Fasting and post-oral-glucose-load levels of methylglyoxal are associated with microvascular, but not macrovascular, disease in individuals with and without (pre)diabetes: The Maastricht Study.

Reactive dicarbonyl compounds, such as methylglyoxal (MGO), rise during an oral glucose tolerance test (OGTT), particularly in (pre)diabetes. Fasting MGO levels are associated with chronic kidney disease (CKD) and cardiovascular disease (CVD) in patients with poorly controlled type 2 diabetes mellitus (T2DM). Yet, whether fasting or post-OGTT plasma MGO levels are associated with vascular disease in people with (pre)diabetes is unknown. Subjects with normal glucose metabolism (n=1796; age: 57.9±8.2 years; 43.3% men), prediabetes (n=478; age: 61.6±7.6 years; 54.0% men) and T2DM (n=669; age: 63.0±7.5 years; 67.0% men) from the Maastricht Study underwent OGTTs. Plasma MGO levels were measured at baseline and 2h after OGTT by mass spectrometry. Prior CVD was established via questionnaire. CKD was reflected by estimated glomerular filtration rate (eGFR) and albuminuria; retinopathy was assessed using retinal photographs. Data were analyzed using logistic regression adjusted for gender, age, smoking, systolic blood pressure, total-to-HDL cholesterol ratio, triglycerides, HbA1c, BMI and medication use. Odd ratios (ORs) were expressed per standard deviation of LN-transformed MGO. Fasting and post-OGTT MGO levels were associated with higher ORs for albuminuria ≥30mg/24h [fasting: 1.12 (95% CI: 0.97-1.29); post-OGTT: 1.19 (1.01-1.41)], eGFR<60mL/min/1.73 m2 [fasting: 1.58 (95% CI: 1.38-1.82), post-OGTT: 1.57 (1.34-1.83)] and retinopathy [fasting: 1.59 (95% CI: 1.01-2.53), post-OGTT: 1.38 (0.77-2.48)]. No associations with prior CVD were found. Fasting and post-OGTT MGO levels were associated with microvascular disease, but not prior CVD. Thus, therapeutic strategies directed at lowering MGO levels may prevent microvascular disease.

Hanssen NMJ ，Scheijen JLJM ，Houben AJHM ，van de Waarenburg M ，Berendschot TTJM ，Webers CAB ，Reesink KD ，van Greevenbroek MMJ ，van der Kallen C ，Schaper NC ，Schram MT ，Henry RMA ，Stehouwer CDA ，Schalkwijk CG ... -  《-》

Higher Plasma Methylglyoxal Levels Are Associated With Incident Cardiovascular Disease and Mortality in Individuals With Type 2 Diabetes.

Methylglyoxal (MGO) is a reactive dicarbonyl compound and a potential key player in diabetic cardiovascular disease (CVD). Whether plasma MGO levels are associated with CVD in type 2 diabetes is unknown. We included 1,003 individuals (mean ± SD age 59.1 ± 10.5 years, 69.3% male, and 61.6% with prior CVD) with type 2 diabetes from the Second Manifestations of ARTerial disease cohort (SMART). We measured plasma MGO levels and two other dicarbonyls (glyoxal [GO] and 3-deoxyglucosone [3-DG]) at baseline with mass spectrometry. Median follow-up of CVD events was 8.6 years. Data were analyzed with Cox regression with adjustment for sex, age, smoking, systolic blood pressure, total cholesterol, HbA1c, BMI, prior CVD, and medication use. Hazard ratios are expressed per SD Ln-transformed dicarbonyl. A total of 287 individuals suffered from at least one CVD event (n = 194 fatal events, n = 146 myocardial infarctions, and n = 72 strokes); 346 individuals died, and 60 individuals underwent an amputation. Higher MGO levels were associated with total (hazard ratio 1.26 [95% CI 1.11-1.42]) and fatal (1.49 [1.30-1.71]) CVD and with all-cause mortality (1.25 [1.11-1.40]), myocardial infarction (1.22 [1.02-1.45]), and amputations (1.36 [1.05-1.76]). MGO levels were not apparently associated with stroke (1.03 [0.79-1.35]). Higher GO levels were significantly associated with fatal CVD (1.17 [1.00-1.37]) but not with other outcomes. 3-DG was not significantly associated with any of the outcomes. Plasma MGO and GO levels are associated with cardiovascular mortality in individuals with type 2 diabetes. Influencing dicaronyl levels may therefore be a target to reduce CVD in type 2 diabetes.

Hanssen NMJ ，Westerink J ，Scheijen JLJM ，van der Graaf Y ，Stehouwer CDA ，Schalkwijk CG ，SMART Study Group ... -  《-》

Post-Glucose Load Plasma α-Dicarbonyl Concentrations Are Increased in Individuals With Impaired Glucose Metabolism and Type 2 Diabetes: The CODAM Study.

There is increasing evidence that postprandial glucose excursions play an important role in the development of vascular complications. The underlying mechanism is unknown, but glucose-derived formation of reactive α-dicarbonyl compounds may explain why acute hyperglycemia leads to increased risk for diabetes complications. In the current study, we investigated whether α-dicarbonyls are increased after a glucose load in individuals without or with impaired glucose metabolism (IGM) and type 2 diabetes. Cross-sectional, linear analyses were performed in the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM [n = 574, 61% men, 60 years old]) study. Individuals with normal glucose metabolism (n = 279), IGM (n = 120), and type 2 diabetes (n = 92) who had complete data on an oral glucose tolerance test (OGTT) and were not on insulin treatment were included in the study population. Plasma α-dicarbonyl (methylglyoxal [MGO], glyoxal [GO], and 3-deoxyglucosone [3-DG]) levels were measured in the fasting state and in samples of the OGTT by ultra-performance liquid chromatography-tandem mass spectrometry. The presence of both IGM and type 2 diabetes was significantly associated with higher α-dicarbonyl incremental areas under the curve (iAUCs), as calculated from the OGTT (for IGM, MGO β = 0.190 [95% CI 0.106-0.274], GO β = 0.287 [95% CI 0.172-0.401], and 3-DG β = 0.285 [95% CI 0.221-0.349]; for type 2 diabetes, MGO β = 0.293 [95% CI 0.180-0.405], GO β = 0.536 [95% CI 0.382-0.689], and 3-DG β = 0.542 [95% CI 0.456-0.628]). Adjustment for glucose iAUC attenuated these associations. iAUCs of the α-dicarbonyls correlated highly with glucose iAUC but not with fasting glucose levels or HbA1c. The increased levels of α-dicarbonyls during an OGTT in individuals with IGM and type 2 diabetes underline the potential importance of α-dicarbonyl stress as a candidate to explain the increased risk of diabetes complications in individuals with postprandial hyperglycemia.

Maessen DE ，Hanssen NM ，Scheijen JL ，van der Kallen CJ ，van Greevenbroek MM ，Stehouwer CD ，Schalkwijk CG ... -  《-》

Prediabetes and Type 2 Diabetes Are Associated With Generalized Microvascular Dysfunction: The Maastricht Study.

Type 2 diabetes (T2DM) is associated with an increased risk of cardiovascular disease. This can be partly explained by large-artery dysfunction, which already occurs in prediabetes ("ticking clock hypothesis"). Whether a similar phenomenon also applies to microvascular dysfunction is not known. We therefore tested the hypothesis that microvascular dysfunction is already present in prediabetes and is more severe in T2DM. To do so, we investigated the associations of prediabetes, T2DM, and measures of hyperglycemia with microvascular function measured as flicker light-induced retinal arteriolar dilation and heat-induced skin hyperemia. In the Maastricht Study, a T2DM-enriched population-based cohort study (n=2213, 51% men, aged [mean±standard deviation] 59.7±8.2 years), we determined flicker light-induced retinal arteriolar %-dilation (Dynamic Vessel Analyzer), heat-induced skin %-hyperemia (laser-Doppler flowmetry), and glucose metabolism status (oral glucose tolerance test; normal glucose metabolism [n=1269], prediabetes [n=335], or T2DM [n=609]). Differences were assessed with multivariable regression analyses adjusted for age, sex, body mass index, smoking, physical activity, systolic blood pressure, lipid profile, retinopathy, estimated glomerular filtration rate, (micro)albuminuria, the use of lipid-modifying and blood pressure-lowering medication, and prior cardiovascular disease. Retinal arteriolar %-dilation was (mean±standard deviation) 3.4±2.8 in normal glucose metabolism, 3.0±2.7 in prediabetes, and 2.3±2.6 in T2DM. Adjusted analyses showed a lower arteriolar %-dilation in prediabetes (B=-0.20, 95% confidence interval -0.56 to 0.15) with further deterioration in T2DM (B=-0.61 [-0.97 to -0.25]) versus normal glucose metabolism (P for trend=0.001). Skin %-hyperemia was (mean±standard deviation) 1235±810 in normal glucose metabolism, 1109±748 in prediabetes, and 937±683 in T2DM. Adjusted analyses showed a lower %-hyperemia in prediabetes (B=-46 [-163 to 72]) with further deterioration in T2DM (B=-184 [-297 to -71]) versus normal glucose metabolism (P for trend=0.001). In addition, higher glycohemoglobin A1c and fasting plasma glucose were associated with lower retinal arteriolar %-dilation and skin %-hyperemia in fully adjusted models (for glycohemoglobin A1c, standardized B=-0.10 [-0.15 to -0.05], P<0.001 and standardized B=-0.13 [-0.19 to -0.07], P<0.001, respectively; for fasting plasma glucose, standardized B=-0.09 [-0.15 to -0.04], P<0.001 and standardized B=-0.10 [-0.15 to -0.04], P=0.002, respectively). Prediabetes, T2DM, and measures of hyperglycemia are independently associated with impaired microvascular function in the retina and skin. These findings support the concept that microvascular dysfunction precedes and thus may contribute to T2DM-associated cardiovascular disease and other complications, which may in part have a microvascular origin such as impaired cognition and heart failure.

Sörensen BM ，Houben AJ ，Berendschot TT ，Schouten JS ，Kroon AA ，van der Kallen CJ ，Henry RM ，Koster A ，Sep SJ ，Dagnelie PC ，Schaper NC ，Schram MT ，Stehouwer CD ... -  《-》

Higher Plasma Methylglyoxal Levels Are Associated With Incident Cardiovascular Disease in Individuals With Type 1 Diabetes: A 12-Year Follow-up Study.

Methylglyoxal (MGO), a major precursor for advanced glycation end products, is increased in diabetes. In diabetic rodents, inhibition of MGO prevents cardiovascular disease (CVD). Whether plasma MGO levels are associated with incident CVD in people with type 1 diabetes is unknown. We included 159 individuals with persistent normoalbuminuria and 162 individuals with diabetic nephropathy (DN) from the outpatient clinic at Steno Diabetes Center. We measured MGO at baseline and recorded fatal and nonfatal CVD over a median follow-up of 12.3 years (interquartile range 7.6-12.5 years). Data were analyzed by Cox regression, with adjustment for sex, age, HbA1c, DN, diabetes duration, smoking, systolic blood pressure, antihypertensive medication, and BMI. During follow-up, 73 individuals suffered at least one CVD event (36 fatal and 53 nonfatal). Higher MGO levels were associated with total, fatal, and nonfatal incident CVD (hazard ratios [HRs] 1.47 [95% CI 1.13-1.91], 1.42 [1.01-1.99], and 1.46 [1.08-1.98], respectively). We observed a similar trend for total mortality (HR 1.24 [0.99-1.56]). This study shows for the first time in our knowledge that plasma MGO levels are associated with cardiovascular events in individuals with type 1 diabetes. MGO may explain, at least in part, the increased risk for CVD in type 1 diabetes.

Hanssen NMJ ，Scheijen JLJM ，Jorsal A ，Parving HH ，Tarnow L ，Rossing P ，Stehouwer CDA ，Schalkwijk CG ... -  《-》