Leisure time physical activity is associated with poor glycemic control in type 1 diabetic women: the FinnDiane study.

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 <10 MET h/week, n = 247), moderately active (LTPA 10-40 MET h/week, n = 568), and active (LTPA >40 MET h/week, n = 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 = -0.12, P = 0.007) but not in men (r = -0.03, P = 0.592). Sedentary women had higher HbA(1c) than moderately active and active women: 8.8 +/- 1.4% vs. 8.3 +/- 1.4% vs. 8.3 +/- 1.4% (P = 0.004), whereas HbA(1c) in men was 8.4 +/- 1.3% vs. 8.2 +/- 1.4% vs. 8.2 +/- 1.3% (P = 0.774), respectively. In men, insulin doses were 0.74 +/- 0.21 vs. 0.71 +/- 0.20 vs. 0.68 +/- 0.23 IU . kg(-1) . 24 h(-1) (P = 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 . kg(-1) . min(-1); P < 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.

Serum adiponectin is increased in type 1 diabetic patients with nephropathy.

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 = 66) had no antihypertensive medication, while patients with microalbuminuria (n = 63) or macroalbuminuria (n = 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 +/- 12.0 mg/l) than in patients with microalbuminuria (13.1 +/- 4.8 mg/l) or normoalbuminuria (11.8 +/- 4.2 mg/l). In a univariate analysis, adiponectin was positively associated with creatinine (r = 0.41; P < 0.0001), AER (r = 0.33; P < 0.0001), interleukin-6 (r = 0.22; P = 0.002), systolic blood pressure (r = 0.22; P = 0.004), HbA(1c) (r = 0.17; P = 0.02), total cholesterol (r = 0.16; P = 0.03), and HDL cholesterol (r = 0.16; P = 0.03) and negatively with estimated glomerular filtration rate (GFR; r = -0.52; P < 0.0001) and waist-to-hip ratio (WHR; r = -0.16; P = 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) = 0.32). CONCLUSIONS: Serum adiponectin concentrations are increased in type 1 diabetic patients with nephropathy, and levels are further associated with renal insufficiency.

Metabolic syndrome in type 1 diabetes: association with diabetic nephropathy and glycemic control (the FinnDiane study).

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 = 1,261), microalbuminuria (n = 326), macroalbuminuria (n = 383), or end-stage renal disease (ESRD) (n = 164). Glycemic control was classified as good (HbA1c <7.5%), intermediate (7.5-9.0%), or poor (>9.0%). 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 < 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 < 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.

Altered age-related blood pressure pattern in type 1 diabetes.

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 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 <40 years but lower in those >45 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.

Leucine 7 to proline 7 polymorphism in the preproneuropeptide Y is associated with proteinuria, coronary heart disease, and glycemic control in type 1 diabetic patients.

OBJECTIVE: Neuropeptide Y is a potent vasoconstrictor thought to enhance the development of atherosclerosis. The leucine 7 to proline 7 (Leu7Pro) polymorphism, located in the signal peptide part of the human preproneuropeptide Y, has been associated with serum lipid levels, intima-media thickness of the common carotid arteries, and diabetic retinopathy in type 2 diabetic patients. Therefore, we investigated the impact of the Leu7Pro polymorphism on diabetic nephropathy, cardiovascular risk factors, and cardiovascular disease in type 1 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 996 patients from the Finnish Diabetic Nephropathy study were studied in a case-control, cross-sectional study. The carrier frequency of the Pro7 substitution was 13% in the entire study population. RESULTS: The Pro7 substitution was more common in patients with proteinuria than in those with a normal albumin excretion rate (16 vs. 11%, P < 0.05). Patients with the Pro7 allele had worse glycemic control (HbA(1c) 8.8 vs. 8.5%, P < 0.005), more coronary heart disease (CHD) (14 vs. 8%, P < 0.05), and higher serum triglycerides (1.65 vs. 1.35 mmol/l, P < 0.005) than patients with the wild-type genotype. There were no differences in the plasma neuropeptide Y levels between the patients with Pro7 compared with those with the wild-type genotype. The Leu7Pro polymorphism was independently associated with HbA(1c) (P < 0.001), proteinuria (P < 0.01), and CHD (P < 0.01) in multiple regression analyses. CONCLUSIONS: We conclude that the Leu7Pro polymorphism may contribute to the genetic susceptibility to diabetic nephropathy and CHD in type 1 diabetic patients, possibly by influencing glycemic control and triglycerides.

Association of the SLC22A1, SLC22A2, and SLC22A3 genes encoding organic cation transporters with diabetic nephropathy and hypertension.

BACKGROUND: Diabetic nephropathy (DN) is a severe long-term complication of diabetes characterized by continuous albuminuria, a relentless decline in renal function, and an increased arterial blood pressure. AIMS: Our aim was to find out if single nucleotide polymorphisms (SNPs) within the SLC22A1, SLC22A2, and SLC22A3 genes encoding organic cation transporters (OCTs) associate with DN or hypertension. SUBJECTS AND METHODS: We selected 90 SNPs ( approximately 1 SNP/4 kb) in and surrounding SLC22A1, SLC22A2, and SLC22A3 using the HapMap data. The SNPs were tested for association with DN and hypertension in 1,086 unrelated Finnish patients with type 1 diabetes mellitus (T1DM). Eight of the SNPs were genotyped in 1,252 additional Finnish patients to verify the findings. RESULTS: We detected nominal evidence of association (P < 0.05) between the SLC22A2 (SNPs rs653753, rs596881, and rs316019) and SLC22A3 (SNPs rs376563, rs2048327, rs2457576, and rs1567438) genes and DN and hypertension in Finnish men with T1DM. We were not, however, able to replicate the associations, and none of them reached the significance limit adjusted for multiple testing (P < 0.00009). CONCLUSIONS: There was no clear association between the SLC22A1, SLC22A2, and SLC22A3 genes and DN or hypertension. Although several SLC22A2 and SLC22A3 SNPs indicated association, lack of association was evident after the replication study.

Elevated MBL concentrations are not an indication of association between the MBL2 gene and type 1 diabetes or diabetic nephropathy.

OBJECTIVE: Mannose-binding lectin (MBL) is an essential component of the acute-phase immune response and may thus play a role in the pathogenesis of type 1 diabetes and diabetic nephropathy. The serum concentration of MBL is mainly genetically determined, and elevated concentrations have been associated with both type 1 diabetes and diabetic nephropathy. Previous genetic studies have not been conclusive due to the small number of patients and polymorphisms studied. We investigated whether MBL2 polymorphisms are associated with type 1 diabetes or diabetic nephropathy and whether patients with nephropathy have elevated MBL concentrations as indicated previously. Furthermore, we studied the association between MBL2 polymorphisms and MBL concentration. RESEARCH DESIGN AND METHODS: We genotyped 20 MBL2 single nucleotide polymorphisms (SNPs) in a large, well-characterized Finnish case-control sample consisting of 1,297 patients with type 1 diabetes with or without nephropathy and 701 nondiabetic individuals. The serum concentration of MBL was available for 1,064 patients. RESULTS: We found that 19 SNPs were associated with the MBL concentration (P = 3 x 10(-81)-7 x 10(-4)). MBL concentrations were higher in patients with macroalbuminuria compared with patients without nephropathy even when the patients were stratified by the MBL2 genotypic background in accordance with previous studies. However, no evidence of association between any of the SNPs or their haplotype combinations and type 1 diabetes or diabetic nephropathy was observed. CONCLUSIONS: Although most of the MBL2 SNPs studied were associated with the MBL concentration, no common variations (neither single SNPs nor their haplotype combinations) confer risk of type 1 diabetes or diabetic nephropathy.

Clustering of risk factors in parents of patients with type 1 diabetes and nephropathy.

OBJECTIVE: To assess the impact of parental risk factors for diabetic nephropathy. RESEARCH DESIGN AND METHODS: This cross-sectional study included 2,355 type 1 diabetic patients from the FinnDiane (Finnish Diabetic Nephropathy) study. Diabetic nephropathy was defined as macroalbuminuria (urinary albumin excretion rate >200 microg/min or >300 mg/24 h) or end-stage renal disease. Information was available from 4,676 parents. Parental scores were calculated based on the number of various traits in the parents. RESULTS: Patients with diabetic nephropathy, compared with those without diabetic nephropathy, had a higher prevalence of maternal (41 vs. 35%, P = 0.046) and parental (62 vs. 55%, P = 0.044) hypertension, maternal stroke (7.6 vs. 5.1%, P = 0.044), and maternal (1.4 vs. 0.7%, P = 0.058) and parental (4.3 vs. 2.9%, P = 0.030) type 1 diabetes. If both, compared with none, of the parents had hypertension, the adjusted odds ratio (OR) for diabetic nephropathy in offspring was 1.56 (95% CI 1.13-2.15). The adjusted OR for diabetic nephropathy was 2.13 (1.36-3.33) for the parental hypertension-diabetes score (3-4 vs. 0 points) and 2.13 (1.37-3.33) for the parental hypertension-cardiovascular disease (CVD)-diabetes score (4-6 vs. 0 points). Fathers of patients with diabetic nephropathy, compared with those without diabetic nephropathy, had reduced overall survival (log-rank P = 0.04) and reduced cardiovascular survival (log-rank P = 0.03). CONCLUSIONS: A cluster of parental hypertension, CVD, and diabetes is associated with diabetic nephropathy in type 1 diabetes, as is paternal mortality.

Complex relationship between blood pressure and mortality in type 2 diabetic patients: a follow-up of the Botnia Study.

The presence of hypertension aggravates the high cardiovascular risk in type 2 diabetic patients. Pulse pressure is a marker of arterial stiffness and constitutes a risk factor for cardiovascular mortality. This study examines the relationship between different blood pressure indices and mortality in a cohort of type 2 diabetic patients. A total of 1294 type 2 diabetic patients with a median age of 69.1 years participated in the Botnia Study from 1990 to 1997. In 2004, after a median follow-up of 9.5 years, data on mortality was collected from the national population registry and hospital records. Systolic and diastolic blood pressure correlated negatively with mortality after adjustment for other risk factors. The association between low systolic and diastolic blood pressure and mortality was pronounced in patients with previous cardiovascular disease. A U-shaped association between pulse pressure and mortality was observed in elderly patients. These observations could be linked to arterial stiffness and heart failure. Low blood pressure in high-risk patients is likely to be a marker of poor health rather than the cause of mortality. The results suggest that the role of blood pressure as a risk marker in elderly type 2 diabetic patients with cardiovascular disease needs to be reevaluated.

Low birth weight does not increase the risk of nephropathy in Finnish type 1 diabetic patients.

BACKGROUND: Low birth weight (LBW) has been linked to renal disease both in animal models and human studies. However, the role of birth weight in the development of diabetic nephropathy is unclear. We, therefore, studied the impact of birth weight on the development of diabetic nephropathy and other related traits, such as diabetic retinopathy and macrovascular disease, in Caucasian type 1 diabetic patients. METHODS: Data on size at birth were obtained from original birth certificates in 1543 Finnish patients with type 1 diabetes. The patients were divided into those with low (LBW; below the 10th percentile), normal (NBW; 11-90th percentile) and high birth weight (HBW; above the 90th percentile). RESULTS: Diabetic nephropathy was equally common in the groups with various birth weight (LBW vs NBW vs HBW: 21 vs 20 vs 17%, P = NS). End-stage renal disease (3 vs 5 vs 4%, P = NS), laser-treated retinopathy (31 vs 31 vs 31%, P = NS) and macrovascular disease (5 vs 5 vs 8%, P = NS) were equally prevalent in the various birth weight groups. The time from the onset of diabetes to the onset of diabetic nephropathy was similar irrespective of birth weight (log-rank test; P = NS). CONCLUSIONS: Based on our cross-sectional data, LBW does not have an impact on the development of diabetic nephropathy, laser-treated retinopathy or macrovascular disease later in life in Caucasians with type 1 diabetes.

Dopamine D3 receptor gene polymorphisms, blood pressure and nephropathy in type 1 diabetic patients.

BACKGROUND: Dopamine modulates blood pressure in the kidney. The aim of this study was to investigate whether two previously known (-707 G/C, Ser9Gly) and one novel (Ala17Ala) polymorphism in the dopamine D3 receptor gene and/or their haplotypes are associated with blood pressure, diabetic nephropathy or renal variables in the study subjects. METHODS: A cross-sectional, case-control study with a total of 996 type 1 diabetic patients from the multicentre, nationwide FinnDiane Study. Patients were recruited consecutively and classified into four groups according to their renal status. RESULTS: The frequencies of the genotypes harbouring the minor allele were 33, 51 and 19% for the -707 G/C, Ser9Gly and Ala17Ala polymorphisms, respectively. Frequencies of the -707 G/C minor genotypes were 35 (normoalbuminuria), 32 (microalbuminuria), 28 (proteinuria) and 39% (end-stage renal disease) (chi(2) = 6.3, df = 3, P = 0.1), of the Ser9Gly 52, 51, 46 and 57% (chi(2) = 6.3, df = 3, P = 0.1) and of the Ala17Ala polymorphism 18, 19, 19 and 21% (chi(2) = 0.7, df = 3, P = 0.9), respectively. Five haplotypes were identified, but no differences were seen between those with and without diabetic nephropathy. Furthermore, there were no differences in blood pressure levels nor in any renal variables between genotypes or haplotypes. CONCLUSIONS: These results do not provide evidence for an involvement of the dopamine D3 receptor gene in blood pressure levels or in the pathogenesis of diabetic nephropathy in type 1 diabetic patients.

Birth weight is inversely correlated to adult systolic blood pressure and pulse pressure in type 1 diabetes.

In the general population, there is an inverse relationship between birth weight and adult systolic blood pressure. Because blood pressure in diabetic patients at least in part seems to be regulated by different mechanisms than in nondiabetic subjects, it is not known whether a similar correlation exists in diabetic individuals. Therefore, we obtained data on birth weight from original birth certificates in 1543 type 1 diabetic patients. Blood pressure was measured auscultatorily on a single occasion. In the 1225 patients born at term (after 37 weeks of gestation), the age- and sex-adjusted regression coefficients between systolic blood pressure and birth weight was -1.90 mm Hg/kg (95% confidence interval [CI], -3.71 to -0.09). The finding remained unchanged after adjustment for body mass index, current smoking, duration of diabetes, social class, antihypertensive therapy, glomerular filtration rate, glycemic control, and elevated albuminuria. The regression coefficient between birth weight and pulse pressure was of a similar magnitude. The age-adjusted regression coefficient between systolic blood pressure and birth weight seemed stronger in females (-3.34 mm Hg/kg; 95% CI, -6.06 to -0.62) than in males (-0.42 mm Hg/kg; 95% CI, -2.80 to 1.95), although this difference was not statistically significant. As a new finding, we report an inverse relationship between weight at birth and systolic blood pressure and pulse pressure in adult type 1 diabetic patients. Given the deleterious effects of elevated arterial blood pressure in diabetes, the impact of intrauterine growth retardation on the development of end-organ damage needs to be clarified.