Publications by authors named "Kerstin Brismar"

204 Publications

Repression of hypoxia-inducible factor-1 contributes to increased mitochondrial reactive oxygen species production in diabetes.

Elife 2022 02 15;11. Epub 2022 Feb 15.

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

Background: Excessive production of mitochondrial reactive oxygen species (ROS) is a central mechanism for the development of diabetes complications. Recently, hypoxia has been identified to play an additional pathogenic role in diabetes. In this study, we hypothesized that ROS overproduction was secondary to the impaired responses to hypoxia due to the inhibition of hypoxia-inducible factor-1 (HIF-1) by hyperglycemia.

Methods: The ROS levels were analyzed in the blood of healthy subjects and individuals with type 1 diabetes after exposure to hypoxia. The relation between HIF-1, glucose levels, ROS production and its functional consequences were analyzed in renal mIMCD-3 cells and in kidneys of mouse models of diabetes.

Results: Exposure to hypoxia increased circulating ROS in subjects with diabetes, but not in subjects without diabetes. High glucose concentrations repressed HIF-1 both in hypoxic cells and in kidneys of animals with diabetes, through a HIF prolyl-hydroxylase (PHD)-dependent mechanism. The impaired HIF-1 signaling contributed to excess production of mitochondrial ROS through increased mitochondrial respiration that was mediated by Pyruvate dehydrogenase kinase 1 (PDK1). The restoration of HIF-1 function attenuated ROS overproduction despite persistent hyperglycemia, and conferred protection against apoptosis and renal injury in diabetes.

Conclusions: We conclude that the repression of HIF-1 plays a central role in mitochondrial ROS overproduction in diabetes and is a potential therapeutic target for diabetic complications. These findings are timely since the first PHD inhibitor that can activate HIF-1 has been newly approved for clinical use.

Funding: This work was supported by grants from the Swedish Research Council, Stockholm County Research Council, Stockholm Regional Research Foundation, Bert von Kantzows Foundation, Swedish Society of Medicine, Kung Gustaf V:s och Drottning Victorias Frimurarestifelse, Karolinska Institute's Research Foundations, Strategic Research Programme in Diabetes, and Erling-Persson Family Foundation for S-B.C.; grants from the Swedish Research Council and Swedish Heart and Lung Foundation for T.A.S.; and ERC consolidator grant for M.M.
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http://dx.doi.org/10.7554/eLife.70714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8846593PMC
February 2022

Reduced expression of OXPHOS and DNA damage genes is linked to protection from microvascular complications in long-term type 1 diabetes: the PROLONG study.

Sci Rep 2021 10 20;11(1):20735. Epub 2021 Oct 20.

Department of Clinical Science, Center for Diabetes Research, University of Bergen, 5032, Bergen, Norway.

Type 1 diabetes is a chronic autoimmune disease requiring insulin treatment for survival. Prolonged duration of type 1 diabetes is associated with increased risk of microvascular complications. Although chronic hyperglycemia and diabetes duration have been considered as the major risk factors for vascular complications, this is not universally seen among all patients. Persons with long-term type 1 diabetes who have remained largely free from vascular complications constitute an ideal group for investigation of natural defense mechanisms against prolonged exposure of diabetes. Transcriptomic signatures obtained from RNA sequencing of the peripheral blood cells were analyzed in non-progressors with more than 30 years of diabetes duration and compared to the patients who progressed to microvascular complications within a shorter duration of diabetes. Analyses revealed that non-progressors demonstrated a reduction in expression of the oxidative phosphorylation (OXPHOS) genes, which were positively correlated with the expression of DNA repair enzymes, namely genes involved in base excision repair (BER) machinery. Reduced expression of OXPHOS and BER genes was linked to decrease in expression of inflammation-related genes, higher glucose disposal rate and reduced measures of hepatic fatty liver. Results from the present study indicate that at transcriptomic level reduction in OXPHOS, DNA repair and inflammation-related genes is linked to better insulin sensitivity and protection against microvascular complications in persons with long-term type 1 diabetes.
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http://dx.doi.org/10.1038/s41598-021-00183-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528906PMC
October 2021

HIF-1 mediated activation of antimicrobial peptide LL-37 in type 2 diabetic patients.

J Mol Med (Berl) 2022 01 15;100(1):101-113. Epub 2021 Oct 15.

Department of Microbiology, Tumor and Cell Biology, Division of Clinical Microbiology, Karolinska Institutet and Karolinska University Hospital, 17176, Stockholm, Sweden.

Infections are common in patients with diabetes, but increasing antibiotic resistance hampers successful bacterial clearance and calls for alternative treatment strategies. Hypoxia-inducible factor 1 (HIF-1) is known to influence the innate immune defense and could therefore serve as a possible target. However, the impact of high glucose on HIF-1 has received little attention and merits closer investigation. Here, we show that higher levels of proinflammatory cytokines and CAMP, encoding for the antimicrobial peptide cathelicidin, LL-37, correlate with HIF-1 in type 2 diabetic patients. Chemical activation of HIF-1 further enhanced LL-37, IL-1β, and IL-8 in human uroepithelial cells exposed to high glucose. Moreover, HIF-1 activation of transurethrally infected diabetic mice resulted in lower bacterial load. Drugs activating HIF-1 could therefore in the future potentially have a therapeutic role in clearing bacteria in diabetic patients with infections where antibiotic treatment failed. KEY MESSAGES: • Mohanty et al. "HIF-1 mediated activation of antimicrobial peptide LL-37 in type 2 diabetic patients." • Our study highlights induction of the antimicrobial peptide, LL-37, and strengthening of the innate immunity through hypoxia-inducible factor 1 (HIF-1) in diabetes. • Our key observations are: 1. HIF-1 activation increased LL-37 expression in human urothelial cells treated with high glucose. In line with that, we demonstrated that patients with type 2 diabetes living at high altitude had increased levels of the LL-37. 2. HIF-1 activation increased IL-1β and IL-8 in human uroepithelial cells treated with high glucose concentration. 3. Pharmacological activation of HIF-1 decreased bacterial load in the urinary bladder of mice with hereditary diabetes. • We conclude that enhancing HIF-1 may along with antibiotics in the future contribute to the treatment in selected patient groups where traditional therapy is not possible.
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http://dx.doi.org/10.1007/s00109-021-02134-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8724101PMC
January 2022

Comparison of quantitative ultrasound of calcaneus and dual energy X-ray absorptiometry in measuring bone density and predicting fractures in patients with diabetic polyneuropathy: A prospective cohort study.

Diabetes Res Clin Pract 2021 Oct 22;180:109064. Epub 2021 Sep 22.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Solna (L1:00), SE-171 76 Stockholm, Sweden; The Rolf Luft Research Center for Diabetes and Endocrinology, Box 1421, 111 84 Stockholm, Sweden.

Aims: Compare quantitative ultrasound (QUS) of calcaneus and dual energy X-ray absorptiometry (DXA) as measurements of bone density, calculate 20-year fracture incidence in patients with T1DM and T2DM and multiple complications, and compare the methods' predictive ability.

Methods: Sixty-two hospital foot clinic patients with T1DM or T2DM and complications were followed (1995-2015; 610 person-years). Clinical assessments and QUS of calcaneus were performed on all at inclusion and DXA of the spine and femoral neck on a subgroup (n = 34). Fracture incidence was assessed at follow-up and compared to incidence in the general population. We evaluated the correlation between QUS of calcaneus and DXA (Pearson's correlation test) and the association between bone density and fracture incidence at follow-up (logistic regression).

Results: Bone density (QUS of calcaneus) correlated with hip bone density (DXA). Incidence of all fractures (30/62 patients; 48%) and hip fractures (6/62 patients; 10%) was higher in patients than the general population. Twelve (19%) experienced foot fracture. QUS of calcaneus predicted hip, lower leg, and foot fractures; DXA did not.

Conclusions: Because QUS of calcaneus predicted fractures in patients with diabetes and multiple complications, it seems appropriate to test QUS of calcaneus as a fracture risk predictor in primary care.
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http://dx.doi.org/10.1016/j.diabres.2021.109064DOI Listing
October 2021

Effects of a three-armed randomised controlled trial using self-monitoring of daily steps with and without counselling in prediabetes and type 2 diabetes-the Sophia Step Study.

Int J Behav Nutr Phys Act 2021 09 8;18(1):121. Epub 2021 Sep 8.

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

Background: This aimed to evaluate the effects of self-monitoring of daily steps with or without counselling support on HbA1c, other cardiometabolic risk factors and objectively measured physical activity (PA) during a 2-year intervention in a population with prediabetes or type 2 diabetes.

Methods: The Sophia Step Study was a three-armed parallel randomised controlled trial. Participants with prediabetes or type 2 diabetes were recruited in a primary care setting. Allocation (1:1:1) was made to a multi-component intervention (self-monitoring of steps with counselling support), a single-component intervention (self-monitoring of steps without counselling support) or standard care. Data were collected for primary outcome HbA1c at baseline and month 6, 12, 18 and 24. Physical activity was assessed as an intermediate outcome by accelerometer (ActiGraph GT1M) for 1 week at baseline and the 6-, 12-, 18- and 24-month follow-up visits. The intervention effects were evaluated by a robust linear mixed model.

Results: In total, 188 subjects (64, 59, 65 in each group) were included. The mean (SD) age was 64 (7.7) years, BMI was 30.0 (4.4) kg/m and HbA1c was 50 (11) mmol/mol, 21% had prediabetes and 40% were female. The dropout rate was 11% at 24 months. Effect size (CI) for the primary outcome (HbA1c) ranged from -1.3 (-4.8 to 2.2) to 1.1 (-2.4 to 4.6) mmol/mol for the multi-component vs control group and from 0.3 (-3.3 to 3.9) to 3.1 (-0.5 to 6.7) mmol/mol for the single-component vs control group. Effect size (CI) for moderate-to-vigorous physical activity ranged from 8.0 (0.4 to 15.7) to 11.1 (3.3 to 19.0) min/day for the multi-component vs control group and from 7.6 (-0.4 to 15.6) to 9.4 (1.4 to 17.4) min/day for the single-component group vs control group.

Conclusion: This 2-year intervention, including self-monitoring of steps with or without counselling, prevented a decrease in PA but did not provide evidence for improved metabolic control and cardiometabolic risk factors in a population with prediabetes or type 2 diabetes.

Trial Registration: ClinicalTrials.gov, NCT02374788 . Registered 2 March 2015-Retrospectively registered.
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http://dx.doi.org/10.1186/s12966-021-01193-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424865PMC
September 2021

IGF-I and IGFBP-1 in Relation to Body Composition and Physical Performance in Female Olympic Athletes.

Front Endocrinol (Lausanne) 2021 16;12:708421. Epub 2021 Aug 16.

Department of Women's and Children's Health, Division of Neonatology, Obstetrics and Gynecology, Karolinska Institutet, Stockholm, Sweden.

Introduction: Insulin- like growth factor-I (IGF-I) is an anabolic hormone that may affect athletic performance in female athletes, and insulin-like growth factor binding protein-1 (IGFBP-1) is an important regulator of bioactive IGF-I. There is limited knowledge of the role of endogenous IGF-I and IGFBP-1 for body composition and physical performance in female elite athletes.

Purpose: To examine IGF-I, age adjusted IGF-I (IGFSD), IGFBP-1 and insulin in female Olympic athletes compared with controls and different sport categories, and in relation to body composition and physical performance in the athletes.

Methods: Female athletes (n=103) and untrained controls (n=113) were included in this cross-sectional study. Body composition was established by dual-energy X-ray absorptiometry. Serum IGF-I and IGFBP-1 were analyzed by radioimmunoassay and IGFSD was calculated. Insulin was analyzed by electrochemiluminescence immunoassay. Athletes were offered to participate in standardized physical fitness tests.

Results: The athletes demonstrated significantly higher IGF-I, IGFSD and IGFBP-1 and lower insulin levels than controls (p<0.05, p<0.05, p<0.01, p<0.001 respectively). Power athletes had significantly higher IGFSD compared to both endurance and technical athletes (p<0.05, p<0.01, respectively). In athletes and controls combined, significant positive correlations were found between IGF variables and higher bone mineral density (BMD) and lean mass and lower fat percent. IGF-I was positively correlated with squat jump (r = 0.28, p<0.05) and IGFBP-1 correlated positively with squats (r =0.35, p<0.05).

Conclusion: We found higher IGF-I, IGFSD and IGFBP-1 in female athletes than controls, and the highest IGFSD in power athletes. IGF-I and IGFBP-1 were related to increased BMD and lean mass and lower fat percent, as well as were positively associated with physical fitness tests. Future studies are needed to elucidate if these results reflect adaptive responses to physical activity or genetic predisposition.
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http://dx.doi.org/10.3389/fendo.2021.708421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415455PMC
February 2022

Dehydro-Tocotrienol-β Counteracts Oxidative-Stress-Induced Diabetes Complications in Mice.

Antioxidants (Basel) 2021 Jul 2;10(7). Epub 2021 Jul 2.

Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-17177 Stockholm, Sweden.

Hyperglycemia, hyperlipidemia, and adiposity are the main factors that cause inflammation in type 2 diabetes due to excessive ROS production, leading to late complications. To counteract the effects of increased free radical production, we searched for a compound with effective antioxidant properties that can induce coenzyme Q biosynthesis without affecting normal cellular functions. Tocotrienols are members of the vitamin E family, well-known as efficient antioxidants that are more effective than tocopherols. Deh-T3β is a modified form of the naturally occurring tocotrienol-β. The synthesis of this compound involves the sequential modification of geranylgeraniol. In this study, we investigated the effects of this compound in different experimental models of diabetes complications. Deh-T3β was found to possess multifaceted capacities. In addition to enhanced wound healing, deh-T3β improved kidney and liver functions, reduced liver steatosis, and improved heart recovery after ischemia and insulin sensitivity in adipose tissue in a mice model of type 2 diabetes. Deh-T3β exerts these positive effects in several organs of the diabetic mice without reducing the non-fasting blood glucose levels, suggesting that both its antioxidant properties and improvement in mitochondrial function are involved, which are central to reducing diabetes complications.
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http://dx.doi.org/10.3390/antiox10071070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301068PMC
July 2021

Process evaluation of the Sophia Step Study- a primary care based three-armed randomized controlled trial using self-monitoring of steps with and without counseling in prediabetes and type 2 diabetes.

BMC Public Health 2021 06 22;21(1):1191. Epub 2021 Jun 22.

Department of Health Promoting Science, Sophiahemmet University, Lindstedsvägen 8, Box 5605, 114 86, Stockholm, Sweden.

Background: Describing implementation features of an intervention is required to compare interventions and to inform policy and best practice. The aim of this study was to conduct a process evaluation of the first 12 months of the Sophia Step Study: a primary care based RCT evaluating a multicomponent (self-monitoring of daily steps plus counseling) and a single component (self-monitoring of steps only) physical activity intervention to standard care on cardiometabolic health.

Methods: The evaluation was guided by the Medical Research Council Guidance for complex interventions. To describe the implementation communication with the health professionals implementing the interventions, attendance records and tracking of days with self-monitored pedometer-determined steps were used. Change in physical activity behaviour was measured at baseline, 6 and 12 months as daily steps by accelerometry.

Results: During April 2013 to January 2018 188 participants were randomized and intervened directly after inclusion. Response rate was 49% and drop out was 10%. A majority, 78%, had type 2 diabetes and 22% were diagnosed with prediabetes. Mean [Standard deviation (SD)] body mass index was 30.4 (4.4) kg/m and steps per day was 6566 (3086). The interventions were delivered as intended with minor deviation from the protocol and dose received was satisfying for both the multicomponent and single component group. The mean [95% Confidence Interval (CI)] change in daily steps from baseline to 6 months was 941(227, 1655) steps/day for the multicomponent intervention group, 990 (145, 1836) step/day for the single component group and - 506 (- 1118, 107) for the control group. The mean (95% CI) change in daily steps from baseline to 12 months was 31(- 507, 570) steps/day for the multicomponent intervention group, 144 (- 566, 853) step/day for the single component group and - 890 (- 1485, - 294) for the control group. There was a large individual variation in daily steps at baseline as well as in step change in all three groups.

Conclusions: Applying self-monitoring of steps is a feasible method to implement as support for physical activity in the primary care setting both with and without counseling support.

Trial Registration: ClinicalTrials.gov , NCT02374788 . Registered 2 March 2015.
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http://dx.doi.org/10.1186/s12889-021-11222-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220758PMC
June 2021

L-Carnosine Stimulation of Coenzyme Q10 Biosynthesis Promotes Improved Mitochondrial Function and Decreases Hepatic Steatosis in Diabetic Conditions.

Antioxidants (Basel) 2021 May 17;10(5). Epub 2021 May 17.

The Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-17177 Stockholm, Sweden.

Mitochondrial dysfunction in type 2 diabetes leads to oxidative stress, which drives disease progression and diabetes complications. L-carnosine, an endogenous dipeptide, improves metabolic control, wound healing and kidney function in animal models of type 2 diabetes. Coenzyme Q (CoQ), a component of the mitochondrial electron transport chain, possesses similar protective effects on diabetes complications. We aimed to study the effect of carnosine on CoQ, and assess any synergistic effects of carnosine and CoQ on improved mitochondrial function in a mouse model of type 2 diabetes. Carnosine enhanced CoQ gene expression and increased hepatic CoQ biosynthesis in mice, a type 2 diabetes model. Co-administration of Carnosine and CoQ improved mitochondrial function, lowered ROS formation and reduced signs of oxidative stress. Our work suggests that carnosine exerts beneficial effects on hepatic CoQ synthesis and when combined with CoQ, improves mitochondrial function and cellular redox balance in the liver of diabetic mice. (4) Conclusions: L-carnosine has beneficial effects on oxidative stress both alone and in combination with CoQ on hepatic mitochondrial function in an obese type 2 diabetes mouse model.
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http://dx.doi.org/10.3390/antiox10050793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156016PMC
May 2021

Type 2 diabetes risk in sarcoidosis patients untreated and treated with corticosteroids.

ERJ Open Res 2021 Apr 24;7(2). Epub 2021 May 24.

Clinical Epidemiology Division, Dept of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

Background: The rate of type 2 diabetes mellitus (T2D) is increased in sarcoidosis patients but it is unknown if corticosteroid treatment plays a role. We investigated whether the T2D risk is higher in untreated and corticosteroid-treated sarcoidosis patients compared with the general population.

Methods: In this cohort study, individuals with two or more International Statistical Classification of Diseases and Related Health Problems (ICD) codes for sarcoidosis were identified from the Swedish National Patient Register (NPR) (n=5754). Corticosteroid dispensations within 3 months before or after the first sarcoidosis diagnosis were identified from the Swedish Prescribed Drug Register (PDR). General population comparators without sarcoidosis were matched to cases 10:1 on age, sex and region of residence (n=61 297). Incident T2D was identified using ICD codes (NPR) and antidiabetic drug dispensations (PDR). Follow-up was from the second sarcoidosis diagnosis/matching date until T2D, emigration, death or study end (December 2013). Cox regression models adjusted for age, sex, education, country of birth, healthcare regions and family history of diabetes were used to estimate hazard ratios (HRs). We used flexible parametric models to examine the T2D risk over time.

Results: 40% of sarcoidosis patients were treated with corticosteroid at diagnosis. The T2D rate was 7.7 per 1000 person-years in untreated sarcoidosis, 12.7 per 1000 person-years in corticosteroid-treated sarcoidosis and 5.5 per 1000 person-years in comparators. The HR for T2D was 1.4 (95% CI 1.2-1.8) associated with untreated sarcoidosis and 2.3 (95% CI 2.0-3.0) associated with corticosteroid-treated sarcoidosis. The T2D risk was highest for corticosteroid-treated sarcoidosis in the first 2 years after diagnosis.

Conclusions: Sarcoidosis is associated with an increased risk of T2D especially in older, male, corticosteroid-treated patients at diagnosis. Screening for T2D for these patients is advisable.
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http://dx.doi.org/10.1183/23120541.00028-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141704PMC
April 2021

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
June 2021

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 2021

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
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