Christian M. Madsen’s research while affiliated with Novo Nordisk and other places

Aims Plasma levels of Vitamin D (25(OH)D) have been suggested as a predictor for developing type 2 diabetes. The purpose of this study was therefore to investigate if a measurement of plasma 25(OH)D could predict the development of type 2 diabetes in a cohort of 222,311 individuals from primary healthcare in Denmark. Methods The CopD-study database containing data from the Copenhagen General Practitioners Laboratory on blood tests conducted from April 2004 to January 2012 was used for identification of the study population. Incident type 2 diabetes was then defined as having at least two redeemed prescriptions of antidiabetics or at least two hospital contacts due to type 2 diabetes or one redeemed prescription and one hospital contact regarding type 2 diabetes. Results A total of 222,311 individuals were included in the study, of whom 7652 (3.4%) developed type 2 diabetes during the follow-up period of minimum one year. Individuals who developed type 2 diabetes had a significantly lower median 25(OH)D level than persons in the non-diabetes group. The hazard ratio for development of type 2 diabetes increased by 15% per 10 n mol/L decrease in 25(OH)D level. Conclusion In this study of 222,311 persons from primary health care in Denmark, we found a clear inverse relationship between 25(OH)D and the risk of developing type 2 diabetes. Further studies should be conducted to clarify the mechanisms behind the relationship between 25(OH)D and type 2 diabetes and the effect of oral vitamin D supplementation on the development of type 2 diabetes.

The chemotactic G protein-coupled receptor GPR183 and its most potent endogenous oxysterol ligand 7α,25-dihydroxycholesterol (7α,25-OHC) are important for immune cell positioning in secondary lymphoid tissues. This receptor-ligand pair is associated with various diseases, in some cases contributing favorably and in other cases adversely, making GPR183 an attractive target for therapeutic intervention. We investigated the mechanisms underlying GPR183 internalization and the role of internalization in the main biological function of the receptor, chemotaxis. We found that the C terminus of the receptor was important for ligand-induced internalization but less so for constitutive (ligand-independent) internalization. β-arrestin potentiated ligand-induced internalization but was not required for ligand-induced or constitutive internalization. Caveolin and dynamin were the main mediators of both constitutive and ligand-induced receptor internalization in a mechanism independent of G protein activation. Clathrin-mediated endocytosis also contributed to constitutive GPR183 internalization in a β-arrestin-independent manner, suggesting the existence of different pools of surface-localized GPR183. Chemotaxis mediated by GPR183 depended on receptor desensitization by β-arrestins but could be uncoupled from internalization, highlighting an important biological role for the recruitment of β-arrestin to GPR183. The role of distinct pathways in internalization and chemotaxis may aid in the development of GPR183-targeting drugs for specific disease contexts.

Incidences of pancreatic cancer and acute and chronic pancreatitis are rising globally, and often no curative treatment is available at the time of diagnosis. We tested the hypothesis that low and high plasma concentrations of pancreatic amylase are associated with increased risk of pancreatic cancer, acute pancreatitis, and chronic pancreatitis in the general population. We included 101,765 individuals (55% women) aged 20–100 years from the Copenhagen General Population Study with baseline measurements of plasma pancreatic amylase. After recruitment in 2004–2015 during a median 9 years of follow-up (range 0–15), we collected information about diagnoses of pancreatic cancer, acute pancreatitis, and chronic pancreatitis from the national Danish Patient Registry, the national Danish Cancer Registry, and the national Danish Causes of Death Registry. The median age was 58 years (interquartile range: 48–67) and the median plasma pancreatic amylase 32 U/L (26–40). During follow-up, 442 individuals were diagnosed with pancreatic cancer, 282 with chronic pancreatitis, and 401 with acute pancreatitis. Compared to individuals with pancreatic amylase levels in the 41st–60th percentiles, those with extreme low (1st–2.5th percentiles) and extreme high (97.5th–100th percentiles) pancreatic amylase had hazard ratios of 2.4 (95% confidence interval; 1.6–3.6) and 2.2 (1.4–3.7) for pancreatic cancer, of 1.8 (1.1–3.3) and 3.2 (1.8–5.6) for chronic pancreatitis, and of 1.1 (0.6–1.8) and 1.5 (0.8–2.7) for acute pancreatitis, respectively. In apparently healthy individuals from the general population, extreme low and extreme high plasma pancreatic amylase were associated with 2–threefold higher risk of both pancreatic cancer and chronic pancreatitis.

Purpose: The aim of this study is to assess the possible association between thyroid-stimulating hormone (TSH) and mortality in hip fracture patients. Patients and methods: The study is based on a hip fracture database from Bispebjerg University Hospital (Copenhagen, Denmark). This database includes all hip fracture patients (ICD-10 codes DS720 (femoral neck), DS721 (pertrochanteric), and DS722 (subtrochanteric)) admitted to Bispebjerg Hospital from 1996 to 2012. From this database, we identified all surgically treated hip fracture patients aged > 60 years with available plasma TSH-measurements at admission. Results: Of the 914 included patients (24% men and 76% women), 10.5% died within 30 days. At inclusion, 161 (17.6%) of the patients were hyperthyroid (TSH < 0.65 mIU/L), 58 (6.4%) were hypothyroid (TSH > 4.8 mIU/L), while 695 (76.0%) were euthyroid (0.65 < TSH < 4.80 mIU/L), p = 0.03. Mortality was significantly higher in the two higher quartiles of TSH [Q3 (13.0%) and Q4 (15.4%)] compared to the two lower quartiles [Q1 (7.4%) and Q2 (6.2%), p = 0.0003. After adjustment for age, sex and Charlson Comorbidity Index (CCI) in a Cox proportional hazard model, the risk of 30-day mortality continued to be increased in patients with TSH above the median as compared to patients with TSH below the median (HR 2.1 (1.4-3.3), p = 0.0006]. Conclusion: The study demonstrates increased 30-day mortality in surgically treated hip fracture patients with plasma TSH levels above the median (1.41 mIU/L) at admission, even after adjusting for age, sex and CCI.

The vast majority of research about HDL (high-density lipoprotein) has for decades revolved around the possible role of HDL in atherosclerosis and its therapeutic potential within cardiovascular disease prevention; however, failures with therapies aimed at increasing HDL cholesterol has left questions as to what the role and function of HDL in human health and disease is. Recent observational studies have further shown that extreme high HDL cholesterol is associated with high mortality leading to speculations that HDL could in some instances be harmful. In addition, evidence from observational, and to a lesser extent genetic, studies has emerged indicating that HDL might be associated with the development of other major noncardiovascular diseases, such as infectious disease, autoimmune disease, cancer, type 2 diabetes, kidney disease, and lung disease. In this review, we discuss (1) the association between extreme high HDL cholesterol and mortality and (2) the emerging human evidence linking HDL to several major diseases outside the realm of cardiovascular disease.

Background: The high-density lipoprotein (HDL) hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors which failed to show significant reductions in cardiovascular events. Plasma levels of HDL-cholesterol (HDL-C) decline drastically during sepsis and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacologic inhibition of CETP would preserve HDL levels and decrease mortality in clinical cohorts and animal models of sepsis. Methods: We examined the effect of a gain-of-function variant in CETP (rs1800777, p.Arg468Gln) and a genetic score for decreased CETP function on 28-day sepsis survival using Cox proportional hazard models adjusted for age and sex in the UK Biobank (n=5,949), Identification of SNPs Predisposing to Altered Acute Lung Injury Risk (iSPAAR; n=882), Copenhagen General Population Study (n=2,068), Copenhagen City Heart Study (n=493), Early Infection (n=200), St. Paul's Intensive Care Unit 2 (n=203), and Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock studies (n=632). We then studied the effect of the CETP inhibitor anacetrapib in adult, female APOE*3-Leiden mice with or with human CETP expression using the cecal-ligation and puncture model of sepsis. Results: A fixed-effect meta-analysis of all 7 cohorts found that the CETP gain-of-function variant was significantly associated with increased risk of acute sepsis mortality (hazard ratio [95% confidence interval]: 1.44 [1.22-1.70], p<0.0001). In addition, a genetic score for decreased CETP function was associated with significantly decreased sepsis mortality in the UK Biobank (hazard ratio [95% confidence interval]: 0.77 [0.59-1.00] per 1 mmol/L increase in HDL-C) and iSPAAR cohorts (hazard ratio [95% confidence interval]: 0.60 [0.37-0.98] per 1 mmol/L increase HDL-C). APOE*3-Leiden.CETP mice treated with anacetrapib had preserved levels of HDL-C and apolipoprotein-AI and increased survival relative to placebo treatment (70.6% vs 35.3%, Log-rank p=0.03), while there was no effect of anacetrapib on the survival of APOE*3-Leiden mice which do not express CETP (50.0% vs 42.9%, Log-rank p=0.87). Conclusions: Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve HDL levels and improve outcomes for individuals with sepsis.

Background Vitamin D has a role in bone turnover and potentially bone-metastatic spread of prostate cancer (PCa). The aim of this observational study was to address the association between levels of serum vitamin D, diagnosis of PCa and subsequent mortality in men who underwent a biopsy of the prostate. Methods All men who underwent prostatic biopsy in the Danish PCa Registry (DaPCaR) and who had a serum vitamin D measurement during the period 2004 to 2010 (n = 4,065) were identified. Men were categorized by clinical cut-offs based on seasonally adjusted serum vitamin D levels in <25 (deficient), 25–50 (insufficient), 50–75 (sufficient) and >75 nmol/L (high) serum vitamin D. Logistic regression model for association between vitamin D and risk of PCa diagnosis and multivariate survival analyses were applied. Results No association between serum vitamin D and risk of PCa was found. Overall survival was lowest for serum vitamin D deficiency and a significantly higher PCa specific mortality (HR: 2.37, 95%CI: 1.45–3.90, p < .001) and other cause mortality (HR: 2.08, 95%CI: 1.33–3.24, p = .001) was found for PCa patients with serum vitamin D deficiency compared to serum vitamin D sufficiency. Conclusion No association was found between serum vitamin D categories and risk of PCa in men who underwent biopsy of the prostate. Men with PCa and serum vitamin D deficiency had a higher overall and PCa specific mortality compared to men with a sufficient level of serum vitamin D.

Background & Aims Almost one third of adults in the West have increased plasma levels of triglycerides. Even mild to moderate hypertriglyceridemia (2–10 mmol/L or 177–886 mg/dL) is associated with an increased risk of acute pancreatitis. However, it is not clear whether hypertriglyceridemia is a cause or result of acute pancreatitis. Lipoprotein lipase degrades plasma triglycerides. Variants in LPL, APOA5, APOC3, ANGPTL3, and ANGPTL4, which regulate the lipoprotein lipase pathway, result in increased or reduced plasma triglyceride levels. We investigated associations between these variants and acute pancreatitis in a study of the general population. Methods In a prospective cohort study, men and women randomly selected from the population of Denmark were invited to complete a questionnaire, undergo a physical examination, and provide blood samples for biochemical and genetic analyses, from 2003 through 2015. We obtained triglyceride measurements from 117,427 participants. We examined for 15 genetic variants that associate with lipoprotein lipase function in DNA samples from 102,888 participants and analyzed data from 117,427 participants in observational analyses. Diagnoses of acute pancreatitis (970 diagnoses among participants in the genetic analysis and 527 among participants in the observational study) were obtained from Danish registries. We performed a 1-sample Mendelian randomization analysis in which specific variants were used as markers of plasma level of triglycerides to determine the association between plasma level of triglyceride and acute pancreatitis. We calculated unweighted, internally weighted, and externally weighted allele scores for each participant by adding numbers of triglyceride-increasing alleles. Results The highest genetic allele score correlated with a higher plasma level of triglycerides of 0.54 mmol/L (48 mg/dL). Among participants with the highest vs the lowest genetic allele score, the odds ratio for acute pancreatitis was 1.55 (95% CI, 1.08-2.23). Using instrumental variable analysis, integrating the effect of genotype on both triglycerides levels and risk of acute pancreatitis, we associated higher unweighted allele scores (level of triglycerides 1 mmol/L or 89 mg/dL higher) with increased risk of acute pancreatitis (OR, 1.76; 95% CI, 1.16–2.65), as well as internally weighted higher allele scores (OR, 1.41; 95% CI, 1.01–1.97) and externally weighted higher allele scores (OR, 1.44; 95% CI, 1.01–2.04). Every 1 mmol/L (89 mg/dL) increase in triglycerides was observationally associated with an increase in OR of 1.09 (95% CI, 1.05–1.14) after multivariable adjustment. Conclusions Based on an analysis of individuals with genetic variants associated with an increased level of triglycerides, via their effects on the lipoprotein lipase pathway, we associated increased plasma levels of triglycerides with increased risk of acute pancreatitis. Strategies to reduce plasma levels of triglyceride, by increasing lipoprotein lipase function, might be developed for prevention of acute pancreatitis.