OBJECTIVE -The aim of this study was to estimate the prevalence of the metabolic syndrome in Finnish type 1 diabetic patients and to assess whether it is associated with diabetic nephropathy or poor glycemic control.RESEARCH DESIGN AND METHODS -In all, 2,415 type 1 diabetic patients (51% men, mean age 37 years, duration of diabetes 22 years) participating in the nationwide, multicenter Finnish Diabetic Nephropathy (FinnDiane) study were included. Metabolic syndrome was defined according to the National Cholesterol Education Program diagnostic criteria. Patients were classified as having normal albumin excretion rate (AER) (n ϭ 1,261), microalbuminuria (n ϭ 326), macroalbuminuria (n ϭ 383), or end-stage renal disease (ESRD) (n ϭ 164). Glycemic control was classified as good (HbA 1c Ͻ7.5%), intermediate (7.5-9.0%), or poor (Ͼ9.0%). Creatinine clearance was estimated with the Cockcroft-Gault formula.RESULTS -The overall prevalence of metabolic syndrome was 38% in men and 40% in women. The prevalence was 28% in those with normal AER, 44% in microalbuminuric patients, 62% in macroalbuminuric patients, and 68% in patients with ESRD (P Ͻ 0.001). Patients with metabolic syndrome had a 3.75-fold odds ratio for diabetic nephropathy (95% CI 2.89 -4.85), and all of the separate components of the syndrome were independently associated with diabetic nephropathy. The prevalence of metabolic syndrome was 31% in patients with good glycemic control, 36% in patients with intermediate glycemic control, and 51% in patients with poor glycemic control (P Ͻ 0.001). Similarly, metabolic syndrome increased with worsening creatinine clearance.CONCLUSIONS -The metabolic syndrome is a frequent finding in type 1 diabetes and increases with advanced diabetic nephropathy and worse glycemic control.

Aims/hypothesis. The incidence of Type 1 diabetes has increased 2.5 times during the time period from 1966 to 2000 in Finland -a general trend seen in almost all developed countries that can only be explained by environmental factors. The aim of this study was to test the possible effect of a changing environment on distribution of genotypes associated with disease susceptibility. Methods. HLA DRB1-DQA1-DQB1 genes and two diabetes-associated polymorphisms at IDDM2 and IDDM12 were analyzed. The frequencies of genotypes were compared between cases diagnosed with childhood-onset Type 1 diabetes during the period of 1939-1965 (n=367) and those diagnosed between 1990 and 2001 (n=736). Chi-square statistics or the Fisher's Exact test were used for the comparison of frequencies of analyzed haplotypes and genotypes in the two groups.

OBJECTIVE -To elucidate whether serum adiponectin is associated with renal function, low-grade inflammatory markers, metabolic control, and insulin resistance in type 1 diabetic patients with and without nephropathy. RESEARCH DESIGN AND METHODS-A total of 189 type 1 diabetic patients from the Finnish Diabetic Nephropathy Study were divided into three groups based on their urinary albumin excretion rate (AER): patients with normal AER (n ϭ 66) had no antihypertensive medication, while patients with microalbuminuria (n ϭ 63) or macroalbuminuria (n ϭ 60) were all treated with an ACE inhibitor. Renal function was estimated with the Cockcroft-Gault formula. Adiponectin was measured by an in-house time-resolved immunofluorometric assay.RESULTS -Adiponectin concentrations were higher in women than in men, but since there was no significant difference in sex distribution between the groups, data were pooled. Adiponectin concentrations were higher in patients with macroalbuminuria (19.8 Ϯ 12.0 mg/l) than in patients with microalbuminuria (13.1 Ϯ 4.8 mg/l) or normoalbuminuria (11.8 Ϯ 4.2 mg/l). In a univariate analysis, adiponectin was positively associated with creatinine (r ϭ 0.41; P Ͻ 0.0001), AER (r ϭ 0.33; P Ͻ 0.0001), interleukin-6 (r ϭ 0.22; P ϭ 0.002), systolic blood pressure (r ϭ 0.22; P ϭ 0.004), HbA 1c (r ϭ 0.17; P ϭ 0.02), total cholesterol (r ϭ 0.16; P ϭ 0.03), and HDL cholesterol (r ϭ 0.16; P ϭ 0.03) and negatively with estimated glomerular filtration rate (GFR; r ϭ Ϫ0.52; P Ͻ 0.0001) and waist-to-hip ratio (WHR; r ϭ Ϫ0.16; P ϭ 0.03). In a multiple linear regression analysis including the above variables, estimated GFR, AER, and WHR were independently associated with adiponectin levels (r 2 ϭ 0.32).CONCLUSIONS -Serum adiponectin concentrations are increased in type 1 diabetic patients with nephropathy, and levels are further associated with renal insufficiency. Diabetes Care 28:1410 -1414, 2005D iabetic nephropathy is associated with insulin resistance and low-grade inflammation in type 1 diabetes (1,2). Circulatory levels of adiponectin, a hormone that is secreted exclusively from the adipocytes (3), correlate negatively with insulin resistance (4 -6), serum triglycerides, fasting serum insulin, and fasting plasma glucose concentrations (5-7). Low plasma adiponectin concentrations are found in obesity (8,9), type 2 diabetes (7,8), and in patients with coronary artery disease (7,10). Women have higher adiponectin concentrations than men (6,7), a difference that may be explained by the effect of testosterone (11). Weight reduction increases adiponectin in both diabetic and nondiabetic subjects (7). Interestingly, the thiazolidinediones (peroxisome proliferatoractivated receptor ␥ agonists) have emerged as an effective treatment for insulin-resistant states (12), and one of the mechanisms may be their ability to stimulate adiponectin synthesis (13,14).The fact that adiponectin may have an anti-inflammatory effect is supported by the reciprocal association between adiponectin and C-reactive protein (CRP) in pat...

on behalf of the Finnish Diabetic Nephropathy (FinnDiane) Study Group Background-Pulse pressure (PP) increases with age as a result of arterial stiffening and is a powerful predictor of cardiovascular disease. Type 1 diabetes is associated with excessive cardiovascular mortality and increased arterial stiffness. We examined whether the age-related blood pressure changes in type 1 diabetic patients differ from those of the nondiabetic background population. Methods and Results-We performed a cross-sectional, case-control study of 2988 consecutively selected diabetic subjects and 5486 randomly selected nondiabetic control subjects. Blood pressure was measured twice by mercury sphygmomanometry on a single occasion. Compared with controls, diabetic subjects had a higher systolic blood pressure in all age groups, whereas diastolic blood pressure was higher in those Ͻ40 years but lower in those Ͼ45 years of age. Consequently, diabetic subjects had a higher PP and a higher prevalence of isolated systolic hypertension. The early age-related rise in PP was more pronounced in subjects with diabetic nephropathy but was also evident in diabetic subjects with normal albumin excretion rate. In a multiple regression analysis, PP in diabetic patients was associated with age, male sex, duration of diabetes, and albuminuria. Conclusions-A higher systolic pressure and an earlier decrease in diastolic pressure result in a higher and more rapidly increasing PP in type 1 diabetic patients. Our findings indicate accelerated arterial aging, which may contribute to the higher cardiovascular morbidity and mortality in these patients.

The hyperglycemic milieu in diabetes results in the formation of advanced glycation end products (AGEs) that predominantly act through specific receptors, particularly the receptor for AGEs (RAGE). Two functional polymorphisms in the promoter of the RAGE gene (؊429 T/C and ؊374 T/A) and one in the AGE binding domain in exon 3 (G82S) were studied in 996 Finnish type 1 diabetic patients. In patients with poor metabolic control (HbA 1c >9.5%), the AA genotype of the ؊374 T/A polymorphism was more common in those with a normal albumin excretion rate than in those with proteinuria (30 vs. 10%, P ‫؍‬ 0.01). We observed less coronary heart disease (6 vs. 14%, P < 0.05), acute myocardial infarction (2 vs. 14%, P ‫؍‬ 0.01), and peripheral vascular disease (2 vs. 14%, P < 0.05) in patients with the AA genotype of the ؊374 T/A polymorphism than in those with the TT ؉ TA genotype. Thus, the association between the RAGE ؊374 T/A homozygous AA genotype and cardiovascular disease as well as albumin excretion in type 1 diabetic patients with poor metabolic control suggests a gene-environment interaction in the development of diabetic nephropathy and cardiovascular complications. Diabetes 52:891-894, 2003 E levated arterial blood pressure, proteinuria, progressive decline in renal function, and high cardiovascular morbidity and mortality are clinical characteristics of nephropathy in type 1 diabetic subjects (1,2). The chronic hyperglycemia associated with this condition results in formation and accumulation of irreversible advanced glycation end products (AGEs) that cause a plethora of adverse effects, resulting in dysfunction of the vasculature (3). These include changes in lipid metabolism, platelet function, and extracellular matrix composition (4), effects shown to be mediated by specific AGE binding receptors. The candidate receptor most likely to be involved in these processes is the receptor for AGEs (RAGE). Blockade of AGE/RAGE binding prevents the underlying cellular changes associated with vascular disease and the formation of atherosclerosis in animal models of diabetes (5,6). RAGE is normally expressed at low levels in the vasculature; however, studies of human subjects and animal models of diabetes reveal major upregulation of RAGE in the presence of vascular disease (7,8). The role for RAGE in diabetic renal disease is emphasized by animal models engineered to overexpress RAGE, which develop diabetic nephropathy more rapidly than their nontransgenic counterparts (9).The role for a genetic influence on the pathogenesis is supported by studies that show familial clustering of diabetic nephropathy (10,11), although few genes have been identified as having a role in this disorder. The upregulation and pathogenic effects of RAGE in diabetic vascular disease highlight the RAGE gene as a candidate for involvement in the pathogenesis of nephropathy. The gene for RAGE is located on chromosome 6p21.3 near the HLA locus (12), and at least 30 polymorphisms have been identified (13-16). Most of the polymorphisms are rare codin...

Aims/hypothesis: Diabetic nephropathy is associated with insulin resistance, and low-grade inflammation and activation of the complement system may contribute to this cascade. Mannan-binding lectin (MBL) activates the complement system, and elevated MBL concentrations have been observed in normoalbuminuric type 1 diabetic patients. The aim of this study was to assess whether MBL is associated with diabetic nephropathy in type 1 diabetes, and whether there is an association between MBL and low-grade inflammatory markers or insulin resistance. Methods: A total of 191 type 1 diabetic patients from the Finnish Diabetic Nephropathy Study were divided into three groups based upon their AER. Patients with normal AER (n=67) did not take antihypertensive medication, while patients with microalbuminuria (n=62) or macroalbuminuria (n=62) were all treated with an ACE inhibitor. As a measure of insulin sensitivity we used estimated glucose disposal rate. MBL was measured by an immunofluorometric assay, C-reactive protein by a radioimmunoassay and IL-6 by high-sensitivity enzyme immunoassay. There was a significant correlation between MBL and estimated glucose disposal rate, but not between MBL and C-reactive protein or IL-6 levels in univariate analysis. However, in a multiple regression analysis, HbA1c was the single variable independently associated with MBL (β±SEM: 0.26±0.08; p=0.003). Conclusions/interpretation: MBL concentrations are increased in type 1 diabetic patients with diabetic nephropathy. MBL was not associated with low-grade inflammatory markers.

OBJECTIVE -We studied the association between leisure time physical activity (LTPA) and glycemic control, insulin dose, and estimated glucose disposal rate (eGDR) in type 1 diabetes. RESEARCH DESIGN AND METHODS-This is a cross-sectional study of 1,030 type 1 diabetic patients participating in the Finnish Diabetic Nephropathy Study, a nationwide multicenter study. LTPA was assessed by a validated 12-month questionnaire and expressed in metabolic equivalent (MET) units. Patients were grouped as sedentary (LTPA Ͻ10 MET h/week, n ϭ 247), moderately active (LTPA 10 -40 MET h/week, n ϭ 568), and active (LTPA Ͼ40 MET h/week, n ϭ 215). Outcome measures were HbA 1c , insulin dose, and eGDR (estimate of insulin sensitivity based on waist-to-hip ratio, hypertension, and HbA 1c ).RESULTS -LTPA correlated with HbA 1c in women (r ϭ Ϫ0.12, P ϭ 0.007) but not in men (r ϭ Ϫ0.03, P ϭ 0.592). Sedentary women had higher HbA 1c than moderately active and active women: 8.8 Ϯ 1.4% vs. 8.3 Ϯ 1.4% vs. 8.3 Ϯ 1.4% (P ϭ 0.004), whereas HbA 1c in men was 8.4 Ϯ 1.3% vs. 8.2 Ϯ 1.4% vs. 8.2 Ϯ 1.3% (P ϭ 0.774), respectively. In men, insulin doses were 0.74 Ϯ 0.21 vs. 0.71 Ϯ 0.20 vs. 0.68 Ϯ 0.23 IU ⅐ kg -1 ⅐ 24 h -1 (P ϭ 0.003). In both sexes, sedentary patients had lower eGDRs than active patients [median (interquartile range) 5.5 (4.0 -8.2) vs. 6.8 (4.7-8.8) vs. 6.7 (4.6 -8.6) mg ⅐ kg -1 ⅐ min -1 ; P Ͻ 0.01 for sedentary vs. others]. Age, obesity, smoking, insulin dose, social class, diabetic nephropathy, or cardiovascular disease did not explain the results.CONCLUSIONS -Low levels of LTPA were associated with poor glycemic control in type 1 diabetic women. Men seem to use less insulin when physically active. Increased LTPA levels were associated with increased estimated insulin sensitivity. Longitudinal studies are needed to further clarify the effects of LTPA on type 1 diabetes. Diabetes Care 28:777-782, 2005S everal recent studies have emphasized the importance of physical activity in the prevention of type 2 diabetes (1-4). These studies have shown that progression from the state of impaired glucose tolerance to overt diabetes can be inhibited, or at least postponed, by changing dietary habits and/or increasing the amount of physical activity. In a metaanalysis of 14 studies, exercise resulted in a clinically significant reduction in postintervention HbA 1c in type 2 diabetic patients (5). Type 1 diabetic patients present features of peripheral insulin resistance that can be improved by increasing physical activity (6 -8), rendering a theoretical basis for exercise to also improve glycemic control in type 1 diabetic patients.One recent cross-sectional study (9) and several intervention studies in the 1980s (6,7,10 -17) failed to show any significant improvements in glycemic control by physical activity in type 1 diabetic patients. Only a few studies have shown a positive effect on glycemic control (18 -21). Available studies were, however, limited by small numbers of patients or semiquantitative assessments of physical activity. Therefore,...

Conflicting results have been reported on the relationship between familial predisposition to hypertension and development of diabetic nephropathy in IDDM. In our case-control study, we assessed the prevalence of hypertension among parents of 73 IDDM patients with diabetic nephropathy (DN+; persistent albuminuria > 200 microg/min or > 300 mg/24 h) and 73 IDDM patients without diabetic nephropathy (DN-; urinary albumin excretion < 20 microg/min or < 30 mg/24 h). Arterial hypertension, defined as antihypertensive therapy or a 24-h ambulatory blood pressure (SpaceLabs 90207) > or = 135/85 mmHg, was present in 57% of parents of DN+ patients compared with 41% of parents of DN- patients (P = 0.034; difference 16% [95% CI 1.3-29.6%]). In addition, the cumulative incidence of hypertension was higher among parents of DN+ patients (log-rank test P < 0.001), with a shift toward younger age at onset of hypertension in this group. However, the difference in prevalence of parental hypertension was not evident using office blood pressure measurements (64 vs. 57%; NS; difference 7% [-5.8-20%). Furthermore, patients with DN+ and with antihypertensive therapy in both parents were themselves more frequently treated for hypertension than were patients with DN+ and without parental treatment for hypertension (100 vs. 61%; P = 0.034; difference 39% [21-57%]). In conclusion, familial predisposition to essential hypertension increases the risk of diabetic nephropathy and may also contribute to the development of systemic hypertension in patients with IDDM and diabetic nephropathy.