| 1. |
- Thuesen, Anne Cathrine Baun, et al.
(författare)
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Identification of pathogenic GCK variants in patients with common type 2 diabetes can lead to discontinuation of pharmacological treatment
- 2023
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Ingår i: Molecular Genetics and Metabolism Reports. - : Elsevier BV. - 2214-4269. ; 35
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Tidskriftsartikel (refereegranskat)abstract
- Background: Functionally disruptive variants in the glucokinase gene (GCK) cause a form of mild non-progressive hyperglycemia, which does not require pharmacological treatment. A substantial proportion of patients with type 2 diabetes (T2D) carry GCK variants. We aimed to investigate whether carriers of rare GCK variants diagnosed with T2D have a glycemic phenotype and treatment response consistent with GCK-diabetes. Methods: Eight patients diagnosed with T2D from the Danish DD2 cohort who had previously undergone sequencing of GCK participated. Clinical examinations at baseline included an oral glucose tolerance test and continuous glucose monitoring. Carriers with a glycemic phenotype consistent with GCK-diabetes took part in a three-month treatment withdrawal. Results: Carriers of pathogenic and likely pathogenic variants had lower median fasting glucose and C-peptide levels compared to carriers of variants of uncertain significance and benign variants (median fasting glucose: 7.3 (interquartile range: 0.4) mmol/l vs. 9.5 (1.6) mmol/l, p = 0.04; median fasting C-peptide 902 (85) pmol/l vs. 1535 (295) pmol/l, p = 0.03). Four participants who discontinued metformin treatment and one diet-treated participant were reevaluated after three months. There was no deterioration of HbA1c or fasting glucose (median baseline HbA1c: 49 (3) vs. 51 (6) mmol/mol after three months, p = 0.4; median baseline fasting glucose: 7.3 (0.4) mmol/l vs. 7.0 (0.6) mmol/l after three months, p = 0.5). Participants did not consistently fulfill best practice guidelines for GCK screening nor clinical criteria for monogenic diabetes. Discussion: Carriers of pathogenic or likely pathogenic GCK variants identified by unselected screening in T2D should be reported, as they have a glycemic phenotype and treatment response consistent with GCK-diabetes. Variants of uncertain significance should be interpreted with care. Systematic genetic screening of patients with common T2D receiving routine care can lead to the identification and precise care of patients with misclassified GCK-diabetes who are not identifiable through common genetic screening criteria.
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| 2. |
- Axelrad, Jordan E., et al.
(författare)
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Inflammatory bowel disease and risk of small bowel cancer : a binational population-based cohort study from Denmark and Sweden
- 2021
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Ingår i: Gut. - : BMJ Publishing Group Ltd. - 0017-5749 .- 1468-3288. ; 70:2, s. 297-308
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Crohn's disease (CD) is associated with increased risk of small bowel cancer (SBC), but previous studies have been small. We aimed to examine the risk of incident SBC and death from SBC in patients with inflammatory bowel disease (IBD).DESIGN: In a binational, population-based cohort study from Sweden and Denmark of patients with IBD during 1969-2017 and matched reference individuals from the general population, we evaluated the risk of incident SBC and death from SBC. Cox regression was used to estimate adjusted hazard ratios (aHRs).RESULTS: We identified 161 896 individuals with IBD (CD: 47 370; UC: 97 515; unclassified IBD: 17 011). During follow-up, 237 cases of SBC were diagnosed in patients with IBD (CD: 24.4/100 000 person-years; UC: 5.88/100 000 person-years), compared with 640 cases in reference individuals (2.81/100 000 person-years and 3.32/100 000 person-years, respectively). This corresponded to one extra case of SBC in 385 patients with CD and one extra case in 500 patients with UC, followed up for 10 years. The aHR for incident SBC was 9.09 (95% CI 7.34 to 11.3) in CD and 1.85 (95% CI 1.43 to 2.39) in UC. Excluding the first year after an IBD diagnosis, the aHRs for incident SBC decreased to 4.96 in CD and 1.69 in UC. Among patients with CD, HRs were independently highest for recently diagnosed, childhood-onset, ileal and stricturing CD. The relative hazard of SBC-related death was increased in both patients with CD (aHR 6.59, 95% CI 4.74 to 9.15) and patients with UC (aHR 1.57; 95% CI 1.07 to 2.32).CONCLUSION: SBC and death from SBC were more common in patients with IBD, particularly among patients with CD, although absolute risks were low.
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| 3. |
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| 4. |
- Erichsen, Rune, et al.
(författare)
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Hepatobiliary Cancer Risk in Patients with Inflammatory Bowel Disease : A Scandinavian Population-Based Cohort Study
- 2021
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 30:5, s. 886-894
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Tidskriftsartikel (refereegranskat)abstract
- Background: Inflammatory bowel disease (IBD) has been associated with hepatobiliary cancer, but existing evidence is poor. We evaluated risk of death from hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and extrahepatic cholangiocarcinoma (ECC) among patients with IBD.Methods: This Swedish/Danish population-based cohort study (1969-2017) followed patients with IBD and 1:10 matched population comparators from their diagnosis/match date until death, emigration, or end of follow-up.Results: Among the 97,496 patients with ulcerative colitis/963,026 comparators, we found 66/390 HCC-deaths, 120/173 ICC-deaths, and 91/220 ECC-deaths (median follow-up 10 years); the 10-year-mortality was 0.5% (per mille) for HCC, 0.6% for ICC, and 0.4% for ECC, which decreased to 0.3%, 0.4%, and 0.2%, respectively, in 2003-2017. Overall hazard ratios (HR) were 1.83 [95% confidence interval (CI), 1.41-2.38] for HCC-, 7.33 (95% CI, 5.81-9.25) for ICC-, and 4.46 (95% CI, 3.49-5.70) for ECC-deaths. A total of 22/66 HCC-deaths, 87/120 ICC-deaths, and 55/91 ECC-deaths occurred among patients with ulcerative colitis with primary sclerosing cholangitis (PSC), corresponding to 10-year-mortality of 6.7%, 26.2%, and 17.2%, respectively. Among 47,399 patients with Crohn's disease (median follow-up 11 years), 10-year-mortality from HCC (n = 28), ICC (n = 28), and ECC (n = 24) were 0.3%, 0.1%, and 0.3%, respectively, and corresponding HRs were 1.96 (95% CI, 1.31-2.93), 3.33 (95% CI, 2.19-5.09), and 3.10 (95% CI, 1.97-4.87). One of 28 HCC-deaths, 14/28 ICC-deaths (10-year-mortality 19%), and 12/24 ECC-deaths (10-year-mortality 14%) occurred after PSC.Conclusions: Risk of HCC-, ICC-, and ECC-deaths was low in patients with IBD and decreased over time. However, a large proportion of deaths occurred after PSC.Impact: Guidelines on specific surveillance strategies for patients with IBD with PSC, but not those without PSC, are needed.
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| 5. |
- Everhov, Åsa H., et al.
(författare)
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Colorectal Cancer in Childhood-onset Inflammatory Bowel Disease : A Scandinavian Register-based Cohort Study, 1969-2017
- 2022
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Ingår i: Journal of Pediatric Gastroenterology and Nutrition - JPGN. - : Lippincott Williams & Wilkins. - 0277-2116 .- 1536-4801. ; 75:4, s. 480-484
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Tidskriftsartikel (refereegranskat)abstract
- Through linkage of data from Danish and Swedish national registers we identified 6937 patients with childhood (<18 years)-onset Crohn disease (CD), 8514 patients with childhood-onset ulcerative colitis (UC) and up to 10 times as many matched (sex, age, residence) reference individuals 1969-2017. During follow-up to a median age of 27 (interquartile range = 21-39) years, 25 (0.36%) CD patients were diagnosed with colorectal cancer (CRC) versus 43 (0.06%) reference individuals, and 113 (1.33%) UC patients versus 45 (0.05%) reference individuals. The hazard ratio (HR) for CRC was 6.46 (95% CI = 3.95-10.6) in CD and 32.5 (95% CI = 23.0-45.9) in UC and increased with decreasing age at diagnosis. The HR for CRC was increased for all phenotypes, but with higher estimates for colonic CD [17.9 (95% CI = 7.43-43.3)] and UC with extensive/pancolitis [36.3 (95% CI = 22.8-57.8)]. The relative risk of CRC was increased for all phenotypes of childhood-onset inflammatory bowel disease. Age at onset may be considered an additional risk factor when implementing surveillance programs.
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| 6. |
- Everhov, Åsa H., et al.
(författare)
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Colorectal cancer in elderly-onset inflammatory bowel disease : A 1969-2017 Scandinavian register-based cohort study
- 2022
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Ingår i: Alimentary Pharmacology and Therapeutics. - : John Wiley & Sons. - 0269-2813 .- 1365-2036. ; 56:7, s. 1168-1182
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Previous research indicates that the increased relative risk of colorectal cancer (CRC) in inflammatory bowel disease (IBD) is limited to young-onset IBD.AIM: To estimate risks of incident CRC and death from CRC in elderly-onset IBD METHODS: Patients diagnosed with IBD at age ≥ 60 years between 1969 and 2017 were identified using Danish and Swedish National Patient Registers and histopathology data. We linked data to Cancer and Causes of Death Registers and used Cox regression to estimate hazard ratios (HRs) for CRC diagnosis and death compared to matched (by sex, age, and region) IBD-free individuals.RESULTS: Among 7869 patients with Crohn's disease followed for 54,220 person-years, and 21,224 patients with ulcerative colitis (UC) followed for 142,635 person-years, 2.10% and 1.90% were diagnosed with CRC, compared to 2.26% and 2.34% of reference individuals (median follow-up 6 and 7 years). The incidence of CRC was elevated during the first year after IBD diagnosis: 4.36 (95% CI = 3.33-5.71) in Crohn's disease and 2.48 (95% CI = 2.03-3.02) in UC, but decreased after the first year of follow-up: 0.69 (95% CI = 0.56-0.86) and 0.78 (95% CI = 0.69-0.88). Once diagnosed with CRC, the risk of CRC death was similar for IBD patients and the general population.CONCLUSION: The excess risk of CRC in elderly-onset IBD was probably due to bias and not observed beyond the first year. From 2010, the HR for CRC diagnosis more than 1 year after initial IBD diagnosis was lower than in the largely unscreened reference population, supporting the benefit of endoscopic screening and surveillance in patients with IBD.
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| 7. |
- Everhov, Åsa H., et al.
(författare)
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Inflammatory bowel disease and pancreatic cancer : a Scandinavian register-based cohort study 1969-2017
- 2020
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Ingår i: Alimentary Pharmacology and Therapeutics. - : John Wiley & Sons. - 0269-2813 .- 1365-2036. ; 52:1, s. 143-154
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with inflammatory bowel disease (IBD) have an increased risk of cancer.Aim: To assess the risk of pancreatic cancer in IBD compared to the general population.Methods: Patients with incident IBD 1969-2017 were identified in Danish and Swedish National Patient Registers and through biopsy data, and were matched to IBD-free reference individuals by sex, age, place of residence and year of IBD diagnosis. We linked data to Cancer and Causes of Death Registers and examined the absolute and relative risks of pancreatic cancer and pancreatic cancer death.Results: Among 161 926 patients followed for 2 000 951 person years, 442 (0.27%) were diagnosed with pancreatic cancer compared to 3386 (0.21%) of the 1 599 024 reference individuals. The 20-year cumulative incidence was 0.34% (95% confidence interval 0.30-0.38) vs 0.29% (0.28-0.30). The incidence rate was 22.1 (20.1-24.2)/100 000 person years in the patients (excluding the first year of follow-up: 20.8 [18.8-23.0]), and 16.6 (16.0-17.2) in the reference individuals. The hazard ratio (HR) for pancreatic cancer was increased overall: 1.43 (1.30-1.58), in subtypes (Crohn's disease: 1.44 [1.18-1.74]; ulcerative colitis: 1.35 [1.19-1.53]; IBD unclassified: 1.99 [1.50-2.64]) and especially in IBD patients with primary sclerosing cholangitis: 7.55 (4.94-11.5). Patients and reference individuals with pancreatic cancer did not differ in cancer stage (P = 0.17) or pancreatic cancer mortality (HR 1.07 [0.95-1.21]).Conclusions: Patients with IBD had an excess risk of pancreatic cancer, in particular patients with primary sclerosing cholangitis. However, the cumulative incidence difference after 20 years was small: 0.05%, that is, one extra pancreatic cancer per 2000 IBD patients.
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| 8. |
- Gedebjerg, Anne, et al.
(författare)
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CRP, C-Peptide, and Risk of First-Time Cardiovascular Events and Mortality in Early Type 2 Diabetes : A Danish Cohort Study
- 2023
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 46:5, s. 1037-1045
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the relationship between hs-CRP, a marker of low-grade inflam-mation, alone or in combination with C-peptide, a marker of hyperinsulinemia/ insulin resistance, and risk for cardiovascular events (CVEs) and mortality in patients recently diagnosed with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS In patients with recent-onset T2D, we measured serum hs-CRP (n = 7,301) and C-peptide (n = 5,765) in the prospective Danish Centre for Strategic Research in Type 2 Diabetes cohort study. Patients with no prior CVE (n = 6,407) were followed until first myocardial infarction, stroke, coronary revascularization, or cardiovascular death, and all patients (n = 7,301) were followed for all-cause mortality. We com-puted adjusted hazard ratios (aHRs) by Cox regression and tested for the interaction between hs-CRP and C-peptide. RESULTS During follow-up (median 4.8 years), high (>3 mg/L) versus low (<1 mg/L) hs-CRP was associated with increased CVE risk (aHR 1.45 [95% CI 1.07–1.96]) and with even greater risk of all-cause mortality (2.47 [1.88–3.25]). Compared with patients with low hs-CRP (£3 mg/L) and low C-peptide (<1,470 pmol/L), those with high lev-els of both biomarkers had the highest CVE (1.61 [1.10–2.34]) and all-cause mortality risk (2.36 [1.73–3.21]). Among patients with high C-peptide, risk of CVEs did not differ by low or high hs-CRP, whereas risk of all-cause mortality did. CONCLUSIONS The finding of high hs-CRP as a stronger prognostic biomarker of all-cause mortality than of CVEs may facilitate improved early detection and prevention of deadly diseases besides CVEs. Conversely, elevated C-peptide as a strong CVE biomarker sup-ports the need to target hyperinsulinemia/insulin resistance in T2D CVE prevention.
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| 9. |
- Kjær, Christina, et al.
(författare)
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A new setup for low-temperature gas-phase ion fluorescence spectroscopy
- 2021
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Ingår i: Review of Scientific Instruments. - : AIP Publishing. - 0034-6748 .- 1089-7623. ; 92:3
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Tidskriftsartikel (refereegranskat)abstract
- Here, we present a new instrument named LUNA2 (LUminescence iNstrument in Aarhus 2), which is purpose-built to measure dispersed fluorescence spectra of gaseous ions produced by electrospray ionization and cooled to low temperatures (<100 K). LUNA2 is, as an earlier room-temperature setup (LUNA), optimized for a high collection efficiency of photons and includes improvements based on our operational experience with LUNA. The fluorescence cell is a cylindrical Paul trap made of copper with a hole in the ring electrode to permit laser light to interact with the trapped ions, and one end-cap electrode is a mesh grid combined with an aspheric condenser lens. The entrance and exit electrodes are both in physical contact with the liquid-nitrogen cooling unit to reduce cooling times. Mass selection is done in a two-step scheme where, first, high-mass ions are ejected followed by low-mass ions according to the Mathieu stability region. This scheme may provide a higher mass resolution than when only one DC voltage is used. Ions are irradiated by visible light delivered from a nanosecond 20-Hz pulsed laser, and dispersed fluorescence is measured with a spectrometer combined with an iCCD camera that allows intensification of the signal for a short time interval. LUNA2 contains an additional Paul trap that can be used for mass selection before ions enter the fluorescence cell, which potentially is relevant to diminishing RF heating in the cold trap. Successful operation of the setup is demonstrated from experiments with rhodamine dyes and oxazine-4, and spectral changes with temperature are identified.
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| 10. |
- Kristensen, Frederik Pagh Bredahl, et al.
(författare)
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The Prevalence of Polyneuropathy in Type 2 Diabetes Subgroups Based on HOMA2 Indices of b-Cell Function and Insulin Sensitivity
- 2023
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Ingår i: Diabetes Care. - 0149-5992. ; 46:8, s. 1546-1555
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE Metabolic syndrome components may cumulatively increase the risk of diabetic polyneuropathy (DPN) in type 2 diabetes mellitus (T2DM) patients, driven by insulin resistance and hyperinsulinemia. We investigated the prevalence of DPN in three T2DM subgroups based on indices of b-cell function and insulin sensitivity. RESEARCH DESIGN AND METHODS We estimated b-cell function (HOMA2-B) and insulin sensitivity (HOMA2-S) in 4,388 Danish patients with newly diagnosed T2DM. Patients were categorized into subgroups of hyperinsulinemic (high HOMA2-B, low HOMA2-S), classical (low HOMA2-B, low HOMA2-S), and insulinopenic (low HOMA2-B, high HOMA2-S) T2DM. After a median follow-up of 3 years, patients filled the Michigan Neuropathy Screening Instrument questionnaire (MNSIq) to identify DPN (score ‡ 4). We used Poisson regression to calculate adjusted prevalence ratios (PRs) for DPN, and spline models to examine the association with HOMA2-B and HOMA2-S. RESULTS A total of 3,397 (77%) patients filled in the MNSIq. The prevalence of DPN was 23% among hyperinsulinemic, 16% among classical, and 14% among insulinopenic pa-tients. After adjusting for demographics, diabetes duration and therapy, lifestyle behaviors, and metabolic syndrome components (waist circumference, triglycer-ides, HDL cholesterol, hypertension, and HbA1c), the PR of DPN was 1.35 (95% CI 1.15–1.57) for the hyperinsulinemic compared with the classical patients. In spline analyses, we observed a linear relation of higher DPN prevalence with increasing HOMA2-B, independent of both metabolic syndrome components and HOMA2-S. CONCLUSIONS Hyperinsulinemia marked by high HOMA2-B is likely an important risk factor for DPN beyond metabolic syndrome components and insulin resistance. This should be considered when developing interventions to prevent DPN.
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