Diabetes, Diabetic Complications, and Phosphate Toxicity: A Scoping Review

Brown, Ronald B.

doi:10.2174/1573399815666191104113236

Cited by 15 publications

(12 citation statements)

References 186 publications

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“…Mitochondrial dysfunction also induces apoptosis by Pi uptake [79]. In turn, induced apoptosis generates oxidative stress, further mitochondrial dysfunction, apoptotic bodies, and MVs [135][136][137][138], events that have been mechanistically linked to DNA damage, ER stress, autophagy or mitophagy, and calcium phosphate deposition. It can also induce osteogenic gene induction and transformation into osteogenic phenotype of VSMCs [139][140][141][142].…”

Section: Apoptosismentioning

confidence: 99%

Vascular Calcification—New Insights into Its Mechanism

Lee

Jeon

2020

IJMS

283

254

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Vascular calcification (VC), which is categorized by intimal and medial calcification, depending on the site(s) involved within the vessel, is closely related to cardiovascular disease. Specifically, medial calcification is prevalent in certain medical situations, including chronic kidney disease and diabetes. The past few decades have seen extensive research into VC, revealing that the mechanism of VC is not merely a consequence of a high-phosphorous and -calcium milieu, but also occurs via delicate and well-organized biologic processes, including an imbalance between osteochondrogenic signaling and anticalcific events. In addition to traditionally established osteogenic signaling, dysfunctional calcium homeostasis is prerequisite in the development of VC. Moreover, loss of defensive mechanisms, by microorganelle dysfunction, including hyper-fragmented mitochondria, mitochondrial oxidative stress, defective autophagy or mitophagy, and endoplasmic reticulum (ER) stress, may all contribute to VC. To facilitate the understanding of vascular calcification, across any number of bioscientific disciplines, we provide this review of a detailed updated molecular mechanism of VC. This encompasses a vascular smooth muscle phenotypic of osteogenic differentiation, and multiple signaling pathways of VC induction, including the roles of inflammation and cellular microorganelle genesis.

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Section: Apoptosismentioning

confidence: 99%

Vascular Calcification—New Insights into Its Mechanism

Lee

Jeon

2020

IJMS

283

254

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“…Vascular calcification is closely associated with a high risk of cardiovascular events and mortality [1,2]. In patients with diabetes mellitus, vascular calcification is accelerated [3][4][5][6] and may contribute to the development of cardiovascular diseases [3], which in turn are responsible in large part for the high mortality of these patients [3,7]. Nonetheless, no broadly applicable treatment against the development of vascular calcification is currently available [1,8].…”

Section: Introductionmentioning

confidence: 99%

Zinc Ameliorates the Osteogenic Effects of High Glucose in Vascular Smooth Muscle Cells

Henze

Estepa

Pieske

et al. 2021

Cells

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In diabetic patients, medial vascular calcification is common and associated with increased cardiovascular mortality. Excessive glucose concentrations can activate the nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-kB) and trigger pro-calcific effects in vascular smooth muscle cells (VSMCs), which may actively augment vascular calcification. Zinc is able to mitigate phosphate-induced VSMC calcification. Reduced serum zinc levels have been reported in diabetes mellitus. Therefore, in this study the effects of zinc supplementation were investigated in primary human aortic VSMCs exposed to excessive glucose concentrations. Zinc treatment was found to abrogate the stimulating effects of high glucose on VSMC calcification. Furthermore, zinc was found to blunt the increased expression of osteogenic and chondrogenic markers in high glucose-treated VSMCs. High glucose exposure was shown to activate NF-kB in VSMCs, an effect that was blunted by additional zinc treatment. Zinc was further found to increase the expression of TNFα-induced protein 3 (TNFAIP3) in high glucose-treated VSMCs. The silencing of TNFAIP3 was shown to abolish the protective effects of zinc on high glucose-induced NF-kB-dependent transcriptional activation, osteogenic marker expression, and the calcification of VSMCs. Silencing of the zinc-sensing receptor G protein-coupled receptor 39 (GPR39) was shown to abolish zinc-induced TNFAIP3 expression and the effects of zinc on high glucose-induced osteogenic marker expression. These observations indicate that zinc may be a protective factor during vascular calcification in hyperglycemic conditions.

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“…Scant in the literature however, is a commentary highlighting the role of serum phosphate changes mediated by SGLT2i on CVD, considering CVOT have vindicated SGLT2i in mitigating CVD burden. Nevertheless, the pharmacology of SGLT2i theoretically induces increased serum phosphate, which is associated with vascular calcification and stiffness, cardiac remodeling, and other pathologic changes conductive to MACE (observed in settings independent of SGLT2i administration), especially in populations with aberrant metabolic derangements such as T2DM and diabetic CKD[ 45 - 49 ]. A discussion of the relative degrees of phosphate induction with SGLT2i therapy in relation to the attenuation of T2DM and its sequelae conferred with therapy (as is supported by multiple clinical trials) is prudent for giving full context on the pharmacology of SGLT2i while affirming that these drugs are still associated with remarkably beneficial cardiovascular benefit.…”

Section: Introductionmentioning

confidence: 99%

Cardiovascular benefits from SGLT2 inhibition in type 2 diabetes mellitus patients is not impaired with phosphate flux related to pharmacotherapy

Nashawi¹,

Ahmed²,

Amin³

et al. 2021

WJC

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The beneficial cardiorenal outcomes of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM) have been substantiated by multiple clinical trials, resulting in increased interest in the multifarious pathways by which their mechanisms act. The principal effect of SGLT2i (-flozin drugs) can be appreciated in their ability to block the SGLT2 protein within the kidneys, inhibiting glucose reabsorption, and causing an associated osmotic diuresis. This ameliorates plasma glucose elevations and the negative cardiorenal sequelae associated with the latter. These include aberrant mitochondrial metabolism and oxidative stress burden, endothelial cell dysfunction, pernicious neurohormonal activation, and the development of inimical hemodynamics. Positive outcomes within these domains have been validated with SGLT2i administration. However, by modulating the sodium-glucose cotransporter in the proximal tubule (PT), SGLT2i consequently promotes sodium-phosphate cotransporter activity with phosphate retention. Phosphatemia, even at physiologic levels, poses a risk in cardiovascular disease burden, more so in patients with type 2 diabetes mellitus (T2DM). There also exists an association between phosphatemia and renal impairment, the latter hampering cardiovascular function through an array of physiologic roles, such as fluid regulation, hormonal tone, and neuromodulation. Moreover, increased phosphate flux is associated with an associated increase in fibroblast growth factor 23 levels, also detrimental to homeostatic cardiometabolic function. A contemporary commentary concerning this notion unifying cardiovascular outcome trial data with the translational biology of phosphate is scant within the literature. Given the apparent beneficial outcomes associated with SGLT2i administration notwithstanding negative effects of phosphatemia, we discuss in this review the effects of phosphate on the cardiometabolic status in patients with T2DM and cardiorenal disease, as well as the mechanisms by which SGLT2i counteract or overcome them to achieve their net effects. Content drawn to develop this conversation begins with proceedings in the basic sciences and works towards clinical trial data.

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Diabetes, Diabetic Complications, and Phosphate Toxicity: A Scoping Review

Cited by 15 publications

References 186 publications

Vascular Calcification—New Insights into Its Mechanism

Vascular Calcification—New Insights into Its Mechanism

Zinc Ameliorates the Osteogenic Effects of High Glucose in Vascular Smooth Muscle Cells

Cardiovascular benefits from SGLT2 inhibition in type 2 diabetes mellitus patients is not impaired with phosphate flux related to pharmacotherapy

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