Publications by authors named "Kerstin Brismar"

194 Publications

Selenium and Coenzyme Q10 Supplementation Improves Renal Function in Elderly Deficient in Selenium: Observational Results and Results from a Subgroup Analysis of a Prospective Randomised Double-Blind Placebo-Controlled Trial.

Nutrients 2020 Dec 9;12(12). Epub 2020 Dec 9.

Department of Medical Sciences, Uppsala University, SE-751 85 Uppsala, Sweden.

A low selenium intake is found in European countries, and is associated with increased cardiovascular mortality. There is an association between selenium level and the severity of kidney disease. An association between inflammation and selenium intake is also reported. The coenzyme Q10 level is decreased in kidney disease. The aim of this study was to examine a possible association between selenium and renal function in an elderly population low in selenium and coenzyme Q, and the impact of intervention with selenium and coenzyme Q on the renal function. The association between selenium status and creatinine was studied in 589 elderly persons. In 215 of these (mean age 71 years) a randomised double-blind placebo-controlled prospective trial with selenium yeast (200 µg/day) and coenzyme Q (200 mg/day) ( = 117) or placebo ( = 98) was conducted. Renal function was determined using measures of glomerular function at the start and after 48 months. The follow-up time was 5.1 years. All individuals were low on selenium (mean 67 μg/L (SD 16.8)). The changes in renal function were evaluated by measurement of creatinine, cystatin-C, and the use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) algorithm, and by the use of T-tests, repeated measures of variance and ANCOVA analyses. An association between low selenium status and impaired renal function was observed. Intervention causes a significantly lower serum creatinine, and cystatin-C concentration in the active treatment group compared with those on placebo ( = 0.0002 and = 0.001 resp.). The evaluation with CKD-EPI based on both creatinine and cystatin-C showed a corresponding significant difference ( < 0.0001). All validations showed corresponding significant differences. In individuals with a deficiency of selenium and coenzyme Q low selenium status is related to impaired renal function, and thus supplementation with selenium and coenzyme Q10 results in significantly improved renal function as seen from creatinine and cystatin-C and through the CKD-EPI algorithm. The explanation could be related to positive effects on inflammation and oxidative stress as a result of the supplementation.
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http://dx.doi.org/10.3390/nu12123780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764721PMC
December 2020

Increased Plasma Soluble Interleukin-2 Receptor Alpha Levels in Patients With Long-Term Type 1 Diabetes With Vascular Complications Associated With and Gene Polymorphisms.

Front Endocrinol (Lausanne) 2020 30;11:575469. Epub 2020 Oct 30.

Center for Diabetes Research, Department of Clinical Science, Faculty of Medicine, University of Bergen, Bergen, Norway.

Type 1 diabetes (T1D) is largely considered an autoimmune disease leading to the destruction of insulin-producing pancreatic β cells. Further, patients with T1D have 3-4-fold increased risk of developing micro- and macrovascular complications. However, the contribution of immune-related factors contributing to these diabetes complications are poorly understood. Individuals with long-term T1D who do not progress to vascular complications offer a great potential to evaluate end-organ protection. The aim of the present study was to investigate the association of inflammatory protein levels with vascular complications (retinopathy, nephropathy, cardiovascular disease) in individuals with long-term T1D compared to individuals who rapidly progressed to complications. We studied a panel of inflammatory markers in plasma of patients with long-term T1D with (n = 81 and 26) and without (n = 313 and 25) vascular complications from two cross-sectional Scandinavian cohorts (PROLONG and DIALONG) using Luminex technology. A subset of PROLONG individuals (n = 61) was screened for circulating immune cells using multicolor flow cytometry. We found that elevated plasma levels of soluble interleukin-2 receptor alpha (sIL-2R) were positively associated with the complication phenotype. Risk carriers of polymorphisms in the and gene region had elevated plasma levels of sIL-2R. In addition, cell surface marker analysis revealed a shift from naïve to effector T cells in T1D individuals with vascular complications as compared to those without. In contrast, no difference between the groups was observed either in IL-2R cell surface expression or in regulatory T cell population size. In conclusion, our data indicates that and gene variants might increase the risk of developing vascular complications in people with T1D, by affecting sIL-2R plasma levels and potentially lowering T cell responsiveness. Thus, elevated sIL-2R plasma levels may serve as a biomarker in monitoring the risk for developing diabetic complications and thereby improve patient care.
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http://dx.doi.org/10.3389/fendo.2020.575469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664831PMC
October 2020

Predictors of normalized HbA1c after gastric bypass surgery in subjects with abnormal glucose levels, a 2-year follow-up study.

Sci Rep 2020 09 15;10(1):15127. Epub 2020 Sep 15.

Department of Molecular Medicine and Surgery, D02:04, Karolinska Institutet, 171 76, Stockholm, Sweden.

Clinical biomarkers can predict normalization of HbA1c after Roux-en-Y gastric bypass (RYGB) surgery, but it is unclear which are the most predictive.The aim of this study was to compare biomarkers for insulin sensitivity and other clinical parameters in the prediction of normalization of HbA1c after RYGB surgery. This study included 99 (23 men) obese subjects (BMI > 35 kg/m) undergoing a laparoscopic RYGB. Clinical and biochemical examinations were performed pre-operatively and up to 2 years after surgery. Pre-operatively, normal fasting glucose levels were found in 25 individuals (NG), prediabetes in 46 and type 2 diabetes (T2DM) in 28. At baseline IGF-I (SD), IGFBP-1 and adiponectin levels were low while leptin was high. Weight loss was observed in all three groups, most in the prediabetes group. After 2 years HbA1c was decreased in prediabetes and T2DM. In all three groups insulin, HOMA-IR, lipids and blood pressure improved, IGFBP-1 and adiponectin increased and leptin decreased. IGF-I (SD) increased only in T2DM. In those with prediabetes or T2DM (n = 74), HbA1c at 2 years correlated to baseline BMI (r = -0.27, p = 0.028), age (r = 0.43, p < 0.001), HbA1c (r = 0.37, p = 0.001) and IGFBP-1 (r = 0.25, p = 0.038), and was normalized in 45/74 (61%) at 1 year and in 36 subjects (49%) at 2 years. These responders were younger, had higher BMI, larger waist circumference, lower HbA1c and lower IGFBP-1 levels at baseline. In a multiple regression model age (negative, p = 0.021) and waist circumference (positive, p = 0.047) were the only predictors for normalized HbA1c. RYGB normalized HbA1c in 49% at two years follow-up, which was predicted by low baseline IGFBP-1 level, a marker of hepatic insulin sensitivty and insulin secretion. However,. younger age and larger waist circumference were the only predictors of normalized HbA1c in multivariate analysis.
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http://dx.doi.org/10.1038/s41598-020-72141-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492212PMC
September 2020

Liver nucleotide biosynthesis is linked to protection from vascular complications in individuals with long-term type 1 diabetes.

Sci Rep 2020 07 14;10(1):11561. Epub 2020 Jul 14.

Department of Clinical Science/Diabetes and Endocrinology, Lund University Diabetes Centre, 205 02, Malmö, Sweden.

Identification of biomarkers associated with protection from developing diabetic complications is a prerequisite for an effective prevention and treatment. The aim of the present study was to identify clinical and plasma metabolite markers associated with freedom from vascular complications in people with very long duration of type 1 diabetes (T1D). Individuals with T1D, who despite having longer than 30 years of diabetes duration never developed major macro- or microvascular complications (non-progressors; NP) were compared with those who developed vascular complications within 25 years from diabetes onset (rapid progressors; RP) in the Scandinavian PROLONG (n = 385) and DIALONG (n = 71) cohorts. The DIALONG study also included 75 healthy controls. Plasma metabolites were measured using gas and/or liquid chromatography coupled to mass spectrometry. Lower hepatic fatty liver indices were significant common feature characterized NPs in both studies. Higher insulin sensitivity and residual ß-cell function (C-peptide) were also associated with NPs in PROLONG. Protection from diabetic complications was associated with lower levels of the glycolytic metabolite pyruvate and APOCIII in PROLONG, and with lower levels of thiamine monophosphate and erythritol, a cofactor and intermediate product in the pentose phosphate pathway as well as higher phenylalanine, glycine and serine in DIALONG. Furthermore, T1D individuals showed elevated levels of picolinic acid as compared to the healthy individuals. The present findings suggest a potential beneficial shunting of glycolytic substrates towards the pentose phosphate and one carbon metabolism pathways to promote nucleotide biosynthesis in the liver. These processes might be linked to higher insulin sensitivity and lower liver fat content, and might represent a mechanism for protection from vascular complications in individuals with long-term T1D.
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http://dx.doi.org/10.1038/s41598-020-68130-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360755PMC
July 2020

Genetic and Biological Effects of ICAM-1 E469K Polymorphism in Diabetic Kidney Disease.

J Diabetes Res 2020 12;2020:8305460. Epub 2020 Jun 12.

Center for Pathophysiology, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.

Diabetic kidney disease (DKD) is a complex disease, in which local inflammatory stress results from both metabolic and hemodynamic derangements. Intercellular adhesion molecule 1 (ICAM-1) is an acute-phase protein marker of inflammation. In the recent years, clinical observations have reported that increased serum/plasma ICAM-1 levels are positively correlated with albuminuria in the patients with type 1 (T1D) and type 2 diabetes (T2D). Genetic association studies have demonstrated that genetic polymorphisms, including SNP rs5498 (E469K, G/A), in the gene is associated with DKD. rs5498 is a nonsynonymous SNP and caused by substitution between E (Glu) and K (Lys) for ICAM-1 protein. In this review, we first summarized the genetic effects of E469K polymorphism in DKD and then demonstrated the possible changes of ICAM-1 protein crystal structures according to the genotypes of this polymorphism. Finally, we discussed the genetic effects of the E469K polymorphism and the biological role of increased circulating ICAM-1 protein and its formation changes in DKD.
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http://dx.doi.org/10.1155/2020/8305460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313107PMC
June 2020

Human apolipoprotein CIII levels; evaluation of three assay methods.

Scand J Clin Lab Invest 2020 May 28;80(3):230-235. Epub 2020 Feb 28.

Unit of Clinical Chemistry, Department of Laboratory Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.

Apolipoprotein CIII (apoCIII) is associated with triglyceride (TG)-rich particles like VLDL and exerts an inhibitory effect of lipoprotein lipase. Increased levels are related to cardiovascular diseases and diabetes and therefore apoCIII has been proposed as a useful biomarker. Even if several commercial assays for measuring apoCIII in human plasma/serum are available, data is scarce concerning their reliability and none is used clinically. In the present study a comparative investigation has been done. Two ELISA-based methods (Cusabio Biotech and Assay Pro) and one nephelometric assay (Siemens Healthcare) were investigated. Serum and plasma samples were obtained from healthy volunteers and from samples sent to the Laboratory of Clinical Chemistry, preferably with higher levels of TGs. The Cusabio Biotech assay did not yield any valid results. However, both the methods from Assay Pro and Siemens Healthcare showed good performance with similar dynamic ranges. The latter assay had lower CV and required less work. In healthy individuals, apoCIII levels were not affected by fasting, freezing or thawing, nor did we find any gender differences. Individuals with elevated levels of TG displayed higher apoCIII values. Females with oral intake of contraceptives had higher levels. In conclusion, the nephelometric assay showed the best performance with the lowest CV, was less labor intensive than an assay based on ELISA and could therefore be suitable for clinical use.
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http://dx.doi.org/10.1080/00365513.2020.1725976DOI Listing
May 2020

Metabolic phenotype in Darier disease: a cross-sectional clinical study.

Diabetol Metab Syndr 2020 5;12:12. Epub 2020 Feb 5.

1Dermatology and Venereology Division, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden.

Background: Human data supporting a role for endoplasmic reticulum (ER) stress and calcium dyshomeostasis in diabetes is scarce. Darier disease (DD) is a hereditary skin disease caused by mutations in the gene encoding the sarcoendoplasmic-reticulum ATPase 2 (SERCA2) calcium pump, which causes calcium dyshomeostasis and ER stress. We hypothesize that DD patients have a diabetes-like metabolic phenotype and the objective of this study was to examine the association between DD with impaired glucose tolerance and diabetes.

Methods: Cross-sectional clinical study on 25 DD patients and 25 matched controls. Metabolic status was assessed primarily by fasting blood glucose, oral glucose tolerance test, HOMA2-%S (insulin resistence) and HOMA2-%B (beta cell function).

Results: DD subjects showed normal oral glucose tolerance test and HOMA2-%S, while fasting blood glucose was lower and c-peptide as well as HOMA2-%B was higher.

Conclusion: Increased HOMA2-%B values are indicative of increased basal insulin secretion which is a type of beta cell dysfunction associated to diabetes development. These results supports a role of ER stress in diabetes pathophysiology and contribute to the understanding of DD as a multi-organ syndrome.
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http://dx.doi.org/10.1186/s13098-020-0520-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003329PMC
February 2020

Associations of Different Types of Maternal Diabetes and Body Mass Index With Offspring Psychiatric Disorders.

JAMA Netw Open 2020 02 5;3(2):e1920787. Epub 2020 Feb 5.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

Importance: Maternal obesity, pregestational type 1 and 2 diabetes, and gestational diabetes have been reported to increase the risk of autism spectrum disorder and attention-deficit/hyperactivity disorder in the mothers' offspring. However, the associations of maternal diabetes disorders and body mass index jointly with psychiatric disorders among offspring are less well documented, especially for type 2 diabetes.

Objective: To examine the associations of different types of maternal diabetes, separately and together with maternal obesity, with psychiatric disorders in the mothers' offspring.

Design, Setting, And Participants: This population-based cohort study used data from nationwide registries in Finland encompassing all 649 043 live births occurring between 2004 and 2014. The study and data analysis were conducted from January 1, 2019, to July 5, 2019.

Exposures: Maternal prepregnancy body mass index, insulin-treated pregestational diabetes, and pregestational type 2 diabetes and gestational diabetes without insulin treatment.

Main Outcomes And Measures: Psychiatric diagnoses and prescription of psychotropic drugs among the mothers' offspring. Cox proportional hazards models were adjusted for birth year, sex, mode of delivery, maternal age, number of fetuses, parity, mother's country of birth, mother's marital status, maternal smoking, maternal psychiatric disorder, and maternal systemic inflammatory disease.

Results: The mean (SD) age of mothers was 30.20 (5.37) years; 357 238 of 394 302 mothers (90.6%) were born in Finland. Of the 647 099 births studied, 4000 fetuses (0.62%) were exposed to maternal insulin-treated pregestational diabetes, 3724 (0.57%) were exposed to type 2 diabetes, and 98 242 (15.18%) were exposed to gestational diabetes; 34 892 offspring (5.39%) later received a diagnosis of a mild neurodevelopmental or psychiatric disorder. Non-insulin-treated type 2 diabetes in severely obese mothers, compared with normal-weight mothers without diabetes, was associated with psychiatric disorders in the offspring (hazard ratio, 1.97; 95% CI, 1.64-2.37), although with a lower effect size than that for severely obese mothers with insulin-treated pregestational diabetes (hazard ratio, 2.71; 95% CI, 2.03-3.61). The largest effect sizes were found for mood disorders, attention-deficit/hyperactivity disorder and conduct disorders, and autism. Gestational diabetes in severely obese mothers had a lower overall effect size (hazard ratio, 1.61; 95% CI, 1.50-1.72). Diabetes in normal-weight mothers was not associated with psychopathologic disorders in the offspring.

Conclusions And Relevance: Severe obesity in mothers with diabetes was associated with an increased overall risk for psychiatric disorders in their offspring. The risk was highest for those exposed to insulin-treated pregestational diabetes, followed by non-insulin-treated type 2 diabetes and gestational diabetes. These findings may have implications for managing pregnancies.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.20787DOI Listing
February 2020

Associations of physical activity and sedentary behavior with cardiometabolic biomarkers in prediabetes and type 2 diabetes: a compositional data analysis.

Phys Sportsmed 2020 05 12;48(2):222-228. Epub 2019 Nov 12.

Department of Health Promotion Science, Sophiahemmet University, Stockholm, Sweden.

: To investigate the associations between objectively measured sedentary behavior (SB), light-intensity physical activity (LIPA) and moderate-to-vigorous physical activity (MVPA) and cardiometabolic and endocrine biomarkers, and to estimate the associations of reallocating time from one behavior to another with cardiometabolic and endocrine biomarkers.: Baseline data from participants diagnosed with prediabetes or type 2 diabetes, n = 175, 58% men, mean (SD) age = 64.4 (7.7), recruited to a physical activity intervention was used. Time spent in SB, LIPA and MVPA was measured by accelerometer and transformed into isometric log-ratio coordinates. The associations between time spent in SB, LIPA and MVPA and biomarkers were examined by linear regression models. The change in each outcome of reallocating time between the three behaviors was estimated.: The findings show strong positive associations of time spent in MVPA and negative associations of time spent in SB relative to time spent in the other behaviors with sagittal abdominal diameter (SAD) and homeostasis model assessment for insulin resistance (HOMA-IR) and negative associations of time spent in SB with high-density lipoprotein (HDL) cholesterol. Theoretically, reallocation of 19 minutes MVPA to SB or to LIPA was associated with a 17% and 17% larger SAD, 39% and 36% larger HOMA-IR values and 3.3% and 2.3% lower levels of HDL, respectively.: In conclusion, our analysis from a time-use perspective supports the current evidence that sedentary time is devastating for the cardiometabolic health. While LIPA probably requires more time, maintaining or increasing time in MVPA are the most important features of the time use behaviors when promoting a favorable cardiometabolic risk profile in adults with prediabetes and type 2 diabetes.: ClinicalTrials.gov, NCT02374788. Registered 2 March 2015 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02374788.
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http://dx.doi.org/10.1080/00913847.2019.1684811DOI Listing
May 2020

Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen.

J Am Soc Nephrol 2019 10 19;30(10):2000-2016. Epub 2019 Sep 19.

Department of Biostatistics and.

Background: Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown.

Methods: To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function.

Results: Our GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain ( gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition ( or renal biology ( and ).

Conclusions: The 16 diabetic kidney disease-associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.
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http://dx.doi.org/10.1681/ASN.2019030218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779358PMC
October 2019

Effects of drospirenone and norethisterone acetate combined with estradiol on mammographic density and proliferation of breast epithelial cells-A prospective randomized trial.

Maturitas 2019 Aug 4;126:18-24. Epub 2019 Apr 4.

Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Department of Pregnancy Care and Delivery, Karolinska University Hospital, Stockholm, Sweden. Electronic address:

Objective: There are no previous data on the influence of drospirenone (DRSP) in combination with estradiol (E2) on the breast in postmenopausal women. The objective of this study was to evaluate the effect of DRSP or norethisterone acetate (NETA) in continuous combination with E2 on two surrogate markers for breast cancer - mammographic breast density and proliferation of breast epithelial cells - in healthy postmenopausal women.

Study Design: 120 healthy, naturally postmenopausal women were randomized to either 2 mg of DRSP or 0.5 mg of NETA in continuous combination with 1 mg of oral E2. The women underwent mammography and fine-needle aspiration biopsy of the breast at baseline and after six months of treatment.

Main Outcome Measures: Digitized mammographic breast density and breast cell proliferation.

Results: There was a significant increase in mammographic breast density after treatment in both groups (median increase 5.5% for E2/DRSP and 2.3% for E2/NETA, respectively, p < 0.001), but with no significant difference between groups. The proliferation of breast epithelial cells also increased in both groups (p < 0.001, respectively), with a significantly larger increase in the E2/DRSP group than in the E2/NETA group (2.5% versus 0.7%, respectively, p < 0.05). Systolic blood pressure had decreased significantly after 6 months of treatment in the E2/DRSP group (p < 0.05) but not in the E2/NETA group.

Conclusions: Breast density increased to a similar degree with E2/DRSP and E2/NETA. Proliferation of breast epithelial cells also increased significantly in both groups but was slightly more pronounced in the E2/DRSP group.
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http://dx.doi.org/10.1016/j.maturitas.2019.04.205DOI Listing
August 2019

Darier disease is associated with type 1 diabetes: Findings from a population-based cohort study.

J Am Acad Dermatol 2019 12 1;81(6):1425-1426. Epub 2019 Jun 1.

Dermatology and Venereology Division, Department of Medicine (Solna), Karolinska Institutet, Stockholm, Sweden; Dermato-Venereology, Karolinska University Hospital, Stockholm, Sweden. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2019.05.087DOI Listing
December 2019

Analyses of IGFBP2 DNA methylation and mRNA expression in visceral and subcutaneous adipose tissues of obese subjects.

Growth Horm IGF Res 2019 04 20;45:31-36. Epub 2019 Mar 20.

Department of Clinical Science, Danderyds Hospital, Karolinska Institutet, Danderyd, Stockholm 18288, Sweden; Department of Surgery, Ersta Hospital, Karolinska Institutet, Stockholm 11691, Sweden. Electronic address:

Insulin-like growth factor binding-protein 2 (IGFBP-2) is secreted by differentiating white adipocytes. Clinical studies demonstrate that circulating IGFBP-2 levels associated inversely with body mass index (BMI) and insulin resistance. To explore possible epigenetic changes of the IGFBP2 gene in obesity, we analyzed DNA methylation and mRNA expression in adipocytes from different depots. Healthy lean controls (BMI = 24.5 ± 0.3 kg/m, n = 19) and obese subjects (BMI > 35 kg/m, n = 24) were recruited. All subjects were Swedish Caucasian. Visceral abdominal adipose tissue (VAT) and subcutaneous adipose tissue (SAT) fragments were homogenized. Genomic DNA and total RNAs were extracted. Four CpG sites in the IGFBP2 gene promoter region were analyzed with bisulfite pyrosequencing. IGFBP2 gene expression at mRNA levels was determined with TaqMan real time RT-PCR. Serum samples were used for measurement of circulating IGFBP-2 and leptin levels. IGFBP2 DNA methylation levels in VAT were increased in obese subjects compared with controls (P < .05). By contrast, IGFBP2 mRNA expression levels in VAT were lower in obesity subjects than in controls (P < .05). In SAT, IGFBP2 DNA methylation and RNA expression levels were lower than in VAT, irrespective of obesity. Obese subjects demonstrated increased serum leptin levels (P < .001) and reduced serum IGFBP-2 levels compared to controls (P < .05). In conclusion, the current study demonstrates that IGFBP2 DNA methylation levels are increased in VAT from obese subjects. This suggests that IGFBP-2 is epigenetically regulated in abdominal obesity.
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http://dx.doi.org/10.1016/j.ghir.2019.03.002DOI Listing
April 2019

Copeptin and insulin-like growth factor binding protein-1 during follow-up after an acute myocardial infarction in patients with type 2 diabetes: A report from the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction 2 cohort.

Diab Vasc Dis Res 2019 01 11;16(1):22-27. Epub 2018 Oct 11.

1 Division of Cardiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.

Purpose: Copeptin and insulin-like growth factor binding protein-1 analysed at admission for a myocardial infarction in patients with type 2 diabetes mellitus predicts cardiovascular events. The present aim was to study the association between copeptin and insulin-like growth factor binding protein-1, the development of the levels over time, and if the predictive value remained when measured at hospital discharge and 3 months thereafter.

Methods: Copeptin and insulin-like growth factor binding protein-1 were analysed in patients (median age = 70, male = 68%) with type 2 diabetes mellitus + myocardial infarction at admission (n = 393), discharge (n = 309) and 3 months later (n = 288). The primary endpoint was cardiovascular event (cardiovascular death/non-fatal myocardial infarction/stroke) with the three time points as separate baselines.

Results: The median copeptin levels were 21.8 pmol/L at admission, 8.5 pmol/L at discharge and 8.4 pmol/L after 3 months, while insulin-like growth factor binding protein-1 levels continued to increase. There were significant correlations between the biomarkers at all occasions. During an average follow-up of 2.5 years, copeptin, but not insulin-like growth factor binding protein-1, predicted cardiovascular event at all occasions in unadjusted analyses. Copeptin remained as a predictor at discharge and after 3 months in the final multiple model (including: heart failure/age/creatinine clearance).

Conclusion: The relationship between copeptin and insulin-like growth factor binding protein-1 during the initial phase of a myocardial infarction persisted in a less-stressful situation, and copeptin remained as a prognostic indicator at discharge and 3 months later.
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http://dx.doi.org/10.1177/1479164118804451DOI Listing
January 2019

Red Blood Cells in Type 2 Diabetes Impair Cardiac Post-Ischemic Recovery Through an Arginase-Dependent Modulation of Nitric Oxide Synthase and Reactive Oxygen Species.

JACC Basic Transl Sci 2018 Aug 18;3(4):450-463. Epub 2018 Jul 18.

Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockhom, Sweden.

This study tested the hypothesis that red blood cell (RBC) arginase represents a potential therapeutic target in ischemia-reperfusion in type 2 diabetes. Post-ischemic cardiac recovery was impaired in hearts from db/db mice compared with wild-type hearts. RBCs from mice and patients with type 2 diabetes attenuated post-ischemic cardiac recovery of nondiabetic hearts. This impaired cardiac recovery was reversed by inhibition of RBCs arginase or nitric oxide synthase. The results suggest that RBCs from type 2 diabetics impair cardiac tolerance to ischemia-reperfusion via a pathway involving arginase activity and nitric oxide synthase-dependent oxidative stress.
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http://dx.doi.org/10.1016/j.jacbts.2018.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115643PMC
August 2018

Elevated levels of insulin-like growth factor-binding protein 1 predict outcome after acute myocardial infarction: A long-term follow-up of the glucose tolerance in patients with acute myocardial infarction (GAMI) cohort.

Diab Vasc Dis Res 2018 09 11;15(5):387-395. Epub 2018 Jul 11.

1 Cardiology Unit, Department of Medicine, Solna, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.

Objective: To investigate the long-term prognostic value of insulin-like growth factor-binding protein 1 in patients with acute myocardial infarction.

Methods: Patients ( n = 180) with admission glucose < 11 mmol/L without previously known diabetes admitted for an acute myocardial infarction in 1998-2000 were followed for mortality and cardiovascular events (first of cardiovascular mortality/acute myocardial infarction/stroke/severe heart failure) until the end of 2011 (median 11.6 years). Fasting levels of insulin-like growth factor-binding protein 1 at day 2 were related to outcome in Cox proportional hazard regression analyses.

Results: Median age was 64 years, 69% were male and median insulin-like growth factor-binding protein 1 was 20 µg/L. Total mortality was 34% ( n = 61) and 44% ( n = 80) experienced a cardiovascular event during a median follow-up time of 11.6 years. After age adjustment, insulin-like growth factor-binding protein 1 was associated with all-cause (1.40; 1.02-1.93, p = 0.039) and cancer mortality (2.09; 1.15-3.79, p = 0.015) but not with cardiovascular death ( p = 0.29) or cardiovascular events ( p = 0.57). After adjustments also for previous myocardial infarction, previous heart failure and body mass index, insulin-like growth factor-binding protein 1 was still associated with all-cause mortality (1.38; 1.01-1.89, p = 0.046).

Conclusion: In patients with acute myocardial infarction without previously known diabetes, high insulin-like growth factor-binding protein 1 was associated with long-term all-cause and cancer mortality but not with cardiovascular events.
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http://dx.doi.org/10.1177/1479164118781892DOI Listing
September 2018

Diet-induced β-cell insulin resistance results in reversible loss of functional β-cell mass.

FASEB J 2019 01 29;33(1):204-218. Epub 2018 Jun 29.

The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden.

Although convincing in genetic models, the relevance of β-cell insulin resistance in diet-induced type 2 diabetes (T2DM) remains unclear. Exemplified by diabetes-prone, male, C57B1/6J mice being fed different combinations of Western-style diet, we show that β-cell insulin resistance occurs early during T2DM progression and is due to a combination of lipotoxicity and increased β-cell workload. Within 8 wk of being fed a high-fat, high-sucrose diet, mice became obese, developed impaired insulin and glucose tolerances, and displayed noncompensatory insulin release, due, at least in part, to reduced expression of syntaxin-1A. Through reporter islets transplanted to the anterior chamber of the eye, we demonstrated a concomitant loss of functional β-cell mass. When mice were changed from diabetogenic diet to normal chow diet, the diabetes phenotype was reversed, suggesting a remarkable plasticity of functional β-cell mass in the early phase of T2DM development. Our data reinforce the relevance of diet composition as an environmental factor determining different routes of diabetes progression in a given genetic background. Employing the in vivo reporter islet-monitoring approach will allow researchers to define key times in the dynamics of reversible loss of functional β-cell mass and, thus, to investigate the underlying, molecular mechanisms involved in the progression toward T2DM manifestation.-Paschen, M., Moede, T., Valladolid-Acebes, I., Leibiger, B., Moruzzi, N., Jacob, S., García-Prieto, C. F., Brismar, K., Leibiger, I. B., Berggren, P.-O. Diet-induced β-cell insulin resistance results in reversible loss of functional β-cell mass.
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http://dx.doi.org/10.1096/fj.201800826RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355083PMC
January 2019

Comparison of Prognostic Usefulness of Serum Insulin-Like Growth Factor-Binding Protein 7 in Patients With Heart Failure and Preserved Versus Reduced Left Ventricular Ejection Fraction.

Am J Cardiol 2018 06 14;121(12):1558-1566. Epub 2018 Mar 14.

Department of Medicine, Cardiology unit, Karolinska Institutet, Stockholm, Sweden.

We aimed to characterize of the role of insulin-like growth factor-binding protein 7 (IGFBP-7) in heart failure (HF) pathophysiology. IGFBP-7 has been associated with cardiac hypertrophy and diastolic dysfunction in HF. In 86 patients with HF with a preserved ejection fraction (HFpEF) (ejection fraction [EF] ≥45%) and 79 with HF with a reduced ejection fraction (HFrEF), we assessed concentrations of serum IGFBP-7, correlations between serum IGFBP-7 and clinical data, diastolic function, and associations with outcome. IGFBP-7 was lower in HFpEF than HFrEF (102 vs 152 µg/L, p <0.001) and correlated with New York Heart Association class (HFpEF: r = 0.25, p = 0.020; HFrEF: r = 0.26, p = 0.022), N-terminal pro-brain natriuretic peptide (NT-proBNP) (HFpEF: r = 0.53, p <0.001; HFrEF: r = 0.50, p <0.001), and estimated glomerular filtration rate (eGFR) (HFpEF: r = -0.47, p <0.001; HFrEF: r = -0.45, p <0.001). In HFpEF, IGFBP-7 correlated with E/e' (r = 0.31, p = 0.012) and E/A ratio (r = 0.31, p = 0.011). In HFrEF, but not HFpEF, IGFBP-7 correlated with age (r = 0.29, p = 0.009) and atrial fibrillation (r = 0.34, p = 0.002). IGFBP-7 predicted the outcome in HFpEF (hazard ratio 4.19 [1.01 to 17.35], p = 0.048]) but not in HFrEF (0.72 [0.24 to 2.14], p = 0.554). In conclusion in HFrEF, IGFBP-7 was elevated and associated with HF severity but not prognostic, suggesting a marker of risk. In HFpEF, IGFBP-7 was less elevated but associated with markers of diastolic dysfunction, HF severity, and prognosis. IGFBP-7 may contribute to the progression of HFpEF possibly through inflammation and oxidative stress.
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http://dx.doi.org/10.1016/j.amjcard.2018.02.041DOI Listing
June 2018

SNAP-25a and SNAP-25b differently mediate interactions with Munc18-1 and Gβγ subunits.

Neurosci Lett 2018 05 13;674:75-80. Epub 2018 Mar 13.

Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden. Electronic address:

SNAP-25 is a protein involved in regulated membrane fusion and part of the SNARE complex. It exists as two splicing variants, SNAP-25a and SNAP-25b, which differ in 9 out of 206 amino acids. SNAP-25 together with Syntaxin 1 and VAMP-2 forms the ternary SNARE complex essential for mediating activity-dependent release of hormones and neurotransmitters. The functional difference between SNAP-25a and SNAP-25b is poorly understood as both can participate in SNARE complexes and mediate membrane fusion. However, we recently demonstrated that SNAP-25b-deficiency results in metabolic disease and increased insulin secretion. Here we investigated if SNAP-25a and SNAP-25b differently affect interactions with other SNAREs and SNARE-interacting proteins in mouse hippocampus. Adult mice almost exclusively express the SNAP-25b protein in hippocampus whereas SNAP-25b-deficient mice only express SNAP-25a. Immunoprecipitation studies showed no significant differences in amount of Syntaxin 1 and VAMP-2 co-precipitated with the different SNAP-25 isoforms. In contrast, Munc18-1, that preferentially interacts with SNAP-25 via Syntaxin 1 and/or the trimeric SNARE complex, demonstrated an increased ability to bind protein-complexes containing SNAP-25b. Moreover, we found that both SNAP-25 isoforms co-precipitated the Gβγ subunits of the heterotrimeric G proteins, an interaction known to play a role in presynaptic inhibition. We have identified Gβ and Gβ as the interacting partners of both SNAP-25 isoforms in mouse hippocampus, but Gβ was less efficiently captured by SNAP-25a. These results implicate that the two SNAP-25 isoforms could differently mediate protein interactions outside the ternary SNARE core complex and thereby contribute to modulate neurotransmission.
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http://dx.doi.org/10.1016/j.neulet.2018.03.024DOI Listing
May 2018

Deficiency of liver-derived insulin-like growth factor-I (IGF-I) does not interfere with the skin wound healing rate.

PLoS One 2018 13;13(3):e0193084. Epub 2018 Mar 13.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Solna, Stockholm, Sweden.

Objective: IGF-I is a growth factor, which is expressed in virtually all tissues. The circulating IGF-I is however derived mainly from the liver. IGF-I promotes wound healing and its levels are decreased in wounds with low regenerative potential such as diabetic wounds. However, the contribution of circulating IGF-I to wound healing is unknown. Here we investigated the role of systemic IGF-I on wound healing rate in mice with deficiency of liver-derived IGF-I (LI-IGF-I-/- mice) during normal (normoglycemic) and impaired wound healing (diabetes).

Methods: LI-IGF-I-/- mice with complete inactivation of the IGF-I gene in the hepatocytes were generated using the Cre/loxP recombination system. This resulted in a 75% reduction of circulating IGF-I. Diabetes was induced with streptozocin in both LI-IGF-I-/- and control mice. Wounds were made on the dorsum of the mice, and the wound healing rate and histology were evaluated. Serum IGF-I and GH were measured by RIA and ELISA respectively. The expression of IGF-I, IGF-II and the IGF-I receptor in the skin were evaluated by qRT-PCR. The local IGF-I protein expression in different cell types of the wounds during wound healing process was analyzed using immunohistochemistry.

Results: The wound healing rate was similar in LI-IGF-I-/- mice to that in controls. Diabetes significantly delayed the wound healing rate in both LI-IGF-I-/- and control mice. However, no significant difference was observed between diabetic animals with normal or reduced hepatic IGF-I production. The gene expression of IGF-I, IGF-II and IGF-I receptor in skin was not different between any group of animals tested. Local IGF-I levels in the wounds were similar between of LI-IGF-I-/- and WT mice although a transient reduction of IGF-I expression in leukocytes in the wounds of LI-IGF-I-/- was observed seven days post wounding.

Conclusion: Deficiency in the liver-derived IGF-I does not affect wound healing in mice, neither in normoglycemic conditions nor in diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193084PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849293PMC
June 2018

IGFBP-1 and IGF-I as markers for advanced fibrosis in NAFLD - a pilot study.

Scand J Gastroenterol 2017 Dec 19;52(12):1427-1434. Epub 2017 Sep 19.

d Department of Molecular Medicine and Surgery , Rolf Luft Research Centre for Diabetes and Endocrinology, Karolinska Institutet , Stockholm , Sweden.

Background And Aims: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease globally. Advanced fibrosis (stage 3-4) is the most robust marker for future mortality, but diagnosis requires liver biopsy. Current non-invasive scoring systems aimed to identify advanced fibrosis are imperfect. Insulin-like growth factor I (IGF-I) and its binding protein IGFBP-1 are liver derived proteins, that are involved in various liver disorders. The aim of this study was to examine the possible association between advanced fibrosis and IGF-I and IGFBP-1 in NAFLD.

Methods: Fasting blood samples were obtained from 52 patients diagnosed with NAFLD by liver biopsy. Total IGF-I and IGFBP-1 concentrations were determined in serum by in-house radio-immuno-assays. IGF-I levels were age-standardized (IGF-SD). A logistic regression model was used to investigate the association of IGF-SD and IGFBP-1 with advanced fibrosis (stage 3-4).

Results: Patients with advanced fibrosis (stage 3-4 vs. 0-2) had lower IGF-SD (-1.17 vs. 0.11, p = .01) and higher mean levels of IGFBP-1 (29.9 vs. 18.8 µg/l, p = .02). IGFBP-1 was associated with presence of advanced fibrosis (OR 1.04 per unit increase, 95%CI 1.0-1.07, p = .05), while IGF-1 was negatively associated with advanced fibrosis (OR 0.63 per standard deviation, 95%CI 0.44-0.92, p = .02).

Conclusions: This pilot study suggests an association between serum IGFBP-1 and IGF-I levels with advanced fibrosis in NAFLD patients. IGFBP1 and IGF-1 could be of interest as future biomarkers. Similar studies in larger cohorts are needed.
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http://dx.doi.org/10.1080/00365521.2017.1379556DOI Listing
December 2017

Obesity is a strong predictor of worse clinical outcomes and treatment responses in early rheumatoid arthritis: results from the SWEFOT trial.

RMD Open 2017 9;3(2):e000458. Epub 2017 Aug 9.

Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.

Objectives: The aim of this paper was to analyse the impact of obesity, in addition to known predictors, on disease outcome in early rheumatoid arthritis (RA).

Methods: Body mass index (BMI) was available in 260 patients from the Swedish pharmacotherapy trial (SWEFOT). Differences in disease activity (DAS28), functional impairment (HAQ), pain (Visual Analogue Scale, VAS-pain) and radiographic damage were evaluated over 24 months between BMI categories (obese BMI >30, n=43; overweight BMI=25-29.9, n=74; normal BMI <25, n=143) using non-parametric testing. Predictors of European League Against Rheumatism non-remission (DAS28 ≥2.6) at 24 months of follow-up were evaluated using binary univariate and multivariate logistic regression.

Results: Obesity at baseline was associated with worse continuous-scale clinical outcomes over 24 months (DAS28, HAQ and VAS-pain at last visit: obese vs normal: p<0.001; obese vs overweight: p<0.05). Furthermore, obese patients compared with non-obese patients had significantly greater odds of non-remission at 24 months (adjusted OR (aOR) 5.2; 95% CI 1.8 to 15.2). Other independent predictors were female sex (aOR 2.6; 95% CI 1.1 to 5.8), current smoking (aOR 2.6; 95% CI 1.1 to 6.3) and HAQ (per-unit increase, aOR 1.9; 95% CI 1.1 to 3.4). The pattern was similar among seropositive and seronegative patients; and in the subgroups of methotrexate responders and patients randomised at 3 months to add-on of sulfasalazine+hydroxychloroquine, although not significant with add-on of infliximab. Obesity had no independent association to radiographic progression.

Conclusions: In this early RA trial reflecting today's standard treatment, obesity, in addition to sex, smoking and functional impairment strongly lowered the chance of attaining good clinical outcomes, including remission, today's treatment goal. This highlights the importance of considering lifestyle modification as one of the cornerstones of RA care.

Trial Registration Number: NCT00764725; Post-results. WHO database at the Karolinska University Hospital: CT20080004.
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http://dx.doi.org/10.1136/rmdopen-2017-000458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5574420PMC
August 2017

SNAP-25b-deficiency increases insulin secretion and changes spatiotemporal profile of Caoscillations in β cell networks.

Sci Rep 2017 08 10;7(1):7744. Epub 2017 Aug 10.

The Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 76, Stockholm, Sweden.

SNAP-25 is a protein of the core SNARE complex mediating stimulus-dependent release of insulin from pancreatic β cells. The protein exists as two alternatively spliced isoforms, SNAP-25a and SNAP-25b, differing in 9 out of 206 amino acids, yet their specific roles in pancreatic β cells remain unclear. We explored the effect of SNAP-25b-deficiency on glucose-stimulated insulin release in islets and found increased secretion both in vivo and in vitro. However, slow photo-release of caged Ca in β cells within pancreatic slices showed no significant differences in Ca-sensitivity, amplitude or rate of exocytosis between SNAP-25b-deficient and wild-type littermates. Therefore, we next investigated if Ca handling was affected in glucose-stimulated β cells using intracellular Ca-imaging and found premature activation and delayed termination of [Ca] elevations. These findings were accompanied by less synchronized Ca-oscillations and hence more segregated functional β cell networks in SNAP-25b-deficient mice. Islet gross morphology and architecture were maintained in mutant mice, although sex specific compensatory changes were observed. Thus, our study proposes that SNAP-25b in pancreatic β cells, except for participating in the core SNARE complex, is necessary for accurate regulation of Ca-dynamics.
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http://dx.doi.org/10.1038/s41598-017-08082-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5552776PMC
August 2017

Reallocating bouted sedentary time to non-bouted sedentary time, light activity and moderate-vigorous physical activity in adults with prediabetes and type 2 diabetes.

PLoS One 2017 28;12(7):e0181053. Epub 2017 Jul 28.

Department of Neurobiology, Care Sciences and Society, Division of Physiotherapy, Karolinska Institutet, Stockholm, Sweden.

Aim: The aim of this study was to investigate the potential associations of reallocating 30 minutes sedentary time in long bouts (>60 min) to sedentary time in non-bouts, light intensity physical activity (LPA) and moderate- to vigorous physical activity (MVPA) with cardiometabolic risk factors in a population diagnosed with prediabetes or type 2 diabetes.

Methods: Participants diagnosed with prediabetes and type 2 diabetes (n = 124, 50% men, mean [SD] age = 63.8 [7.5] years) were recruited to the physical activity intervention Sophia Step Study. For this study baseline data was used with a cross-sectional design. Time spent in sedentary behaviors in bouts (>60 min) and non-bouts (accrued in <60 min bouts) and physical activity was measured using the ActiGraph GT1M. Associations of reallocating bouted sedentary time to non-bouted sedentary time, LPA and MVPA with cardiometabolic risk factors were examined using an isotemporal substitution framework with linear regression models.

Results: Reallocating 30 minutes sedentary time in bouts to MVPA was associated with lower waist circumference (b = -4.30 95% CI:-7.23, -1.38 cm), lower BMI (b = -1.46 95% CI:-2.60, -0.33 kg/m2) and higher HDL cholesterol levels (b = 0.11 95% CI: 0.02, 0.21 kg/m2. Similar associations were seen for reallocation of sedentary time in non-bouts to MVPA. Reallocating sedentary time in bouts to LPA was associated only with lower waist circumference.

Conclusion: Reallocation of sedentary time in bouts as well as non-bouts to MVPA, but not to LPA, was beneficially associated with waist circumference, BMI and HDL cholesterol in individuals with prediabetes and type 2 diabetes. The results of this study confirm the importance of reallocation sedentary time to MVPA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181053PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533318PMC
October 2017

High insulin-like growth factor-binding protein-1 (IGFBP-1) is associated with low relative muscle mass in older women.

Metabolism 2017 08 1;73:36-42. Epub 2017 May 1.

Unit of Nutritional Epidemiology, The National Institute for Environmental Medicine, Karolinska Institutet, Box 210, 171 77, Stockholm, Sweden. Electronic address:

Objective: Skeletal muscles serve several important roles in maintaining good health. Insulin-like growth factor-1 (IGF-1) is a promoter of protein synthesis in skeletal muscle. Its binding protein, Insulin-like growth factor-binding protein-1 (IGFBP-1) can be one determinant of IGF-1 activity. In the present study we investigate the association between serum IGFBP-1 and muscle mass.

Design: Cross-sectional analysis of 4908 women, between 55 and 85years old, participating in the Swedish Mammography Cohort-Clinical.

Methods: We defined low relative muscle mass (LRMM) as an appendicular lean mass divided by height squared of less than 5.45 (kg/m), assessed by dual energy x-ray absorptiometry. IGFBP-1 was measured by radioimmunoassay. Logistic regression was used to calculate odds-ratios of LRMM across quartiles of IGFBP-1.

Results: The odds of LRMM increased across quartiles of IGFBP-1. In the age-adjusted model the odds-ratio (OR) of LRMM was 3.41 (95% CI: 2.55-4.56), comparing the highest to the lowest quartile. This estimate was attenuated in multivariate models (OR: 1.84, 95% CI: 1.34-2.53), mainly due to inclusion of fat mass index.

Conclusion: Women with higher IGFBP-1 were more likely to have a low relative muscle mass. High IGFBP-1 may be a marker of a catabolic state.
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http://dx.doi.org/10.1016/j.metabol.2017.04.013DOI Listing
August 2017

Increase in insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 1 after supplementation with selenium and coenzyme Q10. A prospective randomized double-blind placebo-controlled trial among elderly Swedish citizens.

PLoS One 2017 13;12(6):e0178614. Epub 2017 Jun 13.

Department of Molecular Medicine and Surgery, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.

Background: Insulin-like growth factor-1(IGF-1) has a multitude of effects besides cell growth and metabolism. Reports also indicate anti-inflammatory and antioxidative effects. The concentrations of IGF-1 decrease with age and during inflammation. As selenium and coenzyme Q10 are involved in both the antioxidative defense and the inflammatory response, the present study aimed to examine the effects of supplementation with selenium and coenzyme Q10 on concentrations of IGF-1 and its binding protein IGFBP-1 in a population showing reduced cardiovascular mortality following such supplementation.

Methods: 215 elderly individuals were included and given the intervention for four years. A clinical examination was performed and blood samples were taken at the start and after 48 months. Evaluations of IGF-1, the age adjusted IGF-1 SD score and IGFBP-1 were performed using group mean values, and repeated measures of variance.

Findings: After supplementation with selenium and coenzyme Q10, applying group mean evaluations, significantly higher IGF-1 and IGF-1 SD scores could be seen in the active treatment group, whereas a decrease in concentration could be seen of the same biomarkers in the placebo group. Applying the repeated measures of variance evaluations, the same significant increase in concentrations of IGF-1 (F = 68; P>0.0001), IGF-1 SD score (F = 29; P<0.0001) and of IGFBP-1 (F = 6.88; P = 0.009) could be seen, indicating the effect of selenium and coenzyme Q10 also on the expression of IGF-1 as one of the mechanistic effects of the intervention.

Conclusion: Supplementation with selenium and coenzyme Q10 over four years resulted in increased levels of IGF-1 and the postprandial IGFBP-1, and an increase in the age-corrected IGF-1 SD score, compared with placebo. The effects could be part of the mechanistic explanation behind the surprisingly positive clinical effects on cardiovascular morbidity and mortality reported earlier. However, as the effects of IGF-1 are complex, more research on the result of intervention with selenium and coenzyme Q10 is needed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0178614PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469470PMC
October 2017

Elevated levels of adipokines predict outcome after acute myocardial infarction: A long-term follow-up of the Glucose Tolerance in Patients with Acute Myocardial Infarction cohort.

Diab Vasc Dis Res 2017 03 21;14(2):77-87. Epub 2016 Dec 21.

1 Unit of Cardiology, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Objective: Adiponectin and leptin are associated with insulin resistance and cardiovascular disease. Information on the prognostic value after an acute myocardial infarction is still conflicting.

Methods: Patients (n = 180) without known diabetes and with admission glucose of <11 mmol/L admitted for an acute myocardial infarction in 1998-2000 were followed for mortality and cardiovascular events (first of cardiovascular mortality/acute myocardial infarction/stroke/heart failure) until the end of 2011 (median: 11.6 years). Plasma adiponectin and leptin were related to outcome in Cox proportional-hazard regression analyses.

Results: Median age was 64 years and 69% were male. Total mortality was 34% (n = 61) and 44% (n = 80) experienced a cardiovascular event. Adiponectin at discharge predicted cardiovascular events (hazard ratio; 95% confidence interval; 1.45; 1.02-2.07, p = 0.038), total mortality (2.53; 1.64-3.91, p < 0.001) and cancer mortality (3.64; 1.51-8.74, p = 0.004). After adjustment for age, sex, body mass index, previous myocardial infarction and heart failure, adiponectin predicted total mortality (1.79; 1.07-3.00, p = 0.027) but not cardiovascular events. High levels of leptin were associated with cardiovascular events during the first 7 years, after which the association was attenuated. Leptin did not predict total mortality.

Conclusion: In patients with acute myocardial infarction but without previously known diabetes, high levels of adiponectin at discharge predicted total mortality. The present results support the hypothesis that high rather than low levels of adiponectin predict mortality after acute myocardial infarction.
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http://dx.doi.org/10.1177/1479164116678156DOI Listing
March 2017

BMI and waist circumference cut-offs for corresponding levels of insulin sensitivity in a Middle Eastern immigrant versus a native Swedish population - the MEDIM population based study.

BMC Public Health 2016 12 9;16(1):1242. Epub 2016 Dec 9.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

Background: The aim of this study was to identify corresponding body mass index (BMI) and waist circumference cut-offs for equivalent levels of insulin sensitivity in a Middle Eastern immigrant population compared with native Swedes.

Methods: Citizens of Malmö, Sweden aged 30 to 75 years, who were born in Iraq or Sweden, were in 2010-2012 invited to participate in a health examination including anthropometrics, oral glucose tolerance test, fasting samples and interviews concerning sociodemographic factors and lifestyle behaviours.

Results: In total, 1176 individuals born in Iraq and 688 born in Sweden, without previously diagnosed type 2 diabetes, participated in the study. In normal weight participants (BMI < 25 kg/m), 21.2% of Iraqis vs 9.3% of Swedes were insulin resistant. Corresponding figures in participants without abdominal obesity (waist circumference, men < 94 cm, women < 80 cm) were 28.2% of Iraqis vs 9.4% of Swedes. The age-adjusted insulin sensitivity index (ISI) for obese Swedes (BMI 30 kg/m) corresponded in Iraqi men with BMI of 28.5 kg/m, and in Iraqi women with BMI of 27.5 kg/m. The ISI level in abdominally obese Swedes corresponded with waist circumference cut-offs of 84.0 cm and 71.0 cm in Iraqi men and women, respectively. In men only, larger waist circumference (P  = 0.026) presented a stronger association with impaired ISI in Iraqis as compared to Swedes.

Conclusions: Our data shows that the impact of BMI and waist circumference on ISI is ethnic- and gender-specific, indicating a disturbed fat metabolism in Iraqi males in particular. Our data suggests that 10 cm lower cut-off values for abdominal obesity, than is currently recommended by major organisations, should be considered when estimating diabetes risk in Middle Eastern populations.
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http://dx.doi.org/10.1186/s12889-016-3892-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5148840PMC
December 2016

HFpEF and HFrEF exhibit different phenotypes as assessed by leptin and adiponectin.

Int J Cardiol 2017 Feb 9;228:709-716. Epub 2016 Nov 9.

Department of Medicine, Stockholm, Karolinska Institutet, Sweden; Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.

Background: Heart failure with reduced ejection fraction (HFrEF) exhibits a "reverse metabolic profile". Whether this profile exists in HF with preserved ejection fraction (HFpEF) is unknown. We tested the hypothesis that HFpEF and HFrEF are similar regarding concentrations of and prognostic impact of leptin and adiponectin.

Methods: In patients with HFpEF(n=79), HFrEF(n=84), and controls(n=71), we analyzed serum leptin and adiponectin concentrations, their correlations, and associations with outcome.

Results: Leptin levels in HFpEF and HFrEF were increased (p<0.05) compared to controls; with the highest levels in HFpEF, median (IQR), 23.1 (10.2-51.0), vs. HFrEF 15.0 (6.2-33.2), and vs. controls 10.8 (5.4-18.9) ng/mL.There was no difference between HFpEF and HFrEF p=0.125 (adjusted for gender, BMI and age). Leptin was inversely associated with NT-proBNP (r=-0.364 p=0.001) and associated with better outcome in HFrEF (HR per ln increase of leptin 0.76, 95% CI 0.58-0.99, p=0.044) but not in HFpEF. Crude levels of adiponectin were similar in HFpEF: 11.8 (7.9-20.1), HFrEF: 13.7 (7.0-21.1), and controls: 10.5 (7.4-15.1) μg/L. In men, adjusted similarly as leptin, there was no difference between HFpEF and HFrEF, p=0.310 but, compared to controls, higher levels in HFpEF (p=0.044) and HFrEF (p=0.001). Adiponectin correlated positively with NT-proBNP; r=0.396 p<0.001 and higher levels were associated with adverse outcome only in HFrEF (HR per ln increase 2.88 (95% CI 1.02-8.14, p=0.045).

Conclusion: HFpEF and HFrEF share elevated levels of leptin and adiponectin. However, the concept of reverse metabolic profile could not be confirmed in HFpEF, suggesting that HFpEF might have a conventional metabolic profile, rather than a distinct HF syndrome.
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http://dx.doi.org/10.1016/j.ijcard.2016.11.194DOI Listing
February 2017

Mono-epoxy-tocotrienol-α enhances wound healing in diabetic mice and stimulates in vitro angiogenesis and cell migration.

J Diabetes Complications 2017 01 18;31(1):4-12. Epub 2016 Oct 18.

The Rolf Luft Center for Diabetes Research, Department of Molecular Medicine, Karolinska Institutet and Department of Endocrinology, Diabetes and Metabolism Karolinska Hospital, SE-171 76 Stockholm, Sweden. Electronic address:

Diabetes mellitus is characterized by hyperglycemia and capillary hypoxia that causes excessive production of free radicals and impaired antioxidant defense, resulting in oxidative stress and diabetes complications such as impaired wound healing. We have previously shown that modified forms of tocotrienols possess beneficial effects on the biosynthesis of the mevalonate pathway lipids including increase in mitochondrial CoQ. The aim of this study is to investigate the effects of mono-epoxy-tocotrienol-α on in vitro and in vivo wound healing models as well as its effects on mitochondrial function. Gene profiling analysis and gene expression studies on HepG2 cells and human dermal fibroblasts were performed by microarray and qPCR, respectively. In vitro wound healing using human fibroblasts was studied by scratch assay and in vitro angiogenesis using human dermal microvascular endothelial cells was studied by the tube formation assay. In vivo wound healing was performed in the diabetic db/db mouse model. For the study of mitochondrial functions and oxygen consumption rate Seahorse XF-24 was employed. In vitro, significant increase in wound closure and cell migration (p<0.05) both in normal and high glucose and in endothelial tube formation (angiogenesis) (p<0.005) were observed. Microarray profiling analysis showed a 20-fold increase of KIF26A gene expression and 11-fold decrease of lanosterol synthase expression. Expression analysis by qPCR showed significant increase of the growth factors VEGFA and PDGFB. The epoxidated compound induced a significantly higher basal and reserve mitochondrial capacity in both HDF and HepG2 cells. Additionally, in vivo wound healing in db/db mice, demonstrated a small but significant enhancement on wound healing upon local application of the compound compared to treatment with vehicle alone. Mono-epoxy-tocotrienol-α seems to possess beneficial effects on wound healing by increasing the expression of genes involved in cell growth, motility and angiogenes as well as on mitochondrial function.
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http://dx.doi.org/10.1016/j.jdiacomp.2016.10.010DOI Listing
January 2017