Residual microvascular risk in diabetes: unmet needs and future directions

Fioretto, Paola; Dodson, P M; Ziegler, Dan; Rosenson, Robert S.

doi:10.1038/nrendo.2009.213

Cited by 97 publications

(70 citation statements)

References 59 publications

(62 reference statements)

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“…Diabetes mellitus is a global health problem with as many as 246 million people being affected worldwide [Fioretto et al 2010]. Diabetes is one of the leading causes of blindness and end-stage renal failure which is due to changes in the microvasculature [Burrows et al 2010].…”

Section: Introductionmentioning

confidence: 99%

Serum myeloid-related protein 8/14 complex is associated with microalbuminuria in patients with type 2 diabetes

Schmaderer

Kemmner

Burkhardt³

et al. 2014

Therapeutic Advances in Cardiovascular Disease

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Objectives: Microalbuminuria (MA) is associated independently with cardiovascular risk and progression of renal disease in patients with diabetes and the normal population. MA is an accepted factor for microvascular defects, in particular in patients with diabetes, and is associated with inflammation. Activated transmigrating macrophages are key cells in these inflammatory processes. Based on the theory that myeloid-related protein 8/14 complex (MRP8/14) is secreted by transmigrating macrophages, we hypothesized that MA was accompanied by elevated MRP8/14 and investigated whether MA predicts MRP8/14 in patients with type 2 diabetes. Methods: A total of 86 men with type 2 diabetes were grouped according to urinary albumin excretion in normoalbuminuria and MA. Serum MRP8/14 levels were measured by enzymelinked immunosorbent assay. Established cardiovascular risk factors were quantified in both groups and compared with urinary albumin excretion. Results: Albuminuria (mg/day) was positively associated with MRP8/14 (r = 0.34) and systemic blood pressure (r = 0.33). Patients with type 2 diabetes and MA demonstrated significantly higher MRP8/14 levels than patients with normoalbuminuria [median (interquartile range), 1.24 (0.97-2.28) µg/ml versus 0.97 (0.67-1.35) µg/ml, p < 0.05]. Serum creatinine levels, systolic blood pressure (SBP), very low density lipoprotein levels and the incidence of hypertension and coronary artery disease were significantly higher in the group with MA. Both groups did not differ significantly in other cardiovascular risk factors. MA was an independent predictor of serum MRP8/14 levels (β = 0.454) as well as SBP (β = 0.625) and haemoglobin A1c (β = 0.322). Conclusion: Our data demonstrate that albumin excretion is associated with the process of macrophage activation determined by MRP8/14 levels. These data not only suggest tissue inflammation as a factor for elevated cardiovascular risk in patients with type 2 diabetes, they further point to a role of macrophage activation in this process.

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Section: Introductionmentioning

confidence: 99%

Serum myeloid-related protein 8/14 complex is associated with microalbuminuria in patients with type 2 diabetes

Schmaderer

Kemmner

Burkhardt³

et al. 2014

Therapeutic Advances in Cardiovascular Disease

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“…In contrast, the clinical trials with renin-angiotensin-aldosterone system (RAAS) blockade versus other antihypertensive agents in primary prevention of DN have provided conflicting results and are confounded, when albuminuria (urinary albumin excretion rate) is the primary outcome, by the rapid but reversible decreases in urinary albumin excretion rate and by the differences in blood pressure control. Current conventional therapies to prevent DN and slow its progression, based on blood glucose (2-6) and blood pressure control and RAAS blockade (7-9), are only partially effective, and a substantial residual risk to develop end-stage renal disease still remains (10). Thus, in addition to current therapies, new therapeutic approaches leading to additional risk reduction are needed.…”

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confidence: 99%

SGLT2 Inhibitors and the Diabetic Kidney

et al. 2016

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Diabetic nephropathy (DN) is the most common cause of end-stage renal disease worldwide. Blood glucose and blood pressure control reduce the risk of developing this complication; however, once DN is established, it is only possible to slow progression. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, the most recent glucose-lowering oral agents, may have the potential to exert nephroprotection not only through improving glycemic control but also through glucose-independent effects, such as blood pressure-lowering and direct renal effects. It is important to consider, however, that in patients with impaired renal function, given their mode of action, SGLT2 inhibitors are less effective in lowering blood glucose. In patients with high cardiovascular risk, the SGLT2 inhibitor empagliflozin lowered the rate of cardiovascular events, especially cardiovascular death, and substantially reduced important renal outcomes. Such benefits on DN could derive from effects beyond glycemia. Glomerular hyperfiltration is a potential risk factor for DN. In addition to the activation of the renin-angiotensin-aldosterone system, renal tubular factors, including SGLT2, contribute to glomerular hyperfiltration in diabetes. SGLT2 inhibitors reduce sodium reabsorption in the proximal tubule, causing, through tubuloglomerular feedback, afferent arteriole vasoconstriction and reduction in hyperfiltration. Experimental studies showed that SGLT2 inhibitors reduced hyperfiltration and decreased inflammatory and fibrotic responses of proximal tubular cells. SGLT2 inhibitors reduced glomerular hyperfiltration in patients with type 1 diabetes, and in patients with type 2 diabetes, they caused transient acute reductions in glomerular filtration rate, followed by a progressive recovery and stabilization of renal function. Interestingly, recent studies consistently demonstrated a reduction in albuminuria. Although these data are promising, only dedicated renal outcome trials will clarify whether SGLT2 inhibitors, in addition to their glycemic and blood pressure benefits, may provide nephroprotective effects.Diabetes is a worldwide growing public health problem with high risks of severe microvascular and macrovascular complications. Diabetic nephropathy (DN) is a major burden among the chronic complications of diabetes, given that it affects ;30% of patients with diabetes. Indeed, DN is the most common cause of end-stage renal disease in the U.S. (1) and worldwide. Known risk factors for DN include hyperglycemia, hypertension, dyslipidemia, smoking, and obesity as well as ethnic, familial, and genetic predispositions (2). Key clinical trials have demonstrated that early interventions, especially those aimed at primary prevention, are by far more effective and that it is only possible to slow progression once DN is established (2). Thus, large intervention trials on the impact of long-term intensified glucose control on chronic diabetes complications, both in type 1 and type 2 diabetes (2-6), have documented the critical role of glycemic control i...

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“…3,5 This chain of events favors the development of coronary atherosclerotic lesions, as well as microvascular disease. 4 Although the link between diabetes mellitus and atherosclerosis is well established, a better comprehension of the underlying mechanisms is of utmost importance to identify novel molecular targets. Epigenetic modifications are emerging as key players in cardiovascular disease.…”

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confidence: 99%

Adverse Epigenetic Signatures by Histone Methyltransferase Set7 Contribute to Vascular Dysfunction in Patients With Type 2 Diabetes Mellitus

Paneni

Costantino

Battista

et al. 2015

Circ Cardiovasc Genet

144

123

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T ype 2 diabetes mellitus (T2DM) is associated with increased risk of micro and macrovascular complications and ≈2-fold greater risk of mortality when compared with the general population.1,2 Advances in therapy have reduced morbidity and mortality in patients with T2DM. However, cardiovascular risk is far to be eradicated, and mechanism-based therapeutic approaches are needed. 3,4 In patients with diabetes mellitus, high-glucose levels trigger endothelial inflammation, mitochondrial oxidative stress, and reduced availability of nitric oxide, a key effector of vascular health. 3,5 This chain of events favors the development of coronary atherosclerotic lesions, as well as microvascular disease. 4 Although the link between diabetes mellitus and atherosclerosis is well established, a better comprehension of the underlying mechanisms is of utmost importance to identify novel molecular targets. Epigenetic modifications are emerging as key players in cardiovascular disease.6 Acetylation and methylation occurring at DNA/histone complexes significantly alter gene transcription Background-Cellular studies showed that histone methyltransferase Set7 mediates high glucose-induced inflammation via epigenetic regulation of the transcription factor NF-kB. However, the link between Set7 and vascular dysfunction in patients with diabetes mellitus remains unknown. This study was designed to investigate whether Set7 contributes to vascular dysfunction in patients with type 2 diabetes mellitus (T2DM). Methods and Results-Set7-driven epigenetic changes on NF-kB p65 promoter and expression of NF-kB-dependent genes, cyclooxygenase 2 and inducible endothelial nitric oxide synthase, were assessed in peripheral blood mononuclear cells isolated from 68 subjects (44 patients with T2DM and 24 age-matched controls). Brachial artery flow-mediated dilation, 24-hour urinary levels of 8-isoprostaglandin F 2α , and plasma adhesion molecules, intercellular cell adhesion molecule-1 and monocyte chemoattractant protein-1, were also determined. Experiments in human aortic endothelial cells exposed to high glucose were performed to elucidate the mechanisms of Set7-driven inflammation and oxidative stress. Set7 expression increased in peripheral blood mononuclear cells from patients with T2DM when compared with controls.Patients with T2DM showed Set7-dependent monomethylation of lysine 4 of histone 3 on NF-kB p65 promoter. This epigenetic signature was associated with upregulation of NF-kB, subsequent transcription of oxidant/inflammatory genes, and increased plasma levels of intercellular cell adhesion molecule-1 and monocyte chemoattractant protein-1. Interestingly, we found that Set7 expression significantly correlated with oxidative marker 8-isoprostaglandin F 2α (r=0.38; P=0.01) and flow-mediated dilation (r=−0.34; P=0.04). In human aortic endothelial cells, silencing of Set7 prevented monomethylation of lysine 4 of histone 3 and abolished NF-kB-dependent oxidant and inflammatory signaling. Conclusions-Set7-induced epigenetic changes contribute to...

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Residual microvascular risk in diabetes: unmet needs and future directions

Cited by 97 publications

References 59 publications

Serum myeloid-related protein 8/14 complex is associated with microalbuminuria in patients with type 2 diabetes

Serum myeloid-related protein 8/14 complex is associated with microalbuminuria in patients with type 2 diabetes

SGLT2 Inhibitors and the Diabetic Kidney

Adverse Epigenetic Signatures by Histone Methyltransferase Set7 Contribute to Vascular Dysfunction in Patients With Type 2 Diabetes Mellitus

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