The tight blood sugar control among type 1 (T1DM) and type 2 (T2DM) diabetes mellitus patients is recommended by different specialists concerned with this disease aiming at avoidance of long term complications of diabetes. In spite of the significant impact of this approach on decreasing of these complications, still these complications are still frequently encountered. This weak success is partly explained by the frequent failure to achieve glycemic targets. In addition, the conventional hypoglycemic agents do not properly control the underlying pathogenic mechanisms of these complications. The last decade has witnessed the evolution of new hypoglycemic and antioxidant agents the carry additional features enabling them to adequately fight these pathogenic mechanisms. In this review, we are going to thoroughly discuss these mechanisms and highlight the therapeutic value of initiating treatment of new onset diabetes using these agents instead of the long standing traditional approach.

INTRODUCTION

Diabetes mellitus is a pandemic disease that affected 108 million persons worldwide in 1980 [1]. This figure is exponentially increasing to approach 430 million persons in 2014 [1]. In spite of the increased awareness about this disease and the worldwide efforts to follow guidelines in management, 3.7 million persons lost their lives in 2012 because of diabetes and its complications [2]. The hazard ratio of cardiovascular mortality among diabetic patients is 2.3 folds that in non-diabetic personnel [3]. The average life span of the diabetic patients is 10-15 years shorter than non-diabetic subjects [4]. Beside this increased mortality, diabetes is the cause of many disabling morbidities. Diabetic retinopathy is the leading cause of blindness among working-age adults worldwide in spite of the energetic treatment of the established cases of retinopathy that can reduce the risk of visual loss by 60% [5]. Diabetes is the leading cause of non-traumatic lower-extremity amputation [6]. Diabetic peripheral neuropathy (PN) is the most prevalent cause of sensory neuropathy [7]. Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease (ESRD). One third of T1DM develop ESRD, while only 10-20% of type 2 diabetes mellitus (T2DM) patients progress to ESRD [8,9]. The prevalence of congestive heart failure (CHF) among diabetic patients aged 55 to 64 years is 5.5 folds the prevalence among non-diabetic personnel of the same age [10]. Diabetes is an independent risk factor for the development of ischemic heart disease (IHD). CHF and IHD are the main causes of death in T1DM and T2DM patients [11]. Diabetes mellitus confers a greater risk of cerebrovascular stroke [12]. Endothelial dysfunction is a common pathology underlying the etiopathogenic mechanism of all these complications [13]. This endothelial dysfunction is a sequel of many metabolic changes that are usually encountered in hyperglycemic personnel. These metabolic changes include increased oxidative stress [14], hyperuricemia [15], stimulation of sodium hydrogen exchangers  (NHE)  [13]  and  stimulation  of  renal  sodium hydrogen exchangers (NHE) [13] and stimulation of renal sodium glucose transporters (SGLT) [16].

25 years ago, the Diabetes Control and Complications Trial (DCCT) research group announced the significant impact of tight blood sugar control on development of micro-vascular complications among T1DM [17]. Five years later, the United Kingdom Prospective Diabetes Study (UKPDS) group announced similar findings among T2DM patients [18]. However, reduction of micro-vascular complications in the intensive insulin treatment group was by 50% compared to poorly controlled cases in DCCT trial. In addition, the tight blood sugar control only has a marginal impact on cardiovascular disease and all-cause mortality among diabetic patients [19]. On the other hand, the tight blood sugar control using sulphonyl urea compounds and insulin is associated with increased risk of severe hypoglycemia and/or weight gain [17,18]. IN UKPDS study, T2DM patients allocated to metformin had 32% reduction for any diabetes-related endpoint, 42% for diabetes-related death and 36% for all-cause mortality when compared with patients allocated to sulphonyl urea or insulin [20]. These favorable effects of metformin were suggested as consequence of the impact of this agent on body weight and hypoglycemic attacks. According to these results and others, the American College of Endocrinology (ACE) and the American Association of Clinical Endocrinology (AACE) recommend that the choice of anti-diabetic therapies must be based on many attributes that include anti-hyperglycemic efficacy, risk of inducing hypoglycemia and risk of weight gain [21]. The last 15 years have witnessed the introduction of three new hypoglycemic agents, namely, glucagon like peptide-1 receptor agonists (GLP-1RA), dipeptidyl peptidase 4 inhibitors (DPP4Is) and sodium glucose co-transporter-2 inhibitors (SGLT2Is). These 3 agents carry common features, namely, the minimal incidence of hypoglycemic events and the favorable impact on body weight. GLP-1RA and SGLT2Is are associated with body weight reduction while DPP4Is are weight neutral [22,23]. Compared to older hypoglycemic agents, these newer groups carry potential favorable protective effects on endothelium, and can significantly reduce adverse cardiovascular events of diabetes in case of SGLT2Is and GLP-1RA and are reno-protective. In addition, SGLT2Is could prevent or withhold diabetic retinal complications [24]. This review will highlight the possible new strategy to prevent the development and/or progression of diabetic complications, the main target of this disease management.

THE ENDOTHELIUM IN DIABETES

The role of the endothelium as an important regulator of local vascular tone was first reported in 1980 [25]. The vascular endothelium is an important component of diabetic complications. Endothelial dysfunction is eminent not only in diabetic patients, but also in patients suffering obesity or metabolic syndrome. Decreased synthesis of nitric oxide (NO), a potent vasodilator, is the eminent feature of endothelial dysfunction. Decreased NO underlies insulin resistance by reducing insulin access to tissue [26]. Beside the blood flow effect, insulin has to cross endothelial cells to reach target tissues [27,28]. In addition, hyperglycemia is associated with endothelial mitochondrial fragmentation with increased production of reactive oxygen species (ROS) [29]. Increased endothelial ROS is associated with increased breakdown of NO [30]. Impaired endothelial function was demonstrated within visceral fat [31], cardiac and skeletal muscles [32]. Endothelial dysfunction is associated with accelerated atherosclerosis in an animal model [33], diabetic retinopathy [34], nephropathy [35], neuropathy [36] and cerebral dysfunction [37]. In order to affirm the role of endothelial dysfunction in development of diabetic nephropathy, 2 separate studies have disclosed that endothelial nitric-oxide synthase (eNOS) deficient mice robustly develop diabetic nephropathy [38,39].

SODIUM HYDROGEN EXCHANGERS

The sodium hydrogen exchangers (NHE) are trans-membrane ion channels that are responsible for intracellular pH regulation through extrusion of hydrogen ion in exchange with sodium influx (Figure 1). NHE exist in nine isoforms [40,41]. NHE1 is present on the surface of endothelium, vascular smooth muscle cells (VSMCs), cardiomyocytes and platelets, while the isoform encountered on the surface of renal tubular and intestinal epithelium is NHE3. Activation of the NHE1 within endothelium, VSMCs and cardiomyocytes may underlie micro-vascular and macro-vascular complications of diabetes. It can also have a role in insulin resistance and systemic hypertension. These exchangers cause increased sodium influx that stimulates sodium calcium exchanger with consequent increase of intracellular calcium. Within endothelium, increased cytoplasmic calcium inhibits eNOS with consequent decrease of NO synthesis (Figure 2). In addition increased intracellular calcium is associated with increased intracellular and mitochondrial activity of calpain, a cysteine protease that can damage the inner mitochondrial membrane, a process that ends with cell apoptosis [42]. Activation of NHE1 in diabetic patients is a consequence of high blood glucose, insulin, angiotensin or adipokines [43]. Endothelial NHE1 activation leads to increased influx of calcium into the cytoplasm and mitochondria associated with increased calpain enzyme activity. These changes lead to endothelial dysfunction and senescence. The development of systemic hypertension, increased insulin resistance, diabetic retinopathy, nephropathy and neuropathy are consequences of decreased eNOS activity and accelerated endothelial senescence. It can also explain the increased frequency of vascular calcification, peripheral vascular disease and diabetic cerebrovascular dysfunction [44]. Mitochondrial injury is associated with impaired antioxidant defense [45]. Inhibition of NHE1 using cariporide was associated with increased NO release, eNOS activity simultaneously decreased ROS production, decreased nuclear factor-κB (NF-κB) activation and decreased production of tumor necrosis factor-α and intercellular adhesion molecule-1 [46]. Increased intracellular calcium induced by NHE1 isoform on the surface of cardiomyocytes leads to cardiac hypertrophy. Peripheral coronary ischemia secondary to endothelial dysfunction can further activate cardiac NHE1. In addition active NHE1 increases intracellular and intra-mitochondrial calpain that contributes to degeneration, apoptosis and fibrosis of myocardium (Figure 3) [43]. NHE3 is the isoform within the cytoplasmic membrane of the renal proximal tubular epithelium and ascending limb of loop of Henle. Activation of renal NHE3 causes sodium retention and can thus contribute to development of systemic hypertension in diabetic patients (Figure 4) [43,47]. Activation of NHE1 on the surface of platelets plays a significant role in platelet activation. This effect is mediated through increased intracellular calcium and can contribute to the pro-coagulant state in diabetes [48]. Accordingly, activation of NHE1 on the surface of endothelial cells, VSMCs, platelets and cardiomyocytes beside the activation of renal NHE3 share in the pathogenesis of systemic hypertension, microvascular complications and macrovascular complications of diabetes that finally result in heart failure and end stage renal disease.

OXIDATIVE STRESS

Increased oxidative stress is one of the metabolic derangements encountered in diabetes. Diabetic patients have increased production of free oxygen radicals and decreased wash out of these radicals. Increased production of free oxygen radicals is attributed to increased activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [49,50], cyclo-oxygenase [51] and lipoxygenase [52] enzymes. All these enzymes are induced by hyperglycemia. Sodium-glucose cotransporter 2 (SGLT2) within the brush border of proximal convoluted tubular epithelium (PCT) is another pathway of free oxygen radicals’ overproduction. Increased intracellular uric acid (UA) induces NADPH oxidase [53]. Mitochondrial damage results in impaired antioxidant defense [45]. Increased free oxygen radicals activate NF-κB [54]. When NF-κB is free from its inhibitor, it translocate from the cytoplasm to the nucleus where it triggers the genes encoding transforming growth factor-β1 (TGF-β1) and monocyte chemo-attractant protein-1 (MCP-1) and intercellular adhesion molecule 1 (ICAM1) [55-57]. Reactive oxygen species (ROS) stimulate overproduction of protein kinase C (PKC) and mitogen-activated protein (MAP) kinase within mesangial cells (MCs) and pericytes. All these factors stimulate overproduction of extracellular matrix proteins [58].

URIC ACID

Serum uric acid (SUA) is a strong predictor for development of proteinuria in T1DM patients. The risk for proteinuria increases by 80% with every 1 mg/dL rise in SUA [59]. In addition, the risk of decline of glomerular filtration rate (GFR) is significantly higher (2.4 folds) in T1DM patients with SUA>6.6 mg/dL when compared with candidates with lower level [60]. In T1DM patients followed-up for more than 18 years, SUA was an independent predictor of overt proteinuria [61]. In T2DM patients, 68% of the hyperuricemic versus 41.5% with normal SUA had diabetic nephropathy (DN) [62]. Further prospective studies confirmed the increased risk of development of proteinuria and decline of GFR among T2DM with high SUA [63,64]. SUA>7 mg/dL in males and >6 mg/dL in females were associated with higher rate of DN progression and overall mortality among T2DM patients that have the disease for fifteen years or more [65]. Treatment of T2DM patients suffering DN and high SUA with allopurinol was associated with a significant decrease of urine albumin excretion (UAE) and serum creatinine and a significant increase of GFR over three years of follow-up [66]. The significant favorable effect of urate-lowering therapy on the rate of GFR decline has been confirmed in a recent meta-analysis of 19 randomized controlled trials that enrolled 992 patients [67].

Increased level of SUA is associated with endothelial dysfunction. High mobility group box chromosomal protein 1 (HMGB1) is a pro-inflammatory mediator synthesized and secreted by activated phagocytes or monocytes. When secreted extracellular, HMGB1 can interact with the receptor for advanced glycation end products (RAGE), inducing the production of multiple cytokines, and the induction of vascular adhesion molecules [68]. In a recent in vitro study, high UA concentration inhibited eNOS expression and NO production in human umbilical vein endothelial cells (HUVECs), increased extracellular HMGB1 secretion, up-regulated RAGE expression, activated NF-κB and increased the level of inflammatory cytokines. Blocking RAGE significantly suppressed the DNA binding activity of NF-κB and the levels of inflammatory cytokines [69]. In addition, high SUA is a significant predictor of systemic hypertension [122].

ROLE OF GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS (GLP-1RA)

Glucagon like peptide-1 (GLP-1) is a peptide hormone secreted by the neuro-endocrine cells within the mucosa of the small intestine [70]. In healthy individuals, GLP-1 activates insulin secretion, inhibits glucagon secretion and slows gastric emptying and increases sense of satiety [70]. The susceptibility of this peptide hormone to enzyme breakdown by the dipeptidyl peptidase-4 enzyme (DPP-4) is responsible for the very short plasma half-life of GLP-1. It cannot be used therapeutically except as continuous intravenous infusion [71]. GLP-1RA is exogenous GLP-1 analogues with variable sequence similarity to the human GLP-1 [72]. The variability involved mainly two sites in the GLP-1 molecule susceptible to cleavage by DPP4, namely, alanine at position 8 and lysine at position 34. These changes beside other modifications have helped to find out many peptides that simulate GLP-1 action but with longer half-life [71]. GLP-1RAs were found to decrease body weight and some cardiovascular morbidity, without increasing the risk of hypoglycemia [73]. Robust indications for GLP-1RAs in T2DM patients not responding to metformin monotherapy, dual therapy, or insulin include overweight, inability to control appetite, high risk of cardiovascular disease, and the need of high doses of insulin [71]. Several clinical studies have shown that the use of GLP-1 RAs is associated with reduction in systolic and to a minor degree, diastolic blood pressure [74]. However, long term use of GLP-1 RAs was frequently reported to be associated with increased heart rate [74,75]. In addition, the current evidence does not support any beneficial effect of GLP-1RAs in patients with heart failure and/or impaired ventricular function [76,77]. The evaluation of lixisenatide in acute coronary syndrome (ELIXA) trial was the first cardiovascular outcome trial (CVOT) of GLP-1RAs in T2DM. Based on this trial, treatment with lixisenatide in addition to conventional therapy had no impact on the cardiovascular risk in patients with T2DM and recent acute coronary syndrome [78]. In the liraglutide effect and action in diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, which was finalized in December 2015, liraglutide was significantly associated with reduced rate of death from any cause and cardiovascular events in patients with T2DM at high risk for cardiovascular events. In addition, patients with eGFR<60 ml/min/1.73 m2 and patients aged 50 years or more may have greater benefit of liraglutide treatment. On the other hand, hospitalizations for heart failure were not different between liraglutide and placebo groups [79]. Although the incidence of retinopathy was similar in this trial, the chance of development of nephropathy was significantly lower in patients treated with liraglutide [79]. In SUSTAIN-6 trial, semaglutide was associated with significantly less incidence and progression of nephropathy. On the other hand, higher percentage of patients in semaglutide group developed retinopathy. Semaglutide was also associated with 26% reduction in the hazard of cardiovascular mortality, non-fatal myocardial infarction or non-fatal stroke [80]. In EXSCEL trial, extended release exenatide failed to significantly decrease the incidence of cardiovascular events [81]. This result could be due to the broader T2DM population studied in EXSCEL trial as regard to age and cardiovascular risk, the shorter follow-up period, the lower HbA1c levels and the concomitant hypoglycemic treatment (SGLT2Is were frequently used in the placebo group) [82]. A meta-analysis including nine randomized trials with dulaglutide in 6010 T2DM patients has shown that 0.67% of patients treated with dulaglutide vs. 1.18% of the placebo group developed one of the end points. This difference was not significant [83].

Other glucose-independent effects of GLP-1RAs include decrease in blood pressure, dyslipidemia, inflammation and fibrosis. Through inhibition of renal NHE3, GLP-1RAs can promote natriuresis and diuresis. Additional effects include inhibition of the intrarenal renin angiotensin system, inflammation, and apoptosis. The mechanism of these effects remains to be established. Recent studies suggest important antioxidant and anti-apoptotic activities of GLP-1RAs (Figure 5) [84].

DIPEPTIDYL PEPTIDASE 4 INHIBITORS

The discovery of non-enzymatic functions for DPP4 within the kidney has attracted the attention for the reno-protective functions of this hypoglycemic agent especially after disclosure of the anti-proteinuric effect of saxagliptin in T2DM patients during “Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus - Thrombolysis in Myocardial Infarction 53” (SAVOR-TIMI 53) trial [85-89]. In addition experimental pharmacologic and genetic inhibition of DPP4 had proven efficacy in preventing progressive renal damage in animal models of acute and chronic kidney disease [90,91].

The glucose lowering action of DPP4Is is through inhibition of breakdown of endogenous GLP and glucose-dependent insulinotropic peptide (GIP). These incretins improve sensitivity of pancreatic β cells to glucose [92]. DPP4 exists in 2 forms, membrane bound form and soluble form [93]. Membrane bound DPP4 was encountered on the cell membrane of epithelial cells in the kidneys, lungs, and small intestine. It also exists on endothelial cells, and immune cells [94-96]. DPP4 on the surface of immune cells was initially recognized as cluster of differentiation 26 (CD26) [95,96]. The soluble form (sDPP4) is the consequence of shedding of the membrane bound form. sDPP4 level increases in obese subjects and in T2DM patients and may participated in increased insulin resistance in these cases [97]. Membrane bound DPP4 expression is induced under conditions of hypoxia as well as its’ shedding [98,99].

Within the kidney, DPP4 in S1-S3 segments of the proximal convoluted tubules (PCT) are linked to NHE3 and plays a role in salt and water retention through stimulation of this exchanger, NHE3 activity decreases on inhibition of angiotensin II synthesis by captopril [100] or inhibition of DPP4 [101]. Angiotensin II inhibits megalin receptor endocytosis protein expression. This process is reversed by DPP4Is [102]. Treatment with DPP4 inhibitors may reverse reduced uptake of albumin and other low molecular weight proteins by PCT [103]. DPP4 was also localized on the glomerular endothelium and the base of the foot processes of podocytes [104]. DPP4 is expressed on T-cells, B-cells, macrophages and dendritic cells in the kidney [96]. Stimulation of DPP4 on the surface of different immune and inflammatory cells may mediate inflammatory response within the kidney in diabetic patients. Inflammation as a common feature in diabetes is reduced with DPP4Is. This finding highly suggests inflammation as a major player in DPP4-mediated kidney injury [105].

However, in spite of the reduction in urine albumin excretion observed in 3 randomized controlled studies (RCT) in T2DM patients treated with DPP4Is [106-108], the only study that specifically looked for the anti-proteinuric effect of linagliptin failed to find a significant impact [109]. Moreover, DPP4Is failed to have a significant impact on doubling of serum creatinine, change in GFR or ESRD [106-108]. On the other hand, administration of linagliptin to T2DM patients that had renal dysfunction and were already treated with ACE inhibitors or ARBs has led to further significant reduction in albuminuria [110].

In normoglycemic milieu, microRNA-29 (miR29) suppresses DPP4 gene. In hyperglycemic state, this suppression is lost. As a consequence, cell surface DPP4 activity increases [111]. In diabetic mice, activated endothelial DPP4 induces phosphorylation of adjacent integrin β1 on the surface of the endothelium. The activated DPP4 together with the phosphorylated integrin β1 form a complex that up-regulates TGF β receptor and activates the surface vascular endothelial growth factor receptor type 1 (VEGFR1). Up-regulated TGF β receptor and VEGFR1 stimulate endothelial-mesenchymal transition (EndMT) that increases transition to fibroblasts with consequent increased fibrogenesis (Figure 6) [112]. However, the lack of significant impact of DPP4Is on rate of decline of GFR in human studies would cast doubts on their favorable effect on renal fibrosis in humans.

In addition, the impact of DPP4Is on the retina is debatable. While some investigators reported an increase in retinal endothelial leakage and vascularity [113], others have reported a significant reduction in the risk of diabetic retinopathy progression [114].

The lack of strong favorable effect of DDP4Is on diabetic microvascular and macrovascular complications of diabetes in spite of the attractive and favorable molecular and experimental mechanisms can be attributed to potentiation of the stem cell chemokine, stromal cell-derived factor-1 (SDF-1), which promotes inflammation, proliferation and neovascularization [115]. SDF-1 enhances atheromatous plaque growth and instability, and promotes cardiac inflammation and fibrosis [116]. The renal effects of DPP4Is are mainly through potentiation of SDF-1which in turn can promote podocyte injury and glomerulosclerosis. In addition, SDF-1 induces natriuresis in the distal tubules, contrary to SGLT2Is and NHE3 inhibitors that act on PCT. Hence, SDF-1 cannot utilize tubuloglomerular feedback to modulate the glomerular hyper filtration (Figure 7) [115,117]. SDF-1 may also aggravate both retinopathy and neuropathy [115,118].

SODIUM GLUCOSE CO-TRANSPORTERS INHIBITORS

SGLT2Is constitute a recently introduced group that has insulin independent hypoglycemic effect. Three members of this group, namely empagliflozin, canagliflozin and dapagliflozin are FDA approved and are used in USA and Europe. By inhibiting the upregulated SGLT2 co-transporters in the brush border of S1 segment of the PCT, SGLT2Is can reduce the renal threshold for plasma glucose from 196 to 22 mg/dL, thereby enhancing urinary excretion of glucose [119]. They also increase distal sodium delivery and hence distal tubular sodium absorption. Increased adenosine triphosphate (ATP) consumption during sodium absorption with a consequent increase of adenosine production causes afferent arteriolar vasoconstriction and fall in renal blood flow, reversal of hyper filtration and accordingly reduces renal injury (Figure 8). In addition, SGLT2Is exert other beneficial effects, including reductions in body weight, SUA and blood pressure [120]. Excess glucose within the tubular lumen triggers the uric acid transporter GLUT9 within S3 segment of the PCT and in the collecting duct to excrete UA in exchange with glucose [121]. The antihypertensive effect of SGLT2Is is related to volume depletion, loss of body weight, inhibition of endothelial NHE1 and renal NHE3 and reduction in SUA.

SGLT2Is not only decrease SUA, but through inhibition of the aldose reductase activity, they can decrease intracellular fructose metabolism and UA synthesis in PCT epithelium [123]. Intracellular UA is pro-oxidant. NADPH oxidase is thus activated with increased production of ROS, this leads to premature senescence of these cells, activation of renin angiotensin system, epithelial mesenchymal transition, and activation of inflammatory cascade through activation of NF-κB (Figure 5) [124-126]. Cyclin-dependent kinase (CDK) inhibits cell senescence. P21 is an inhibitor of CDK and thus promote cell senescence. Hyperglycemia induces P21 while SGLT2Is inhibit this factor within PCT cells (Figure 9) [127,128]. In addition, SGLT2Is muffle the expression of toll-like receptor-4, the binding of nuclear DNA for activator protein 1, the increased collagen IV expression as well as the increase in interleukin-6 secretion and interstitial macrophage infiltration induced by hyperglycemia within the renal parenchyma [129]. Moreover, fibrotic and inflammatory genes are suppressed within the diabetic kidney by SGLT2Is [130,131].

Through suppression of intracellular UA production, SGLT2Is inhibits renal gluconeogenesis. Intracellular UA stimulates adenosine monophosphate dehydrogenase (AMPD) enzyme and inhibits adenosine monophosphate kinase (AMPK) enzyme activities. Intracellular AMPD stimulates while AMPK inhibits gluconeogenesis [132]. In healthy personnel, the kidneys participate in endogenous glucose production. In the fasting state, 20%-25% of endogenous glucose production takes place through renal gluconeogenesis. In T2DM, renal gluconeogenesis increases threefold [133].

Over a median observation time of 3.1 years, empagliflozin in EMPA-REG trial achieved 55% reduction of the chance of ESRD in T2DM patients with established cardiovascular disease and an eGFR>30 mL/min/1.73m² [134]. In comparison, losartan treatment of similar population having DN was associated with 28% delay in the onset of ESRD during a mean follow-up of 3.4 years [135]. In addition, empagliflozin was associated with 39% reduction in incident or worsening nephropathy, 38% reduction in progression to overt albuminuria and 44% reduction in doubling of serum creatinine [134]. The significant favorable outcome of SGLT2Is is attributable to their effect on glomerular hyper filtration, blood pressure, body weight and serum UA in diabetic patients [136-138]. In addition, SGLT2Is inhibit NHEs on surface of cardiomyocytes, endothelial cells and renal tubular epithelial cells. NHE inhibition can explain the unique cardioprotective and renoprotective actions of SGLT2Is [139-141]. Decreased renal blood flow induced by SGLT2Is is related to tubuloglomerular feedback and not related to RAS blockade. Empagliflozin and dapagliflozin increase plasma aldosterone and angiotensin II [142,143], together with urinary angiotensin converting enzyme and angiotensin converting enzyme [144].

When T2DM patients (total of 1450 cases) receiving metformin were randomly assigned to either once-daily canagliflozin 100 mg, canagliflozin 300 mg or glimepiride titrated to 6-8 mg for 2 years, eGFR declined by 3.3, 0.5 and 0.9 ml/min/1.73 m²/year in glimepiride, canagliflozin 100 mg and canagliflozine 300 mg groups respectively (P<0.01 for each canagliflozin group versus glimepiride) in spite of comparable reductions in HbA1c. In addition, UAE declined more with canagliflozin 100 mg or canagliflozin 300 mg than with glimepiride. These results further support that the renoprotective effect of SGLT2Is is independent of their glycemic effect [145]. Contrary to DPP4Is and sulfonylureas that are significantly associated with increased risk of diabetic retinopathy, SGLT2Is were not associated with a higher risk of diabetic retinopathy than placebo among 100 928 patients with T2DM included in 37 independent randomized controlled trials with 1806 diabetic retinopathy events [146].

FREE OXYGEN RADICALS SCAVENGERS

The role of reactive oxygen species (ROS) in the pathogenesis of diabetic complications is overwhelmed by many preclinical studies. However, the less favorable outcomes of different antioxidants to prohibit the development or progression of diabetic complications in large clinical trials have dampened the enthusiasm for the use of antioxidant agents in diabetes [147]. Clinical studies using vitamin A, C and E as antioxidant agents in pre-diabetic and T2DM patients were disappointing. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that protects and restores cell homeostasis upon activation. Although Nrf2 is adaptively activated in hyperglycemic status, this activation does not reach the sufficient level capable to combat the oxidative stress fueled by hyperglycemia [148]. Insufficient Nrf2 activity is often associated with the pathogenesis of diabetes and its complications [149]. Natural products can activate Nrf2, as a potential therapeutic target to control diabetic complications [149,150]. Cruciferous vegetables are rich source of sulforaphane, resveratrol is present in grapes, rutin is found in buckwheat, black tea, citrus fruits, and apple peels, cinnamic aldehyde is found in cinnamon essential oil, curcumin is found in turmeric, berberine in Berberis mahonia plant, actinidia callosa in kiwi fruits, Sinomenine in the root of the climbing plant Sinomenium acutum, garlic and bitter melon. All these agents are natural Nrf2 activators [151-154].

Consumption of 10 g of broccoli sprouts powder, a rich source of sulforaphane, daily for four weeks was associated with significant improvement in insulin resistance in sixty three T2DM patients [155]. In a double blind trial in T2DM patients, the study candidates consumed oral 2 × 5 mg resveratrol (resveratrol group) or a placebo (control group) for four weeks. Resveratrol significantly decreased insulin resistance, urine ortho-tyrosine/creatinine ratio as an index of ROS production and platelets’ phosphorylated protein kinase B (pAkt):protein kinase B (Akt) ratio. These results indicated that resveratrol improves insulin sensitivity in humans, propably due to decreased oxidative stress with consequent more efficient insulin signaling via the Akt pathway [156]. A more recent study of ten T2DM subjects, 12 week daily consumption of 3 g of resveratrol increased skeletal muscle Sirtuin1 and adenosine monophosphate kinase enzymes expression. These findings can further support the insulin sensitizing effect of resveratrol [157]. On the other hand, resveratrol supplementation over five weeks in fourteen T2DM diet controlled patients did not have significant effect on glycemic control [158].

In seventy-five patients undergoing primary cardiovascular disease prevention including diabetic patients, resveratrol-rich grape supplement significantly decreased high-sensitivity C-reactive protein, tumor necrosis factor-α, plasminogen activator inhibitor type 1 and increased anti-inflammatory interleukin-10. The authors concluded that 1 year consumption of a resveratrol-rich grape supplement improved the inflammatory and fibrinolytic status in high cardiovascular risk and diabetic patients [159]. The beneficial anti-inflammatory effect of resveratrol-rich grape supplement was further supported in a later study of 35 T2DM male patients. One year consumption of resveratrol-rich grape supplement down-regulated the expression of pro-inflammatory cytokines in circulating mononuclear cells [160]. However, a more recent and larger study failed to prove a significant impact of low dose (40 mg/day) and higher dose (500 mg/day) used for 6 months on fasting blood sugar, glycated hemoglobin or c-reactive protein [161]. When 36 dementia-free, T2DM 49-78 years old patients consumed single doses of synthetic trans-resveratrol (75, 150 and 300 mg) at weekly intervals, trans-cranial Doppler ultrasound both before and 45 min after treatment had shown that only the 75 mg dose was efficacious to improve the cerebral vasodilator responsiveness in both middle and posterior cerebral arteries [162]. In addition, a single 75 mg dose of resveratrol was found to improve neurovascular coupling and cognitive performance in 36 T2DM adults aged 40-80 years [163]. A more recent study has shown that a daily 100 mg resveratrol supplementation for 12 weeks in 50 T2DM patients was associated with a significant decrease of arterial stiffness estimated by cardio-ankle vascular index [164].

When endothelial function was assessed using digital volume plethysmography to measure change in reflective index, oral intake of curcumin 150 mg twice daily for eight weeks has led to significant improvement in endothelial function [165]. Supplementation of twenty T2DM patients suffering overt proteinuria with 22 mg of curcumin three times daily for 2 months significantly decreased urinary protein excretion and urine IL-8 beside serum levels of TGF-β and IL-8 [166]. Curcumin in a dose of 500 mg administered three times daily for 9 months in 120 pre-diabetic patients significantly improved insulin resistance and beta cell function with consequent prevention of diabetes [167]. Further studies supported the favorable anti-diabetic effect of curcumin [168-170].

RECOMMENDATIONS OF DIABETES ASSOCIATIONS

In October 2018, the European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA) have issued an updated consensus statement on management of hyperglycemia in type 2 diabetes patients. This consensus was published during the annual meeting of EASD in Berlin, Germany. In this consensus, patients with clinical cardiovascular disease should receive one of SGLT2Is or GLP-1RAs, while in patients with chronic kidney disease (CKD) or clinical heart failure and atherosclerotic cardiovascular disease (ASCVD), SGLT2Is should be considered [171]. The choice of diabetes therapies as recommended by the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) must be individualized based on many attributes including the risk reduction in heart and kidney disease [172].

NOVEL MARKERS OF DIABETIC COMPLICATIONS

Mannose-binding lectin (MBL) is a recognized protein of the innate immune system. It is composed of a lectin (carbohydrate-binding) moiety attached to a collagenous moiety. MBL binds to a wide range of sugars that permits MBL permits to interact with a wide range of viruses, bacteria, yeasts, fungi and protozoa containing such sugars within their cell walls or membranes. When bound to its target sugar moiety, MBL can activate the complement system in the classic pathway or in C1-independent manner [173]. MBL is independently associated with HbA1c among diabetic patients [174]. MBL is involved in complement activation within the diabetic kidney [175] and was discovered as a possible independent predictor of DR, DN and other vascular complications in type 1 and type 2 diabetes [176-181].

In 297 newly diagnosed type 2 diabetic patients, serum fibrinogen was a strong predictor for DN [182]. Serum Adiponectin was proved as strong predictor of DN in both type 1 and type 2 diabetic patients according to a recent meta-analysis of 13 studies including more than five thousand cases [183]. 

DISCUSSION

The annual mortality rate secondary to kidney disease has risen over the last decade to above 5 million worldwide. This alarming rate is mainly attributed to the increased rate of obesity with consequent increase in the rate of type 2 diabetes, hypertension and cardiovascular disease [184]. Diabetic complications pose a huge public health and economic burden. Before the last 2 decades, the medical community has witnessed long term inertia in the available therapeutic tools that can prevent or delay progression of these complications. The introduction of GLP1RAs, DPP4Is and SGLT2Is has revived the hope to effectively prevent or slow the rate of progression of these complications. Beside their efficiency to control blood sugar, these agents have a favorable effect on body weight with decreased likelihood to experience hypoglycemia. In view of these valuable effects, the American diabetes association considered SGLT2Is as second- or third-line anti-hyperglycemic treatment [185]. In addition, the updated consensus statement on management of hyperglycemia in type 2 diabetes issued by EASD and ADA has recommended the early introduction of SGLT2Is and GLP1RAs to diabetic patients with clinical cardiovascular disease and SGLT2Is to patients with CKD or clinical heart failure and ASCVD. The results of CREDENCE trial that appeared couple of days ago have supported the significant cardioprotective and renoprotective of SGLT2Is in diabetic CKD patients. Canagliflozine 100 mg daily succeeded to convince the investigators to prematurely terminate the trial prematurely after a planned interim analysis on the recommendation of the data and safety monitoring committee. This analysis has shown a highly significant reduction of the primary composite end point by 34% after 2.6 years of treatment. All patients in this study had albuminuria >300 mg/day and had eGFR between 60 and 30 ml/min/1.73m². These data highly suggest that the beneficial effect of SGLT2Is is not likely related to the anti-hyperglycemic effect of these agents [186].

In view of these results and according to the accumulating evidence, more energetic primary preventive approach should be tailored. Routine screening of diabetic patients for likelihood to develop diabetic nephropathy using the early predictors like serum MBL, fibrinogen or adiponectin can help researchers to select patients prone to develop diabetic nephropathy. These patients should be studied looking for the capability of SGLT2Is to prevent the development of the disease instead of waiting till they develop albuminuria. Similar studies should be designed to study the possible impact of administration of GLP1RA, SGLT2Is and/or DPP4Is on the rate of development of different cardiovascular events in selected high risk diabetic population.

FUNDS

This study did not receive funds. 

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