Plasma levels of matrix metalloproteinase-2, -3, -10, and tissue inhibitor of metalloproteinase-1 are associated with vascular complications in patients with type 1 diabetes: The EURODIAB Prospective Complications Study

Impaired regulation of extracellular matrix remodeling by matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) may contribute to vascular complications in patients with type 1 diabetes. We investigated associations between plasma MMP-1, -2, -3, -9, -10 and TIMP-1, and cardiovascular disease (CVD) or microvascular complications in type 1 diabetic patients. We also evaluated to which extent these associations could be explained by low-grade inflammation (LGI) or endothelial dysfunction (ED). Methods: 493 type 1 diabetes patients (39.5 ± 9.9 years old, 51% men) from the EURODIAB Prospective Complications Study were included. Linear regression analysis was applied to investigate differences in plasma levels of MMP-1, -2, -3, -9, -10, and TIMP-1 between patients with and without CVD, albuminuria or retinopathy. All analyses were adjusted for age, sex, duration of diabetes, Hba1c and additionally for other cardiovascular risk factors including LGI and ED. Results: Patients with CVD (n = 118) showed significantly higher levels of TIMP-1 [β = 0.32 SD (95%CI: 0.12; 0.52)], but not of MMPs, than patients without CVD (n = 375). Higher plasma levels of MMP-2, MMP-3, MMP-10 and TIMP-1 were associated with higher levels of albuminuria (p-trends were 0.028, 0.004, 0.005 and 0.001, respectively). Severity of retinopathy was significantly associated with higher levels of MMP-2 (p-trend = 0.017). These associations remained significant after further adjustment for markers of LGI and ED. Conclusions: These data support the hypothesis that impaired regulation of matrix remodeling by actions of MMP-2, -3 and-10 and TIMP-1 contributes to the pathogenesis of vascular complications in type 1 diabetes

Relationship Between Risk Factors and Mortality in Type 1 Diabetic Patients in Europe: The EURODIAB Prospective Complications Study (PCS)

OBJECTIVE—The purpose of this study was to examine risk factors for mortality in patients with type 1 diabetes

Evidence that even "normal" albuminuria may denote incipient GFR reduction in patients with type 2 diabetes mellitus

Aims: In patients with diabetes and microalbuminuria, small changes of GFR could have been missed, due to the lack of sensitive methodology for GFR determination in clinical practice (creatinine based calculations). Therefore we explored the relation of the degree of albumin excretion with Cystatin C, which has been recently proved to be a better marker of GFR, compared to serum creatinine. Methods: We studied 179 patients with type 2 diabetes, in whom renal function and microalbuminuria were evaluated. Results: In patients with normal renal function, GFR/MDRD ≥ 60 ml/min/1.73 m2, (n = 79), urinary albumin concentration (UAC) was significantly correlated with Cystatin C, both in patients with normoalbuminuria (r = 0.547, p < 0.023) or microalbuminuria (r = 0.305, p < 0.035), while it was not correlated either with serum creatinine or calculated creatinine clearance. In patients with GFR/MDRD < 60 ml/min/1.73 m2, (n = 100), UAC was significantly correlated with Cystatin C, also both in patients with normoalbuminuria (r = 0.536, p < 0.032) or microalbuminuria (r = 0.340, p < 0.016), while it was significantly correlated with serum creatinine and calculated creatinine clearance only in those with microalbuminuria. Conclusions: Subtle changes in renal function, as judged by Cystatin C concentration, may parallel the degree of albuminuria, even in the normoalbuminuric stage. This finding needs further confirmation by more appropriate methodology in prospective follow up studies. © 2009 Elsevier Ireland Ltd. All rights reserved

Diabetic retinopathy is associated with mortality and cardiovascular disease incidence: The EURODIAB Prospective Complications Study

OBJECTIVE - To study the relationship of nonproliferative and proliferative retinopathy with all-cause mortality and cardiovascular disease (CVD) incidence in type 1 diabetic patients and, additionally, the role of cardiovascular risk factors in these associations. RESEARCH DESIGN AND METHODS - This prospective study included 2,237 type 1 diabetic patients from 31 centers in 16 European countries at baseline, aged 15-60 years, who were examined for retinopathy by taking two-field 45 degrees fundus photographs, which were centrally graded. Mortality and cardiovascular morbidity follow-up was assessed 6-8 years after baseline examination according to a standardized protocol. RESULTS - After 7.9 years of follow-up, 64 patients had died and 128 patients had incident CVD. The age- and sex-adjusted hazard ratios (HRs) of all-cause mortality were 1.45 (95% CI 0.71-2.96) and 4.16 (1.96 - 8.84) in patients with nonproliferative and proliferative retinopathy at baseline, respectively. Adjustments for cardiovascular risk factors completely obliterated the association with nonproliferative retinopathy, whereas the association with proliferative retinopathy remained twofold increased, although nonsignificant. The age- and sex-adjusted HRs of incident CVD were 1.73 (1.15-2.60) and 2.05 (1.22-3.45) in patients with nonproliferative and proliferative retinopathy, respectively. After adjustments for cardiovascular risk factors, both associations were attenuated and lost statistical significance. CONCLUSIONS - This study shows that type 1 diabetic patients with nonproliferative or proliferative retinopathy have an increased risk for all-cause mortality and incident CVD. The presence of cardiovascular risk factors explained the associations to a large extent, except for the associations with proliferative retinopathy, which suggests that other shared mechanisms may be involved