26 research outputs found
The hemoglobin glycation index is not an independent predictor of the risk of microvascular complications in the Diabetes Control and Complications Trial
W badaniu DCCT wykazano, że intensywne leczenie
mające na celu poprawę wyrównania glikemii znacząco
zmniejszyło ryzyko powikłań cukrzycowych
w porównaniu z konwencjonalnym leczeniem. Najistotniejszym
wyznacznikiem ryzyka był wywiad
dotyczący stężenia glukozy we krwi. Ostatnio McCarter
i wsp. (Diabetes Care 2004; 27: 1259-1264) przedstawili
analizę ogólnie dostępnych danych z DCCT
dotyczących indeksu glikacji (HGI), obliczonego jako
różnica między obserwowanym stężeniem HbA1c
a stężeniem przewidywanym na podstawie wartości
glikemii. W tej analizie wykazano, że wartość HGI
była znamiennym czynnikiem predykcyjnym progresji
retinopatii i nefropatii w DCCT, co autorzy uznali
za poparcie tezy, że biologiczna skłonność do glikacji, tak zwana biologiczna wariacja glikacji, jest kolejnym
mechanizmem, który odpowiada za ryzyko
powstawania powikłań. Jednak w niniejszej pracy
skrytykowano te analizy i wnioski, ponieważ
z zasad statystyki wynika, że HGI musi być dodatnio
skorelowany ze stężeniem HbA1c i dlatego może je
zastępować. Autorzy przedstawiają statystyczne
własności HGI w celu udokumentowania jego wysokiej
korelacji z HBA1c. Następnie powtarzają analizę
McCartera i wsp. z użyciem zarówno HGI, jak
i HbA1c. W analizie wykazano ostatecznie, że HGI nie
jest niezależnym czynnikiem ryzyka powikłań mikronaczyniowych
i że stężenie HbA1c całkowicie tłumaczy
wpływ indeksu glikacji na to ryzyko. Nie należy
używać HGI do oceny ryzyka powikłań ani uzależniać
od niego decyzji terapeutycznych.The Diabetes Control and Complications Trial (DCCT)
demonstrated that intensive therapy aimed at improved
glucose control markedly reduced the risk
of diabetes complications compared with conventional
therapy. The principal determinant of risk was
the history of glycemia. Recently, McCarter et al.
(Diabetes Care 2004; 27: 1259–1264) have presented
analyses of the publicly available DCCT data using their hemoglobin glycation index (HGI), which is
computed as the difference between the observed
HbA1c (A1C) and that predicted from the level of blood
glucose. In their analyses, the HGI level was
a significant predictor of progression of retinopathy
and nephropathy in the DCCT, which the authors
claimed to support the hypothesis that the biological
propensity for glycation, socalled biological variation
in glycation, is another mechanism that determines
risk of complications. However, we have
criticized these analyses and conclusions because,
from statistical principles, the glycation index must
be positively correlated with the A1C level and thus
may simply be a surrogate for A1C. Herein, we present
the statistical properties of the glycation index
to document its high correlation with A1C. We then
replicate the analyses of McCarter et al. using both
the HGI and the A1C together. Analyses show conclusively
that the glycation index is not an independent
risk factor for microvascular complications and
that the effect of the glycation index on risk is wholly
explained by the associated level of A1C. The HGI
should not be used to estimate risk of complications
or to guide therapy
Skin collagen advanced glycation endproducts (AGEs) and the long-term progression of sub-clinical cardiovascular disease in type 1 diabetes
BACKGROUND:
We recently reported strong associations between eight skin collagen AGEs and two solubility markers from skin biopsies obtained at DCCT study closeout and the long-term progression of microvascular disease in EDIC, despite adjustment for mean glycemia. Herein we investigated the hypothesis that some of these AGEs (fluorescence to be reported elsewhere) correlate with long-term subclinical cardiovascular disease (CVD) measurements, i.e. coronary artery calcium score (CAC) at EDIC year 7-9 (n = 187), change of carotid intima-media thickness (IMT) from EDIC year 1 to year 6 and 12 (n = 127), and cardiac MRI outcomes at EDIC year 15-16 (n = 142). METHODS:
Skin collagen AGE measurements obtained from stored specimens were related to clinical data from the DCCT/EDIC using Spearman correlations and multivariable logistic regression analyses. RESULTS:
Spearman correlations showed furosine (early glycation) was associated with future mean CAC (p \u3c 0.05) and CAC \u3e0 (p = 0.39), but not with CAC score100. Glucosepane and pentosidine crosslinks, methylglyoxal hydroimidazolones (MG-H1) and pepsin solubility (inversely) correlated with IMT change from year 1 to 6(all P \u3c 0.05). Left ventricular (LV) mass (cMRI) correlated with MG-H1, and inversely with pepsin solubility (both p \u3c 0.05), while the ratio LV mass/end diastolic volume correlated with furosine and MG-H1 (both p \u3c 0.05), and highly with CML (p \u3c 0.01). In multivariate analysis only furosine (p = 0.01) was associated with CAC. In contrast IMT was inversely associated with lower collagen pepsin solubility and positively with glucosepane, CONCLUSIONS:
In type 1 diabetes, multiple AGEs are associated with IMT progression in spite of adjustment for A1c implying a likely participatory role of glycation and AGE mediated crosslinking on matrix accumulation in coronary arteries. This may also apply to functional cardiac MRI outcomes, especially left ventricular mass. In contrast, early glycation measured by furosine, but not AGEs, was associated with CAC score, implying hyperglycemia as a risk factor in calcium deposition perhaps via processes independent of glycation. TRIAL REGISTRATION:
Registered at Clinical trial reg. nos. NCT00360815 and NCT00360893, http://www.clinicaltrials.gov
Haptoglobin Genotype and the Rate of Renal Function Decline in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study
Many patients with type 1 diabetes develop renal disease despite moderately good metabolic control, suggesting other risk factors may play a role. Recent evidence suggests that the haptoglobin (HP) 2-2 genotype, which codes for a protein with reduced antioxidant activity, may predict renal function decline in type 1 diabetes. We examined this hypothesis in 1,303 Caucasian participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. HP genotype was determined by polyacrylamide gel electrophoresis. Glomerular filtration rate was estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and albumin excretion based on timed urine samples. Participants were followed up for a mean of 22 years. HP genotype was significantly associated with the development of sustained estimated glomerular filtration rate (GFR) \u3c60 mL/min/1.73 m2and with end-stage renal disease (ESRD), with HP 2-2 having greater risk than HP 2-1 and 1-1. No association was seen with albuminuria. Although there was no treatment group interaction, the associations were only significant in the conventional treatment group, where events rates were much higher. We conclude that the HP genotype is significantly associated with the development of reduced GFR and ESRD in the DCCT/EDIC study
The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study
Objectives To investigate potential determinants of severe hypoglycaemia, including baseline characteristics, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the association of severe hypoglycaemia with levels of glycated haemoglobin (haemoglobin A1C) achieved during therapy
Plasma advanced glycation end products and the subsequent risk of microvascular complications in type 1 diabetes in the DCCT/EDIC
INTRODUCTION: To assess impact of glycemic control on plasma protein-bound advanced glycation end products (pAGEs) and their association with subsequent microvascular disease. RESEARCH DESIGN AND METHODS: Eleven pAGEs were measured by liquid chromatography-mass spectrometry in banked plasma from 466 participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study at three time points (TPs): DCCT year 4 (TP1) and year 8 (TP2) and EDIC year 5/6 (TP3). Correlation coefficients assessed cross-sectional associations, and Cox proportional hazards models assessed associations with subsequent risk of microvascular complications through EDIC year 24. RESULTS: Glucose-derived glycation products fructose-lysine (FL), glucosepane (GSPN) and carboxymethyl-lysine (CML) decreased with intensive glycemic control at both TP1 and TP2 (p\u3c0.0001) but were similar at TP3, and correlated with hemoglobin A1c (HbA1c). At TP1, the markers were associated with the subsequent risk of several microvascular outcomes. These associations did not remain significant after adjustment for HbA1c, except methionine sulfoxide (MetSOX), which remained associated with diabetic kidney disease. In unadjusted models using all 3 TPs, glucose-derived pAGEs were associated with subsequent risk of proliferative diabetic retinopathy (PDR, p\u3c0.003), clinically significant macular edema (CSME, p\u3c0.015) and confirmed clinical neuropathy (CCN, p\u3c0.018, except CML, not significant (NS)). Adjusted for age, sex, body mass index, diabetes duration and mean updated HbA1c, the associations remained significant for PDR (FL: p\u3c0.002, GSPN: p≤0.02, CML: p\u3c0.003, pentosidine: p\u3c0.02), CMSE (CML: p\u3c0.03), albuminuria (FL: p\u3c0.02, CML: p\u3c0.03) and CCN (FL: p\u3c0.005, GSPN : p\u3c0.003). CONCLUSIONS: pAGEs at TP1 are not superior to HbA1c for risk prediction, but glucose-derived pAGEs at three TPs and MetSOX remain robustly associated with progression of microvascular complications in type 1 diabetes even after adjustment for HbA1c and other factors
Skin advanced glycation end products glucosepane and methylglyoxal hydroimidazolone are independently associated with long-term microvascular complication progression of type 1 diabetes.
Six skin collagen advanced glycation end products (AGEs) originally measured near to the time of the Diabetes Control and Complications Trial (DCCT) closeout in 1993 may contribute to the “metabolic memory” phenomenon reported in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. We have now investigated whether the addition of four originally unavailable AGEs (i.e., glucosepane [GSPNE], hydroimidazolones of methylglyoxal [MG-H1] and glyoxal, and carboxyethyl-lysine) improves associations with incident retinopathy, nephropathy, and neuropathy events during 13–17 years after DCCT. The complete 10-AGE panel is associated with three-step Early Treatment of Diabetic Retinopathy Study scale worsening of retinopathy (P ≤ 0.002), independent of either mean DCCT or EDIC study A1C level. GSPNE and fructose-lysine (furosine [FUR]) correlate with retinopathy progression, independently of A1C level. The complete panel also correlates with microalbuminuria (P = 0.008) and FUR with nephropathy independently of A1C level (P ≤ 0.02). Neuropathy correlates with the complete panel despite adjustment for A1C level (P ≤ 0.005). MG-H1 and FUR are dominant, independent of A1C level (P < 0.0001), whereas A1C loses significance after adjustment for the AGEs. Overall, the added set of four AGEs enhances the association of the original panel with progression risk of retinopathy and neuropathy (P < 0.04) but not nephropathy, while GSPNE and MG-H1 emerge as the principal new risk factors. Skin AGEs are robust long-term markers of microvascular disease progression, emphasizing the importance of early and sustained implementation of intensive therapy
The association between skin collagen glucosepane and past progression of microvascular and neuropathic complications in type 1 diabetes
PURPOSE: We determined the association between novel and acid-labile skin collagen-linked advanced glycation endproducts (AGEs) and the progression of microvascular and neuropathic complications from baseline to near study closeout in the Diabetes Control and Complications Trial (DCCT). METHODS: From a skin biopsy obtained near the close of the DCCT, proteolytic collagen digests were analyzed by liquid chromatography/mass spectrometry (LC/MS/MS) for glucosepane (GSPNE), glyoxal and methylglyoxal hydroimidazolones (G-H1 and MG-H1) and the glycation product fructose-lysine(FL) using isotope dilution method. RESULTS: GSPNE and MG-H1 correlated with age and diabetes duration (p<0.02), while GSPNE and FL correlated with the history of glycemia expressed as mean A1c(p≤0.003). Age and duration-adjusted GSPNE and FL levels were lower in intensive (INT) vs. conventional (CONV) treatment subjects in the primary prevention DCCT cohort (p < 0.0001), and FL lower in INT in the secondary intervention cohort (p < 0.0001). GSPNE was associated with increased incidence of retinopathy progression (odds ratio (OR)/unit increase in GSPNE: 2.5 for 3 step progression on the ETDRS scale, p=0.003) and sustained ≥ 3 microaneurysms (MA) (OR=4.8, p<0.0001) from DCCT baseline up to the time of the biopsy, and prevalence of microalbuminuria or AER>40 mg/24 hr (OR=5.3, P<0.0001), and confirmed clinical neuropathy (OR=3.4, p=0.015) at the time of the biopsy. GSPNE adjusted for mean A1c remained significant for ≥ 3 MA (p=0.0252) and AER (p=0.0006). The strong association of complications with A1c was reduced or eliminated when adjusted for GSPNE. CONCLUSIONS: Glucosepane is a novel AGE marker of diabetic complications that is robustly associated with nephropathic, retinopathic and neuropathic outcomes despite adjustment for A1c, suggesting that it could be one mediator of these complications with possible diagnostic implications