Role of Hyperglycemia in Nitrotyrosine Postprandial Generation

Ceriello, Antonio; Quagliaro, Lisa; Catone, Barbara; Pascon, Roberta; Piazzola, Marta; Bais, Bruno; Marra, Giampiero; Tonutti, Laura; Taboga, C.; Motz, Enrico

doi:10.2337/diacare.25.8.1439

Cited by 234 publications

(160 citation statements)

References 39 publications

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“…Our results, within the context of the data obtained from Ceriello et al and Scognamiglio et al, indicate a significantly reduced oxidative stress and improved postprandial microvascular blood flow following injection of rapid-acting insulin analogs (such as insulin glulisine) compared with regular human insulin (4,12).…”

Section: Discussionsupporting

confidence: 52%

“…There are considerable data indicating that postprandial glucose levels may be an independent risk factor for cardiovascular disease and are more predictive than fasting hyperglycemia (10,11). It has been shown that acute hyperglycemia affects endothelial function and impairs microvascular blood flow (4), which could be attributed to an increase in nitrotyrosine, leading to the generation of superoxide anions and an increase in oxidative stress (12). In addition, hyperglycemia decreases the bioavailability of nitric oxide (NO) and reduces the ability of the vasculature to respond to NO, which leads to vasoconstriction and an increase in atherogenic potency (13).…”

Section: Discussionmentioning

confidence: 99%

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Effect of Insulin Glulisine on Microvascular Blood Flow and Endothelial Function in the Postprandial State

et al. 2008

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OBJECTIVE -To investigate the effect of insulin glulisine on postprandial microvascular blood flow in type 2 diabetes.RESEARCH DESIGN AND METHODS -A total of 15 patients with type 2 diabetes received insulin glulisine or human insulin before a liquid meal test. Thereafter, skin microvascular blood flow was measured by laser Doppler fluxmetry and blood samples were taken for measurement of plasma levels of glucose, insulin, intact proinsulin, asymmetric dimethylarginine, nitrotyrosine, interleukin-18, matrix metalloproteinase-9, oxidized LDL, and free fatty acids.RESULTS -Insulin glulisine injections resulted in higher postprandial insulin levels (means Ϯ SEM area under the curve [AUC] 0 -120 51.0 Ϯ 6.8 vs. 38.2 Ϯ 5.4 mU/l; P ϭ 0.004), while plasma glucose (AUC 0 -240 158 Ϯ 9 vs. 180 Ϯ 9 mg/dl; P Ͻ 0.05) and intact proinsulin (AUC 0 -240 26.2 Ϯ 3.5 vs. 31.2 Ϯ 4.3 pmol/l; P ϭ 0.002) were lower. Microvascular blood flow increased after insulin glulisine injection (27.9 Ϯ 3.1 to 51.7 Ϯ 9.9 arbitrary units [AU]; P Ͻ 0.05), while only a minor increase was found during human insulin (27.9 Ϯ 3.1 to 34.4 Ϯ 7.8 AU; not significant). Asymmetric dimethylarginine and nitrotyrosine levels were reduced after insulin glulisine (P Ͻ 0.05).CONCLUSIONS -Insulin glulisine is superior to human insulin in restoring postprandial metabolic and microvascular physiology. Diabetes Care 31:1021-1025, 2008S everal epidemiological studies have demonstrated an association between glucose spikes and the development of vascular complications in patients with type 2 diabetes. Postprandial generation of oxidative stress and impaired endothelial function are major contributors in the development of early vascular damage and atherosclerosis. Recent studies have shown that microvascular blood flow increases after a meal in gut, skin, heart, and adipose tissues (1-5). Postprandial regulation of microvascular blood flow is a complex process inversely affected by postprandial glucose and insulin excursions (2,6,7).Diminished prandial insulin secretion and an increase in postprandial plasma glucose excursions with increased postprandial oxidative stress and impaired endothelial function are early features of type 2 diabetes. Insulin glulisine attenuates the postprandial increase in plasma levels of intact proinsulin compared with regular human insulin, which may lead to a corresponding reduction in cardiovascular risk and ␤-cell protection. Therefore, the pharmacokinetics of prandial insulin formulations may be important not only in controlling postprandial glucose excursions, but also in the maintenance of normal endothelial function and microvascular blood flow. The aim of this study was to compare the effect of insulin glulisine with regular human insulin in terms of postprandial microvascular blood flow and several laboratory markers of endothelial function and oxidative stress in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS -This investigation wasa single-center, open-label, randomized, two-way crossover study of patients with type 2 ...

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Effect of Insulin Glulisine on Microvascular Blood Flow and Endothelial Function in the Postprandial State

et al. 2008

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“…1), compared with exposure to continuous normal glucose or high glucose. The markers chosen were: (1) the basement membrane protein fibronectin, shown to be overexpressed in the vessels of diabetic patients [23]; (2) the signalling kinase PKC-β, stimulated by high glucose through a cofactor, diacylglycerol [24,25]; (3) the mitochondrial pro-apoptotic protein BCL-2 family member Bax, indicative of mitochondrial stress [26] and associated with vascular diabetic complications [27]; (4) the DNA damage protein PAR, a product of PARP, shown to be a critical factor in the development of vascular diabetic complications [7]; (5) p47phox, an inducible subunit of the enzyme NAD(P)H oxidase, shown to be a source of ROS in the endothelium of diabetic patients [28]; and (6) the protein adduct 3-NY, a marker of oxidative stress and vascular diabetic complications [29][30][31][32]. As has been shown previously, chronic high glucose resulted in significantly increased levels of: fibronectin [10]; phospho-(activated) PKC-α/βII [25]; p47phox [33]; and 3-NY [31], while the increase in Bax was not statistically significant [27] (Fig.…”

Section: Resultsmentioning

confidence: 99%

Reactive oxygen species mediate a cellular ‘memory’ of high glucose stress signalling

et al. 2007

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Aims/hypothesis A long-term 'memory' of hyperglycaemic stress, even when glycaemia is normalised, has been previously reported in endothelial cells. In this report we sought to duplicate and extend this finding. Materials and methods HUVECs and ARPE-19 retinal cells were incubated in 5 or in 30 mmol/l glucose for 3 weeks or subjected to 1 week of normal glucose after being exposed for 2 weeks to continuous high glucose. HUVECs were also treated in this last condition with several antioxidants. Similarly, four groups of rats were studied for 3 weeks: (1) normal rats; (2) diabetic rats not treated with insulin; (3) diabetic rats treated with insulin during the last week; and (4) diabetic rats treated with insulin plus α-lipoic acid in the last week. Results In human endothelial cells and ARPE-19 retinal cells in culture, as well as in the retina of diabetic rats, levels of the following markers of high glucose stress remained induced for 1 week after levels of glucose had normalised: protein kinase C-β, NAD(P)H oxidase subunit p47phox, BCL-2-associated X protein, 3-nitrotyrosine, fibronectin, poly(ADPribose) Blockade of reactive species using different approaches, i.e. the mitochondrial antioxidant α-lipoic acid, overexpression of uncoupling protein 2, oxypurinol, apocynin and the poly(ADP-ribose) polymerase inhibitor PJ34, interrupted the induction both of high glucose stress markers and of the fluorescent reactive oxygen species (ROS) probe CM-H 2 DCFDA in human endothelial cells. Similar results were obtained in the retina of diabetic rats with α-lipoic acid added to the last week of normalised glucose. Conclusions/interpretation These results provide proofof-principle of a ROS-mediated cellular persistence of vascular stress after glucose normalisation.

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“…However, the possibility that postprandial hyperglycaemia increases oxidative stress and inflammation in healthy subjects has previously been reported [12,13]. Furthermore, evidence showing that modulation of postprandial hyperglycaemia by diet or an insulin analogue in type 2 diabetes [25][26][27], and by pramlintide [28] in type 1 diabetes, is accompanied by a significant decrease of oxidative stress, while nuclear factor kappa B activation is decreased when controlling postprandial hyperglycaemia by acarbose [24], convincingly suggests that the effect of S21403 on postprandial oxidative stress and inflammation is related to its ability to reduce postprandial hyperglycaemia.…”

Section: Discussionmentioning

confidence: 98%

Effects of S21403 (mitiglinide) on postprandial generation of oxidative stress and inflammation in type 2 diabetic patients

Assaloni

Ros

Quagliaro³

et al. 2005

Diabetologia

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Aim/hypothesis: Evidence suggests that postprandial hyperglycaemia may be a cardiovascular risk factor in diabetes. Oxidative stress and inflammation are involved in the pathogenesis of diabetic complications and previous studies have shown increased oxidative stress and inflammation in the postprandial phase in diabetic patients. The aim of the present study was to evaluate whether controlling postprandial hyperglycaemia with S21403 (mitiglinide) is accompanied by a reduced generation of oxidative stress and inflammation. Subjects and methods: Forty type 2 diabetic patients participated in the study. Two different breakfast-tests were performed in each patient, with placebo or S21403. Plasma nitrotyrosine, plasma malondialdehyde (MDA), oxidised LDL (oxLDL), plasma total radical-trapping antioxidant parameter (TRAP), IL-6, IL-18, TNF-α, plasma glucose and insulin were measured. Results: After the administration of S21403, 40 mg, a rapid stimulation of insulin secretion was observed, accompanied by a reduction of postprandial hyperglycaemia. With S21403, a significant decrease of either nitrotyrosine, MDA and oxLDL levels, and a preservation of plasma TRAP compared with placebo was found. Significant decreases of IL-6, IL-18 and TNF-α were also observed with S21403 compared with placebo. Conclusions/interpretation: This study shows that controlling postprandial hyperglycaemia with S21403 significantly improves the cluster of oxidative stress and inflammation markers that are increased in the postprandial state in diabetic patients.

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Role of Hyperglycemia in Nitrotyrosine Postprandial Generation

Cited by 234 publications

References 39 publications

Effect of Insulin Glulisine on Microvascular Blood Flow and Endothelial Function in the Postprandial State

Effect of Insulin Glulisine on Microvascular Blood Flow and Endothelial Function in the Postprandial State

Reactive oxygen species mediate a cellular ‘memory’ of high glucose stress signalling

Effects of S21403 (mitiglinide) on postprandial generation of oxidative stress and inflammation in type 2 diabetic patients

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