Publications by authors named "Per-Henrik Groop"

302 Publications

Nut Consumption Is Associated with Lower Risk of Metabolic Syndrome and Its Components in Type 1 Diabetes.

Nutrients 2021 Oct 30;13(11). Epub 2021 Oct 30.

Folkhälsan Institute of Genetics, Folkhälsan Research Center, 00290 Helsinki, Finland.

Although nut consumption has been associated with several health benefits, it has not been investigated in individuals with type 1 diabetes. Therefore, our aim was to assess nut consumption and its association with metabolic syndrome in adult individuals with type 1 diabetes taking part in the Finnish Diabetic Nephropathy Study. The nut intake of the 1058 participants was assessed from 3-day food records that were completed twice, and the number of weekly servings, assuming a serving size of 28.4 g, was calculated. Metabolic syndrome was defined as the presence of ≥3 of the cardiovascular risk factors: central obesity, high blood pressure (≥130/85 mmHg or use of antihypertensive medication), high triglyceride concentration (≥1.70 mmol/L or use of lipid-lowering medication), low HDL-cholesterol concentration (<1.00 mmol/L in men and <1.30 mmol/L in women or use of lipid-lowering medication), and hyperglycaemia. Overweight/obesity was defined as a BMI ≥25 kg/m. HbA > 59 mmol/mol (>7.5%) was used as a criterion for suboptimal glycaemic control. Of the 1058 (mean age 46 years, 41.6% men) participants, 689 (54.1%) reported no nut intake. In the remaining sample, the median weekly nut intake was 40.8 g. In the adjusted models, higher nut intake, as the continuous number of weekly servings and the comparison of those with <2 and ≥2 weekly servings, was associated with lower metabolic syndrome score, waist circumference, HbA, and BMI. Nut consumption as a continuous variable was negatively associated with the presence of metabolic syndrome, its blood pressure, triglyceride, and HDL-cholesterol components, and suboptimal glycaemic control. Consumption of ≥2 weekly servings was associated with lower odds of suboptimal glycaemic control (by 51.5%), overweight/obesity (by 33.4%), and metabolic syndrome (by 51.8%) and meeting the waist (by 37.3%), blood pressure (by 44.5%), triglyceride (by 37.7%), and HDL-cholesterol (by 36.2%) components of the metabolic syndrome. In conclusion, a weekly nut intake of ≥2 servings was beneficially associated with all the components of the metabolic syndrome in type 1 diabetes. The causality of this association will need to be investigated.
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http://dx.doi.org/10.3390/nu13113909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8620387PMC
October 2021

Apolipoprotein C-III predicts cardiovascular events and mortality in individuals with type 1 diabetes and albuminuria.

J Intern Med 2021 Nov 24. Epub 2021 Nov 24.

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.

Objectives: We studied apolipoprotein C-III (apoC-III) in relation to diabetic kidney disease (DKD), cardiovascular outcomes, and mortality in type 1 diabetes.

Methods: The cohort comprised 3966 participants from the prospective observational Finnish Diabetic Nephropathy Study. Progression of DKD was determined from medical records. A major adverse cardiac event (MACE) was defined as acute myocardial infarction, coronary revascularization, stroke, or cardiovascular mortality through 2017. Cardiovascular and mortality data were retrieved from national registries.

Results: ApoC-III predicted DKD progression independent of sex, diabetes duration, blood pressure, HbA , smoking, LDL-cholesterol, lipid-lowering medication, DKD category, and remnant cholesterol (hazard ratio [HR] 1.43 [95% confidence interval 1.05-1.94], p = 0.02). ApoC-III also predicted the MACE in a multivariable regression analysis; however, it was not independent of remnant cholesterol (HR 1.05 [0.81-1.36, p = 0.71] with remnant cholesterol; 1.30 [1.03-1.64, p = 0.03] without). DKD-specific analyses revealed that the association was driven by individuals with albuminuria, as no link between apoC-III and the outcome was observed in the normal albumin excretion or kidney failure categories. The same was observed for mortality: Individuals with albuminuria had an adjusted HR of 1.49 (1.03-2.16, p = 0.03) for premature death, while no association was found in the other groups. The highest apoC-III quartile displayed a markedly higher risk of MACE and death than the lower quartiles; however, this nonlinear relationship flattened after adjustment.

Conclusions: The impact of apoC-III on MACE risk and mortality is restricted to those with albuminuria among individuals with type 1 diabetes. This study also revealed that apoC-III predicts DKD progression, independent of the initial DKD category.
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http://dx.doi.org/10.1111/joim.13412DOI Listing
November 2021

Glycemic control is not related to cerebral small vessel disease in neurologically asymptomatic individuals with type 1 diabetes.

Acta Diabetol 2021 Nov 15. Epub 2021 Nov 15.

Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Aims: To determine if medium- and long-term blood glucose control as well as glycemic variability, which are known to be strong predictors of vascular complications, are associated with underlying cerebral small vessel disease (cSVD) in neurologically asymptomatic individuals with type 1 diabetes.

Methods: A total of 189 individuals (47.1% men; median age 40.0, IQR 33.0-45.2 years) with type 1 diabetes (median diabetes duration of 21.7, IQR 18.3-30.7 years) were enrolled in a cross-sectional retrospective study, as part of the Finnish Diabetic Nephropathy (FinnDiane) Study. Glycated hemoglobin (HbA) values were collected over the course of ten years before the visit including a clinical examination, biochemical sampling, and brain magnetic resonance imaging. Markers of glycemic control, measured during the visit, included HbA, fructosamine, and glycated albumin.

Results: Signs of cSVD were present in 66 (34.9%) individuals. Medium- and long-term glucose control and glycemic variability did not differ in individuals with signs of cSVD compared to those without. Further, no difference in any of the blood glucose variables and cSVD stratified for cerebral microbleeds (CMBs) or white matter hyperintensities were detected. Neither were numbers of CMBs associated with the studied glucose variables. Additionally, after dividing the studied variables into quartiles, no association with cSVD was observed.

Conclusions: We observed no association between glycemic control and cSVD in neurologically asymptomatic individuals with type 1 diabetes. This finding was unexpected considering the large number of signs of cerebrovascular pathology in these people after two decades of chronic hyperglycemia and warrants further studies searching for underlying factors of cSVD.
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http://dx.doi.org/10.1007/s00592-021-01821-8DOI Listing
November 2021

Urinary metabolite profiling and risk of progression of diabetic nephropathy in 2670 individuals with type 1 diabetes.

Diabetologia 2021 Oct 22. Epub 2021 Oct 22.

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.

Aims/hypothesis: This prospective, observational study examines associations between 51 urinary metabolites and risk of progression of diabetic nephropathy in individuals with type 1 diabetes by employing an automated NMR metabolomics technique suitable for large-scale urine sample collections.

Methods: We collected 24-h urine samples for 2670 individuals with type 1 diabetes from the Finnish Diabetic Nephropathy study and measured metabolite concentrations by NMR. Individuals were followed up for 9.0 ± 5.0 years until their first sign of progression of diabetic nephropathy, end-stage kidney disease or study end. Cox regressions were performed on the entire study population (overall progression), on 1999 individuals with normoalbuminuria and 347 individuals with macroalbuminuria at baseline.

Results: Seven urinary metabolites were associated with overall progression after adjustment for baseline albuminuria and chronic kidney disease stage (p < 8 × 10): leucine (HR 1.47 [95% CI 1.30, 1.66] per 1-SD creatinine-scaled metabolite concentration), valine (1.38 [1.22, 1.56]), isoleucine (1.33 [1.18, 1.50]), pseudouridine (1.25 [1.11, 1.42]), threonine (1.27 [1.11, 1.46]) and citrate (0.84 [0.75, 0.93]). 2-Hydroxyisobutyrate was associated with overall progression (1.30 [1.16, 1.45]) and also progression from normoalbuminuria (1.56 [1.25, 1.95]). Six amino acids and pyroglutamate were associated with progression from macroalbuminuria.

Conclusions/interpretation: Branched-chain amino acids and other urinary metabolites were associated with the progression of diabetic nephropathy on top of baseline albuminuria and chronic kidney disease. We found differences in associations for overall progression and progression from normo- and macroalbuminuria. These novel discoveries illustrate the utility of analysing urinary metabolites in entire population cohorts.
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http://dx.doi.org/10.1007/s00125-021-05584-3DOI Listing
October 2021

Genetic Profile of Endotoxemia Reveals an Association With Thromboembolism and Stroke.

J Am Heart Assoc 2021 Nov 20;10(21):e022482. Epub 2021 Oct 20.

Oral and Maxillofacial Diseases University of Helsinki and Helsinki University Hospital Helsinki Finland.

Background Translocation of lipopolysaccharide from gram-negative bacteria into the systemic circulation results in endotoxemia. In addition to acute infections, endotoxemia is detected in cardiometabolic disorders, such as cardiovascular diseases and obesity. Methods and Results We performed a genome-wide association study of serum lipopolysaccharide activity in 11 296 individuals from 6 different Finnish study cohorts. Endotoxemia was measured by limulus amebocyte lysate assay in the whole population and by 2 other techniques (Endolisa and high-performance liquid chromatography/tandem mass spectrometry) in subpopulations. The associations of the composed genetic risk score of endotoxemia and thrombosis-related clinical end points for 195 170 participants were analyzed in FinnGen. Lipopolysaccharide activity had a genome-wide significant association with 741 single-nucleotide polymorphisms in 5 independent loci, which were mainly located at genes affecting the contact activation of the coagulation cascade and lipoprotein metabolism and explained 1.5% to 9.2% of the variability in lipopolysaccharide activity levels. The closest genes included , , , , , , , , , and . The genetic risk score of endotoxemia was associated with deep vein thrombosis, pulmonary embolism, pulmonary heart disease, and venous thromboembolism. Conclusions The biological activity of lipopolysaccharide in the circulation (ie, endotoxemia) has a small but highly significant genetic component. Endotoxemia is associated with genetic variation in the contact activation pathway, vasoactivity, and lipoprotein metabolism, which play important roles in host defense, lipopolysaccharide neutralization, and thrombosis, and thereby thromboembolism and stroke.
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http://dx.doi.org/10.1161/JAHA.121.022482DOI Listing
November 2021

Urinary extracellular vesicles: Assessment of pre-analytical variables and development of a quality control with focus on transcriptomic biomarker research.

J Extracell Vesicles 2021 10;10(12):e12158

Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.

Urinary extracellular vesicles (uEV) are a topical source of non-invasive biomarkers for health and diseases of the urogenital system. However, several challenges have become evident in the standardization of uEV pipelines from collection of urine to biomarker analysis. Here, we studied the effect of pre-analytical variables and developed means of quality control for uEV isolates to be used in transcriptomic biomarker research. We included urine samples from healthy controls and individuals with type 1 or type 2 diabetes and normo-, micro- or macroalbuminuria and isolated uEV by ultracentrifugation. We studied the effect of storage temperature (-20°C vs. -80°C), time (up to 4 years) and storage format (urine or isolated uEV) on quality of uEV by nanoparticle tracking analysis, electron microscopy, Western blotting and qPCR. Urinary EV RNA was compared in terms of quantity, quality, and by mRNA or miRNA sequencing. To study the stability of miRNA levels in samples isolated by different methods, we created and tested a list of miRNAs commonly enriched in uEV isolates. uEV and their transcriptome were preserved in urine or as isolated uEV even after long-term storage at -80°C. However, storage at -20°C degraded particularly the GC-rich part of the transcriptome and EV protein markers. Transcriptome was preserved in RNA samples extracted with and without DNAse, but read distributions still showed some differences in e.g. intergenic and intronic reads. MiRNAs commonly enriched in uEV isolates were stable and concordant between different EV isolation methods. Analysis of never frozen uEV helped to identify surface characteristics of particles by EM. In addition to uEV, qPCR assays demonstrated that uEV isolates commonly contained polyoma viruses. Based on our results, we present recommendations how to store and handle uEV isolates for transcriptomics studies that may help to expedite standardization of the EV biomarker field.
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http://dx.doi.org/10.1002/jev2.12158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517090PMC
October 2021

Circulating CD5L is associated with cardiovascular events and all-cause mortality in individuals with chronic kidney disease.

Aging (Albany NY) 2021 10 10;13(19):22690-22709. Epub 2021 Oct 10.

Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau and Sant Pau Biomedical Research Institute (IIB Sant Pau), Barcelona 08041, Spain.

This study assessed the association of CD5L and soluble CD36 (sCD36) with the risk of a cardiovascular event (CVE), including CV death and all-cause mortality in CKD. We evaluated the association of CD5L and sCD36 with a predefined composite CV endpoint (unstable angina, myocardial infarction, transient ischemic attack, cerebrovascular accident, congestive heart failure, arrhythmia, peripheral arterial disease [PAD] or amputation by PAD, aortic aneurysm, or death from CV causes) and all-cause mortality using Cox proportional hazards regression, adjusted for CV risk factors. The analysis included 1,516 participants free from pre-existing CV disease followed up for 4 years. The median age was 62 years, 38.8% were female, and 26.8% had diabetes. There were 98 (6.5%) CVEs and 72 (4.8%) deaths, of which 26 (36.1%) were of CV origin. Higher baseline CD5L concentration was associated with increased risk of CVE (HR, 95% CI, 1.17, 1.0-1.36), and all-cause mortality (1.22, 1.01-1.48) after adjusting for age, sex, diabetes, systolic blood pressure, dyslipidemia, waist circumference, smoking, and CKD stage. sCD36 showed no association with adverse CV outcomes or mortality. Our study showed for the first time that higher concentrations of CD5L are associated with future CVE and all-cause mortality in individuals with CKD.
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http://dx.doi.org/10.18632/aging.203615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8544330PMC
October 2021

Genome-Wide Association Study of Peripheral Artery Disease.

Circ Genom Precis Med 2021 10 4;14(5):e002862. Epub 2021 Oct 4.

Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health (A.S., J.C.H.), University of Oxford, United Kingdom.

Background: Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in the contexts of diabetes and smoking status.

Methods: We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. Next, we ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD by diabetic or smoking status.

Results: We identified 5 genome-wide significant ( ≤5×10) associations with PAD in 449 548 (N=12 086) individuals of European ancestry near ) loci (which overlapped previously reported associations). Meta-analysis with variants previously associated with PAD showed that 18 of 19 published variants remained genome-wide significant. In individuals with diabetes, rs116405693 at the ) locus was associated with PAD (odds ratio [95% CI], 1.51 [1.32-1.74], =2.5×10, =5.3×10). Furthermore, in smokers, rs12910984 at the locus was associated with PAD (odds ratio [95% CI], 1.15 [1.11-1.19], =9.3×10, =3.9×10).

Conclusions: Our analyses confirm the published genetic associations with PAD and identify novel variants that may influence susceptibility to PAD in the context of diabetes or smoking status.
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http://dx.doi.org/10.1161/CIRCGEN.119.002862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542067PMC
October 2021

Waist-height ratio and the risk of severe diabetic eye disease in type 1 diabetes: a 15-year cohort study.

J Clin Endocrinol Metab 2021 Sep 11. Epub 2021 Sep 11.

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.

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, anti-VEGF 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 (IQR 7.8-17.5) years, 886 SDED events occurred. Visceral/android fat ratio was associated with SDED (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 showed the strongest association with the SDED risk (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 type 1 diabetes.
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http://dx.doi.org/10.1210/clinem/dgab671DOI Listing
September 2021

Cerebral small-vessel disease is associated with the severity of diabetic retinopathy in type 1 diabetes.

BMJ Open Diabetes Res Care 2021 08;9(1)

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.

Introduction: Cerebral small-vessel disease is common in neurologically asymptomatic individuals with type 1 diabetes. The retinal vasculature is thought to mirror the brain's vasculature, but data on this association are limited in type 1 diabetes. Our aim was to study associations between diabetic retinopathy severity and cerebral small-vessel disease in type 1 diabetes.

Research Design And Methods: For this cross-sectional study, we enrolled 189 participants with type 1 diabetes (median age 40 (33-45) years; 53% female; diabetes duration 21.6 (18.2-30.7) years) and 29 healthy age-matched and sex-matched controls as part of the Finnish Diabetic Nephropathy Study. Participants underwent a clinical investigation, brain MRI, and fundus imaging. Signs of cerebral small-vessel disease in brain MRIs were analyzed in relation to diabetic retinopathy severity (Early Treatment Diabetic Retinopathy Study (ETDRS) score).

Results: In type 1 diabetes, participants with cerebral small-vessel disease had higher ETDRS scores (35 (20-61) vs 20 (20-35), p=0.022) and a higher prevalence of proliferative diabetic retinopathy than those without cerebral small-vessel disease (25% vs 9%, p=0.002). In adjusted analysis, proliferative diabetic retinopathy was associated with cerebral small-vessel disease (OR 2.57 (95% CI 1.04 to 6.35)). Median ETDRS score (35 (20-65) vs 20 (20-35), p=0.024) and proliferative diabetic retinopathy prevalence were higher (29% vs 13%, p=0.002) in participants with versus without cerebral microbleeds. ETDRS scores increased by number of cerebral microbleeds (p=0.001), both ETDRS score (OR 1.05 (95% CI 1.02 to 1.09)) and proliferative diabetic retinopathy (8.52 (95% CI 1.91 to 37.94)) were associated with >2 cerebral microbleeds in separate multivariable analysis. We observed no association with white matter hyperintensities or lacunar infarcts.

Conclusions: Presence of cerebral small-vessel disease on brain MRI, particularly cerebral microbleeds, is associated with the severity of diabetic retinopathy.
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http://dx.doi.org/10.1136/bmjdrc-2021-002274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386215PMC
August 2021

Primary kidney disease modifies the effect of comorbidities on kidney replacement therapy patients' survival.

PLoS One 2021 20;16(8):e0256522. Epub 2021 Aug 20.

Finnish Registry for Kidney Diseases, Helsinki, Finland.

Background: Comorbidities are associated with increased mortality among patients receiving long-term kidney replacement therapy (KRT). However, it is not known whether primary kidney disease modifies the effect of comorbidities on KRT patients' survival.

Methods: An incident cohort of all patients (n = 8696) entering chronic KRT in Finland in 2000-2017 was followed until death or end of 2017. All data were obtained from the Finnish Registry for Kidney Diseases. Information on comorbidities (coronary artery disease, peripheral vascular disease, left ventricular hypertrophy, heart failure, cerebrovascular disease, malignancy, obesity, underweight, and hypertension) was collected at the start of KRT. The main outcome measure was relative risk of death according to comorbidities analyzed in six groups of primary kidney disease: type 2 diabetes, type 1 diabetes, glomerulonephritis (GN), polycystic kidney disease (PKD), nephrosclerosis, and other or unknown diagnoses. Kaplan-Meier estimates and Cox regression were used for survival analyses.

Results: In the multivariable model, heart failure increased the risk of death threefold among PKD and GN patients, whereas in patients with other kidney diagnoses the increased risk was less than twofold. Obesity was associated with worse survival only among GN patients. Presence of three or more comorbidities increased the age- and sex-adjusted relative risk of death 4.5-fold in GN and PKD patients, but the increase was only 2.5-fold in patients in other diagnosis groups.

Conclusions: Primary kidney disease should be considered when assessing the effect of comorbidities on survival of KRT patients as it varies significantly according to type of primary kidney disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256522PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378722PMC
August 2021

Identifying volatile in vitro biomarkers for oral bacteria with proton-transfer-reaction mass spectrometry and gas chromatography-mass spectrometry.

Sci Rep 2021 08 19;11(1):16897. Epub 2021 Aug 19.

Department of Chemistry, University of Helsinki, Helsinki, Finland.

We have measured the volatile fingerprints of four pathogenic oral bacteria connected to periodontal disease and dental abscess: Porphyromonas gingivalis (three separate strains), Prevotella intermedia, Prevotella nigrescens and Tannerella forsythia. Volatile fingerprints were measured in vitro from the headspace gas of the bacteria cultured on agar. Concrete identification of new and previously reported bacterial volatiles were performed by a combination of solid phase microextraction (SPME) and offline gas chromatography-mass spectrometry (GC-MS). We also studied the effect of the reduced electric field strength (E/N) on the fragmentation patterns of bacterial volatiles in online proton-transfer-reaction time-of-flight mass spectrometry (PTR-ToF-MS). We aimed to discover possible new biomarkers for the studied oral bacteria, as well as to validate the combination of GC-MS and PTR-MS for volatile analysis. Some of the most promising compounds produced include: 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), indole, and a cascade of sulphur compounds, such as methanethiol, dimethyl disulphide (DMDS) and dimethyl trisulphide (DMTS). We also found that several compounds, especially alcohols, aldehydes and esters, fragment significantly with the PTR-MS method, when high E/N values are used. We conclude that the studied oral bacteria can be separated by their volatile fingerprints in vitro, which could have importance in clinical and laboratory environments. In addition, using softer ionization conditions can improve the performance of the PTR-MS method in the volatile analysis of certain compounds.
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http://dx.doi.org/10.1038/s41598-021-96287-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377122PMC
August 2021

Acute effects of dapagliflozin on renal oxygenation and perfusion in type 1 diabetes with albuminuria: A randomised, double-blind, placebo-controlled crossover trial.

EClinicalMedicine 2021 Jul 28;37:100895. Epub 2021 Jun 28.

Steno Diabetes Center Copenhagen, Denmark.

Background: Inhibitors of the sodium-glucose cotransporter 2 (SGLT2) slow the progression of diabetic kidney disease, possibly by reducing the proximal tubule transport workload with subsequent improvement of renal oxygenation. We aimed to test this hypothesis in individuals with type 1 diabetes and albuminuria.

Methods: A randomised, double-blind, placebo-controlled, crossover trial with a single 50 mg dose of the SGLT2 inhibitor dapagliflozin and placebo in random order, separated by a two-week washout period. Magnetic resonance imaging (MRI) was used to assess renal R* (a low value corresponds to a high tissue oxygenation), renal perfusion (arterial spin labelling) and renal artery flow (phase contrast imaging) at baseline, three- and six hours from tablet ingestion. Exploratory outcomes, including baroreflex sensitivity, peripheral blood oxygen saturation, peripheral blood mononuclear cell mitochondrial oxygen consumption rate, and biomarkers of inflammation were evaluated at baseline and 12 h from medication. The study is registered in the EU Clinical Trials Register (EudraCT 2019-004,557-92), on ClinicalTrials.gov (NCT04193566), and is completed.

Findings: Between February 3, 2020 and October 23, 2020, 31 individuals were screened, and 19 eligible individuals were randomised. Three dropped out before receiving any of the interventions and one dropped out after receiving only placebo. We included 15 individuals (33% female) in the per-protocol analysis with a mean age of 58 (SD 14) years, median urinary albumin creatinine ratio of 46 [IQR 21-58] mg/g and an eGFR of 73 (32) ml/min/1·73m. The mean changes in renal cortical R* from baseline to six hours were for dapagliflozin -1·1 (SD 0·7) s and for placebo +1·3 (0·7) s, resulting in a difference between interventions of -2·3 s [95% CI -4·0 to -0·6];  = 0·012. No between-intervention differences were found in any other MRI outcomes, physiological parameters or exploratory outcomes. There were no adverse events.

Interpretation: A single dose of 50 mg dapagliflozin acutely improved renal cortical R* without changing renal perfusion or blood flow. This suggests improved renal cortical oxygenation due to a reduced tubular transport workload in the proximal tubules. Such improved oxygenation may in part explain the long-term beneficial renal effects seen with SGLT2 inhibitors, but it remains to be determined whether the observed effects can be achieved with lower doses, with chronic treatment and if they occur in type 2 diabetes as well.
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http://dx.doi.org/10.1016/j.eclinm.2021.100895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8343250PMC
July 2021

The impact of central obesity on the risk of hospitalization or death due to heart failure in type 1 diabetes: a 16-year cohort study.

Cardiovasc Diabetol 2021 07 27;20(1):153. Epub 2021 Jul 27.

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.

Background: Obesity and type 2 diabetes are well-known risk factors for heart failure (HF). Although obesity has increased in type 1 diabetes, studies regarding HF in this population are scarce. Therefore, we investigated the impact of body fat distribution on the risk of HF hospitalization or death in adults with type 1 diabetes at different stages of diabetic nephropathy (DN).

Methods: From 5401 adults with type 1 diabetes in the Finnish Diabetic Nephropathy Study, 4668 were included in this analysis. The outcome was HF hospitalization or death identified from the Finnish Care Register for Health Care or the Causes of Death Register until the end of 2017. DN was based on urinary albumin excretion rate. A body mass index (BMI)  ≥  30 kg/m defined general obesity, whilst WHtR  ≥  0.5 central obesity. Multivariable Cox regression was used to explore the associations between central obesity, general obesity and the outcome. Then, subgroup analyses were performed by DN stages. Z statistic was used for ranking the association.

Results: During a median follow-up of 16.4 (IQR 12.4-18.5) years, 323 incident cases occurred. From 308 hospitalizations due to HF, 35 resulted in death. Further 15 deaths occurred without previous hospitalization. The WHtR showed a stronger association with the outcome [HR  1.51, 95% CI (1.26-1.81), z  =  4.40] than BMI [HR 1.05, 95% CI (1.01-1.08), z = 2.71]. HbA [HR 1.35, 95% CI (1.24-1.46), z = 7.19] was the most relevant modifiable risk factor for the outcome whereas WHtR was the third. Individuals with microalbuminuria but no central obesity had a similar risk of the outcome as those with normoalbuminuria. General obesity was associated with the outcome only at the macroalbuminuria stage.

Conclusions: Central obesity associates with an increased risk of heart failure hospitalization or death in adults with type 1 diabetes, and WHtR may be a clinically useful screening tool.
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http://dx.doi.org/10.1186/s12933-021-01340-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314504PMC
July 2021

Faecal biomarkers in type 1 diabetes with and without diabetic nephropathy.

Sci Rep 2021 07 26;11(1):15208. Epub 2021 Jul 26.

Steno Diabetes Center Copenhagen, Niels Steensens Vej 2, 2820, Gentofte, Denmark.

Gastrointestinal dysbiosis is common among persons with type 1 diabetes (T1D), but its potential impact on diabetic nephropathy (DN) remains obscure. We examined whether faecal biomarkers, previously associated with low-grade gastrointestinal inflammation, differ between healthy controls and T1D subjects with and without DN. Faecal samples were analyzed for levels of calprotectin, intestinal alkaline phosphatase (IAP), short-chain fatty acids (SCFA) and immunoglobulins in subjects with T1D (n = 159) and healthy controls (NDC; n = 50). The subjects with T1D were stratified based on albuminuria: normoalbuminuria (< 30 mg/g; n = 49), microalbuminuria (30-299 mg/g; n = 50) and macroalbuminuria (≥ 300 mg/g; n = 60). aecal calprotectin, IAP and immunoglobulin levels did not differ between the T1D albuminuria groups. However, when subjects were stratified based on faecal calprotectin cut-off level (50 µg/g), macroalbuminuric T1D subjects exceeded the threshold more frequently than NDC (p = 0.02). Concentrations of faecal propionate and butyrate were lower in T1D subjects compared with NDC (p = 0.04 and p = 0.03, respectively). Among T1D subjects, levels of branched SCFA (BCFA) correlated positively with current albuminuria level (isobutyrate, p = 0.03; isovalerate, p = 0.005). In our study cohort, fatty acid metabolism seemed to be altered among T1D subjects and those with albuminuria compared to NDC. This may reflect gastrointestinal imbalances associated with T1D and renal complications.
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http://dx.doi.org/10.1038/s41598-021-94747-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313679PMC
July 2021

Long-term population-based trends in the incidence of cardiovascular disease in individuals with type 1 diabetes from Finland: a retrospective, nationwide, cohort study.

Lancet Diabetes Endocrinol 2021 09 22;9(9):575-585. Epub 2021 Jul 22.

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia.

Background: Cardiovascular disease is the main determinant of premature mortality in patients with type 1 diabetes. However, time trends regarding different types of cardiovascular disease in childhood-onset type 1 diabetes with a long timespan from the diagnosis of diabetes are not well established. This study aimed to investigate the cumulative incidence of cardiovascular disease in individuals with type 1 diabetes in a population-based cohort in Finland, the country with the world's highest incidence of type 1 diabetes.

Methods: In this retrospective, nationwide registry-based, cohort study, all patients who were diagnosed between Jan 1, 1965, and Dec 31, 1999 with type 1 diabetes when they were younger than 15 years old in Finland were followed up and monitored for the occurrence of cardiovascular disease (including coronary artery disease, stroke, peripheral artery disease, and heart failure) until the end of 2016 and for cardiovascular disease mortality until 2017. Cumulative incidences of cardiovascular disease were calculated by the Fine and Gray method according to the year of diabetes diagnosis using six diagnosis cohorts: 1965-69, 1970-74, 1975-1979, 1980-84, 1985-89, 1990-94, and 1990-95. Trends in cardiovascular disease event rates were analysed by Fine and Gray competing risks regression models using year of diabetes diagnosis as continuous variable. In addition, non-linearity in trends was assessed with restricted cubic splines. The excess risk of coronary artery disease and stroke was estimated by comparison with the risk in the Finnish general population by calculating standardised incidence ratios (SIRs) and their time trends. The data for Finnish general population were drawn from the Cardiovascular Disease Register of the National Institute of Health and Welfare. The SIRs were calculated as ratios of observed and expected number of events in individuals with type 1 diabetes during 1991-2014.

Findings: 11 766 individuals were included in this study. During 361 033 person-years of follow-up and a median of 29·6 years (IQR 22·3-37·9) follow-up, a total of 1761 individuals had single or multiple types of cardiovascular disease events. 2686 events (864 [32·2%] coronary artery disease events, of which 663 were acute myocardial infarctions; 497 [18·5%] strokes; 854 [31·8%] peripheral artery diseases, of which 498 were lower extremity amputations; and 471 [17·5%] heart failure events) were reported until Dec 31, 2016, and 1467 deaths until Dec 31, 2017. Cardiovascular disease risk decreased linearly by 3·8% (hazard ratio [HR] 0·96 [95% CI 0·96-0·97]; p<0·0001) by later calendar year of diabetes diagnosis (p<0·0001). There was a decrease in the SIRs for both coronary artery disease and stroke within all 10-year age groups under 65 years, except for stroke in the oldest age group. However, the SIR was still 8·9 (95% CI 3·9-17·5) for coronary artery disease and 2·9 (1·3-5·7) for stroke in those diagnosed with type 1 diabetes in the 1990s. Finally, the cardiovascular disease death rate decreased constantly by diagnosis year.

Interpretation: The risk of cardiovascular disease has decreased over time in Finland in individuals with childhood-onset type 1 diabetes. However, there is still considerable excess cardiovascular disease risk in individuals with type 1 diabetes compared with the general population. These results highlight the need for studies on the mechanisms of atherosclerosis from the time of diagnosis of type 1 diabetes to facilitate early and effective prevention of cardiovascular disease in these individuals.

Funding: Folkhälsan Research Foundation, Academy of Finland, Wilhelm and Else Stockmann Foundation, Liv och Hälsa Society, Novo Nordisk Foundation, Finnish Foundation for Cardiovascular Research, Finnish Diabetes Research Foundation, Diabetes Research Foundation, Medical Society of Finland, Sigrid Jusélius Foundation, and Helsinki University Hospital Research Funds.
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http://dx.doi.org/10.1016/S2213-8587(21)00172-8DOI Listing
September 2021

Association of Coding Variants in Hydroxysteroid 17-beta Dehydrogenase 14 () with Reduced Progression to End Stage Kidney Disease in Type 1 Diabetes.

J Am Soc Nephrol 2021 10 14;32(10):2634-2651. Epub 2021 Jul 14.

Research Division, Joslin Diabetes Center, Boston, Massachusetts.

Background: Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage.

Methods: Gene-based exome array analyses of 15,449 genes in five large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time to ESKD, testing the top gene in a sixth cohort (=2372/1115 events all cohorts) and replicating in two retrospective case-control studies (=1072 cases, 752 controls). Deep resequencing of the top associated gene in five cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models.

Results: Protein coding variants in the hydroxysteroid 17- dehydrogenase 14 gene (), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (=4196; value=3.3 × 10). The gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other CKD-associated renal pathologies.

Conclusions: gene is mechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development.
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http://dx.doi.org/10.1681/ASN.2020101457DOI Listing
October 2021

The Low-Expression Variant of Is Associated With Cardiovascular Disease in Type 1 Diabetes.

Diabetes 2021 Oct 9;70(10):2391-2401. Epub 2021 Jul 9.

Folkhälsan Research Center, Helsinki, Finland.

Fatty acid binding protein 4 (FABP4) is implicated in the pathogenesis of cardiometabolic disorders. Pharmacological inhibition or genetic deletion of FABP4 improves cardiometabolic health and protects against atherosclerosis in preclinical models. As cardiovascular disease (CVD) is common in type 1 diabetes, we examined the role of FABP4 in the development of complications in type 1 diabetes, focusing on a functional, low-expression variant (rs77878271) in the promoter of the gene. For this, we assessed the risk of CVD, stroke, coronary artery disease (CAD), end-stage kidney disease, and mortality using Cox proportional hazards models for the rs77878271 in 5,077 Finnish individuals with type 1 diabetes. The low-expression G allele of rs77878271 increased the risk of CVD, independent of confounders. Findings were tested for replication in 852 Danish and 3,678 Finnish individuals with type 1 diabetes. In the meta-analysis, each G allele increased the risk of stroke by 26% ( = 0.04), CAD by 26% ( = 0.006), and CVD by 17% ( = 0.003). In Mendelian randomization, a 1-SD unit decrease in FABP4 increased risk of CAD 2.4-fold. Hence, in contrast with the general population, among patients with type 1 diabetes the low-expression G allele of rs77878271 increased CVD risk, suggesting that genetically low FABP4 levels may be detrimental in the context of type 1 diabetes.
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http://dx.doi.org/10.2337/db21-0056DOI Listing
October 2021

Endothelial Dysfunction is Associated With Early-Onset Cryptogenic Ischemic Stroke in Men and With Increasing Age.

J Am Heart Assoc 2021 07 6;10(14):e020838. Epub 2021 Jul 6.

Department of Neurology Helsinki University Hospital and Clinical NeurosciencesUniversity of Helsinki Finland.

Background The aim of this study was to assess the association between endothelial function and early-onset cryptogenic ischemic stroke (CIS), with subgroup analyses stratified by sex and age groups. Methods and Results We prospectively enrolled 136 consecutive patients aged 18 to 49 years (median age, 41 years; 44% women) with a recent CIS and 136 age- and sex-matched (±5 years) stroke-free controls. Endothelial function was measured with an EndoPAT 2000 device and analyzed as tertiles of natural logarithm of reactive hyperemia index with lower values reflecting dysfunction. We used conditional logistic regression adjusting for age, education, hypertension, diabetes mellitus, dyslipidemia, current smoking, heavy drinking, obesity, and diet score to assess the independent association between endothelial function and CIS. Patients in the lowest tertile of natural logarithm of reactive hyperemia index were more often men and they more frequently had a history of dyslipidemia; they were also more often obese, had a lower diet score, and lower high-density lipoprotein cholesterol. In the entire cohort, we found no association in patients with endothelial function and CIS compared with stroke-free controls. In sex- and age-specific analyses, endothelial dysfunction was associated with CIS in men (adjusted odds ratio [OR], 3.50 for lowest versus highest natural logarithm of reactive hyperemia index tertile; 95% CI, 1.22-10.07) and in patients ≥41 years (OR, 5.78; 95% CI, 1.52-21.95). These associations remained significant when dyslipidemia was replaced with the ratio of total to high-density lipoprotein cholesterol. Conclusions Endothelial dysfunction appears to be an independent player in early-onset CIS in men and patients approaching middle age.
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http://dx.doi.org/10.1161/JAHA.121.020838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483459PMC
July 2021

Presence and Determinants of Cardiovascular Disease and Mortality in Individuals With Type 1 Diabetes of Long Duration: The FinnDiane 50 Years of Diabetes Study.

Diabetes Care 2021 08 23;44(8):1885-1893. Epub 2021 Jun 23.

Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA.

Objective: The aim of this study was to determine the incidence of cardiovascular disease (CVD) and mortality as well as their risk factors in type 1 diabetes (T1D) of >50 years' duration.

Research Design And Methods: From 5,396 individuals included in the Finnish Diabetic Nephropathy Study (FinnDiane), 729 diagnosed in 1967 or earlier survived with T1D for >50 years. In this FinnDiane 50-year cohort, cumulative incidence of CVD events was assessed from the diagnosis of diabetes, and the excess CVD risk, compared with 12,710 matched individuals without diabetes. In addition, risk factors for different types of CVD (both nonfatal and fatal) and mortality were analyzed, and cause-specific hazard ratios were estimated during a median follow-up of 16.6 years from the baseline visit (median duration of diabetes 39 years at baseline).

Results: In individuals with diabetes duration of >50 years, the 60-year cumulative incidence of CVD from the diagnosis of diabetes was 64.3% (95% CI 62.5-66.0). Compared with individuals without diabetes, the standardized incidence ratio for CVD was 7.4 (6.5-8.3); in those with normoalbuminuria, it was 4.9 (4.0-5.9). Mean HbA and HbA variability, dyslipidemia, BMI, kidney disease, age, and diabetes duration were the variables associated with incident CVD. In particular, HbA was associated with peripheral artery disease (PAD). The standardized mortality ratio compared with the Finnish background population was 3.2 (2.8-3.7). The factors associated with mortality were diabetes duration, increased HbA variability, inflammation, insulin resistance, kidney disease, and PAD.

Conclusions: Individuals with T1D of very long duration are at a high risk of CVD. In addition, throughout the lifespan, optimal glycemic control remains central to CVD and excess mortality prevention.
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http://dx.doi.org/10.2337/dc20-2816DOI Listing
August 2021

Persons with type 1 diabetes have low blood oxygen levels in the supine and standing body positions.

BMJ Open Diabetes Res Care 2021 05;9(1)

Complications Research, Steno Diabetes Center Copenhagen, Copenhagen, Denmark.

Introduction: Blood oxygen saturation is low compared with healthy controls (CONs) in the supine body position in individuals with type 1 diabetes (T1D) and has been associated with complications. Since most of daily life occurs in the upright position, it is of interest if this also applies in the standing body position. In addition, tissue oxygenation in other anatomical sites could show different patterns in T1D. Therefore, we investigated blood, arm and forehead oxygen levels in the supine and standing body positions in individuals with T1D (n=129) and CONs (n=55).

Research Design And Methods: Blood oxygen saturation was measured with pulse oximetry. Arm and forehead mixed tissue oxygen levels were measured with near-infrared spectroscopy sensors applied on the skin.

Results: Data are presented as least squares means±SEM and differences (95% CIs). Overall blood oxygen saturation was lower in T1D (CON: 97.6%±0.2%; T1D: 97.0%±0.1%; difference: -0.5% (95% CI -0.9% to -0.0%); p=0.034). In all participants, blood oxygen saturation increased after standing up (supine: 97.1%±0.1%; standing: 97.6%±0.2%; difference: +0.6% (95% CI 0.4% to 0.8%); p<0.001). However, the increase was smaller in T1D compared with CON (CON supine: 97.3%±0.2%; CON standing: 98.0%±0.2%; T1D supine: 96.9%±0.2%; T1D standing: 97.2%±0.1%; difference between groups in the change: -0.4% (95% CI -0.6% to -0.2%); p<0.001). Arm oxygen saturation decreased in both groups after standing and more in those with T1D. Forehead oxygen saturation decreased in both groups after standing and there were no differences between the changes when comparing the groups.

Conclusion: Compared with CON, individuals with T1D exhibit possible detrimental patterns of tissue oxygen adaptation to standing, with preserved adaptation of forehead oxygenation. Further studies are needed to explore the consequences of these differences.
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http://dx.doi.org/10.1136/bmjdrc-2020-001944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169468PMC
May 2021

The Relationship Between Body Fat Distribution and Nonalcoholic Fatty Liver in Adults With Type 1 Diabetes.

Diabetes Care 2021 07 24;44(7):1706-1713. Epub 2021 May 24.

Folkhälsan Research Center, Helsinki, Finland.

Objective: Obesity, which is associated with nonalcoholic fatty liver (NAFL), has increased among people with type 1 diabetes. Therefore, we explored the associations between body fat distribution and NAFL in this population.

Research Design And Methods: This study included 121 adults with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study for whom NAFL was determined by magnetic resonance imaging. Body composition was assessed by dual-energy X-ray absorptiometry. Genetic data concerning rs738409 and rs58542926 were available as a directly genotyped polymorphism. Associations between body fat distribution, waist-to-height ratio (WHtR), BMI, and NAFL were explored using logistic regression. A receiver operating characteristic (ROC) curve was used to determine the WHtR and BMI thresholds with the highest sensitivity and specificity to detect NAFL.

Results: Median age was 38.5 (33-43.7) years, duration of diabetes was 21.2 (17.9-28.4) years, 52.1% were women, and the prevalence of NAFL was 11.6%. After adjusting for sex, age, duration of diabetes, and rs738409, the volume ( = 0.03) and percentage ( = 0.02) of visceral adipose tissue were associated with NAFL, whereas gynoid, appendicular, and total adipose tissues were not. The area under the curve between WHtR and NAFL was larger than BMI and NAFL ( = 0.04). The WHtR cutoff of 0.5 showed the highest sensitivity (86%) and specificity (55%), whereas the BMI of 26.6 kg/m showed 79% sensitivity and 57% specificity.

Conclusions: Visceral adipose tissue is associated with NAFL in adults with type 1 diabetes, and WHtR may be considered when screening for NAFL in this population.
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http://dx.doi.org/10.2337/dc20-3175DOI Listing
July 2021

Symptoms of depression are associated with reduced leisure-time physical activity in adult individuals with type 1 diabetes.

Acta Diabetol 2021 Oct 19;58(10):1373-1380. Epub 2021 May 19.

Folkhälsan Research Center, Folkhälsan Institute of Genetics, Helsinki, Finland.

Aims: Here, we investigated the association between depressive symptoms and leisure-time physical activity (LTPA) in type 1 diabetes.

Methods: Data from adult individuals with type 1 diabetes without evidence of diabetic kidney disease or macrovascular complications, participating in the Finnish Diabetic Nephropathy Study, were included. Based on a questionnaire, weekly LTPA as metabolic equivalent of task hour was calculated. Activity levels (inactive, moderately active, active), weekly frequencies (< 1, 1-2, > 2), intensities (low, moderate, high), and single session durations (< 30, 31-60, > 60 min) were assessed. Depressive symptomatology was evaluated using the Beck Depression Inventory (BDI). We calculated a continuous BDI score and divided participants into those with (BDI score ≥ 16) and without (BDI score < 16) symptoms of depression. For sensitivity analyses, we additionally defined symptoms of depression with antidepressant agent purchases within a year from the study visit.

Results: Of the 1339 participants (41.7% men, median age 41 years), 150 (11.2%) reported symptoms of depression. After adjustments, both higher BDI scores and depressive symptomatology were associated with more inactive lifestyle, and lower frequency and intensity of the LTPA. The BDI score was additionally associated with shorter single session duration. For antidepressant purchases, lower odds were observed in those with higher intensity and longer single session duration of LTPA.

Conclusions: Depressive mood is harmfully related to LTPA in type 1 diabetes. In order to improve the long-term health of individuals with type 1 diabetes, efforts to increase both mental well-being and physical activity should be taken.
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http://dx.doi.org/10.1007/s00592-021-01718-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413160PMC
October 2021

Adiponectin receptor agonist AdipoRon ameliorates renal inflammation in diet-induced obese mice and endotoxin-treated human glomeruli ex vivo.

Diabetologia 2021 Aug 14;64(8):1866-1879. Epub 2021 May 14.

Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Aims/hypothesis: Chronic low-grade inflammation with local upregulation of proinflammatory molecules plays a role in the progression of obesity-related renal injury. Reduced serum concentration of anti-inflammatory adiponectin may promote chronic inflammation. Here, we investigated the potential anti-inflammatory and renoprotective effects and mechanisms of action of AdipoRon, an adiponectin receptor agonist.

Methods: Wild-type DBA/2J mice were fed with high-fat diet (HFD) supplemented or not with AdipoRon to model obesity-induced metabolic endotoxaemia and chronic low-grade inflammation and we assessed changes in the glomerular morphology and expression of proinflammatory markers. We also treated human glomeruli ex vivo and human podocytes in vitro with AdipoRon and bacterial lipopolysaccharide (LPS), an endotoxin upregulated in obesity and diabetes, and analysed the secretion of inflammatory cytokines, activation of inflammatory signal transduction pathways, apoptosis and migration.

Results: In HFD-fed mice, AdipoRon attenuated renal inflammation, as demonstrated by reduced expression of glomerular activated NF-κB p65 subunit (NF-κB-p65) (70%, p < 0.001), TNFα (48%, p < 0.01), IL-1β (51%, p < 0.001) and TGFβ (46%, p < 0.001), renal IL-6 and IL-4 (21% and 20%, p < 0.05), and lowered glomerular F4/80-positive macrophage infiltration (31%, p < 0.001). In addition, AdipoRon ameliorated HFD-induced glomerular hypertrophy (12%, p < 0.001), fibronectin accumulation (50%, p < 0.01) and podocyte loss (12%, p < 0.001), and reduced podocyte foot process effacement (15%, p < 0.001) and thickening of the glomerular basement membrane (18%, p < 0.001). In cultured podocytes, AdipoRon attenuated the LPS-induced activation of the central inflammatory signalling pathways NF-κB-p65, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38-MAPK) (30%, 36% and 22%, respectively, p < 0.001), reduced the secretion of TNFα (32%, p < 0.01), and protected against podocyte apoptosis and migration. In human glomeruli ex vivo, AdipoRon reduced the LPS-induced secretion of inflammatory cytokines IL-1β, IL-18, IL-6 and IL-10.

Conclusions/interpretation: AdipoRon attenuated the renal expression of proinflammatory cytokines in HFD-fed mice and LPS-stimulated human glomeruli, which apparently contributed to the amelioration of glomerular inflammation and injury. Mechanistically, based on assays on cultured podocytes, AdipoRon reduced LPS-induced activation of the NF-κB-p65, JNK and p38-MAPK pathways, thereby impelling the decrease in apoptosis, migration and secretion of TNFα. We conclude that the activation of the adiponectin receptor by AdipoRon is a potent strategy to attenuate endotoxaemia-associated renal inflammation.
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http://dx.doi.org/10.1007/s00125-021-05473-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245393PMC
August 2021

Molecular pathways behind acquired obesity: Adipose tissue and skeletal muscle multiomics in monozygotic twin pairs discordant for BMI.

Cell Rep Med 2021 Apr 30;2(4):100226. Epub 2021 Mar 30.

Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Tissue-specific mechanisms prompting obesity-related development complications in humans remain unclear. We apply multiomics analyses of subcutaneous adipose tissue and skeletal muscle to examine the effects of acquired obesity among 49 BMI-discordant monozygotic twin pairs. Overall, adipose tissue appears to be more affected by excess body weight than skeletal muscle. In heavier co-twins, we observe a transcriptional pattern of downregulated mitochondrial pathways in both tissues and upregulated inflammatory pathways in adipose tissue. In adipose tissue, heavier co-twins exhibit lower creatine levels; in skeletal muscle, glycolysis- and redox stress-related protein and metabolite levels remain higher. Furthermore, metabolomics analyses in both tissues reveal that several proinflammatory lipids are higher and six of the same lipid derivatives are lower in acquired obesity. Finally, in adipose tissue, but not in skeletal muscle, mitochondrial downregulation and upregulated inflammation are associated with a fatty liver, insulin resistance, and dyslipidemia, suggesting that adipose tissue dominates in acquired obesity.
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http://dx.doi.org/10.1016/j.xcrm.2021.100226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080113PMC
April 2021

Genetic factors affect the susceptibility to bacterial infections in diabetes.

Sci Rep 2021 05 4;11(1):9464. Epub 2021 May 4.

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.

Diabetes increases the risk of bacterial infections. We investigated whether common genetic variants associate with infection susceptibility in Finnish diabetic individuals. We performed genome-wide association studies and pathway analysis for bacterial infection frequency in Finnish adult diabetic individuals (FinnDiane Study; N = 5092, Diabetes Registry Vaasa; N = 4247) using national register data on antibiotic prescription purchases. Replication analyses were performed in a Swedish diabetic population (ANDIS; N = 9602) and in a Finnish non-diabetic population (FinnGen; N = 159,166). Genome-wide data indicated moderate but significant narrow-sense heritability for infection susceptibility (h = 16%, P = 0.02). Variants on chromosome 2 were associated with reduced infection susceptibility (rs62192851, P = 2.23 × 10). Homozygotic carriers of the rs62192851 effect allele (N = 44) had a 37% lower median annual antibiotic purchase rate, compared to homozygotic carriers of the reference allele (N = 4231): 0.38 [IQR 0.22-0.90] and 0.60 [0.30-1.20] respectively, P = 0.01). Variants rs6727834 and rs10188087, in linkage disequilibrium with rs62192851, replicated in the FinnGen-cohort (P < 0.05), but no variants replicated in the ANDIS-cohort. Pathway analysis suggested the IRAK1 mediated NF-κB activation through IKK complex recruitment-pathway to be a mediator of the phenotype. Common genetic variants on chromosome 2 may associate with reduced risk of bacterial infections in Finnish individuals with diabetes.
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http://dx.doi.org/10.1038/s41598-021-88273-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096814PMC
May 2021

The pattern-recognition molecule H-ficolin in relation to diabetic kidney disease, mortality, and cardiovascular events in type 1 diabetes.

Sci Rep 2021 04 26;11(1):8919. Epub 2021 Apr 26.

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.

H-ficolin recognizes patterns on microorganisms and stressed cells and can activate the lectin pathway of the complement system. We aimed to assess H-ficolin in relation to the progression of diabetic kidney disease (DKD), all-cause mortality, diabetes-related mortality, and cardiovascular events. Event rates per 10-unit H-ficolin-increase were compared in an observational follow-up of 2,410 individuals with type 1 diabetes from the FinnDiane Study. DKD progression occurred in 400 individuals. The unadjusted hazard ratio (HR) for progression was 1.29 (1.18-1.40) and 1.16 (1.05-1.29) after adjustment for diabetes duration, sex, HbA, systolic blood pressure, and smoking status. After adding triglycerides to the model, the HR decreased to 1.07 (0.97-1.18). In all, 486 individuals died, including 268 deaths of cardiovascular causes and 192 deaths of complications to diabetes. HRs for all-cause mortality and cardiovascular mortality were 1.13 (1.04-1.22) and 1.05 (0.93-1.17), respectively, in unadjusted analyses. These estimates lost statistical significance in adjusted models. However, the unadjusted HR for diabetes-related mortality was 1.19 (1.05-1.35) and 1.18 (1.02-1.37) with the most stringent adjustment level. Our results, therefore, indicate that H-ficolin predicts diabetes-related mortality, but neither all-cause mortality nor fatal/non-fatal cardiovascular events. Furthermore, H-ficolin is associated with DKD progression, however, not independently of the fully adjusted model.
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http://dx.doi.org/10.1038/s41598-021-88352-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076270PMC
April 2021

Carotid intima-media thickness and arterial stiffness in relation to cerebral small vessel disease in neurologically asymptomatic individuals with type 1 diabetes.

Acta Diabetol 2021 Jul 20;58(7):929-937. Epub 2021 Mar 20.

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.

Aims: To determine if arterial functional and structural changes are associated with underlying cerebral small vessel disease in neurologically asymptomatic individuals with type 1 diabetes.

Methods: We enrolled 186 individuals (47.8% men; median age 40.0, IQR 33.0-45.0 years) with type 1 diabetes (median diabetes duration of 21.6, IQR 18.2-30.3 years), and 30 age- and sex-matched healthy controls, as part of the Finnish Diabetic Nephropathy (FinnDiane) Study. All individuals underwent a biochemical work-up, brain magnetic resonance imaging (MRI), ultrasound of the common carotid arteries and arterial tonometry. Arterial structural and functional parameters were assessed by carotid intima-media thickness (CIMT), pulse wave velocity and augmentation index.

Results: Cerebral microbleeds (CMBs) were present in 23.7% and white matter hyperintensities (WMHs) in 16.7% of individuals with type 1 diabetes. Those with type 1 diabetes and CMBs had higher median (IQR) CIMT 583 (525 - 663) μm than those without 556 (502 - 607) μm, p = 0.016). Higher CIMT was associated with the presence of CMBs (p = 0.046) independent of age, eGFR, ApoB, systolic blood pressure, albuminuria, history of retinal photocoagulation and HbA. Arterial stiffness and CIMT were increased in individuals with type 1 diabetes and WMHs compared to those without; however, these results were not independent of cardiovascular risk factors.

Conclusions: Structural, but not functional, arterial changes are associated with underlying CMBs in asymptomatic individuals with type 1 diabetes.
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http://dx.doi.org/10.1007/s00592-021-01678-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187193PMC
July 2021

The impact of parental risk factors on the risk of stroke in type 1 diabetes.

Acta Diabetol 2021 Jul 15;58(7):911-917. Epub 2021 Mar 15.

Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.

Background: Individuals with type 1 diabetes have a markedly increased risk of stroke. In the general population, genetic predisposition has been linked to increased risk of stroke, but this has not been assessed in type 1 diabetes. Our aim was, therefore, to study how parental risk factors affect the risk of stroke in individuals with type 1 diabetes.

Methods: This study represents an observational follow-up of 4011 individuals from the Finnish Diabetic Nephropathy Study, mean age at baseline 37.6 ± 11.9 years. All strokes during follow-up were verified from medical records or death certificates. The strokes were classified as either ischemic or hemorrhagic. All individuals filled out questionnaires concerning their parents' medical history of hypertension, diabetes, stroke, and/or myocardial infarction.

Results: During a median follow-up of 12.4 (10.9-14.2) years, 188 individuals (4.6%) were diagnosed with their first ever stroke; 134 were ischemic and 54 hemorrhagic. In Cox regression analysis, a history of maternal stroke increased the risk of hemorrhagic stroke, hazard ratio 2.86 (95% confidence interval 1.27-6.44, p = 0.011) after adjustment for sex, age, BMI, retinal photocoagulation, and diabetic kidney disease. There was, however, no association between maternal stroke and ischemic stroke. No other associations between parental risk factors and ischemic or hemorrhagic stroke were observed.

Conclusion: A history of maternal stroke increases the risk of hemorrhagic stroke in individuals with type 1 diabetes. Other parental risk factors seem to have limited impact on the risk of stroke.
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http://dx.doi.org/10.1007/s00592-021-01694-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187180PMC
July 2021
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