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

Differences in HDL-cholesterol:apoA-I + apoA-II ratio and apoE phenotype with albuminuric status in Type I diabetic patients

Aims/hypothesis. To examine whether the HDL-cholesterol:apoA-I + apoA-II ratio and the epsilon2 allele are related to albuminuria at baseline and whether they are risk factors for progression of albuminuria in a cohort study of patients with Type I (insulin-dependent) diabetes mellitus. Methods. At baseline, the study cohort comprised 617 patients, aged 15-60 years, from seven European diabetic centres of the EURODIAB study. Albumin excretion rate, measured in a central laboratory, was categorised as normoalbuminuria at 20 mug/min or less, microalbuminuria between 20 and 200 mug/min or macroalbuminuria at 200 mug/min or over. Of the 250 patients who were normoalbuminuric at baseline and had follow-up albuminuria measurements, 34 patients were defined as early progressors. Results. At baseline, the mean HDL-cholesterol:apoA-I + apoA-II ratio was lower in macroalbuminuric patients (0.79, 95% CI:0.74-0.83) compared with normoalbuminuric (0.88, 95% CI:0.87-0.90) patients (p = 0.0002, adjusted for age and sex). At follow-up, 34 patients who progressed from normoalbuminuria to microalbuminuria or macroalbuminuria also had a slightly lower baseline ratio (0.85, 95% CI:0.80-0.89) than those 216 who remained normoalbuminuric (0.89, 95% CI:0.87-0.92) (adjusted p = 0.08). Neither of these relations were independent of LDL-cholesterol or fasting triglyceride. There was no association of the epsilon2 allele with albuminuria either at baseline (OR = 1.4, 95% CI:0.7-2.8) or with progression of albuminuria (OR = 0.4, 95% CI:0.1-3.5). Conclusion/interpretation. There is an inverse relation of HDL-cholesterol:apoA-I + apoA-II ratio with albuminuria at baseline. This lower ratio in microalbuminuric or macroalbuminuric patients could contribute to the increased risk of cardiovascular disease associated with nephropathy. There is weak evidence that HDL-composition is a risk factor for progression of albuminuria and no association of the epsilon2 allele with diabetic nephropathy

The genetic spectrum of familial hypercholesterolemia in south-eastern Poland

BACKGROUND: Familial hypercholesterolemia (FH) is a common autosomal dominant disorder with a frequency of 1 in 200 to 500 in most European populations. Mutations in LDLR, APOB and PCSK9 genes are known to cause FH. In this study, we analyzed the genetic spectrum of the disease in the understudied Polish population. MATERIALS AND METHODS: 161 unrelated subjects with a clinical diagnosis of FH from the south-eastern region of Poland were recruited. High resolution melt and direct sequencing of PCR products were used to screen 18 exons of LDLR, a region of exon 26 in the APOB gene and exon 7 of PCSK9. Multiplex ligation-dependent probe amplification (MLPA) was performed to detect gross deletions and insertions in LDLR. Genotypes of six LDL-C raising SNPs were used for a polygenic gene score calculation. RESULTS: We found 39 different pathogenic mutations in the LDLR gene with 10 of them being novel. 13 (8%) individuals carried the p.Arg3527Gln mutation in APOB, and overall the detection rate was 43.4%. Of the patients where no mutation could be found, 53 (84.1%) had a gene score in the top three quartiles of the healthy comparison group suggesting that they have a polygenic cause for their high cholesterol. CONCLUSIONS: These results confirm the genetic heterogeneity of FH in Poland, which should be considered when designing a diagnostic strategy in the country. As in the UK, in the majority of patients where no mutation can be found, there is likely to be a polygenic cause of their high cholesterol level

Plasma homocysteine and microvascular and macrovascular complications in type 1 diabetes: a cross-sectional nested case-control study

36 years of age. Cases (n=359) were defined as those with one or more complications of diabetes and control subjects (n=174) were all those with no evidence of any complication. Main outcome measures. Retinopathy, albumin excretion rate (AER), glomerular filtration rate (GFR) estimated by Cockcroft-Gault formula, hypertension and cardiovascular disease (CVD) were assessed. RESULTS. In unadjusted models, tHcy (per 5 micromol L(-1)) was significantly associated with nonproliferative retinopathy (OR=1.45, 95% CI: 1.10-1.91), proliferative retinopathy (OR=1.74, 95% CI: 1.34-2.27), macroalbuminuria (OR=1.90, 95% CI: 1.49-2.42), hypertension (OR=2.23, 95% CI: 1.69-2.93) and CVD (OR=1.59, 95% CI: 1.18-2.14). In multivariate models, tHcy was significantly related to macroalbuminuria (OR=1.66, 95% CI: 1.24-2.24) and hypertension (OR=1.57, 95% CI: 1.19-2.07), independent of age, sex, diabetes duration, GFR, microvascular and macrovascular complications and cardiovascular risk factors. There was a significant relationship between tHcy and decreased GFR, independent of established risk factors. The relationship between tHcy and retinopathy was not independent of albuminuria or GFR. The initial positive relationship with CVD was explained by cardiovascular risk factors. CONCLUSION. In this large study of European type 1 diabetic subjects, increased concentrations of tHcy were independently related to macroalbuminuria, renal function and hypertension, which suggests that tHcy might play an important role in the pathogenesis of vascular complications in type 1 diabete