosine monophosphate.
Lipid-lowering drugs including statins, ezetimibe, niacin, PCSK9 inhibitors may be effective in reversing the „metabolic memory” phenomenon in diabetes but more clinical studies are needed in this regard.
Cerielo et al. demonstrated in 20 patients suffering from type 2 diabetes that high fat load and glucose induced through oxidative stress enhancement, a decrease in endothelial function and an increase in inflammatory markers such as C-reactive protein, intercellular adhesion molecule-1, interleukin-6 and nitrotyrosine. Irbesartan and atorvastatin both separately, but even better in combination, reverted these undesired effects35.
On the other hand, Carillo-Ibarra et al evaluated the effects of ezetimibe/simvastatin and rosuvastatin on oxidative DNA damage in patients with diabetic polyneuropathy in a study that included 74 patients and found no significant differences in DNA biomarkers in the three groups- placebo, ezetimibe/simvastatin and rosuvastatin, between baseline and final levels, after treatment36.
Fibrates, acting as PPAR-α agonists demonstrated to improve endothelial protective effects of HDL cholesterol in diabetic patients with dislypidemia. These induce an increase in progenitor cells maturation and differentiation, improving endothelial dysfunction and increasing NO levels and availability37.
Zhao et al. demonstrated that fenofibrate exerts an important anti-inflammatory effect suppresses the cellular metabolic memory of high glucose-induced stress in animal models of diabetic retinopathy, through the NAD+ dependent deacetylase sirtuin 1 which is inhibited in hyperglycemic conditions. The decrease of sirtuin 1 activity was negatively correlated with the expression of nuclear factorκB. Fenofibrate seems to increase the expression of sirtuin 1 in hyperglycemia induced metabolic memory through the peroxisome proliferatoractivated receptor α. Because of these actions this may be a promising treatment for diabetic complications38.
Microvascular and macrovascular complications may continue to evolve even when normal glucose levels are maintained in patients with diabetes mellitus. The term „metabolic memory” refers to this phenomenon which appears to be a major clinical issue with potential life-threatening consequences. Although the molecular processes behind this process are unknown, inflammation, oxidative stress, and epigenetic modification are all indicators of „metabolic memory” in diabetes mellitus. Early, aggressive treatment of hyperglycemia may „program” the metabolic memory. In diabetic patients, early and intensive care of glycemia, blood pressure, and lipid abnormalities may lower the risk of chronic complications and premature death.