Nonenzymatic glucosylation of serum proteins and hemoglobin: response to changes in blood glucose levels in diabetic rats

Day, J. F.; Ingebretsen, C. G.; Ingebretsen, W. R.; Baynes, J. W.; Thorpe, S. R.

doi:10.2337/diabetes.29.7.524

Cited by 47 publications

(21 citation statements)

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“…In our experiments, human endothelial cells cultured in high glucose concentrations maintained an unaltered dose-response for LDL uptake and degradation and the same inverse relationship between the state of confluency and LDL degradation exhibited by control cells. This was observed using glucose concentrations and duration of exposure reported to result in appreciable non-enzymatic glycosylation of various tissues [20,21] and proteins [22]. Thus, possible biochemical changes induced by protracted elevation of ambient glucose do not appear to affect the function of LDL receptors on endothelial cells nor to modify the characteristics of contact inhibition that mediate the decreased internalization of LDL in confluent monolayers of endothelial cells [11].…”

Section: Discussionmentioning

confidence: 90%

Interaction of human endothelial cells with elevated glucose concentrations and native and glycosylated low density lipoproteins

et al. 1984

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Summary.We have investigated whether and how the elevated glucose concentrations characteristic of diabetes may alter the interaction of endothelial cells with low-density lipoproteins (LDL). Protracted exposure of cultured human endothelial cells to 20 mmol/1 glucose failed to affect either the relationship between the degree of confluency of the monolayer and the extent of LDL degradation or the dose-responses for LDL uptake and degradation. In contrast, non-enzymatic glycosylation of LDL by pre-incubation of LDL with glucose markedly inhibited their uptake and degradation by endothelial cells. Thus, at protein concentration of 5 txg/ml, the amount of glycosylated 125I-LDL associated with cells was decreased fourfold compared with native 125I-LDL (47 + 3 versus 194_+ 10ng. mg cell protein -1-24 h -1, mean+ SEM), and degradation was decreased twenty-fold (135+4 versus 2873+ 115 ng-mg cell protein -~. 24 h-l). The degree of inhibition was proportional to the extent of glycosylation. At all concentrations studied, methylated LDL behaved similarly to glycosylated LDL. The decreased recognition of glycosylated LDL by the endothelial lining of small and large blood vessels may have an impact on tissue physiology and on the overall fate of the glycosylated molecules.Key words: Human endothelial cells, glucose, low density lipoproteins, contact inhibition, glycosylation, methylation.Since no unique pathogenic element has yet been implicated as the link between diabetes and the accelerated atherosclerosis affecting diabetic patients of all age groups [1, 2], it seems reasonable to investigate whether and how diabetes may alter the interactions between participants in the atherogenic process: low density lipoproteins (LDL), the source of most of the cholesterol present in vascular lesions [31 and cellular elements of the vessel wall. Previous investigations addressing this question have focussed on the interactions of LDL with fibroblasts or macrophages [4][5][6][7][8][9]. Yet it is the endothelium that is in contact with the blood and first participates in LDL metabolism. Endothelial cells take up and degrade LDL through both receptor-dependent and independent mechanisms [10][11][12]. We sought to determine whether protracted elevation of ambient glucose may alter these interactions. We have thus studied LDL receptor function in human endothelial cells cultured in elevated glucose concentrations and, conversely, the consequences of increased glycosylation of LDL, known to occur in diabetic patients [7,13], on its recognition and handling by endothelial cells. Materials and methods Cell culturesPrimary endothelial cell cultures from human umbilical veins were established according to the method of Jaffe et al. [14] with slight modifications. Briefly, umbilical cords were obtained from normal or Caesarean-section full-term deliveries and stored at 4~ in sterile phosphate-buffered saline (PBS, 0.15 mol/1, pH 7.4), with penicillin (500 units/ml) and streptomycin (500 I.tg/ml) until use 1-3 h later. Under sterile conditi...

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Section: Discussionmentioning

confidence: 90%

Interaction of human endothelial cells with elevated glucose concentrations and native and glycosylated low density lipoproteins

et al. 1984

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“…yoshiuchi et al also recently reported that ga in both type 1 and type 2 diabetic patients was correlated with the maximum blood glucose, but not mean glucose or mean amplitude of glucose excursion (mage), obtained from self monitoring of blood glucose in multiple regression analysis, and they discussed that ga could be a useful indicator for postprandial hyperglycemia [22]. Plasma albumin is directly glycated in the blood at four sites of lysine residues, and the glycating reaction is 10 times faster than that for hemoglobin [23], so, it may be advantageous for reflecting rapid changes of the glucose concentration compared with glycated hemoglobin. however, the exact reason why ga is related to daily excursion of glucose remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Relationship between Clinical Markers of Glycemia and Glucose Excursion Evaluated by Continuous Glucose Monitoring (CGM).

et al. 2010

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Abstract. in order to evaluate the relationship between clinical markers of glycemia and glucose excursion, we performed 48-hour continuous glucose monitoring (Cgm) in 43 diabetic patients. For the clinical markers, hba1c, glycoalbumin (ga), and 1,5-anhydroglucitol (1,5-ag) were measured, and for the parameters of glucose excursion from Cgm, average glucose (ag), standard deviation of glucose (SD), the area under the curve for glucose levels >180 mg/dL (auC>180), and the difference between the maximum and minimum glucose levels during 48 hours (ΔG48hr) were analyzed. all patients were treated without any changes of the dosages of oral anti-diabetic agents or insulin for at least the previous 6 months with coefficient of variation (CV) of HbA1c less than 4 %. in results, while hba1c did not show any single correlation with ag, SD, auC>180, or ΔG48hr, both GA and 1,5-AG were significantly related to all these parameters. Furthermore, GA significantly correlated to all CGM parameters, and SD significantly correlated to GA in multiple regression analyses. These results suggest that ga may be a different marker from hba1c for diabetic complications, because ga, but not hba1c, may reflect not only short-term average glucose but also fluctuation of glucose.Key words: glycoalbumin, glycated hemoglobin, 1,5-anhydroglucitol, Continuous glucose monitoringThe sTAble frAcTion of glycated hemoglobin (hba 1c ) is routinely measured in the majority of patients with diabetes around the world, since hba 1c reflects the mean glucose level over the preceding 3 months [1]. hba 1c is not only used to determine whether a patient's metabolic control has been maintained within the target range, but also to estimate the risk of chronic diabetic complications in each patient. Previous the large-scale prospective studies of diabetic patients have used hba 1c as a marker of glycemic control to evaluate the association of consistent hyperglycemia with the development or progression of chronic diabetic complications [2,3]. however, recent studies have indicated that postprandial hyperglycemia or fluctuations of the glucose level may be an independent risk factor for macrovascular complications in diabetic patients, which cannot be evaluated by measuring hba 1c alone [4]. Since hba 1c is a marker of the average level of glycemia, it does not reflect acute glucose fluctuations and is poorly correlated with glucose excursions [5]. Therefore, in order to assess the risk of diabetic complications, especially macrovascular complications, it may be necessary to evaluate not only the mean level of glycemic control, but also the extent of glucose excursions such as glucose fluctuations or postprandial elevation of glucose.To assess daily blood glucose excursions, portable devices for self-monitoring of blood glucose (Smbg) are now widely used by insulin-treated diabetic patients. although such devices are helpful, the number of measuring times is limited. Recently, a continuous subcutaneous glucose monitoring (Cgm) device was developed to evaluate the...

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“…The measurement of glycated albumin (GA) is a new method that allows mean short-term (approximately 2 weeks) glucose levels to be assessed, which reflects the shorter circulating half-life (17 days) of serum albumin (11). Albumin is glycosylated at approximately 10 times the rate of hemoglobin (12), suggesting that GA levels may change in response to subtle fluctuations in blood glucose levels.…”

Section: Introductionmentioning

confidence: 99%

Glycated Albumin to Glycated Hemoglobin Ratio is a Sensitive Indicator of Blood Glucose Variability in Patients with Fulminant Type 1 Diabetes

et al. 2012

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Background Since serum albumin is glycosylated more rapidly than hemoglobin, it is possible that the glycated albumin (GA) to HbA1c ratio (GA: HbA1c ratio) is potentially a more sensitive indicator of blood glucose excursion than HbA1c. The aim of the present study was to assess the clinical usefulness of GA: HbA1c ratio as a marker of daily glucose excursions in patients with type 1 diabetes according to the subtypes; acute onset type 1A, fulminant and slowly progressive type 1 diabetes. Methods Fifty-six outpatients with type 1 diabetes [16 fulminant, 20 acute-onset type 1A and 20 slowly progressive (SPIDDM)] were recruited consecutively. Each patient performed self-monitoring of blood glucose at seven points a day. The associations among the daily profile of glucose and GA, HbA1c, GA: HbA1c ratio were examined across and within the subtypes of type 1 diabetes. Results GA and GA: HbA1c ratio were each independently correlated with mean amplitude of glucose excursion (MAGE) in patients with type 1 diabetes (F=27.53, p<0.001 and F=13.02, p<0.001, respectively). GA: HbA1c ratio was significantly higher in fulminant type 1 diabetic patients than in SPIDDM patients (3.5 ± 0.2 vs. 3.2 ± 0.5, p=0.015) and it was independently associated with MAGE within fulminant type 1 diabetes (F=21.2, p<0.001). Conclusion In conclusion, the present study demonstrated that GA: HbA1c ratio could be a better marker for glycemic variability than HbA1c in type 1 diabetes, especially in fulminant type 1 diabetes.

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Nonenzymatic glucosylation of serum proteins and hemoglobin: response to changes in blood glucose levels in diabetic rats

Cited by 47 publications

References 0 publications

Interaction of human endothelial cells with elevated glucose concentrations and native and glycosylated low density lipoproteins

Interaction of human endothelial cells with elevated glucose concentrations and native and glycosylated low density lipoproteins

Relationship between Clinical Markers of Glycemia and Glucose Excursion Evaluated by Continuous Glucose Monitoring (CGM).

Glycated Albumin to Glycated Hemoglobin Ratio is a Sensitive Indicator of Blood Glucose Variability in Patients with Fulminant Type 1 Diabetes

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