Remnant cholesterol predicts progression of diabetic nephropathy and retinopathy in type 1 diabetes.

BACKGROUND: We aimed to assess whether remnant cholesterol concentration and variability predict the progression of diabetic nephropathy (DN) and severe diabetic retinopathy (SDR) in type 1 diabetes. METHODS: This observational prospective study covered 5150 FinnDiane Study participants. Remnant cholesterol was calculated as total cholesterol - LDL cholesterol - HDL cholesterol and variability as the coefficient of variation. DN category was based on consensus albuminuria reference limits and the progression status was confirmed from medical files. SDR was defined as retinal laser treatment. For 1338 individuals, the severity of diabetic retinopathy (DR) was graded using the ETDRS classification protocol. Median (IQR) follow-up time was 8.0 (4.9-13.7) years for DN and 14.3 (10.4-16.3) for SDR. RESULTS: Remnant cholesterol (mmol L-1 ) was higher with increasing baseline DN category (P < 0.001). A difference was also seen comparing non-progressors (0.41 [0.32-0.55]) with progressors (0.55 [0.40-0.85]), P < 0.001. In a Cox regression analysis, remnant cholesterol predicted DN progression, independently of diabetes duration, sex, HbA1c , systolic blood pressure, smoking, BMI, estimated glucose disposal rate and estimated glomerular filtration rate (HR: 1.51 [1.27-1.79]). Remnant cholesterol was also higher in those who developed SDR (0.47 [0.36-0.66]) than those who did not (0.40 [0.32-0.53]), P < 0.001, and the concentration increased stepwise with increasing DR severity (P < 0.001). Regarding SDR, the HR for remnant cholesterol was 1.52 (1.26-1.83) with the most stringent adjustment. However, remnant cholesterol variability was not independently associated with the outcomes. CONCLUSIONS: Remnant cholesterol concentration, but not variability, predicts DN progression and development of SDR. However, it remains to be elucidated whether the associations are causal or not.

Assessment of differentially methylated loci in individuals with end-stage kidney disease attributed to diabetic kidney disease: an exploratory study.

BACKGROUND: A subset of individuals with type 1 diabetes mellitus (T1DM) are predisposed to developing diabetic kidney disease (DKD), the most common cause globally of end-stage kidney disease (ESKD). Emerging evidence suggests epigenetic changes in DNA methylation may have a causal role in both T1DM and DKD. The aim of this exploratory investigation was to assess differences in blood-derived DNA methylation patterns between individuals with T1DM-ESKD and individuals with long-duration T1DM but no evidence of kidney disease upon repeated testing to identify potential blood-based biomarkers. Blood-derived DNA from individuals (107 cases, 253 controls and 14 experimental controls) were bisulphite treated before DNA methylation patterns from both groups were generated and analysed using Illumina's Infinium MethylationEPIC BeadChip arrays (n = 862,927 sites). Differentially methylated CpG sites (dmCpGs) were identified (false discovery rate adjusted p ≤ × 10-8 and fold change ± 2) by comparing methylation levels between ESKD cases and T1DM controls at single site resolution. Gene annotation and functionality was investigated to enrich and rank methylated regions associated with ESKD in T1DM. RESULTS: Top-ranked genes within which several dmCpGs were located and supported by functional data with methylation look-ups in other cohorts include: AFF3, ARID5B, CUX1, ELMO1, FKBP5, HDAC4, ITGAL, LY9, PIM1, RUNX3, SEPTIN9 and UPF3A. Top-ranked enrichment pathways included pathways in cancer, TGF-ß signalling and Th17 cell differentiation. CONCLUSIONS: Epigenetic alterations provide a dynamic link between an individual's genetic background and their environmental exposures. This robust evaluation of DNA methylation in carefully phenotyped individuals has identified biomarkers associated with ESKD, revealing several genes and implicated key pathways associated with ESKD in individuals with T1DM.

Genome-wide search for genes affecting the age at diagnosis of type 1 diabetes.

BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease affecting individuals in the early years of life. Although previous studies have identified genetic loci influencing T1D diagnosis age, these studies did not investigate the genome with high resolution. OBJECTIVE AND METHODS: We performed a genome-wide meta-analysis for age at diagnosis with cohorts from Finland (Finnish Diabetic Nephropathy Study), the United Kingdom (UK Genetic Resource Investigating Diabetes) and Sardinia. Through SNP associations, transcriptome-wide association analysis linked T1D diagnosis age and gene expression. RESULTS: We identified two chromosomal regions associated with T1D diagnosis age: multiple independent variants in the HLA region on chromosome 6 and a locus on chromosome 17q12. We performed gene-level association tests with transcriptome prediction models from two whole blood datasets, lymphocyte cell line, spleen, pancreas and small intestine tissues. Of the non-HLA genes, lower PNMT expression in whole blood, and higher IKZF3 and ZPBP2, and lower ORMDL3 and GSDMB transcription levels in multiple tissues were associated with lower T1D diagnosis age (FDR = 0.05). These genes lie on chr17q12 which is associated with T1D, other autoimmune diseases, and childhood asthma. Additionally, higher expression of PHF20L1, a gene not previously implicated in T1D, was associated with lower diagnosis age in lymphocytes, pancreas, and spleen. Altogether, the non-HLA associations were enriched in open chromatin in various blood cells, blood vessel tissues and foetal thymus tissue. CONCLUSION: Multiple genes on chr17q12 and PHF20L1 on chr8 were associated with T1D diagnosis age and only further studies may elucidate the role of these genes for immunity and T1D onset.

The association between bacterial infections and the risk of coronary heart disease in type 1 diabetes.

BACKGROUND: Diabetes increases the risk of infections and coronary heart disease (CHD). Whether infections increase the risk of CHD and how this applies to individuals with diabetes is unclear. OBJECTIVES: To investigate the association between bacterial infections and the risk of CHD in type 1 diabetes. METHODS: Individuals with type 1 diabetes (n = 3781) were recruited from the Finnish Diabetic Nephropathy Study (FinnDiane), a prospective follow-up study. CHD was defined as incident events: fatal or nonfatal myocardial infarction, coronary artery bypass surgery or percutaneous coronary intervention, identified through national hospital discharge register data. Infections were identified through national register data on all antibiotic purchases from outpatient care. Register data were available from 1 January 1995 to 31 December 2015. Bacterial lipopolysaccharide (LPS) activity was measured from serum samples at baseline. Data on traditional risk factors for CHD were collected during baseline and consecutive visits. RESULTS: Individuals with an incident CHD event (n = 370) had a higher mean number of antibiotic purchases per follow-up year compared to those without incident CHD (1.34 [95% CI: 1.16-1.52], versus 0.79 [0.76-0.82], P < 0.001), as well as higher levels of LPS activity (0.64 [0.60-0.67], versus 0.58 EU mL-1 [0.57-0.59], P < 0.001). In multivariable-adjusted Cox proportional hazards models, the mean number of antibiotic purchases per follow-up year was an independent risk factor for incident CHD (HR 1.21, 95% CI: 1.14-1.29, P < 0.0001). High LPS activity was a risk factor for incident CHD (HR 1.93 [1.34-2.78], P < 0.001) after adjusting for static confounders. CONCLUSION: Bacterial infections are associated with an increased risk of incident CHD in individuals with type 1 diabetes.

Hyperoxia improves autonomic function in individuals with long-duration type 1 diabetes and macroalbuminuria.

AIM: Acute oxygen inhalation and slow deep breathing improve measures of autonomic function transiently in individuals with short-duration type 1 diabetes. Our aims were to examine these interventions and changes in autonomic function in individuals with long-duration type 1 diabetes and to explore interactions with the presence of macroalbuminuria or existing cardiovascular autonomic neuropathy. METHODS: Individuals with type 1 diabetes (n = 54) were exposed to acute oxygen inhalation, slow deep breathing and a combination of both (hereafter 'the combination'). Primary outcomes were change in baroreflex sensitivity and heart rate variability. Associations between changes in outcomes were evaluated using mixed effects models. RESULTS: Mean age ± sd was 60 ± 10 years and diabetes duration was 38 ± 14 years. Changes are presented as per cent difference from baseline with 95% confidence intervals. Acute oxygen inhalation, slow deep breathing and the combination increased baroreflex sensitivity by 21 (10, 34)%, 32 (13, 53)% and 30 (10, 54)%, respectively. Acute oxygen inhalation trended towards increasing heart rate variability 8 (-1, 17)% (P = 0.056), and slow deep breathing and the combination increased heart rate variability by 33 (18, 49)% and 44 (27, 64)% respectively. Macroalbuminuria or cardiovascular autonomic neuropathy did not modify results. CONCLUSION: Autonomic function is improved transiently in individuals with long-duration type 1 diabetes and normoalbuminuria or macroalbuminuria by acute oxygen inhalation and slow deep breathing. There is a risk of survival bias. Autonomic dysfunction might be a reversible condition, and hypoxia might represent a target of intervention.

Associations of dietary macronutrient and fibre intake with glycaemia in individuals with Type 1 diabetes.

AIMS: To study the association between dietary intake and glycaemia in Type 1 diabetes. METHODS: Data on energy and nutrient intakes, and the mean and coefficient of variation of self-monitored blood glucose measurements were obtained from records completed by 1000 adults with Type 1 diabetes. Associations between these measures of glycaemia and dietary intake were investigated using generalized linear regression, with and without macronutrient substitution. RESULTS: In the first set of analyses, fibre intake was associated with lower mean self-monitored blood glucose values (ß = -0.428, 95% CI -0.624 to -0.231; P<0.001). In these same analyses, carbohydrate (ß = 0.011, 95% CI 0.002 to 0.020; P=0.014), alcohol (ß = 0.013, 95% CI 0.003 to 0.023; P=0.009) and monounsaturated fatty acid intakes (ß=0.012, 95% CI 0.001 to 0.023; P=0.029) were associated with higher variability in blood glucose measurements. In the macronutrient substitution analyses, substituting proteins for either carbohydrates (ß = -0.026, 95% CI -0.040 to -0.013; P<0.001), fats (ß = -0.018, 95% CI -0.033 to -0.004; P=0.014), or alcohol (ß = -0.026, 95% CI -0.045 to -0.006; P=0.010), or fats for carbohydrates (ß=-0.009, 95% CI -0.017 to -0.001; P=0.030), were all associated with lower variability in the measured blood glucose values. After adjusting for fibre intake, no significant results were observed in analyses of mean self-monitored blood glucose. CONCLUSIONS: This observational, cross-sectional study indicates that dietary fibre is associated with lower mean blood glucose concentrations in people with Type 1 diabetes. Glycaemic excursions were reduced when protein was substituted for other macronutrients and when fat replaced carbohydrate, after adjusting for fibre intake.

Association between diet and measures of arterial stiffness in type 1 diabetes - Focus on dietary patterns and macronutrient substitutions.

BACKGROUND AND AIMS: Increased arterial stiffness contributes to diabetic vascular complications. We identified dietary factors related to arterial stiffness in individuals with type 1 diabetes, a population with high risk of cardiovascular disease. METHODS AND RESULTS: Altogether, 612 participants (40% men, mean ± standard deviation age 45 ± 13 years) completed a validated diet questionnaire and underwent measurements of arterial stiffness. Of these, 470 additionally completed a food record. Exploratory factor analysis was applied to identify dietary patterns from the diet questionnaires, and nutrient intakes were calculated from food record entries. Arterial stiffness was measured by applanation tonometry. Of the seven dietary factors formed, the factor scores of "Full-fat cheese and eggs" and "Sweet" patterns were negatively associated with measures of arterial stiffness. In the multivariable macronutrient substitution models, favouring carbohydrates over fats was associated with higher aortic mean arterial pressure and aortic pulse wave velocity. When carbohydrates were consumed in place of proteins, higher aortic pulse pressure, aortic mean arterial pressure, and augmentation index were recorded. Replacing energy from alcohol with proteins, was associated with lower aortic pulse pressure, aortic mean arterial pressure, and augmentation index. Relative distributions of dietary fatty acids were neutral with respect to the measures of arterial stiffness. CONCLUSION: The macronutrient distribution of the diet is likely to affect the resilience of the arteries. Our observations suggest that reducing energy intake from carbohydrates and alcohol may be beneficial. These observations, especially those dealing with dietary patterns, need to be confirmed in a longitudinal study.

Association between habitual coffee consumption and metabolic syndrome in type 1 diabetes.

BACKGROUND AND AIMS: In the general population, habitual coffee consumption is inversely associated with the metabolic syndrome, a syndrome that is rather common also in patients with type 1 diabetes. However, whether coffee intake is beneficially related to the metabolic syndrome also in type 1 diabetes, is not known. We, therefore, studied the potential association between coffee consumption and the metabolic syndrome in a large population of individuals with type 1 diabetes. Furthermore, we investigated whether coffee consumption is associated with insulin resistance (estimated glucose disposal rate, eGDR), kidney function (estimated glomerular filtration rate, eGFR), and low-grade chronic inflammation (high-sensitivity C-reactive protein, hsCRP). METHODS AND RESULTS: Data from 1040 participants in the Finnish Diabetic Nephropathy Study were included in these cross-sectional analyses. Metabolic syndrome was assumed if at least 3 of the following cardiovascular risk factors were present: central obesity, high blood pressure, low HDL-cholesterol concentration, high triglyceride concentration, and hyperglycaemia. Subjects were categorized based on self-reported daily coffee intake: non-consumers (<1 cup/d), low (≥1 cups/d < 3), moderate (≥3 cups/d < 5), and high coffee consumption (≥5 cups/d). In multivariable logistic regression analysis, moderate and high coffee consumption was associated with increased odds of the metabolic syndrome. Moreover, any level of coffee consumption was associated with increased risk of the blood pressure-component. An increasing trend was observed in the eGFR with increasing coffee consumption. CONCLUSIONS: In type 1 diabetes, high coffee intake is associated with the metabolic syndrome, and especially its blood pressure-component.

Diabetes and intracerebral hemorrhage: baseline characteristics and mortality.

BACKGROUND AND PURPOSE: Acknowledging the conflicting evidence for diabetes as a predictor of short- and long-term mortality following an intracerebral hemorrhage (ICH), we compared baseline characteristics and 30-day and long-term mortality between patients with and without diabetes after an ICH, paying special attention to differences between type 1 (T1D) and type 2 (T2D) diabetes. METHODS: Patients with a first-ever ICH were followed for a median of 2.3 years. Adjusting for demographics, comorbidities and documented ICH characteristics increasing mortality after ICH, logistic regression analysis assessed factors associated with case fatality and 1-year survival among the 30-day survivors. Diabetes was compared with patients without diabetes in separate models as (i) any diabetes and (ii) T1D or T2D. RESULTS: Of our 969 patients, 813 (83.9%) had no diabetes, 41 (4.2%) had T1D and 115 (11.9%) had T2D. Compared with patients without diabetes, those with diabetes were younger, more often men and more frequently had hypertension, coronary heart disease and chronic kidney disease, with similar ICH characteristics. Patients with T1D were younger, more often had chronic kidney disease and brainstem ICH, and less often had atrial fibrillation and lobar ICH, than did patients with T2D. Diabetes had no impact on case fatality. Any diabetes (odds ratio, 2.57; 1.19-5.52), T1D (odds ratio, 7.04; 1.14-43.48) and T2D (odds ratio, 2.32; 1.04-5.17) were independently associated with 1-year mortality. CONCLUSIONS: Patients with ICH with diabetes exhibited a distinct pattern of comorbidities and disease characteristics with specific differences between T1D and T2D. Despite their younger age, T1D seems to carry a substantially higher likelihood of long-term mortality after an ICH than does T2D.

Intestinal alkaline phosphatase at the crossroad of intestinal health and disease - a putative role in type 1 diabetes.

BACKGROUND: Patients with type 1 diabetes have shown an increase in circulating cytokines, altered lipoprotein metabolism and signs of vascular dysfunction in response to high-fat meals. Intestinal alkaline phosphatase (IAP) regulates lipid transport and inflammatory responses in the gastrointestinal tract. We therefore hypothesized that changes in IAP activity could have profound effects on gut metabolic homeostasis in patients with type 1 diabetes. METHODS: Faecal samples of 41 nondiabetic controls and 46 patients with type 1 diabetes were analysed for IAP activity, calprotectin, immunoglobulins and short-chain fatty acids (SCFAs). The impact of oral IAP supplementation on intestinal immunoglobulin levels was evaluated in C57BL/6 mice exposed to high-fat diet for 11 weeks. RESULTS: Patients with type 1 diabetes exhibited signs of intestinal inflammation. Compared to controls, patients with diabetes had higher faecal calprotectin levels, lower faecal IAP activities accompanied by lower propionate and butyrate concentrations. Moreover, the amount of faecal IgA and the level of antibodies binding to oxidized LDL were decreased in patients with type 1 diabetes. In mice, oral IAP supplementation increased intestinal IgA levels markedly. CONCLUSION: Deprivation of protective intestinal factors may increase the risk of inflammation in the gut - a phenomenon that seems to be present already in patients with uncomplicated type 1 diabetes. Low levels of intestinal IgA and antibodies to oxidized lipid epitopes may predispose such patients to inflammation-driven complications such as cardiovascular disease and diabetic nephropathy. Importantly, oral IAP supplementation could have beneficial therapeutic effects on gut metabolic homeostasis, possibly through stimulation of intestinal IgA secretion.

A drop in the circulating concentrations of soluble receptor for advanced glycation end products is associated with seroconversion to autoantibody positivity but not with subsequent progression to clinical disease in children en route to type 1 diabetes.

BACKGROUND: Advanced glycation end products (AGEs) and their interaction with the receptor for AGEs (RAGE) have been studied for their role in the pathogenesis and complications of type 1 diabetes. Decreased concentrations of soluble RAGE (sRAGE) have been reported in acute autoimmune inflammation. We set out to analyze the changes in sRAGE concentration during preclinical diabetes in children seroconverting to islet autoantibody positivity. METHODS: We measured serum concentrations of sRAGE in 168 children who progressed to clinical disease and 43 children who turned positive for at least 2 diabetes-associated autoantibodies but remained nondiabetic. We analyzed the sRAGE before seroconversion in the first autoantibody-positive sample and annually thereafter until the diagnosis of type 1 diabetes or end of follow-up. RESULTS: Both groups had similar sRAGE before seroconversion, but subsequently, sRAGE concentrations were lower (P < .001) in the progressors. The progressors had significantly higher sRAGE concentrations before than after seroconversion (P < .001). The nonprogressors did not experience a similar decrease. The sRAGE concentrations remained stable after seroconversion in both groups. CONCLUSIONS: These data indicate that sRAGE may be involved in the initiation of beta-cell autoimmunity but not in the progression from beta-cell autoimmunity to clinical disease.

Biochemical pathways of breath ammonia (NH3) generation in patients with end-stage renal disease undergoing hemodialysis.

Breath ammonia (NH3) has been proposed as a potential biomarker in monitoring hemodialysis (HD) adequacy, since a strong correlation between blood urea and mouth-exhaled breath NH3 has been observed in patients with end-stage renal disease (ESRD) undergoing HD. However, the biochemical pathways for breath NH3 generation from blood urea have not been demonstrated. In this study, we show a strong correlation (r s = 0.77, p < 0.001) between blood and salivary urea, indicating that salivary urea levels reflect blood urea levels. Salivary urea is in turn strongly correlated to salivary ammonia ([Formula: see text] + NH3) in most of the patients. This confirms that the hydrolysis of urea by urease generates ammonia in the oral cavity. A further strong correlation between salivary ammonia and breath NH3 indicates that salivary ammonia evaporates into gas phase and turns to breath NH3. Therefore, blood urea is a major biochemical source of breath NH3. Since breath NH3 is generated predominantly in the oral cavity, the levels of breath NH3 are influenced significantly by the patient's oral condition including urease activity and salivary pH. Our results agree with previous studies that have shown a connection between salivary urea and breath NH3.

Podocyte apoptosis is prevented by blocking the Toll-like receptor pathway.

High serum lipopolysaccharide (LPS) activity in normoalbuminuric patients with type 1 diabetes (T1D) predicts the progression of diabetic nephropathy (DN), but the mechanisms behind this remain unclear. We observed that treatment of cultured human podocytes with sera from normoalbuminuric T1D patients with high LPS activity downregulated 3-phosphoinositide-dependent kinase-1 (PDK1), an activator of the Akt cell survival pathway, and induced apoptosis. Knockdown of PDK1 in cultured human podocytes inhibited antiapoptotic Akt pathway, stimulated proapoptotic p38 MAPK pathway, and increased apoptosis demonstrating an antiapoptotic role for PDK1 in podocytes. Interestingly, PDK1 was downregulated in the glomeruli of diabetic rats and patients with type 2 diabetes before the onset of proteinuria, further suggesting that reduced expression of PDK1 associates with podocyte injury and development of DN. Treatment of podocytes in vitro and mice in vivo with LPS reduced PDK1 expression and induced apoptosis, which were prevented by inhibiting the Toll-like receptor (TLR) signaling pathway with the immunomodulatory agent GIT27. Our data show that LPS downregulates the cell survival factor PDK1 and induces podocyte apoptosis, and that blocking the TLR pathway with GIT27 may provide a non-nephrotoxic means to prevent the progression of DN.

Genetic risk factors affecting mitochondrial function are associated with kidney disease in people with Type 1 diabetes.

AIM: To evaluate the association with diabetic kidney disease of single nucleotide polymorphisms (SNPs) that may contribute to mitochondrial dysfunction. METHODS: The mitochondrial genome and 1039 nuclear genes that are integral to mitochondrial function were investigated using a case (n = 823 individuals with diabetic kidney disease) vs. control (n = 903 individuals with diabetes and no renal disease) approach. All people included in the analysis were of white European origin and were diagnosed with Type 1 diabetes before the age of 31 years. Replication was conducted in 5093 people with similar phenotypes to those of the discovery collection. Association analyses were performed using the plink genetic analysis toolset, with adjustment for relevant covariates. RESULTS: A total of 25 SNPs were evaluated in the mitochondrial genome, but none were significantly associated with diabetic kidney disease or end-stage renal disease. A total of 38 SNPs in nuclear genes influencing mitochondrial function were nominally associated with diabetic kidney disease and 16 SNPS were associated with end-stage renal disease, secondary to diabetic kidney disease, with meta-analyses confirming the same direction of effect. Three independent signals (seven SNPs) were common to the replication data for both phenotypes with Type 1 diabetes and persistent proteinuria or end-stage renal disease. CONCLUSIONS: Our results suggest that SNPs in nuclear genes that influence mitochondrial function are significantly associated with diabetic kidney disease in a white European population.

Linagliptin treatment in subjects with type 2 diabetes with and without mild-to-moderate renal impairment.

AIMS: Renal disease is a frequent comorbidity of type 2 diabetes mellitus (T2DM) and an important factor complicating the choice of glucose-lowering drugs. The aim of this analysis was to evaluate the efficacy and safety of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin (5 mg/day) in mono, dual or triple oral glucose-lowering regimens in subjects with T2DM and mild or moderate renal impairment (RI). METHODS: In this pooled analysis of three 24-week, placebo-controlled, phase 3 trials, subjects with mild (estimated glomerular filtration rate (eGFR) 60-<90 ml/min/1.73 m(2) , n = 838) or moderate RI (30-<60 ml/min/1.73 m(2), n = 93) were compared with subjects with normal renal function (≥90 ml/min/1.73 m(2), n = 1212). RESULTS: Subjects with RI were older, had longer duration of diabetes, and increased prevalence of diabetes-related comorbidities. After 24 weeks, linagliptin achieved consistent placebo-corrected mean glycated haemoglobin (HbA1c) changes across the three renal function categories: normal (-0.63%; p < 0.0001), mild RI (-0.67%; p < 0.0001) and moderate RI (-0.53%; p < 0.01), with no inter-group difference (p = 0.74). Renal function with linagliptin remained stable across all categories. In linagliptin-treated subjects, overall adverse event (AE) rates and serious AE rates were similar to placebo. The incidence of hypoglycaemia with linagliptin and placebo was 11.1 versus 6.9%, 11.9 versus 9.0% and 15.9 versus 12.0% in the normal, mild RI and moderate RI categories, respectively. CONCLUSIONS: This pooled analysis provides evidence that linagliptin is an effective, well-tolerated and convenient treatment in subjects with T2DM and mild or moderate RI.

Increased plasma norepinephrine levels in previously pre-eclamptic women.

A history of pre-eclampsia increases the risk of cardiovascular morbidity by mechanisms yet unknown. The aim of the present study was to assess whether plasma norepinephrine (NE) levels are increased 5-6 years after pre-eclamptic pregnancy and to investigate associations with pathophysiological mechanisms of cardiovascular disease: insulin sensitivity, vascular function and arterial pressure. A total of 28 women with previous pre-eclampsia and 20 controls were examined. Blood pressure (BP) and plasma levels of NE and endothelin-1 (ET-1) were measured at rest and after standing for 5 min. Insulin sensitivity was assessed with minimal model analysis and vascular function was assessed using venous occlusion plethysmography and pulse wave analysis. Twenty-four-hour BP measurements were carried out. Women with previous pre-eclampsia had higher levels of NE at rest (P=0.02), which did not associate significantly with insulin sensitivity or overall vasodilatory capacity. The 24-h mean of systolic and diastolic blood pressures (BPs) and heart rate did not differ between the groups (P=0.30, P=0.10 and P=0.46, respectively), and there was no significant association with NE levels. ET-1 levels were similar between the groups, but a positive correlation with systolic (P=0.04) and diastolic (P=0.03) BPs in the upright position was shown in the patient group. Increased levels of plasma NE are sustained in women with previous pre-eclampsia and may contribute to the increased risk for cardiovascular disease in these women.

Patients with Type 1 diabetes consuming alcoholic spirits have an increased risk of microvascular complications.

AIMS: Our aim was to evaluate the effect of the amount of alcohol consumption and the type of beverage on the risk of diabetic nephropathy and severe diabetic retinopathy. METHODS: The alcohol consumption data were available from 3608 patients with Type 1 diabetes participating in the Finnish Diabetic Nephropathy Study (FinnDiane). We assessed the cross-sectional association between alcohol consumption and diabetic nephropathy as well as retinopathy. Patients were divided into different groups according to the amount of alcohol and the type of beverage they were consuming. RESULTS: In the multivariate analysis, the odds ratio for nephropathy was 1.39 (95% CI 1.05-1.84) for abstainers and 2.44 (95% CI 1.49-3.99) for former users compared with light consumers. The results were similar in retinopathy, with an odds ratio of 1.42 (95% CI 1.11-1.82) for abstainers and 1.73 (95% CI 1.07-2.79) for former users. No difference between light consumers and moderate or heavy consumers was observed. Compared with wine drinkers, men consuming mostly alcoholic spirits had a higher risk of nephropathy with an odds ratio of 2.80 (95% CI 1.15-6.81). In women, there was no difference in the risk of nephropathy between the different beverage types. Alcoholic spirit consumers had a higher risk of retinopathy with an odds ratio of 2.32 (95% CI 1.35-4.00). There was no difference between wine and beer consumers. CONCLUSIONS: Alcoholic spirit drinkers carry a higher risk of nephropathy and severe retinopathy compared with wine drinkers. Lifelong abstainers and former users of alcohol have a higher risk of nephropathy and severe retinopathy compared with light consumers.

Metabolic phenotyping of diabetic nephropathy.

Diabetic nephropathy is the most serious complication of type 1 diabetes. There is no treatment to protect the kidneys from poorly controlled diabetes, and therefore prevention of the initial metabolic insults is currently the only effective approach to reducing the high mortality related to diabetic nephropathy. Metabolic phenotyping brings us one step closer to understanding the unique set of regulatory perturbations that predispose to kidney injury and paves the way for multiparametric risk assessment.

Associations and interactions between lipid profiles, retinopathy and nephropathy in patients with type 1 diabetes: the FinnDiane Study.

OBJECTIVES: The aim of this study was to investigate the associations between lipid profiles and retinopathy in the large nationwide FinnDiane Study and to examine interactions and correlations between retinopathy, nephropathy and lipid variables. DESIGN AND SUBJECTS: A total of 1465 patients with type 1 diabetes, available lipid profiles, ophthalmic records and fundus photographs were included in the study. The Early Treatment of Diabetic Retinopathy Study scale was used to assess the severity of retinopathy. In an independent cohort of 1100 patients, laser treatment was used to define severe diabetic retinopathy. RESULTS: HDL cholesterol was associated with proliferative retinopathy (PDR), and triglycerides were associated with mild nonproliferative retinopathy (NPDR) independently of nephropathy and other conventional risk factors (P < 0.01). Significant interactions were seen between albumin excretion rate (AER), retinopathy status and lipid parameters (including triglycerides, non-HDL cholesterol and apolipoprotein B; P < 0.001). Highly different correlations between AER and lipid variables were observed in patients without retinopathy or with mild NPDR compared with patients with moderate to severe NPDR or PDR. Similar interactions and correlations were observed in an independent cohort stratified by laser treatment. In patients without retinopathy or with mild NPDR, AER was low despite HDL cholesterol in the lowest or triglycerides, total cholesterol or LDL cholesterol in the highest quartiles. CONCLUSIONS: Nephropathy had a strong effect on the associations between lipid variables and retinopathy, whilst dyslipidaemia was associated with nephropathy only in the presence of retinopathy. This finding suggests the existence of shared pathogenic mechanisms between retinopathy and nephropathy which could be targeted to prevent complications in patients with metabolic risk factors.