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Metabolic comorbidities are common in patients with cardiorenal disease; they can cause atherosclerotic cardiovascular disease (ASCVD), speed progression, and adversely affect prognosis. Common comorbidities are Type 2 diabetes mellitus (T2DM), obesity/overweight, chronic kidney disease (CKD), and chronic liver disease. The cardiovascular system, kidneys, and liver are linked to many of the same risk factors (e.g. dyslipidaemia, hypertension, tobacco use, diabetes, and central/truncal obesity), and shared metabolic and functional abnormalities lead to damage throughout these organs via overlapping pathophysiological pathways. The COVID-19 pandemic has further complicated the management of cardiometabolic diseases. Obesity, T2DM, CKD, and liver disease are associated with increased risk of poor outcomes of COVID-19 infection, and conversely, COVID-19 can lead to worsening of pre-existing ASCVD. The high rates of these comorbidities highlight the need to improve recognition and treatment of ASCVD in patients with obesity, insulin resistance or T2DM, chronic liver diseases, and CKD and equally, to improve recognition and treatment of these diseases in patients with ASCVD. Strategies to prevent and manage cardiometabolic diseases include lifestyle modification, pharmacotherapy, and surgery. There is a need for more programmes at the societal level to encourage a healthy diet and physical activity. Many pharmacotherapies offer mechanism-based approaches that can target multiple pathophysiological pathways across diseases. These include sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, selective mineralocorticoid receptor antagonists, and combined glucose-dependent insulinotropic peptide/glucagon-like peptide-1 receptor agonist. Non-surgical and surgical weight loss strategies can improve cardiometabolic disorders in individuals living with obesity. New biomarkers under investigation may help in the early identification of individuals at risk and reveal new treatment targets., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Inorganic polyphosphates are evolutionarily conserved bioactive phosphate polymers found as various chain lengths in all living organisms. In mammals, polyphosphates play a vital role in the regulation of cellular metabolism, coagulation, and inflammation. Long-chain polyphosphates are found along with endotoxins in pathogenic gram-negative bacteria and can participate in bacterial virulence. We aimed to investigate whether exogenously administered polyphosphates modulate human leukocyte function in vitro by treating the cells with 3 different chain lengths of polyphosphates (P14, P100, and P700). The long-chain polyphosphates, P700, had a remarkable capacity to downregulate type I interferon signaling dose dependently in THP1-Dual cells while only a slight elevation could be observed in the NF-κB pathway with the highest dose of P700. P700 treatment decreased lipopolysaccharide-induced IFNβ transcription and secretion, reduced STAT1 phosphorylation, and downregulated subsequent interferon-stimulated gene expression in primary human peripheral blood mononuclear cells. P700 also augmented lipopolysaccharide-induced secretion of IL-1α, IL-1β, IL-4, IL-5, IL-10, and IFNγ. Furthermore, P700 has previously been reported to increase the phosphorylation of several intracellular signaling mediators, such as AKT, mTOR, ERK, p38, GSK3α/β, HSP27, and JNK pathway components, which was supported by our findings. Taken together, these observations demonstrate the extensive modulatory effects P700 has on cytokine signaling and the inhibitory effects specifically targeted to type I interferon signaling in human leukocytes., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Leukocyte Biology.)

Background: We used magnetic resonance imaging (MRI) to study kidney energetics in persons with and without type 1 diabetes (T1D)., Methods: In a cross-sectional study, 15 persons with T1D and albuminuria and 15 non-diabetic controls (CONs) underwent multiparametric MRI (3 Tesla Philips Scanner) to quantify renal cortical and medullary oxygenation (R 2 *, higher values correspond to higher deoxyhaemoglobin concentration), renal perfusion (arterial spin labelling) and renal artery blood flow (phase contrast). Analyses were adjusted for age, sex, systolic blood pressure, plasma haemoglobin, body mass index and estimated glomerular filtration rate (eGFR)., Results: Participants with T1D had a higher median (Q1; Q3) urine albumin creatinine ratio (UACR) than CONs [46 (21; 58) versus 4 (3; 6) mg/g; P  < .0001] and a lower mean ± SD eGFR (73 ± 32 mL/min/1.73 m 2  versus 88 ± 15 mL/min/1.73 m 2 ;   P  = .12), although not significantly. Mean medullary R 2 * was lower in T1D (34 ± 6/s versus 38 ± 5/s; P  < .01) corresponding to a higher oxygenation. R 2 * was not different in the cortex. Cortical perfusion was lower in T1D (163 ± 40 versus 224 ± 49 mL/100 g/min; P  < .001). Renal artery blood flow was lower in T1D than in CONs (360 ± 130 versus 430 ± 113 mL/min; P  = .05). In T1D, lower cortical oxygenation and renal artery blood flow were both associated with higher UACR and lower eGFR ( P  < .05)., Conclusions: Participants with T1D and albuminuria exhibited higher medullary oxygenation than CONs, despite lower cortical perfusion and renal artery blood flow. This might reflect perturbed kidney energetics leading to a higher setpoint of medullary oxygenation in T1D. Lower cortical oxygenation and renal artery blood flow were associated with higher UACR and lower eGFR in T1D., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Context: Obesity prevalence has increased in type 1 diabetes (T1D). However, the relationship between body composition and severe diabetic eye disease (SDED) is unknown., Objective: To investigate the associations between body composition and SDED in adults with T1D., Methods: From 5401 adults with T1D in the Finnish Diabetic Nephropathy Study, we assessed 3468, and 437 underwent dual-energy X-ray absorptiometry for body composition analysis. The composite outcome was SDED, defined as proliferative retinopathy, laser treatment, antivascular endothelial growth factor treatment, diabetic maculopathy, vitreous hemorrhage, and vitrectomy. Logistic regression analysis evaluated the associations between body composition and SDED. Multivariable Cox regression analysis assessed the associations between the anthropometric measures and SDED. Subgroup analysis was performed by stages of albuminuria. The relevance ranking of each variable was based on the z statistic., Results: During a median follow-up of 14.5 (interquartile range 7.8-17.5) years, 886 SDED events occurred. Visceral/android fat ratio was associated with SDED [odds ratio (OR) 1.40, z = 3.13], as well as the percentages of visceral (OR 1.80, z = 2.45) and android fat (OR 1.28, z = 2.08) but not the total body fat percentage. Waist-height ratio (WHtR) showed the strongest association with the SDED risk [hazard ratio (HR) = 1.28, z = 3.73], followed by the waist (HR 1.01, z = 3.03), body mass index (HR 1.03, z = 2.33), and waist-hip ratio (HR 1.15, z = 2.22). The results were similar in normo- and microalbuminuria but not significant in macroalbuminuria. A WHtR ≥ 0.5 increased the SDED risk by 28% at the normo- and microalbuminuria stages., Conclusions: WHtR, a hallmark of central obesity, is associated with SDED in individuals with T1D., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Chronic kidney disease (CKD) shows different clinical features in Types1 (T1D) and 2 diabetes (T2D). Metabolomics have recently provided useful contribution to the identification of biomarkers of CKD progression in either form of the disease. However, no studies have so far compared plasma metabolomics between T1D and T2D in order to identify differential signatures of progression of estimated glomerular filtration rate (eGFR) decline., Methods: We used two large cohorts of T1D (from Finland) and T2D (from Italy) patients followed up to 7 and 3 years, respectively. In both groups, progression was defined as the top quartile of yearly decline in eGFR. Pooled data from the two groups were analysed by univariate and bivariate random forest (RF), and confirmed by bivariate partial least squares (PLS) analysis, the response variables being type of diabetes and eGFR progression., Results: In progressors, yearly eGFR loss was significantly larger in T2D [-5.3 (3.0), median (interquartile range)mL/min/1.73 m2/year] than T1D [-3.7 (3.1) mL/min/1.73 m2/year ; P = 0.018]. Out of several hundreds, bivariate RF extracted 22 metabolites associated with diabetes type (all higher in T1D than T2D except for 5-methylthioadenosine, pyruvate and β-hydroxypyruvate) and 13 molecules associated with eGFR progression (all higher in progressors than non-progressors except for sphyngomyelin). Three of the selected metabolites (histidylphenylalanine, leucylphenylalanine, tryptophylasparagine) showed a significant interaction between disease type and progression. Only eight metabolites were common to both bivariate RF and PLS., Conclusions: Identification of metabolomic signatures of CKD progression is partially dependent on the statistical model. Dual analysis identified molecules specifically associated with progressive renal impairment in both T1D and T2D., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Context: The long-term natural history of diabetic ketoacidosis (DKA) and its risk factors are poorly understood., Objective: To determine the long-term incidence and predictors of DKA in adults with longstanding type 1 diabetes (T1D)., Design: All hospitalizations and deaths due to DKA between 1996 and 2016 were identified in 4758 adults with T1D from the Finnish Diabetic Nephropathy Study (FinnDiane), and a cohort of 16 224 adults with T1D from the Finnish general population., Results: Between 1996 and 2015, there were 1228 DKA events in the FinnDiane participants (1.4/100 person-years) and 4914 DKA events (1.8/100 person-years) in adults with T1D from the general population. The majority were hospitalized only once. There was a modest increase in the frequency of DKA in the FinnDiane over the follow-up (~2.4%/year [95% CI, 0.3-4.5%]; P = 0.03). Predictors of DKA were glucose control, CSII, smoking and alcohol consumption, and raised high-density lipoprotein cholesterol and triacylglycerides. Diabetic nephropathy and renal impairment were associated with DKA; patients with end-stage renal disease, macroalbuminuria, and microalbuminuria had 2.09-fol (95% CI, 1.40-3.12), 1.65-fold (95% CI, 1.23-2.19), and 0.87-fold (95% CI, 0.61-1.24) risk of DKA compared with patients with normal albumin excretion rate, respectively. Patients with an estimated glomerular filtration rate <60 mL/min/1.73 m2 were also more likely to be hospitalized for DKA (HR 1.71 [95% CI, 1.26-2.67])., Conclusions: DKA remains a common cause of hospitalization in individuals with longstanding T1D. These data suggest that the goal to use SGLT2 inhibitors for their vasculo- and renoprotective actions may be problematic, as those most likely to benefit may also have the highest risk for DKA., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: The relationship between body mass index (BMI) and mortality may differ between patients with type 1 diabetes and the general population; it is not known which clinical characteristics modify the relationship., Objective: Our aim was to assess the relationship between BMI and mortality and the interaction with clinically meaningful factors., Design, Setting, and Participants: This prospective study included 5836 individuals with type 1 diabetes from the FinnDiane study., Main Outcome Measure and Methods: We retrieved death data for all participants on 31 December 2015. We estimated the effect of BMI on the risk of mortality using a Cox proportional hazards model with BMI as a restricted cubic spline as well as effect modification by adding interaction terms to the spline., Results: During a median of 13.7 years, 876 individuals died. The relationship between baseline BMI and all-cause mortality was reverse J-shaped. When analyses were restricted to those with normal albumin excretion rate, the relationship was U-shaped. The nadir BMI (BMI with the lowest mortality) was in the normal weight region (24.3 to 24.8 kg/m2); however, among individuals with diabetic nephropathy, the nadir BMI was in the overweight region (25.9 to 26.1 kg/m2). Diabetic nephropathy, diabetes-onset age, and sex modified the relationship between BMI and mortality (Pinteraction < 0.05)., Conclusions: Normal weight is optimal for individuals with type 1 diabetes to delay mortality, whereas underweight might be an indication of underlying complications. Maintaining normal weight may translate into reduced risk of mortality in type 1 diabetes, particularly for individuals of male sex, later diabetes-onset age, and normal albumin excretion rate., (Copyright © 2019 Endocrine Society.)

Context: Insulin resistance could increase insulin requirements in type 1 diabetes (T1D). Current insulin immunoassays do not detect insulin analogs. Kinase insulin receptor (IR) activation (KIRA) bioassays specific for human IR isoforms A (IR-A) and B (IR-B) permit assessment of all circulating insulin bioactivity. We studied whether IR-A and IR-B KIRA assays are related to direct measures of insulin sensitivity or insulin doses in T1D., Design: We evaluated 31 adult patients with T1D (age 45.7 ± 1.6 years, body mass index 28.8 ± 0.7 kg/m2). Serum IR-A and IR-B bioactivities were measured by KIRA bioassays. Insulin sensitivity of glucose production (Ra) was measured by the euglycemic hyperinsulinemic clamp technique in which a low insulin dose (0.4 mU/kg/min for 240 minutes) was combined with D-[3-3H] glucose infusion to measure rates of Ra and utilization and insulin action on antilipolysis from suppression of serum free fatty acids., Results: Baseline circulating IR-A bioactivity was 53 ± 7 pmol/L, and IR-B bioactivity was 81 ± 11 pmol/L. Compared with baseline, insulin infusion significantly increased IR-A (P < 0.001) and IR-B (P < 0.001) bioactivities. Fasting IR-A and IR-B bioactivities were positively related to endogenous Ra (r = 0.44, P = 0.01 and r = 0.38, P < 0.05). Fasting IR-A (r = 0.43, P = 0.02) and IR-B (r = 0.47, P = 0.01) bioactivities were significantly correlated with insulin requirements and glycosylated hemoglobin (IR-A: r = 0.52, P = 0.002; IR-B: r = 0.48, P = 0.006)., Conclusions: Circulating IR-A and IR-B bioactivities are associated with insulin resistance, high insulin requirements, and poor glycemic control in T1D. Measurement of IR bioactivity by KIRA assays provides a tool to assess the amount of biologically active insulin in groups of T1D patients treated with insulin analogs., (Copyright © 2017 Endocrine Society)

The increasing prevalence of chronic kidney disease (CKD) and diabetes over the last decade has resulted in increasing numbers of frail older patients with a combination of these conditions. Current treatment guidelines may not necessarily be relevant for such patients, who are mostly excluded from the trials upon which these recommendations are based. There is a paucity of data upon which to base the management of older patients with CKD. Nearly all current guidelines recommend less-tight glycaemic control for the older population, citing the lack of proven medium-term benefits and concerns about the high short-term risk of hypoglycaemia. However, reports from large landmark trials have shown potential benefits for both microvascular and macrovascular complications, though the relevance of these findings to this specific population is uncertain. The trials have also highlighted potential alternative explanations for the hazards of intensive glycaemic control. These include depression, low endogenous insulin reserve, low body mass index and side effects of the medication. Over the last few years, newer classes of hypoglycaemic drugs with a lower risk of hypoglycaemia have emerged. This article aims to present a balanced view of advantages and disadvantages of intense glycaemic control in this group of patients, which we hope will help the clinician and patient to come to an individualized management approach., (© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Context: Patients with type 2 diabetes (T2D) are at an increased risk of cardiovascular disease., Objective: The objective of the study was to determine whether postprandial hyperglycemia affects arterial function in T2D., Design: A single-center, open-label study of three groups of men were studied: 1) T2D patients with albuminuria (n = 22), 2) T2D patients without albuminuria (n = 24), and 3) nondiabetic controls (n = 25). Patients were randomized to a two-period crossover study schedule, ingesting breakfast, with or without insulin lispro (to induce low or high postprandial glycemia)., Main Outcome Measures: Arterial stiffness was assessed by calculating pulse wave velocity (PWV) and augmentation index using applanation tonometry, and endothelial dysfunction was assessed using peripheral arterial tonometry, 30 minutes before breakfast and up to 240 minutes after breakfast., Results: At baseline, arterial stiffness was increased in patients. When adjusted for age and body mass index, in a combined group of patients with and without albuminuria, brachial PWV was higher during low (P = .032) and high (P = .038) postprandial glycemia vs controls. These differences were driven by the albuminuria group vs controls during low (P = .014) and high (P = .018) postprandial glycemia. No differences were observed in aortic PWV, augmentation index, or peripheral arterial tonometry ratio between patients and controls. Endothelin-1 and IL-6 were higher, and superoxide dismutase was lower, during postprandial hyperglycemia in T2D patients vs controls., Conclusions: In patients with T2D and albuminuria, brachial PWV was higher under postprandial hyperglycemic conditions, relative to controls. These data suggest that hyperglycemia induces an increase in stiffness of intermediate-sized arteries. We found no changes in other parts of the arterial bed.

Objectives: Patients with type 1 diabetes mellitus (T1DM) lack the portal/peripheral insulin gradient, which might diminish insulin stimulation of hepatic lipogenesis and protect against development of nonalcoholic fatty liver disease (NAFLD). We compared liver fat content and insulin sensitivity of hepatic glucose production and lipolysis between overweight T1DM patients and nondiabetic subjects., Materials and Methods: We compared 32 overweight adult T1DM patients and 32 nondiabetic subjects matched for age, body mass index (BMI), and gender. Liver fat content was measured using proton magnetic resonance spectroscopy ((1)H-MRS), body composition by magnetic resonance imaging, and insulin sensitivity using the euglycemic-hyperinsulinemic clamp technique (insulin 0.4 mU/kg · min combined with infusion of D-[3-(3)H]glucose). We also hypothesized that low liver fat might protect from obesity-associated increases in insulin requirements and, therefore, determined insulin requirements across BMI categories in 3164 T1DM patients., Results: Liver fat content was significantly lower in T1DM patients than in nondiabetic subjects (0.6% [25th-75th quartiles, 0.3%-1.1%] vs 9.0% [3.0%-18.0%]; P < .001). The endogenous rate of glucose production (R(a)) during euglycemic hyperinsulinemia was significantly lower (0.4 [-0.7 to 0.8] mg/kg fat-free mass · min vs 0.9 [0.2-1.6] fat-free mass · min; P = .012) and the percent suppression of endogenous Ra by insulin was significantly greater (89% [78%-112%] vs 77% [50%-94%]; p = .009) in T1DM patients than in nondiabetic subjects. Serum nonesterified fatty acid concentrations during euglycemic hyperinsulinemia were significantly lower (78.5 [33.0-155.0] vs 306 [200.0-438.0] μmol/L; P < .001) and the percent suppression of nonesterified fatty acids significantly higher (89.1% [78.6%-93.3%] vs 51.4% [36.5%-71.1%]; P < .001) in T1DM patients than in nondiabetic subjects. Insulin doses were similar across BMI categories., Conclusions: T1DM patients might be protected from steatosis and hepatic insulin resistance. Obesity may not increase insulin requirements in T1DM.

Background: The daily treatment of type 1 diabetes with frequent monitoring of blood glucose levels and nuisance caused by insulin administration may affect patients' health-related quality of life (HRQoL). Type 1 diabetes is further burdened with an increased risk of complications which may additionally reduce a patient's HRQoL. We aimed to assess HRQoL and its association with diabetic complications in a large sample of patients with type 1 diabetes., Methods: Altogether, 1070 patients with type 1 diabetes (46% men, mean age 46 +/- 12 years, diabetes duration 29 +/- 13 years) from the Finnish Diabetic Nephropathy Study (FinnDiane Study) participated in this cross-sectional study. Data on HRQoL were obtained from 1023 patients using the 15D instrument. When studying nephropathy, patients were divided into groups based on their albumin excretion rate. Laser-treated patients were classified as having proliferative retinopathy., Results: The mean 15D score was 0.899 +/- 0.095 with no differences between men and women. HRQoL decreased with increasing age among patients with and without diabetic complications. In the Tobit regression model, macroalbuminuria (-0.036), dialysis (-0.082), renal transplant (-0.053), poor glycemic control (-0.006), ageing (-0.002) and longer diabetes duration (-0.001) explained the reduction in HRQoL. In a corresponding model, the presence of proliferative retinopathy did not have a significant negative influence on HRQoL. Of individual dimensions of the 15D instrument, nephropathy affected all but five dimensions, while retinopathy affected vision, mobility, eating and usual activities., Conclusions: The 15D scores decreased with increasing age. The presence of nephropathy, but not retinopathy, reduced the subjective HRQoL in patients with type 1 diabetes.

Objective: Diabetic nephropathy is associated with low-grade inflammation and activation of the complement system. Defensins, as part of the innate immune system, may play a regulatory role in the complement cascade and may also augment the production of proinflammatory cytokines. The aim of this study was therefore to elucidate whether alpha-defensin is associated with diabetic nephropathy, low-grade inflammation and lipid profiles., Research Design and Methods: Data were obtained from 189 patients with type 1 diabetes selected from the FinnDiane Study. Patients were divided into three groups according to their albumin excretion rate (AER) in three consecutive overnight or 24-h urine collections: normoalbuminuria (AER <20 microg/min or <30 mg/24 h), microalbuminuria (20 200 microg/min or >300 mg/24 h). Alpha-defensin was determined by a novel, solid-phase radioimmunoassay (RIA) based on a monoclonal antibody, which recognizes alpha-defensin isoforms 1-3., Results: Total serum alpha-defensin (-1, -2 and -3) concentrations were higher (P < 0.001) in patients with macroalbuminuria compared to micro- and normoalbuminuria, but no difference was observed between normoalbuminuria and microalbuminuria. In multiple linear regression analysis alpha-defensin was associated with systolic blood pressure (P = 0.032), HDL-cholesterol (P = 0.013), total cholesterol (P = 0.008), age (P = 0.001) and estimated glomerular filtration rate (P = 0.001), but not with low-grade inflammatory markers. CONCLUSIONS; Serum alpha-defensin (-1, -2 and -3) concentrations are increased in type 1 diabetic patients with diabetic nephropathy.

Background: Diabetic nephropathy is likely to be a complex genetic trait. To date, most diabetic nephropathy candidate gene studies have tested a limited number of genes and variants in small sized populations, or in populations that were poorly matched or phenotyped. The main objective of the EURAGEDIC study was to address these problems., Methods: Single nucleotide polymorphisms (SNPs) in candidate genes were tested for association with overt diabetic nephropathy (persistent albuminuria >300 mg/24 h) in a large (n=2499) Type 1 diabetes case/control study. Testing for transmission disequilibrium in 541 independent parent-offspring trios with or without diabetic nephropathy was applied for validation of consistency. Candidate genes were selected based on previous linkage studies, knowledge of metabolic pathways, and animal models. A comprehensive SNP discovery in more than 100 candidate genes was performed by direct sequencing., Results: In total, 1176 cases with diabetic nephropathy and 1323 diabetic controls with longstanding normoalbuminuria were included from three European populations (Denmark, Finland, France). Data were collected on HbA(1c), blood pressure, urinary albumin excretion rate, kidney function, retinopathy, smoking, medication and cardiovascular disease. To summarize the relevant non-genetic predictors for diabetic nephropathy a baseline phenotypic model fitted to EURAGEDIC data included the covariates: sex, diabetes duration, HbA(1c) and smoking as well as pair-wise interactions., Conclusions: The EURAGEDIC study is designed and powered to identify and validate common alleles as genetic risk factors for diabetic nephropathy in 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.

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.

Background: Insulin resistance has been associated with hypertension and with renal complications in patients with type 1 diabetes mellitus. Causal relationships have not been fully explained., Methods: We investigated whether insulin resistance precedes microalbuminuria by measuring insulin resistance with a euglycaemic clamp in combination with indirect calorimetry in 16 uncomplicated type 1 diabetic patients and in six healthy control subjects. The patients had over 10 year duration of diabetes, and were expected to experience either a complication-free or complicated disease course within the next few years. They have thereafter been followed for the development of microalbuminuria for 3 years., Results: In a euglycaemic insulin clamp glucose disposal was lower in diabetic patients compared with control subjects (7.5 +/- 2.9 and 12.6 +/- 2.0 mg/kg LBM/min; P<0.002), mainly due to impaired glucose storage (4.3 +/- 2.3 vs 8.6 +/- 1.6 mg/kg LBM/min; P<0.001). Three years later seven IDDM patients had albumin excretion rate over 30 mg/24 h; glucose disposal (5.5 +/- 2.1 vs 9.0 +/- 2.2 mg/kg LBM/min; P<0.01) had been lower in patients who developed microalbuminuria compared with those who remained normoalbuminuric., Conclusions: Insulin resistance predicts the increment in urinary albumin excretion. Insulin resistance depends mainly on impaired glucose storage in uncomplicated IDDM.

Background: Human idiopathic membranous glomerulonephritis (MGN) has a highly variable clinical course and factors determining its outcome are poorly known. Since transforming growth factor-beta 1 (TGF-beta 1) has an essential role in renal fibrogenesis, we studied the possibility to use urinary excretion of TGF-beta 1 in the assessment of progression of the disease in patients with MGN., Methods: Urinary TGF-beta 1 was determined in 41 patients with MGN, 25 healthy subjects, six non-proteinuric renal transplant patients, 10 patients with IgA glomerulonephritis, and seven proteinuric patients (with non-progressive diseases) using a novel, double antibody enzyme immunoassay. The results were compared with renal morphology and clinical indices of activity of MGN over 12 months., Results: The median urinary TGF-beta 1 excretion (pg/mg creatinine) was significantly higher (1730; range 60-16,970) in MGN patients than in the healthy controls (300; 30-1330; P < 0.0001). In renal allograft recipients the excretion was 840 (250-3440; P < 0.0001 vs healthy controls), in IgA GN it was 1130 (30-4910; P = 0.039), and in proteinuric patients it was 39 (29-165; P = NS). In MGN but not in the proteinuric controls or renal allograft recipients, urinary TGF-beta 1 correlated with urinary albumin excretion (r = 0.86, P < 0.0001) but no correlation with renal function or the duration of the disease was found. Urinary TGF-beta 1 at renal biopsy correlated with interstitial cellular inflammation and its excretion 1 year before the biopsy correlated with indices of sclerosis/fibrosis. Immunosuppressive therapy significantly decreased urinary TGF-beta 1 from 2800 (1610-16,960) to 840 (170-1600) pg/mg creatinine (P = 0.028). Patients with persistent nephrotic syndrome and/or declining renal function had a higher initial TGF-beta 1 excretion (median 3680; 1830-7420 pg/mg creatinine) than those entering partial or complete remission (1060; 60-1960; P = 0.003) within 12 months from sampling.