Glucose fluctuations and activation of oxidative stress in type 1 diabetes patients

Department of Internal Medicine, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Diabetologia (Impact Factor: 6.67). 02/2008; 51(1):183-90. DOI: 10.1007/s00125-007-0842-6
Source: PubMed


Glucose fluctuations may help predict diabetic complications. We evaluated the relation between glucose variability and oxidative stress in patients with type 1 diabetes.
Continuous glucose monitors were inserted subcutaneously in 25 patients. During the measurement, patients collected two 24 h urine samples, while 24 healthy controls collected one 24 h urine sample for determination of 15(S)-8-iso-prostaglandin F2alpha(PGF2alpha) using HPLC tandem mass spectrometry. Mean of the daily differences (MODD), mean amplitude of glycaemic excursions (MAGE) and continuous overlapping net glycaemic action calculated with n hour time-intervals (CONGA-n) were calculated as markers for glucose variability and correlation with 15(S)-8-iso-PGF2alpha excretion was calculated.
Median [interquartile range (IQR)] urinary 15(S)-8-iso-PGF2alpha was higher in patients than healthy controls: 161 (140-217) pg/mg creatinine vs 118 (101-146) pg/mg creatinine (p = 0.001). Median (IQR) MODD was 3.7 (3.2-5.0) mmol/l, MAGE 7.6 (6.4-9.0) mmol/l and CONGA-1 2.3 (2.1-2.8) mmol/l. Univariate regression did not reveal an association for MODD (r2 = 0.01), MAGE (0.08) or CONGA-1 (0.07) with 15(S)-8-iso-PGF2alpha excretion, nor was an association revealed when corrected for HbA1c, age, sex and smoking. Spearman correlation coefficients (r) between 15(S)-8-iso-PGF2alpha excretion and MODD, MAGE and CONGA-1 were non-significant: -0.112, -0.381 and -0.177.
We report that there is no relationship between glucose variability and urinary 15(S)-8-iso-PGF2alpha. We also confirm that patients with type 1 diabetes have higher levels of urinary 15(S)-8-iso-PGF2alpha than healthy controls, suggesting that in addition to glucose variability, other factors favouring oxidative stress may exist. We did not see a relation between high glucose variability and elevated levels of oxidative stress in patients with type 1 diabetes.

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    • "This correlation was stronger than that observed with PPG (r = 0.55, p = 0.09), suggesting that GV amplifies the effects of PPG spikes on oxidative stress. These results were consistent with another204,208,230). In a group of T1DM patients, higher levels of urinary 15(S)-8-isoPGF 2α were observed compared to healthy controls, but GV (MAGE, CONGA, and MODD) was not associated with oxidative stress levels (230). "
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    ABSTRACT: The primary therapeutic target for diabetes management is the achievement of good glycemic control, of which glycated hemoglobin (HbA1c) remains the standard clinical marker. However, glycemic variability (GV; the amplitude, frequency, and duration of glycemic fluctuations around mean blood glucose) is an emerging target for blood glucose control. A growing body of evidence supports GV as an independent risk factor for diabetes complications. Several techniques have been developed to assess and quantify intraday and interday GV. Additionally, GV can be influenced by several nutritional factors, including carbohydrate quality, quantity; and distribution; protein intake; and fiber intake. These factors have important implications for clinical nutrition practice and for optimizing blood glucose control for diabetes management. This review discusses the available evidence for GV as a marker of glycemic control and risk factor for diabetes complications. GV quantification techniques and the influence of nutritional considerations for diabetes management are also discussed. Expected final online publication date for the Annual Review of Nutrition Volume 35 is July 17, 2015. Please see for revised estimates.
    Full-text · Article · May 2015 · Annual Review of Nutrition
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    • "In contrast, in T2D patients a positive correlation between blood glucose variability and reactive oxygen species (ROS) production has been evidenced, and ROS remain major determinants of vascular complications [8]. However, this correlation has yet to be confirmed in T1D [9]. "
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    ABSTRACT: Aims HbA1c only partially predicts vascular risk in patients with type 1 diabetes (T1D), and a role for blood glucose variability (BGV) is a matter of debate. For this reason, this study investigated the impact of an educational programme of flexible insulin therapy (FIT) on BGV and oxidative stress. Methods Tests were conducted on 30 adult T1D patients in a prospective, single-centre trial at baseline (M0), and at 3 and 6 months (M3 and M6, respectively) of the FIT programme to determine BGV, as reflected by mean amplitude of glycaemic excursions (MAGE), low blood glucose index (LBGI), lability index (LI), average daily risk range (ADRR), glycaemic lability (scored by two diabetologists), urinary leukotriene E4 (LTE4), 11-dehydro-thromboxane B2 (TXB2) and 8-iso-prostaglandin F2α (PGF2). Results HbA1c (7.7 ± 0.9%), ADRR, MAGE, LBGI and LI did not change from M0 to M3 and M6, although ADRR and LBGI significantly improved at M3 and M6 in patients with the highest baseline indices (≥ 40 and ≥ 5, respectively). TXB2 declined at M6 (832 ± 625 vs. 633 ± 972 pg/mg; P = 0.048), whereas LTE4 and PGF2 remained stable. ADRR showed the strongest correlation with glycaemic lability scores at all visits (r ≥ 0.84, P < 0.0001). Conclusion A FIT educational programme improved BGV only in patients with the highest baseline variability, and led to no changes in HbA1c, while ADRR closely correlated with glycaemic lability score. Our data do not support a relationship between BGV and oxidative stress in T1D patients, although the impact of variability on TXB2 deserves further investigation ( NCT00973492).
    Full-text · Article · Sep 2014 · Diabetes & Metabolism
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    • "It is also not quite clear how increased glycemic variability could induce diabetic complications. Oxidative stress was suggested as a possible common mechanism of the endothelial impairment induced by increased glycemic variability [12] [13] [14] [15] [16]. Endothelial dysfunction, a first event in the process of vascular impairment, can be induced by increased oxidative stress. "
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    ABSTRACT: The aim of this study was to evaluate the effect of acute glycemia increase on microvasculature and endothelium in Type 1 diabetes during hyperinsulinemic clamp. Sixteen patients (51 ± 7 yrs) without complications were examined during iso- and hyperglycemic clamp (glucose increase 5.5 mmol·L(-1)). Insulin, lipid parameters, cell adhesion molecules and fibrinogen were analyzed. Microvascular reactivity (MVR) was measured by laser Doppler flowmetry. Maximum perfusion and the velocity of perfusion increase during PORH were higher in hyperglycemia compared to baseline (47 ± 16 versus 40 ± 16 PU, P < 0.01, and 10.4 ± 16.5 versus 2.6 ± 1.5 PU·s(-1), P < 0.05, resp.). Time to the maximum perfusion during TH was shorter and velocity of perfusion increase during TH higher at hyperglycemia compared to isoglycemic phase (69 ± 15 versus 77 ± 16 s, P < 0.05, and 1.4 ± 0.8 versus 1.2 ± 0.7 PU·s(-1), P < 0.05, resp.). An inverse relationship was found between insulinemia and the time to maximum perfusion during PORH (r = -0.70, P = 0.007). Acute glycemia did not impair microvascular reactivity in this clamp study in Type 1 diabetic patients. Our results suggest that insulin may play a significant role in the regulation of microvascular perfusion in patients with Type 1 diabetes through its vasodilation effect and can counteract the effect of acute glucose fluctuations.
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