| 1. |
- Cervin, Camilla, et al.
(författare)
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An investigation of serum concentration of apoM as a potential MODY3 marker using a novel ELISA.
- 2010
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Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 267, s. 316-321
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Tidskriftsartikel (refereegranskat)abstract
- Abstract. Cervin C, Axler O, Holmkvist J, Almgren P, Rantala E, Tuomi T, Groop L, Dahlbäck B, Karlsson E (Lund University, Malmö, Sweden, Steno Diabetes Center, Gentofte, Denmark, University of Helsinki; and Folkhälsan Research Centre, Helsinki, Finland). An investigation of serum concentration of apoM as a potential MODY3 marker using a novel ELISA. J Intern Med 2009; doi: 10.1111/j.1365-2796.2009.02145.x.Objective. To investigate the fitness of serum apolipoprotein M (apoM) concentration as a marker for maturity-onset diabetes of the young 3 (MODY3). Study design and subjects. This study consisted of two parts. A family study included 71 carriers of the P291fsinsC mutation in hepatocyte nuclear factor-1alpha (HNF-1alpha) from the Finnish Botnia study, 53 of whom were diabetic, and 75 matched family controls. A second, case-control study included 24 MODY3 patients, 17 healthy MODY3 mutation carriers, 11 MODY1 patients, 18 type 2 diabetes patients and 19 healthy control individuals. Subjects in the case-control study were recruited from the Botnia study or the Clinic of Endocrinology, Malmö University Hospital. Serum apoM levels were measured using a novel ELISA based on two monoclonal apoM antibodies. Results. In the family study, mean serum apoM was 10% lower in female carriers of the P291fsinsC mutation compared to the family controls (P = 0.0058), a difference which remained significant after adjustment for diabetes status. There was no observed difference between groups for men. In the case-control study, no significant difference in apoM concentration was observed between MODY3 and type 2 diabetes patients, neither before nor after adjustment for total cholesterol. Conclusions. Female carriers of the P291fsinsC mutation in HNF-1alpha displayed slightly lower apoM serum levels. This difference is too small for apoM to be reliably employed as a biomarker for HNF-1alpha mutation status.
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| 2. |
- Connolly, Stuart J., et al.
(författare)
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Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage
- 2024
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 390:19, s. 1745-1755
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Tidskriftsartikel (refereegranskat)abstract
- Background Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied. Methods We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death. Results A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P=0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P=0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days. Conclusions Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).
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| 3. |
- Dahlin, E, et al.
(författare)
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Impaired vibrotactile sense at low frequencies in fingers in autoantibody positive and negative diabetes.
- 2013
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Ingår i: Diabetes Research and Clinical Practice. - : Elsevier BV. - 1872-8227 .- 0168-8227. ; 100:2, s. 46-50
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Tidskriftsartikel (refereegranskat)abstract
- Vibration thresholds in index and little finger pulps in subjects with autoantibody [GADA, IA-2A and/or ICA] positive and negative diabetes 20 years after diagnosis were higher than in age-matched controls at low frequencies (8 and 16Hz), irrespective of HbA1c values, indicating selective impairment of Meissner's corpuscles and/or their innervating axons.
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| 4. |
- Ekholm, Ella, et al.
(författare)
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Alterations in bile acid synthesis in carriers of HNF1α mutations.
- 2013
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Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 274:3, s. 263-272
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Heterozygous mutations in hepatocyte nuclear factor 1α (HNF1α) cause maturity onset diabetes of the young 3 (MODY3), an autosomal dominant form of diabetes. Deficiency of HNF1α in mice results in diabetes, hypercholesterolaemia and increased bile acid (BA) and cholesterol synthesis. Little is known about alterations in lipid metabolism in patients with MODY3. The aim of this study was to investigate whether MODY3 patients have altered cholesterol and BA synthesis and intestinal cholesterol absorption. A secondary aim was to investigate the effects of HNF1α mutations on the transcriptional regulation of BA metabolism. METHODS: Plasma biomarkers of BA and cholesterol synthesis and intestinal cholesterol absorption were measured in patients with MODY3 (n = 19) and in matched healthy control subjects (n = 15). Co-transfection experiments were performed with several promoters involved in BA metabolism along with expression vectors carrying the mutations found in these patients. RESULTS: Plasma analysis showed higher levels of BA synthesis in MODY3 patients. No differences were observed in cholesterol synthesis or intestinal cholesterol absorption. Co-transfection experiments showed that one of the mutations (P379A) increased the induction of the cholesterol 7α-hydroxylase promoter compared to HNF1α, without further differences in other studied promoters. By contrast, the other four mutations (L107I, T260M, P291fsinsC and R131Q) reduced the induction of the farnesoid X receptor promoter, which was followed by reduced repression of the small heterodimer partner promoter. In addition, these mutations also reduced the induction of the apical sodium-dependent bile salt transporter promoter. CONCLUSIONS: BA synthesis is increased in patients with MODY3 compared with control subjects. Mutations in HNF1α affect promoters involved in BA metabolism. This article is protected by copyright. All rights reserved.
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| 5. |
- Ekholm, Ella, et al.
(författare)
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Can complement factors 5 and 8 and transthyretin be used as biomarkers for MODY 1 (HNF4A-MODY) and MODY 3 (HNF1A-MODY)?
- 2008
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Ingår i: Diabetic Medicine: A journal of the British Diabetic Association. - : Wiley. - 1464-5491. ; May 29, s. 788-791
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Tidskriftsartikel (refereegranskat)abstract
- Aims Genetic testing is needed for the formal diagnosis of maturity-onset diabetes of the young (MODY), but this is not widely available. If any MODY biomarkers were known, these could possibly be used as an alternative. Hepatocyte nuclear factor (HNF)-1alpha and HNF-4alpha regulate transcription of genes encoding complement 5 (C5), complement 8 (C8) and transthyretin (TTR), suggesting that these could be potential biomarkers for the disease. We therefore set out to determine whether serum concentrations of C5, C8 and TTR can be used as biomarkers for patients with HNF4A-MODY and HNF1A-MODY. Methods The serum concentrations of C5, C8 and TTR were analysed in patients with mutations in the HNF-1alpha (n = 29) and EtaNuF-4alpha (n = 13) genes. Type 2 diabetic (n = 14) and healthy subjects (n = 20), matched for body mass index (BMI), served as diabetic and non-diabetic control groups, respectively. Results Type 2 diabetic patients had markedly increased levels of C5 and C8 compared with healthy control subjects. Levels of C5 and C8 correlated with glycated haemoglobin (C5: r = 0.48, P = 0.019). After adjustment for BMI, glycated haemoglobin, age and gender, HNF4A-MODY and HNF1A patients had reduced levels of C5 and C8 compared with Type 2 diabetic patients (C5: P = 0.001; C8: P = 0.004). In addition, patients with HNF4A-MODY, but not those with HNF1A-MODY, had decreased TTR compared with diabetic patients (P = 0.038). Conclusions Serum concentrations of C5 and C8 seem to distinguish HNF4A and HNF1A-MODY from other forms of diabetes. However, hyperglycaemia per se increases the serum concentrations, thereby attenuating their potential role as biomarkers for MODY.
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| 6. |
- Ekholm, Ella, et al.
(författare)
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Characterization of beta cell and incretin function in patients with MODY1 (HNF4A MODY) and MODY3 (HNF1A MODY) in a Swedish patient collection.
- 2011
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Ingår i: Acta Diabetologica. - : Springer Science and Business Media LLC. - 1432-5233 .- 0940-5429.
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to evaluate the beta cell and incretin function in patients with HNF4A and HNF1A MODY during a test meal. Clinical characteristics and biochemical data (glucose, proinsulin, insulin, C-peptide, GLP-1 and GIP) during a test meal were compared between MODY patients from eight different families. BMI-matched T2D and healthy subjects were used as two separate control groups. The early phase of insulin secretion was attenuated in HNF4A, HNF1A MODY and T2D (AUC0-30 controls: 558.2 ± 101.2, HNF4A MODY: 93.8 ± 57.0, HNF1A MODY: 170.2 ± 64.5, T2D: 211.2 ± 65.3, P < 0.01). Markedly reduced levels of proinsulin were found in HNF4A MODY compared to T2D and that tended to be so also in HNF1A MODY (HNF4A MODY: 3.7 ± 1.2, HNF1A MODY: 8.3 ± 3.8 vs. T2D: 26.6 ± 14.3). Patients with HNF4A MODY had similar total GLP-1 and GIP responses as controls (GLP-1 AUC: (control: 823.9 ± 703.8, T2D: 556.4 ± 698.2, HNF4A MODY: 1,257.0 ± 999.3, HNF1A MODY: 697.1 ± 818.4) but with a different secretion pattern. The AUC insulin during the test meal was strongly correlated with the GIP secretion (Correlation coefficient 1.0, P < 0.001). No such correlation was seen for insulin and GLP-1. Patients with HNF4A and HNF1A MODY showed an attenuated early phase of insulin secretion similar to T2Ds. AUC insulin during the test meal was strongly correlated with GIP secretion, whereas no such correlation was seen for insulin and GLP-1. Thus, GIP may be a more important factor for insulin secretion than GLP-1 in MODY patients.
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| 7. |
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| 8. |
- Ekholm, Ella, et al.
(författare)
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No signs of progressive beta cell damage during 20 years of prospective follow-up of autoantibody-negative diabetes.
- 2012
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Ingår i: Acta Diabetologica. - : Springer Science and Business Media LLC. - 1432-5233 .- 0940-5429. ; 49, s. 57-62
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Tidskriftsartikel (refereegranskat)abstract
- Both type 1 and type 2 diabetes are considered to be associated with different degrees of progressive beta cell damage. However, few long-term studies have been made. Our aim was to study the clinical course of 20 years of diabetes disease, including diabetes progression, comorbidity, and mortality in a prospectively studied cohort of consecutively diagnosed diabetic patients. Among all 233 patients diagnosed with diabetes during 1985-1987 in Malmö, Sweden, 50 of 118 surviving patients were followed-up after 20 years. The age at diagnose was 42.3 ± 23.1 and 57.5 ± 13.6 years for antibody-positive and antibody-negative patients, respectively. HbA1c and plasma lipids were analyzed with regard to metabolic control. Islet antibody-negative patients at diagnosis had highly preserved C-peptide levels after 20 years in contrast to antibody-positive patients (antibody negative: C-peptide 0 years 0.78 ± 0.47 and 20 years 0.70 ± 0.46 (nmol/l), P = 0.51 and antibody positive: C-peptide 0 years 0.33 ± 0.35 and 20 years 0.10 ± 0.18; P < 0.001. Islet antibodies but not age, BMI, or C-peptide at diagnosis were predictors of C-peptide levels at 20 years when analyzed by logistic regression (P < 0.05). HbA1c did not differ between the groups after 20 years. The 20-year mortality was higher among antibody-negative patients, dependent on the higher age at diagnosis in this group (number of deaths: antibody positive: 18 of 56 vs. antibody negative: 109 of 188, P < 0.001). Of the deceased, 79% had died from diseases or complications that may be associated with diabetes. We found no progressive beta cell damage in autoantibody-negative diabetes at a 20-year follow-up of the clinical course of diabetes.
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| 9. |
- Shaat, Nael, et al.
(författare)
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A variant in the transcription factor 7-like 2 (TCF7L2) gene is associated with an increased risk of gestational diabetes mellitus.
- 2007
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 50:5, s. 972-979
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Genetic and epidemiological studies suggest an association between gestational diabetes mellitus and type 2 diabetes. Both are polygenic multifactorial disorders characterised by beta cell dysfunction and insulin resistance. Our aim was to investigate whether common genetic variants that have previously been associated with type 2 diabetes or related phenotypes would also confer risk for gestational diabetes mellitus. Materials and methods In 1,881 unrelated pregnant Scandinavian women (649 women with gestational diabetes mellitus, 1,232 non-diabetic control subjects) we genotyped the transcription factor 7-like 2 (TCF7L2 rs7903146), adiponectin (ADIPOQ +276G>T), peroxisome-proliferator activated receptor, gamma 2 (PPARG Pro12Ala), PPARGcoactivator, 1 alpha (PPARGC1A Gly482Ser), forkhead box C2 (FOXC2 −512C>T) and β3-adrenergic receptor (ADRB3 Trp64Arg) polymorphisms using TaqMan allelic discrimination assay or RFLP. Results The CC, CT and TT genotype frequencies of the TCF7L2 rs7903146 variant differed significantly between women with gestational diabetes mellitus and control women (46.3, 43.6 and 10.1% vs 58.5, 35.3 and 6.2%, p=3.7×10−6, corrected p value [Pc] for multiple testing Pc=2.2×10−5). The T-allele was associated with an increased risk of gestational diabetes mellitus (odds ratio 1.49 [95% CI 1.28–1.75], p=4.9×10−7 [Pc=2.8×10−6]). Compared with wild-type CC-genotype carriers, heterozygous (CT-genotype) and homozygous (TT-genotype) carriers had a 1.6-fold (95% CI 1.26–1.93, p=3.7×10−5 [Pc=0.0002]) and a 2.1-fold (95% CI 1.41–2.99, p=0.0001 [Pc=0.0008]) increased risk of gestational diabetes mellitus, respectively. The other polymorphisms studied were not significantly associated with gestational diabetes mellitus (ADIPOQ +276G>T: 1.17 [1.01–1.36], p=0.039 [Pc=0.23]; PPARG Pro12Ala: 1.06 [0.87–1.29], p=0.53; PPARGC1A Gly482Ser: 0.96 [0.83–1.10], p=0.54; FOXC2 −512C>T: 1.01 [0.87–1.16], p=0.94; and ADRB3 Trp64Arg: 1.22 [0.95–1.56], p=0.12). Conclusions/interpretation The TCF7L2 rs7903146 variant is associated with an increased risk of gestational diabetes mellitus in Scandinavian women.
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| 10. |
- Shaat, Nael, et al.
(författare)
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Common variants in MODY genes increase the risk of gestational diabetes mellitus.
- 2006
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 49:7, s. 1545-1551
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Impaired beta cell function is the hallmark of gestational diabetes mellitus (GDM) and MODY. In addition, women with MODY gene mutations often present with GDM, but it is not known whether common variants in MODY genes contribute to GDM. Subjects and methods We genotyped five common variants in the glucokinase (GCK, commonly known as MODY2), hepatocyte nuclear factor 1-α (HNF1A, commonly known as MODY3) and 4-α (HNF4A commonly known as MODY1) genes in 1,880 Scandinavian women (648 women with GDM and 1,232 pregnant non-diabetic control women). Results The A allele of the GCK −30G→A polymorphism was more common in GDM women than in control subjects (odds ratio [OR] 1.28 [95% CI 1.06−1.53], p=0.008, corrected p value, p=0.035). Under a recessive model [AA vs GA+GG], the OR increased further to 2.12 (95% CI 1.21−3.72, p=0.009). The frequency of the L allele of the HNF1A I27L polymorphism was slightly higher in GDM than in controls (1.16 [95% CI 1.001−1.34], p=0.048, corrected p value, p=0.17). However, the OR increased under a dominant model (LL+IL vs II; 1.31 [95% CI 1.08−1.60], p=0.007). The rs2144908, rs2425637 and rs1885088 variants, which are located downstream of the primary beta cell promoter (P2) of HNF4A, were not associated with GDM. Conclusions/interpretation The −30G→A polymorphism of the beta-cell-specific promoter of GCK and the I27L polymorphism of HNF1A seem to increase the risk of GDM in Scandinavian women.
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