Genes, Genetic Polymorphism, Diet, Soluble Mediators, and Their Role in the Pathobiology of Type 2 Diabetes Mellitus and Hypertension

OpenAlex · İngilizce

It is estimated that ~50% of patients with type 2 diabetes mellitus (T2DM) have and/or develop hypertension (HTN) that enhances risk of both micro- and macrovascular complications due to DM.1–3 It is well documented that the risk for cardiovascular disease is almost 4-fold higher in those with both DM and HTN as compared with the normotensive nondiabetics.2,4 DM is responsible for a 2-fold increased risk for coronary heart disease, stroke, and deaths from cardiovascular cause, including heart failure, cardiac arrhythmia, sudden death, hypertensive disease, and aortic aneurysms.5 Thus, one of the major causes of vascular deaths in many countries is DM. In view of the enhanced risk of complications due to DM when concomitant HTN is present, it is important to investigate what factors enhance the risk of development of HTN in those with T2DM. Cheng et al.6 identified a 14 SNPs (single nucleotide polymorphisms) combination for HTN in patients with T2DM and reported that (i) patients with HTN were older, had higher body mass index and hypertriglyceridemia; (ii) those with low hypertriglyceridemia had higher expression levels of NADPH oxidase and MnSOD in their peripheral blood mononuclear cells; and (iii) noted that the SNPs were associated with risk of HTN in a dose-dependent manner in T2DM. In addition, it has also been reported that risk of development of T2DM is high in those who have HTN.3,7,8 These results3,6–8 indicate that HTN and T2DM have some common pathophysiological basis. It has been suggested an increase in the plasma levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP) indicating the existence of low-grade systemic inflammation occurs in both T2DM and HTN that may account for their coexistence.3,7,8 In this context, it is noteworthy that high-fat diet-induced HTN and development of T2DM are known to be associated with increased generation of reactive oxygen species and low levels of nitric oxide (NO) due to decrease in NO synthase activity that could be corrected by l-arginine supplementation.9 NO causes vascular relaxation by enhancing intracellular cGMP and activating cGMP-dependent protein kinase I (PKGI) that control vascular smooth muscle contraction. Mutations in the N-terminal protein interaction domain of PKGI cause smooth muscle cell abnormalities of contraction resulting in development of HTN. Smooth muscle cell contraction depends on the potassium channel activity that is, in turn, regulated by NO10 (see Figure 1). Hence, it is possible that abnormalities in the expression of genes concerned with the potassium channel protein family may result in HTN. Scheme showing involvement of K1 channel-mediated, endothelium-dependent hyperpolarization and its modulation by NO, AA, and its metabolites. Acetylcholine (ACh) may induce the release of several endothelium-derived relaxing factors including NO, PGI2, and EDHF (LXA4, resolvins, protectins, and maresins). These factors may act on vascular muscle through activation of K1 channels. NO and PGI2 enhance intracellular accumulation of cyclic GMP and cAMP, respectively. EDHF and NO may activate K1 channels. Resolvins, protectins, and maresins derived from EPA and DHA may have actions like LXA4 (not shown on the figure). Exercise can prevent obesity, insulin resistance, HTN, and T2DM. Exercise enhances the formation of LXA4, possibly by augmenting the release and conversion of AA to LXA4, increases vagal tone and acetylcholine, the vagal neurotransmitter, is a potent anti-inflammatory molecule that is at least, in part, due to its ability to increase LXA4 formation. Exercise also enhances endothelial NO generation, a vasodilator and platelet anti-aggregator, that has anti-hypertensive and anti-diabetic actions. AA may directly modulate K1 channel by its ability to alter cell membrane fluidity. This figure is modified from ref. 10. Abbreviations: AA, arachidonic acid; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HTN, hypertension; LXA4, lipoxin A4; NO, nitric oxide; T2DM, type 2 diabetes mellitus. Scheme showing involvement of K1 channel-mediated, endothelium-dependent hyperpolarization and its modulation by NO, AA, and its metabolites. Acetylcholine (ACh) may induce the release of several endothelium-derived relaxing factors including NO, PGI2, and EDHF (LXA4, resolvins, protectins, and maresins). These factors may act on vascular muscle through activation of K1 channels. NO and PGI2 enhance intracellular accumulation of cyclic GMP and cAMP, respectively. EDHF and NO may activate K1 channels. Resolvins, protectins, and maresins derived from EPA and DHA may have actions like LXA4 (not shown on the figure). Exercise can prevent obesity, insulin resistance, HTN, and T2DM. Exercise enhances the formation of LXA4, possibly by augmenting the release and conversion of AA to LXA4, increases vagal tone and acetylcholine, the vagal neurotransmitter, is a potent anti-inflammatory molecule that is at least, in part, due to its ability to increase LXA4 formation. Exercise also enhances endothelial NO generation, a vasodilator and platelet anti-aggregator, that has anti-hypertensive and anti-diabetic actions. AA may directly modulate K1 channel by its ability to alter cell membrane fluidity. This figure is modified from ref. 10. Abbreviations: AA, arachidonic acid; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HTN, hypertension; LXA4, lipoxin A4; NO, nitric oxide; T2DM, type 2 diabetes mellitus. Cheng et al.6 reported variations in the expression of genes KCNK5, a member of the potassium channel protein superfamily, expressed in the cortical distal tubules and collecting ducts of the kidney, that plays a critical role in renal potassium transport; ADCY9, a membrane-bound enzyme that regulates cardiac pacemaker activity, stress responses, and cardiac contractility; and ZFAT that has a role in apoptosis and cell survival that may lead to the development of HTN.6 But it is not clear how exactly these genetic factors lead to alterations in various soluble factors that may lead to the development of HTN in T2DM. Diet, genetic factors, inflammation, and its resolution mediators, immunocytes, and cytokines have overlapping and critical role in both HTN and T2DM. Obesity, HTN, T2DM, and insulin resistance are associated with low-grade systemic inflammation.3,7,8 Sodium, potassium, and magnesium have a determining effect on blood pressure. Low potassium intake coupled with increased consumption of sodium may have an effect in the genesis of HTN, though this has been disputed.11–13 A diet rich in fruits, vegetables, and low-fat dairy foods with reduced saturated and total fats can substantially lower blood pressure implying that sodium, calcium, potassium, and magnesium, vitamins, and antioxidants (present in substantial amounts in fruits and vegetables that include anthocyanin pigments) act in concert with each other to determine the degree of blood pressure in a given individual.14–16 Excessive sodium intake causes HTN by volume expansion, altering the renin–angiotensin–aldosterone system, reducing endothelial NO generation, enhancing the formation of asymmetrical dimethyl arginine (ADMA), oxidative stress secondary to excessive production of reactive oxygen species, inflammation, impaired insulin-mediated vasodilatation, increased sympathetic nervous system activation, dysfunctional innate and adaptive immune responses, and abnormal renal handling of sodium.2,13–17 Similar abnormalities are also reported in T2DM.18 These results are in tune with the observation that higher expression levels of NADPH oxidase occur in those with obesity, higher body mass index, and HTN and T2DM14–20 that could be secondary to an increase in the concentrations of proinflammatory cytokines IL-6, TNF-α, and IL-17. Increased salt (sodium chloride) intake and consequent increase in local concentrations even under physiological conditions can boost the induction of human TH17 cells by activating the p38/MAPK pathway and serum/glucocorticoid-regulated kinase 1 (SGK1).21 Under high-salt conditions, upregulation of the proinflammatory cytokines GM-CSF, TNF-α, and IL-2 is observed that may represent 1 potential mechanism by which increased dietary salt intake leads to the development of inflammatory events seen in HTN and T2DM. This modest increase in salt concentration ability to induce SGK1 expression that promotes IL-23R expression which enhances TH17 cell differentiation and accelerates the development of inflammatory events21 can be suppressed by potassium supplementation.22 These results attest to the fact that a delicate balance between salt and potassium needs to be maintained to regulate TH17-induced inflammatory events, vascular tone, insulin resistance and prevents development of HTN and T2DM.14 In addition to the fact that potassium ions are the most abundant cation in the body, it may also regulate T-cell function. Most of the potassium ~98% is intracellular and only ~2% extracellular. The extracellular K+ concentrations need to be tightly controlled, and any abnormality in its levels is harmful. It was reported that excessive intracellular accumulation of K+ as a result of abnormalities in the expression of voltage-gated K+-channel protein Kv1.3 (encoded by the KCNA3 gene) or the calcium-activated K+-channel protein KCa3.1 (encoded by KCNN4 gene) may result in elevated intracellular K+ concentration that suppresses T-cell function by affecting the protein phosphatase PP2A and inhibiting the signaling pathway that acts through Akt and mTOR protein kinases, suppressing T-cell activation.23,24 In contrast, Na+ has opposite action on T-cell activation.21 Since under normal physiological conditions, intracellular K+ concentration is high to ensure normal T-cell function. But when the dietary salt intake is high, this leads to a slight decrease in the intracellular K+ concentration of T cells resulting in their activation. Hence, maintenance of normal balance between Na+ and K+ across the cell membrane of not only T cells but also endothelial and other cells is critical to prevent abnormal activation of T and other cells and prevent inappropriate production of proinflammatory cytokines (even endothelial cells can secrete cytokines). Thus, dietary salt and K+ intake may enhance GM-CSF, TNF-α, IL-2, and IL-17 production and consequently proinflammatory state seen in HTN and T2DM. The observation by Cheng et al.6 of genetic polymorphism of KCNK5, a member of the potassium channel protein superfamily; ADCY9, a membrane-bound enzyme; and ZFAT that has a role in apoptosis and cell survival (apoptotic cells release intracellular potassium that suppresses T-cell function); may account for the abnormal T-cell responses and enhanced production of GM-CSF, TNF-α, IL-2, and IL-17 seen in HTN and T2DM. In this context, it is noteworthy that essential fatty acids (EFAs) {dietary linoleic acid (LA) and alpha-linolenic acid (ALA)} and their metabolites can modify the activity of human leukocyte Na+-K+-ATPase and 5′-nucleotidase activities in both normal and hypertensives implying that these fatty acids modulate cell membrane fluidity, the action of membrane-bound enzymes and thus, regulate intracellular Na+ and K+ concentrations.25 Plasma and tissue concentrations of EFAs and their metabolites gamma-linolenic acid (GLA), dihomo-GLA (DGLA), arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) are low HTN and T2DM.15 In addition, these fatty acids, especially AA, possess potent anti-inflammatory and anti-diabetic actions by virtue of their ability to inhibit IL-6 and TNF-α production and expression of NF-κB.26–28 Furthermore, GLA, DGLA, AA, EPA, and DHA, and their metabolites lipoxin A4 (LXA4), resolvins, protectins, and maresins have anti-inflammatory, anti-diabetic, and anti-hypertensive actions as well.16,26–28 Previously, we showed that EFAs and their metabolites modulate the action of angiotensin-converting enzyme, reactive oxygen species generation, cell membrane fluidity, and the expression of various cell membrane-bound receptors and their affinity to their respective proteins.29–32 Exercise is beneficial in the prevention and management of obesity, HTN, and T2DM. Exercise enhances LXA4 (and possibly, resolvins, protectins, and maresins) generation, a potent anti-inflammatory bioactive lipid derived from AA (both AA and LXA4 also have anti-diabetic actions26–28,33). Exercise augments vagal tone and acetylcholine is a potent anti-inflammatory compound that enhances LXA4 formation, which may explain its anti-inflammatory action.33–35 In contrast, catecholamines of the sympathetic nervous system promote inflammation.36 Magnesium, vitamins B1, B6, B12, folic acid, vitamin C, and insulin are cofactors for the physiological action of desaturases and elongases that are needed for the conversion of dietary EFAs: LA and ALA to their long-chain metabolites, which form precursors to LXA4, resolvins, protectins, and maresins. Hence, any deficiency of these cofactors may also accelerate the development of HTN and T2DM (see Figure 2). Dietary consumption of adequate amounts of l-arginine decreases the formation of ADMA and enhances the formation of NO, a potent vasodilator and anti-hypertensive molecule. EFAs and their metabolites are also potent inducers of endothelial NO generation14–16 and modulate several gene(s) expressions.26–28 Thus, there is a close interaction among genes, genetic polymorphism (as shown by Cheng et al.6), EFAs and their metabolites, dietary factors, and their ability to alter cell membrane fluidity, inflammatory events, and immune response.14–16,18–36 This may account for the overlapping biochemical and clinical features seen among patients with obesity, insulin resistance, HTN, and T2DM. Scheme showing potential interaction(s) among diet, genes, various soluble mediators, cytokines, EFAs, and their metabolites, exercise, autonomic nervous system, and insulin resistance and their role in the pathobiology of HTN and T2DM. For details see text. Abbreviations: EFAs, essential fatty acids; HTN, hypertension; T2DM, type 2 diabetes mellitus. Scheme showing potential interaction(s) among diet, genes, various soluble mediators, cytokines, EFAs, and their metabolites, exercise, autonomic nervous system, and insulin resistance and their role in the pathobiology of HTN and T2DM. For details see text. Abbreviations: EFAs, essential fatty acids; HTN, hypertension; T2DM, type 2 diabetes mellitus. It is evident from the preceding discussion that though dietary factors and genes and genetic polymorphisms are important in the pathogenesis of HTN and T2DM, it is important to understand their close interactions to apply this knowledge in the clinic. Hence, it is crucial to measure plasma/leukocyte levels of EFAs and their metabolites, vitamin C, B1, B6, B12, folic acid, NO, l-arginine, ADMA, insulin resistance, IL-6, TNF-α, IL-17, angiotensin-II and ACE activity, lipid peroxides, acetylcholine, catecholamines, carbon monoxide, hydrogen sulfide (that mediate some of the actions of EFAs and their metabolites), various antioxidants in addition to assessing genetic polymorphisms to arrive at meaningful conclusions. Based on the plasma and tissue (especially peripheral leukocytes) concentrations of various soluble mediators, efforts could be made to rectify their deficiency(ies) by suitable measures that may aid in the prevention or management of HTN and T2DM. This is evident from our studies26–28 where we observed that AA and its anti-inflammatory metabolite LXA4 can prevent both type 1 and type 2 DM. It appears that both AA and LXA4 (and to some extent GLA, DGLA, EPA, DHA, and their metabolites resolvins, protectins, and maresins) may also have the potential to prevent HTN and its associated complications.14–16 These and other studies suggest that a better understanding of the interaction(s) among dietary factors, genes, and genetic polymorphisms, and various soluble mediators involved in the pathobiology of HTN and T2DM and other diseases may lead not only to understand their pathobiology better but also develop appropriate preventive and therapeutic strategies. It is not known whether EFAs and their metabolites can modify the expressions of KCNK5, ADCY9, and ZFAT genes and nullify their inappropriate expression and actions. Such studies may prove to be extremely useful. The author declared no conflict of interest.