Relationship of advanced glycation end-products in hypertension in diabetic patients: a systematic review

Fuhr, Joana Cortelete; Ramos, Maria Eduarda Kegler; Piovesan, Fabiana; Renner, Luciana de Oliveira; Siqueira, Luciano de Oliveira

doi:10.1590/2175-8239-JBN-2022-0006en

Brasil

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Review Articles • Braz. J. Nephrol. 44 (4) • Oct-Dec 2022 • https://doi.org/10.1590/2175-8239-JBN-2022-0006en linkcopy

Relationship of advanced glycation end-products in hypertension in diabetic patients: a systematic review

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Diabetes mellitus and arterial hypertension are among the five risk factors that increase mortality in the world. Both are chronic, non-communicable diseases (NCDs), that have a pathophysiological association. Advanced glycation end products (AGEs), produced by the lack of glycemic control in diabetic patients, interact with their AGE receptors (AGER) resulting in increased arterial stiffness, inflammation and endothelial changes - which increases the risk of developing hypertension and other complications. We ran a systematic review in Pubmed, SciELO, Cochrane Library and Web of Science databases using keywords and Boolean operators to optimize the search, with the objective of assessing the mechanism of non-enzymatic glycation of proteins present in patients with diabetes and its correlation with the onset of hypertension, exposing all the endothelial and cellular damage caused by AGEs. We found 719 papers, of which 99 were read in full, and 26 met the eligibility criteria and were included in the present review. AGEs should be considered one of the main cardiometabolic risk factors. Reducing the AGE-AGER interaction will result in cardiovascular protection and increased life expectancy.

Keywords:
Diabetes Complications; Diabetes Mellitus; Hypertension; Glycation End Products, Advanced; Systematic Review

Paper	Year	Study type	Study goal
(1)	2019	Literature review	Understand the relationship between oxidative stress and AGEs for the prevention and treatment of cardiovascular complications in patients with diabetes.
(2)	2017	Literature review	To review emerging evidence on the role of advanced glycation end-products (AGEs) in the diet as a cardiometabolic risk factor.
(3)	2017	Literature review	Understand the relationship between arterial stiffness and blood pressure.
(4)	2018	Literature review	Expose diabetes and hypertension as comorbidities and discuss the pathophysiological features of vascular complications associated with these conditions.
(5)	2018	Literature review	Associate AGEs to DM and coronary artery disease.
(6)	2020	Literature review	Expose the cellular and molecular basis of AGE-AGER axis signaling pathways in AGE-related diseases and discuss in detail the modes of action of newly discovered biomolecules and phytochemicals such as the Maillard reaction and the Signaling AGE-AGER inhibitors.
(8)	2019	Cross-sectional study with 282 participants without a prior diagnosis of diabetes	To investigate the correlation of the soluble receptor for advanced glycation end-products and endogenous secretory AGER (esAGER) with markers of cardiovascular disease in subjects with normal glucose tolerance and post-load glucose 1 h ≥ 155 mg/dL after an oral test of glucose tolerance.
(9)	2017	Cross-sectional study with 85 DM2 patients	To associate AGE intake with arterial stiffness, inflammatory profile and macronutrient composition in individuals with T2DM without evident cardiovascular disease.
(10)	2017	Literature review	Study in detail the effects caused by the activation of AGE receptors.
(11)	2020	Experimental study with 93 patients with DM and AH	To determine the serum levels of anti-AGEs antibodies in patients with DM and AH.
(12)	2016	Population experimental study with 1051 participants	To associate plasma AGE concentration with central and peripheral blood pressures and central to brachial blood pressure amplification in a Chinese population.
(13)	2018	Literature review	Explore the pathophysiological links between diabetes and hypertension.
(14)	2017	Literature review	To highlight the targets of AGEs in the heart and the mechanisms that lead to heart failure.
(15)	2016	Literature review	Gather the main studies that expose the main adverse effects of hyperglycemia.
(16)	2018	Experimental in vitro study with T-lymphocytes	Investigate the role of ICOS/ICOSL in the pathogenesis of T2DM.
(17)	2018	Experimental study using a subcohort and a case-control subgroup	To determine whether plasma levels of advanced glycation end-products and oxidation products (OP) predict the incidence of cardiovascular disease (CVD) in T2DM.
(18)	2020	Literature review	To expose the consequences of oxidative stress on skeletal muscle proteins in DM2.
(19)	2019	Literature review	To review the pathophysiological role of the AGE-AGER oxidative stress system and its therapeutic intervention in vascular damage in diabetes.
(20)	2019	Literature review	To highlight the consequences of the sustained increase in ROS production and inflammation that infuence the acceleration of atherosclerosis by diabetes.
(21)	2016	Experimental study with 122 patients with DM2	To evaluate the association of tissue AGE, as assessed by skin A F, with coronary artery calcification in Japanese subjects with type 2 diabetes.
(22)	2019	Case-control study in DM2 patients	To assess the association between the main types of advanced glycation end products in serum and selected serum/plasma markers of endothelial dysfunction in black patients with T2DM in a hospital.
(23)	2018	Literature review	Synthesize data from population studies on trends in diabetes complications.
(24)	2016	Experimental study with 862 participants	To evaluate the association of AGEs and arterial stiffening from the measurement by skin autofuorescence.
(25)	2019	Experimental in vitro study in macrophage	Use of methylglyoxal to investigate the infuence of glycation and AGEs on macrophages.
(26)	2016	Experimental study in mice	To investigate the effects of advanced glycation end products diet on diabetic vascular complications using diabetic mice.

Author/ Year	Item 1	Item 2	Item 3	Item 4	Item 5	Item 6	Item 7	Item 8	Item 9	Item 10	Item 11	Item 12	Item 13	Item 14	Item 15	Result
(1)	✓	✓	!	✓	!	!	!	✓	!	✓	-	-	✓	!	✓	LOW
(2)	✓	✕	✓	✓	✓	✓	!	✓	✕	✓	-	-	✓	-	✓	C. LOW
(3)	✓	✕	!	✓	!	!	✕	✕	✕	✓	-	-	✓	-	✓	C. LOW
(4)	✓	✓	✓	✓	✓	!	✓	✓	✓	✓	-	-	✓	✓	✓	HIGH
(5)	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	-	-	✓	✓	✓	HIGH
(6)	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	-	-	✓	!	✓	V. LOW
(8)	✓	✓	✓	✓	✓	!	-	-	✓	✓	✓	✓	✓	✓	✓	HIGH
(9)	✓	✓	✓	✓	✓	✓	-	-	✓	✓	✓	✓	✓	✓	✓	HIGH
(10)	✕	!	!	!	!	!	!	✓	✕	✓	-	-	✓	!	✓	C. LOW
(11)	✓	✓	✓	✓	✓	!	-	-	✓	✓	✓	✓	✓	✓	✓	HIGH
(12)	✓	✓	✓	✓	!	!	✕	✓	!	!	-	-	!	!	✓	LOW
(13)	✓	✓	✓	✓	!	!	!	!	✓	✓	-	-	✓	!	✓	M. LOW
(14)	✓	✓	✓	✓	✓	!	!	!	!	✓	-	-	✓	!	✓	C. LOW
(15)	✓	✓	✓	✓	✓	✓	!	✓	✓	✓	-	-	✓	✓	✓	HIGH
(16)	✓	✓	✓	✓	✓	!	-	-	✓	✓	✓	✓	✓	✓	✓	HIGH
(17)	✓	✓	✓	✓	✓	✓	-	-	✓	✓	✓	✓	✓	✓	✓	HIGH
(18)	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	-	-	✓	✓	✓	HGIH
(19)	✓	✕	✓	✓	!	!	✕	✓	!	✓	-	-	✓	!	✓	C. LOW
(20)	✓	✓	✕	✓	✓	✓	✕	✓	✕	✓	-	-	✓	-	✓	C. LOW
(21)	✓	✓	✓	✓	✓	!	-	-	✓	✓	✓	✓	✓	✓	✓	HIGH
(22)	✓	✓	✓	✓	✓	✓	✓	✓	✓	✓	-	-	-	✓	✓	HIGH
(22)	✓	✓	✓	✓	✓	✓	-	-	✓	✓	✓	✓	✓	✓	✓	HIGH
(23)	✓	✓	✓	✓	✓	✓	!	✓	✓	✓	-	-	✓	-	✓	HIGH
(24)	✓	✓	✓	✓	✓	✓	-	-	✓	✓	✓	✓	✓	✓	✓	HIGH
(25)	✓	✓	✓	✓	✓	✓	-	-	✓	✓	✓	✓	✓	✓	✓	HIGH
(26)	✓	✓	✓	✓	✓	!	-	-	✓	✓	✓	✓	✓	✓	✓	HIGH

Reference:	Model:	Result:	Methodology:
Hangai et al. (2016)²¹	Humans	Increased AGEs: Skin autofuorescence positively correlated with age, sex, duration of diabetes, pulse wave velocity, systolic blood pressure, serum creatinine, and cardiac calcium score.	One hundred and twenty-two Japanese subjects with type 2 diabetes were pooled to study the association of tissue AGE, assessed by skin autofuorescence (AF), with coronary artery calcification. They underwent multi-slice computed tomography to estimate of total coronary artery calcium scores (CACS) and examination with a skin autofuorescence scanner.
Zhang et al. (2018)¹⁶	In vitro	Chronic inflammation: Hyperglycemia and AGES cause T cell-mediated inflammatory response and vascular endothelial dysfunction by upregulation of the ICOS/ICOSL protein	T-lymphocytes in peripheral human blood (CD3) and human endotelial cells from the umbilical vein (HUVECs) were treated with high glucose concentration and advanced glycation fnal products. ELISA and NOx production assays were used to detect the level of cytokines, cell feasibility and NOx production.
Mogale et al. (2019)²²	Humans	AGE increase (carboximetyllisine) linked to higher likelihood of developing endothelial dysfunction.	Case-control study with type-II diabetic African patients, concluded that carboxymetyl-lisine (AGE) predisposes to endothelial dysfunction, through the analysis of serum/plasma markers of endothelial dysfunction.
Bezold et al. (2019)²⁵	In vitro	Chronic inflammation: Glycation caused an increase in macrophage cell AGE formation, increase in the expression of proinflammatory 1β interleukines (IL-1β) and IL-8, and affected the IL-10 and TNF-α expression, causing an increase in inflammation.	THP-1 human monocytic cells were cultivated, differentiated into macrophages by PMA 100 ng/mL and β-ME 50 µM. The macrophages were exposed to metylglioxal (MGO) to investigate the effect of cell glycation.
Koska et al. (2018)¹⁷	Humans	Oxidative stress: Lower levels of MetSO (methionine sulfoxide) and higher levels of selected AGE are associated with increased incidence of cardiovascular disease (CVD) in type II diabetic patients.	Five specific AGEs and two oxidation products were measured at baseline in two intensive glucose-lowering studies: a subgroup from the Veterans Affairs Diabetes Trial (n=445) and a case-control subgroup from the Action to Control Cardiovascular Risk in Diabetes (n=271).
Di Pino et al. (2019)⁸	Humans	AGE-esAGER: Individuals with 1h postload hyperglycemia have low plasma esAGER levels, increased pulse wave velocity and intima-media thickness.	Cross-sectional study with two hundred and eighty-two participants without a previous diagnosis of diabetes. We measured sAGER, esAGER and other markers of inflammation in subjects with 1h postprandial hyperglycemia and examined the association with early markers of cardiovascular damage.
Xing et al. (2016)²⁶	Rodents	AGE-AGER: Diet rich in AGEs increased 24hour urine protein levels, serum nitrogen, urea, creatinine, C-reactive protein, low-density lipoprotein, tumor necrosis factor α (TNF-α) and interleukin-6 ( IL-6) were also elevated. There was histological deterioration of the pancreas, heart and kidneys and caused structural changes to endothelial cells, mesangial cells and podocytes in the renal cortex.	Streptozocin-induced diabetic rodents (STZ) were fed a diet rich in AGEs. The characteristics of diabetes, indicators of renal and cardiovascular functions and the anatomopathology of the pancreas, heart and kidneys were evaluated.
Di Pino et al. (2017)⁹	Humans	AGE-AGER and inflammation: Diet rich in AGE can lead to vascular dysfunction and inflammatory activation, contributing to the development of vascular complications in individuals with type 2 diabetes.	Arterial stiffness, carboxy-methyllysine, endogenous secretory receptor for AGEs (esRAGE), high-sensitivity C-reactive protein (hs-CRP), S100A12 and macronutrient intake were evaluated in 85 diabetic subjects.
Nikolov et al. (2020)¹¹	Humans	Anti-AGE antibodies sérum levels: Serum anti-AGE antibody levels in patients with type 2 diabetes mellitus and arterial hypertension were statistically significantly higher than in the control group, where determination of serum anti-AGE antibody levels can help clinicians make an early diagnosis and prognosis of the severity of late complications of diabetes in hypertensive patients.	ELISA was used to measure advanced glycation end-product antibody levels in serum from ninety-three patients with type 2 diabetes mellitus and high blood pressure.
Van Eupen et al. (2016)²⁴	Humanos	Skin autofluorescence correlated with aortic stiffening: The association between skin autofuorescence, pentosidine and femoral carotid pulse wave velocity were more pronounced in subjects with T2DM.	Eight hundred sixty-two participants (469 normal glucose; 140 altered glucose; 253 type 2 diabetes) were evaluated to determine the association of AGEs and arterial stiffening.

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MEDLINE / PubMed	“Glycation End Products, Advanced” AND “hypertension” “Glycation End Products, Advanced” AND “Diabetes Mellitus” “Glycation End Products, Advanced” AND “Diabetes Mellitus” AND “hypertension”
SciELO	Glycation End Products, Advanced AND hypertension Glycation End Products, Advanced AND Diabetes Mellitus Glycation End Products, Advanced AND Diabetes Mellitus AND hypertension
Cochrane Library	“Glycation End Products, Advanced” AND “hypertension” “Glycation End Products, Advanced” AND “Diabetes Mellitus” “Glycation End Products, Advanced” AND “Diabetes Mellitus” AND “hypertension”
Web of Science	Glycation End Products, Advanced AND hypertension Glycation End Products, Advanced AND Diabetes Mellitus Glycation End Products, Advanced AND Diabetes Mellitus AND hypertension