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.

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.

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.

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.

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.

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.

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.

HbA1c variability is associated with an increased risk of retinopathy requiring laser treatment in type 1 diabetes.

AIMS/HYPOTHESIS: This study aimed to investigate whether variation in long-term glycaemia in type 1 diabetes as measured by HbA1c variability is associated with the cumulative incidence and risk of retinopathy requiring laser treatment. METHODS: The effect of HbA1c variability was assessed in 2,019 Finnish Diabetic Nephropathy (FinnDiane) study patients. The patients were studied in two partially overlapping subcohorts with either verified first laser treatment (n = 1,459) or retinopathy severity graded from ophthalmic records with the Early Treatment of Diabetic Retinopathy Study (ETDRS) scale (n = 1,346). The ratio of intrapersonal SD and mean of serially measured HbA1c was considered an estimate of HbA1c variability. RESULTS: A subcohort of 1,459 patients did not have laser treatment prior to the first FinnDiane visit and 174 of these patients were treated during a mean follow-up period of 5.2 ± 2.2 years. The 5 year cumulative incidence of laser treatment was 19% (95% CI 15, 24) in the highest quartile of HbA1c variability and 10% (95% CI 7, 12) in the lowest quartile (p < 0.001, Gray's test) with a corresponding HR of 1.6 (95% CI 1.1, 2.5; p = 0.02) adjusted for renal status, diabetes duration, mean HbA1c, blood pressure, sex and number of HbA1c measurements. In a subcohort of 1,346 patients, 434 patients had proliferative diabetic retinopathy (PDR). Patients in the highest quartile of HbA1c variability had an increased risk of PDR compared with the lowest quartile (HR 1.7 [95% CI 1.3, 2.2]; p < 0.001]). CONCLUSIONS/INTERPRETATION: HbA1c variability was associated with an increased cumulative incidence and risk of retinopathy requiring laser treatment in type 1 diabetes.

Triglyceride-cholesterol imbalance across lipoprotein subclasses predicts diabetic kidney disease and mortality in type 1 diabetes: the FinnDiane Study.

BACKGROUND: Circulating cholesterol (C) and triglyceride (TG) levels are associated with vascular injury in type 1 diabetes (T1DM). Lipoproteins are responsible for transporting lipids, and alterations in their subclass distributions may partly explain the increased mortality in individuals with T1DM. DESIGN AND SUBJECTS: A cohort of 3544 individuals with T1DM was recruited by the nationwide multicentre FinnDiane Study Group. At baseline, six very low-density lipoprotein VLDL, one intermediate-density lipoprotein IDL, three low-density lipoprotein LDL and four higher high-density lipoprotein HDL subclasses were quantified by proton nuclear magnetic resonance spectroscopy. At follow-up, the baseline data were analysed for incident micro- or macroalbuminuria (117 cases in 5.3 years), progression from microalbuminuria (63 cases in 6.1 years), progression from macroalbuminuria (109 cases in 5.9 years) and mortality (385 deaths in 9.4 years). Univariate associations were tested by age-matched cases and controls and multivariate lipoprotein profiles were analysed using the self-organizing map (SOM). RESULTS: TG and C levels in large VLDL were associated with incident albuminuria, TG and C in medium VLDL were associated with progression from microalbuminuria, and TG and C in all VLDL subclasses were associated with mortality. Large HDL-C was inversely associated with mortality. Three extreme phenotypes emerged from SOM analysis: (i) low C (<3% mortality), (ii) low TG/C ratio (6% mortality), and (iii) high TG/C ratio (40% mortality) in all subclasses. CONCLUSIONS: TG-C imbalance is a general lipoprotein characteristic in individuals with T1DM and high vascular disease risk.

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.

Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families.

Non-insulin dependent diabetes mellitus (NIDDM) affects more than 100 million people worldwide and is associated with severe metabolic defects, including peripheral insulin resistance, elevated hepatic glucose production, and inappropriate insulin secretion. Family studies point to a major genetic component, but specific susceptibility genes have not yet been identified-except for rare early-onset forms with monogenic or mitochondrial inheritance. We have screened over 4,000 individuals from a population isolate in western Finland, identified 26 families (comprising 217 individuals) enriched for NIDDM and performed a genome-wide scan using non-parametric linkage analysis. We found no significant evidence for linkage when the families were analysed together, but strong evidence for linkage when families were classified according to mean insulin levels in affecteds (in oral glucose tolerance tests). Specifically, families with the lowest insulin levels showed linkage (P = 2 x 10(-6)) to chromosome 12 near D12S1349. Interestingly, this region contains the gene causing the rare, dominant, early-onset form of diabetes MODY3. Unlike MODY3 families, the Finnish families with low insulin have an age-of-onset typical for NIDDM (mean = 58 years). We infer the existence of a gene NIDDM2 causing NIDDM associated with low insulin secretion, and suggest that NIDDM2 and MODY3 may represent different alleles of the same gene.

Purchase of antidepressant agents by patients with type 1 diabetes is associated with increased mortality rates in women but not in men.

AIMS/HYPOTHESIS: Individuals with diabetes have increased mortality rates compared with the general population. In patients with type 2 diabetes depression further contributes to the increased mortality. Depression and mortality rates in patients with type 1 diabetes are an understudied phenomenon. We therefore studied their association in a prospective setting. METHODS: We followed 4,174 participants (51% men, age 39 ± 12 years, diabetes duration 22 ± 12 years [mean ± SD]) in the Finnish Diabetic Nephropathy Study (FinnDiane) for an average of 9 years. Depression was defined as purchase of antidepressant agents at baseline and during follow-up. These data were obtained from the Finnish Drug Prescription Register. Data on all-cause mortality and cause of death were obtained from the Finnish Cause of Death Register. RESULTS: At baseline, 313 (7.5%) patients had purchased antidepressant agents. During follow-up 758 (18.2%) additional cases were observed. Purchasers of antidepressant agents at baseline had the highest 10-year cumulative mortality rate (22.5% [95% CI 18.1, 26.6]), followed by those with such purchases during follow-up (18.0% [15.4, 20.5]) and those with no purchases (10.1% [9.0, 11.2], p < 0.001). In the adjusted Cox regression models (age, diabetes duration, diastolic blood pressure, smoking, HbA(1c) and nephropathy), the purchase of antidepressant agents at baseline was associated with mortality in women, but not in men. Cardiovascular diseases were the major cause of death in non-purchasers of antidepressant agents. In antidepressant purchasers, chronic diabetic complications were the most frequent underlying cause of death. CONCLUSIONS/INTERPRETATION: In a population of patients with type 1 diabetes, purchase of antidepressant agents was associated with increased mortality rates in women, but not in men.

HLA class II is a factor in cardiovascular morbidity and mortality rates in patients with type 1 diabetes.

AIMS/HYPOTHESIS: Patients with type 1 diabetes and kidney disease have a higher risk of cardiovascular events. HLA class II genes are expressed on infiltrated inflammatory cells and smooth-muscle cells in atherosclerotic plaques. We hypothesised that HLA class II haplotypes or genotypes might influence the risk of cardiovascular complications and death in Finnish type 1 diabetic patients. METHODS: We included 3,082 patients with type 1 diabetes from the Finnish Diabetic Nephropathy Study. We analysed the 12 and ten most common HLA II haplo- and genotypes, respectively, using χ (2) tests. The positive findings were analysed with three differently adjusted regression models with cardiovascular morbidity and death as endpoints. Different kidney status groups were analysed separately. RESULTS: At baseline, the common (DR1/10)-DQB1*05:01 haplotype (20.4%) and the (DR1/10)-DQB1*05:01/DRB1*04:01-DQB1*03:02 genotype (8.7%) were independently associated with cardiovascular disease in all kidney status groups, except in patients with normal AER. At follow-up (9.45 years; range 0.1-16.1 years), the (DR1/10)-DQB1*05:01/DRB1*04:01-DQB1*03:02 genotype was associated with cardiovascular mortality rates in patients with normal AER and microalbuminuria. CONCLUSIONS/INTERPRETATION: The (DR1/10)-DQB1*05:01 haplotype and the (DR1/10)-DQB1*05:01/DRB1*04:01-DQB1*03:02 genotype are independently associated with cardiovascular events and death in Finnish type 1 diabetic patients.

Hyperfiltration in type 1 diabetes: does it exist and does it matter for nephropathy?

AIMS/HYPOTHESIS: Hyperfiltration is widely regarded as a contributing factor to the development of microalbuminuria and progressive nephropathy in type 1 diabetes. However, recent studies have questioned this conclusion. METHODS: To address this conflicting evidence, we examined the association between hyperfiltration and progression to microalbuminuria in 2,318 adults with type 1 diabetes. We also compared the estimated GFR in our diabetic patients with rates observed in 6,247 adults from the Finnish general population, using age- and sex-specific z scores. RESULTS: The distribution of estimated GFR in adults with type 1 diabetes and normoalbuminuria was not significantly different from that expected in the general population (p = 0.51, Mann-Whitney test). Type 1 diabetic patients with a higher estimated GFR were also no more likely to develop microalbuminuria over a median of 5.2 years of follow-up than those with normal estimated GFR. This was the case regardless of whether hyperfiltration was defined by an absolute threshold, deciles of estimated GFR or a z score, using creatinine- or cystatin-based clearance formulas in men or in women. CONCLUSIONS/INTERPRETATION: Together with other studies, these data suggest that creatinine- or cystatin-based estimates of GFR do not predict the development of microalbuminuria in patients with type 1 diabetes. Moreover, in the absence of incipient or overt nephropathy, conventionally determined renal function in patients with type 1 diabetes appears no different from that in the general population. This is hardly surprising, given that these individuals, by all definitions, do not have kidney disease.

SNP in the genome-wide association study hotspot on chromosome 9p21 confers susceptibility to diabetic nephropathy in type 1 diabetes.

AIMS/HYPOTHESIS: Parental type 2 diabetes mellitus increases the risk of diabetic nephropathy in offspring with type 1 diabetes mellitus. Several single nucleotide polymorphisms (SNPs) that predispose to type 2 diabetes mellitus have recently been identified. It is, however, not known whether such SNPs also confer susceptibility to diabetic nephropathy in patients with type 1 diabetes mellitus. METHODS: We genotyped nine SNPs associated with type 2 diabetes mellitus in genome-wide association studies in the Finnish population, and tested for their association with diabetic nephropathy as well as with severe retinopathy and cardiovascular disease in 2,963 patients with type 1 diabetes mellitus. Replication of significant SNPs was sought in 2,980 patients from three other cohorts. RESULTS: In the discovery cohort, rs10811661 near gene CDKN2A/B was associated with diabetic nephropathy. The association remained after robust Bonferroni correction for the total number of tests performed in this study (OR 1.33 [95% CI 1.14, 1.56], p = 0.00045, p (36tests) = 0.016). In the meta-analysis, the combined result for diabetic nephropathy was significant, with a fixed effects p value of 0.011 (OR 1.15 [95% CI 1.02, 1.29]). The association was particularly strong when patients with end-stage renal disease were compared with controls (OR 1.35 [95% CI 1.13, 1.60], p = 0.00038). The same SNP was also associated with severe retinopathy (OR 1.37 [95% CI 1.10, 1.69] p = 0.0040), but the association did not remain after Bonferroni correction (p (36tests) = 0.14). None of the other selected SNPs was associated with nephropathy, severe retinopathy or cardiovascular disease. CONCLUSIONS/INTERPRETATION: A SNP predisposing to type 2 diabetes mellitus, rs10811661 near CDKN2A/B, is associated with diabetic nephropathy in patients with type 1 diabetes mellitus.

The risk of proliferative retinopathy in siblings with Type 1 diabetes.

AIMS: The siblings first affected by Type 1 diabetes (probands) within a sibship have been shown to have a lower age at onset of Type 1 diabetes compared with their later-affected siblings. The aim of the present study was to investigate whether this difference affects the long-term risk of proliferative diabetic retinopathy. METHODS: A cohort of 396 siblings with Type 1 diabetes in 188 sibships was drawn from a larger Finnish Diabetic Nephropathy Study population (4800 patients). Ophthalmic records were obtained for 369/396 (93%) patients. Retinopathy was graded based on fundus photographs and/or repeated ophthalmoscopies. RESULTS: The median age at onset of Type 1 diabetes was 8.4 (interquartile range 4.2-13.3) years in probands and 16.9 (interquartile range 10.2-27.8) years in later-affected siblings (P < 0.001). Proliferative retinopathy was diagnosed in 115/369 (31%) patients. The cumulative incidence estimates for proliferative retinopathy, accounting for the competing risk of death, were 21% (95% CI 15-27) in probands and 26% (95% CI 19-35) in later-affected siblings at 20 years of diabetes duration, and the respective 30 years' incidences were 37% (95% CI 29-45) and 53% (95% CI 40-64), (P = 0.05, Gray's test). The risk of proliferative retinopathy, adjusted for conventional risk factors, age at onset and sibship size, was higher in later-affected siblings [hazard ratio 1.75 (95% CI 1.13-2.75), P = 0.01] compared with their probands. CONCLUSION: The siblings first affected by Type 1 diabetes had a better long-term prognosis with regards to development of proliferative retinopathy compared with their later-affected siblings.

INPPL1 is associated with the metabolic syndrome in men with Type 1 diabetes, but not with diabetic nephropathy.

AIMS: The metabolic syndrome is a frequent phenomenon in people with Type 1 diabetes and is associated with diabetic nephropathy. The aim of this study was to investigate if the INPPL1 (inositol polyphosphate phosphatase-like 1) gene encoding lipid phosphatase SHIP2 is associated with the metabolic syndrome and diabetic nephropathy in Finnish people with Type 1 diabetes. METHODS: Participants were selected from the FinnDiane study for this cross-sectional study. The individuals were divided into controls without the metabolic syndrome (n = 1074) and cases with the metabolic syndrome (n = 1328), or into groups based upon their albumin excretion rate. Nine single-nucleotide polymorphisms covering the INPPL1 gene +/- 20 kb were genotyped. The associations between the single-nucleotide polymorphisms and outcome variables were analysed with the χ(2) test and logistic regression. RESULTS: Two INPPL1 single-nucleotide polymorphisms, rs2276048 (silent mutation) and rs2276047 (intronic), were associated with the metabolic syndrome in men with odds ratios of 0.23 (95% CI 0.11-0.45, P = 2.1 × 10(-5) ), and 0.37 (0.21-0.65, P = 0.001), adjusted for age, duration of diabetes and history of smoking. When both sexes were included, these associations were less significant. No association between the genotyped single-nucleotide polymorphisms and diabetic nephropathy was observed. CONCLUSIONS: INPPL1 gene variants may contribute to susceptibility to the metabolic syndrome in men with Type 1 diabetes, but not to diabetic nephropathy.

Cumulative cost of prescription medication in outpatients with type 1 diabetes in Finland.

AIMS/HYPOTHESIS: We examined the 11-year cumulative outpatient cost of prescription medication in patients with type 1 diabetes by subgroups according to the presence of complications and duration of diabetes. METHODS: This longitudinal study included a nationally representative cohort of patients with type 1 diabetes (N = 3,717) from the Finnish Diabetic Nephropathy Study (FinnDiane). The data were linked to the Drug Prescription Register. The cumulative cost was calculated between 1998 and 2008. Information on complications was updated until 2008. Patients were divided into 10-year groups according to the duration of diabetes in 1998. Generalised linear mixed models under gamma distribution were used to evaluate the costs. RESULTS: Approximately 25% of the patients had macrovascular disease (MVD) and/or end-stage renal disease (ESRD). The adjusted cumulative cost of medications increased 56% when MVD was present compared with those without complications. In patients with ESRD or with both complications present the cost increased fourfold or 15-fold, respectively, when diabetes medications were excluded. The proportion of renal failure related medications (immunosuppressants, peritoneal dialytics and erythropoietin) accounted for more than 70% of these costs. The cost of diabetes medication was rather stable, irrespective of complication status or duration of diabetes. However, when complications were present these costs were markedly lower in all 10-year duration groups. CONCLUSIONS/INTERPRETATION: This study shows that ESRD has a great impact on outpatient prescription medication costs. Since no considerable differences were observed in the cost of diabetes medication, the increase was completely due to the cost of medications related to comorbidity.

Short-term oxygen administration restores blunted baroreflex sensitivity in patients with type 1 diabetes.

AIMS/HYPOTHESIS: We hypothesised that the blunted baroreflex sensitivity (BRS) typical of type 1 diabetes is caused by a higher degree of tissue hypoxia in diabetes, and tested whether oxygen increased BRS and ventilation less, equally or more than in healthy control participants (the latter suggesting higher tissue hypoxia). In addition, we also considered the possible interference between oxygen and breathing pattern. METHODS: In 96 participants with type 1 diabetes and 40 age-matched healthy controls, we measured BRS (average of six different standard methods), oxygen saturation, end-tidal carbon dioxide and ventilation changes during spontaneous and controlled breathing at 15 and six breaths/min, in normoxia and during 5 l/min oxygen administration. RESULTS: BRS was blunted and blood pressure higher in diabetic participants during spontaneous breathing (p < 0.05). BRS increased with oxygen during spontaneous breathing in diabetic (p < 0.001) but not in control participants, and with oxygen the difference in BRS was no longer significant. Slow breathing in normoxia restored BRS to a similar extent to giving oxygen. Oxygen increased systolic and diastolic blood pressure, RR interval, heart rate variability, minute ventilation and tidal volume to a greater extent in diabetic patients than in controls, and decreased carbon dioxide similarly to controls. CONCLUSIONS/INTERPRETATION: The increased response to hyperoxia suggests a pre-existing condition of tissue hypoxia that functionally restrains parasympathetic activity in patients with type 1 diabetes. Autonomic abnormalities can be partially and temporarily reversed by functional manoeuvres such as slow breathing or oxygen administration through enhancement of parasympathetic activity and/or correction of tissue hypoxia.