Prediagnosis Leisure-Time Physical Activity and Lung Cancer Survival: A Pooled Analysis of 11 Cohorts

Background: Little is known about the association between physical activity before cancer diagnosis and survival among lung cancer patients. In this pooled analysis of 11 prospective cohorts, we investigated associations of prediagnosis leisuretime physical activity (LTPA) with all-cause and lung cancer–specific mortality among incident lung cancer patients. Methods: Using self-reported data on regular engagement in exercise and sports activities collected at study enrollment, we assessed metabolic equivalent hours (MET-h) of prediagnosis LTPA per week. According to the Physical Activity Guidelines for Americans, prediagnosis LTPA was classified into inactivity, less than 8.3 and at least 8.3 MET-h per week (the minimum recommended range). Cox regression was used to estimate hazard ratios (HRs) and 95% confidence interval (CIs) for all-cause and lung cancer–specific mortality after adjustment for major prognostic factors and lifetime smoking history. Results: Of 20 494 incident lung cancer patients, 16 864 died, including 13 596 deaths from lung cancer (overall 5-year relative survival rate ¼ 20.9%, 95% CI ¼ 20.3% to 21.5%). Compared with inactivity, prediagnosis LTPA of more than 8.3 MET-h per week was associated with a lower hazard of all-cause mortality (multivariable-adjusted HR ¼ 0.93, 95% CI ¼ 0.88 to 0.99), but not with lung cancer–specific mortality (multivariable-adjusted HR ¼ 0.99, 95% CI ¼ 0.95 to 1.04), among the overall population. Additive interaction was found by tumor stage (Pinteraction ¼ .008 for all-cause mortality and .003 for lung cancer–specific mortality). When restricted to localized cancer, prediagnosis LTPA of at least 8.3 MET-h per week linked to 20% lower mortality: multivariableadjusted HRs were 0.80 (95% CI¼ 0.67 to 0.97) for all-cause mortality and 0.80 (95% CI¼ 0.65 to 0.99) for lung cancer–specific mortality. Conclusions: Regular participation in LTPA that met or exceeded the minimum Physical Activity Guidelines was associated with reduced hazards of mortality among lung cancer patients, especially those with early stage cancer

First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes

OBJECTIVELatent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype.RESEARCH DESIGN AND METHODSWe performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects (n = 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes (n = 2,454 vs. 968) and type 2 diabetes (n = 2,779 vs. 10,396).RESULTSThe leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring PFKFB3, encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1-associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes.CONCLUSIONSOur results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies.Peer reviewe

Markers of autoimmunity in Latent Autoimmune Diabetes in Adults (LADA) and non-diabetic adults: Impact in phenotype and genetic predisposition: Results from the Nord-Trøndelag health study

Diabetes is mainly classified: type 1 and type 2 diabetes. Type 1 diabetes is an autoimmune disease in which the body's immune system attacks and destroys the beta cells that produce insulin. Patients with type 2 diabetes have somewhat reduced insulin production which coupled to poor insulin efficiency leads to increased levels of blood glucose. In 1986 a group of patients who deviated from the classical type 2 diabetes diagnosis was reported. These patients showed signs of autoimmunity in form of detectable antibodies (mainly antiGAD) against the insulin-producing beta cells, antibodies which are commonly found in type 1 diabetes. The patients had still considerable good betacell function and were initially diet and/or orally treated like type 2 diabetes. However, as a group they developed insulin dependency faster than type 2 diabetes. This patient group was later called Latent Autoimmune Diabetes in Adult (LADA). As with type 2 diabetes the LADA patients are older at diagnosis and often overweight. Nevertheless, the LADA patients display a high risk for progression to insulin dependency. This suggests that the etiology of LADA is a mix of type 1 and type 2 diabetes. The prevalence of LADA is similar to that of type 1 diabetes; however the etiology and phenotype of LADA is less characterized than type 1 and type 2 diabetes. The aim of this study was therefore primarily to investigate the genetic and phenotypic background of LADA. We also looked at the presence and clinical implications of antiGAD positivity in a general adult non-diabetic population. The study was based on data from the second (HUNT2: 1995-1997) and third (HUNT3:2006-2008) Nord-Trøndelag health surveys. Paper I: The aim was to identify genetic risk factors that could affect the development of LADA. This was done by looking at known risk genes for both type 1 and type 2 diabetes and their link to LADA. Genetic similarities were found with both type 1 and type 2 diabetes. Further, the type 1 diabetes genes were associated with LADA with higher degree of autoimmunity (high titres of antiGAD), while type 2 diabetes genes were associated with LADA with lower autoimmunity. Overall, the data suggest that LADA patients with high autoimmunity are genetically more similar to type 1 diabetes, and LADA patients with low autoimmunity are genetically more similar to type 2 diabetes. Paper II: The aim was to study the autoimmune process in LADA patients, both before and after diagnosis of diabetes. We followed the LADA patients who had participated in both HUNT2 and HUNT3 by measuring antibodies that are known to be related to autoimmunity in patients with type 1 diabetes (anti-GAD, anti-IA-2 and anti-ZnT8). Over 50% of the LADA patients, who had participated in both HUNT2 and HUNT3, were antibody negative after the 10-year period between HUNT2 and HUNT3. LADA patients who were antibody negative were more type 2 diabetes like; i.e. they were more obese and older when they developed diabetes, than those who kept their positivity. However, the antibody negative LADA patients had significantly lower C-peptide values than patients with type 2 diabetes. This suggests that even a short period of antibody positivity is of clinical importance. Samples analysed for antiGAD also showed that many of the LADA patients who developed LADA after HUNT2 had detectable antibody in the blood at HUNT2, i.e. before the onset of the disease. Thus, for some LADA patients there is a long period of pre-diabetes in the form of an ongoing autoimmune process. LADA patients with positivity for antibodies at HUNT2 were more type 1 diabetes like compared with those who were antibody negative. These findings show that the antibody patterns in LADA patients affect the LADA patients' disease progression and phenotype. Paper III: The presence and clinical implications of antiGAD positivity in non-diabetic populations are poorly elucidated. We examined these aspects prospectively in a cohort of adult non-diabetic patients (n = 4496) who had participated in both HUNT2 and HUNT3. AntiGAD positivity was found in 1.7% of the group. Positivity was not associated with gender, first-degree family history of diabetes (FHD), smoking, glucose or BMI. However, the HLA-DQA1/DQB1 haplotype, a known risk haplotype for type 1 diabetes was associated with antiGAD positivity. Association was also found with positivity for antiTPO, an antibody found in hypothyroidism. Approximately 50% of the patients who were positive by antiGAD at HUNT2 had turned antiGAD negative at HUNT3. We conclude that antiGAD positivity in persistently non-diabetic individuals is partly consistent, is not associated with clinical parameters related to diabetes, but is associated with high risk HLA haplotypes and autoimmunity in the thyroid gland

Is chronic low back pain a risk factor for diabetes? The Nord-Trøndelag Health Study

Objective: The purpose of this study was to examine the risk of diabetes associated with the presence or absence of chronic low back pain, considering both cross-sectional and cohort data. Research design and methods: Analyses were based on the Norwegian HUNT2 and HUNT3 surveys of Nord-Trøndelag County. The prevalence of diabetes was compared in groups with and without chronic low back pain among 45 157 participants aged 30–69 years. Associations between low back pain at baseline and risk of diabetes were examined in an 11-year follow-up of 30 380 individuals with no baseline diagnosis of diabetes. The comorbidity between diabetes and low back pain was assessed at the end of follow-up. All analyses were carried out considering generalized linear models incorporating adjustment for other relevant risk factors. Results: Cross-sectional analyses did not reveal any association between low back pain and diabetes. With adjustment for age, body mass index, physical activity and smoking, the cohort study of women showed a significant association between low back pain at baseline and risk of diabetes (RR 1.30; 95%  CI 1.09 to 1.54, p=0.003). The association differed between age groups (p=0.015), with a stronger association in relatively young women. In men, no association was found in the whole age range (RR 1.02; 95%  CI 0.86 to 1.21, p=0.82). No association was observed between diabetes and chronic low back pain at the end of follow-up. Conclusion: Among younger women, those with chronic low back pain may have an increased risk of diabetes

Does diabetes influence the probability of experiencing chronic low back pain? A population-based cohort study: the Nord-Trøndelag Health Study

Objective Low back pain (LBP) is a major problem in modern society and it is important to study possible risk factors for this disorder. People with diabetes are often affected by LBP, but whether diabetes represents a risk factor for LBP has not been studied in detail. The aim of this study was to explore the association between diabetes and subsequent risk of chronic LBP. Design An 11-year follow-up study. Setting The Nord-Trøndelag Health Study (HUNT2; 1995–1997) and HUNT3 (2006–2008) surveys of Nord-Trøndelag County in Norway. Main outcome measure Chronic LBP, defined as LBP persisting at least 3 months continuously during the last year. Participants A total of 18 972 persons without chronic LBP at baseline in HUNT2, and 6802 persons who reported chronic LBP at baseline in HUNT2. Methods Associations between diabetes and risk of chronic LBP among individuals aged 30–69 years were examined by generalised linear modelling. Results Men without chronic LBP at baseline showed a significant association between diabetes and risk of chronic LBP (relative risk (RR) 1.43, 95% CI 1.04 to 1.96, p=0.043). In women, no association was found (RR 1.01, 95% CI 0.69 to 1.48, p=0.98). No association could be established between diabetes and recurrence or persistence of chronic LBP after 11 years in either sex. Conclusions Men with a diagnosis of diabetes may have a higher risk of subsequently experiencing chronic LBP

Is chronic low back pain a risk factor for diabetes? The Nord-Trøndelag Health Study

Objective: The purpose of this study was to examine the risk of diabetes associated with the presence or absence of chronic low back pain, considering both cross-sectional and cohort data. Research: design and methods Analyses were based on the Norwegian HUNT2 and HUNT3 surveys of Nord-Trøndelag County. The prevalence of diabetes was compared in groups with and without chronic low back pain among 45 157 participants aged 30–69 years. Associations between low back pain at baseline and risk of diabetes were examined in an 11-year follow-up of 30 380 individuals with no baseline diagnosis of diabetes. The comorbidity between diabetes and low back pain was assessed at the end of follow-up. All analyses were carried out considering generalized linear models incorporating adjustment for other relevant risk factors. Results: Cross-sectional analyses did not reveal any association between low back pain and diabetes. With adjustment for age, body mass index, physical activity and smoking, the cohort study of women showed a significant association between low back pain at baseline and risk of diabetes (RR 1.30; 95%  CI 1.09 to 1.54, p=0.003). The association differed between age groups (p=0.015), with a stronger association in relatively young women. In men, no association was found in the whole age range (RR 1.02; 95%  CI 0.86 to 1.21, p=0.82). No association was observed between diabetes and chronic low back pain at the end of follow-up. Conclusion: Among younger women, those with chronic low back pain may have an increased risk of diabetes

Vitamin D status and risk of type 2 diabetes in the Norwegian HUNT cohort study: Does family history or genetic predisposition modify the association?

Introduction We sought to investigate the relationship between serum 25-hydroxyvitamin D (25(OH)D) level and the risk of type 2 diabetes mellitus (T2DM) in adults who participated in the Trøndelag Health Study (HUNT), and the possible effect modification by family history and genetic predisposition. Research design and methods This prospective study included 3574 diabetes-free adults at baseline who participated in the HUNT2 (1995–1997) and HUNT3 (2006–2008) surveys. Serum 25(OH)D levels were determined at baseline and classified as <50 and ≥50 nmol/L. Family history of diabetes was defined as self-reported diabetes among parents and siblings. A Polygenic Risk Score (PRS) for T2DM based on 166 single-nucleotide polymorphisms was generated. Incident T2DM was defined by self-report and/or non-fasting glucose levels greater than 11 mmol/L and serum glutamic acid decarboxylase antibody level of <0.08 antibody index at the follow-up. Multivariable logistic regression models were applied to calculate adjusted ORs with 95% CIs. Effect modification by family history or PRS was assessed by likelihood ratio test (LRT). Results Over 11 years of follow-up, 92 (2.6%) participants developed T2DM. A higher risk of incident T2DM was observed in participants with serum 25(OH)D level of0.23). Conclusion Serum 25(OH)D<50 nmol/L was associated with an increased risk of T2DM in Norwegian adults. The inverse association was modified by family history of diabetes but not by genetic predisposition to T2DM

Presence of anti-GAD in a non-diabetic population of adults; time dynamics and clinical influence: results from the HUNT study

Background It is well known that anti-GAD (glutamic acid decarboxylase) serves as a marker for development of autoimmune diabetes in adults. On the other hand, the clinical implications of anti-GAD positivity in persistently non-diabetic (PND) adults are poorly elucidated. Our aim was to establish the frequency of anti-GAD in PNDs in an all-population-based cohort from the Nord-Trøndelag health study (HUNT) and to prospectively test for associations with glucose tolerance and thyroid autoimmunity. Methods We formed a primary study population (4496 individuals), selected randomly from the age group 20–90 years (50% men/women), who were non-diabetic both at HUNT2 (1995–1997) and HUNT3 (2006–2008). Anti-GAD-positive individuals at HUNT2, together with anti-GAD-negative individuals aged 20–29 years, were retested for anti-GAD positivity at HUNT3. A secondary study population consisted of individuals with type 2 diabetes (T2D, n=349) at HUNT3 who developed diabetes between HUNT2 and HUNT3. Results The frequency of anti-GAD positivity in PND was 1.7% (n=76) at HUNT2. Positivity did not associate with gender, family history of diabetes, or glucose levels, but was associated with thyroid-associated autoimmunity (increased frequency of positivity for anti-TPO (thyroid peroxidase), p<0.002). HLA-DQA1/DQB1, a risk haplotype for autoimmunity, was also associated with anti-GAD positivity in PND. The incidence of anti-GAD positivity was low (0.4%) in the subsample of individuals who were anti-GAD negative in HUNT2. Anti-GAD positivity in PNDs was frequently evanescent, with 54% losing, usually low-grade, positivity between HUNT2 and HUNT3. An evanescent state of autoimmunity as assessed by anti-GAD positivity during “pre-diabetes” in individuals later diagnosed with T2D could, however, not be affirmed. Conclusions Anti-GAD positivity in PND is associated with HLA risk haplotypes and thyroid autoimmunity but not with clinical parameters of diabetes. Fleeting anti-GAD positivity is common; however, results do not support the notion of a history of autoimmunity in T2D in the present cohort

Hours lying down per day, as a proxy for sedentary behaviour and risk of diabetes in young and middle-aged adults in Norway: an 11-year follow-up of the HUNT study

Objective We aimed to examine relationship between hours lying down per day, as a proxy for sedentary behaviour and risk of diabetes in young and middle-aged adults, and to assess if leisure-time physical activity and body mass index (BMI) modified this relationship. Design A population-based prospective cohort study. Setting Nord-Trøndelag, Norway. Participants The cohort included 17 058 diabetes-free adults, at an age of 20–55 years in 1995–1997, who were followed-up to 2006–2008. Primary outcome measures Incident diabetes was defined by self-report of diabetes or non-fasting glucose levels greater than 11 mmol/L at the follow-up. Methods Multivariable logistic regression models were used to obtain OR with 95% CI for risk of diabetes by the categories of hours lying down (≤7, 8 and ≥9 hours/day). Results 362 individuals (2.1%) developed diabetes during an average of 11-year follow-up. Individuals who reported lying down ≥9 hours/day had an adjusted OR of 1.35 (95% CI 1.01 to 1.80) for incident diabetes compared with those lying down 8 hours/day. Lying down ≤7 hours/day was not associated with the risk of diabetes. In analysis stratified by physical activity, the ORs associated with lying down ≥9 hours/day were 1.41 (95% CI 1.05 to 1.90) and 0.90 (95% CI 0.23 to 3.55), respectively, among the less active and highly active individuals (pinteraction=0.048). There was little evidence that the association differed by BMI status (pinteraction=0.62). Conclusions Prolonged hours lying down per day was associated with an increased risk of diabetes in young and middle-aged adults. The positive association appeared to be modified by physical activity but not by BMI

Exposure to disinfection byproducts and risk of type 2 diabetes: a nested case-control study in the HUNT and Lifelines cohorts

Introduction: Environmental chemicals acting as metabolic disruptors have been implicated with diabetogenesis, but evidence is weak among short-lived chemicals, such as disinfection byproducts (trihalomethanes, THM composed of chloroform, TCM and brominated trihalomethanes, BrTHM). Objectives: We assessed whether THM were associated with type 2 diabetes (T2D) and we explored alterations in metabolic profiles due to THM exposures or T2D status. Methods: A prospective 1:1 matched case–control study (n = 430) and a cross-sectional 1:1 matched case–control study (n = 362) nested within the HUNT cohort (Norway) and the Lifelines cohort (Netherlands), respectively, were set up. Urinary biomarkers of THM exposure and mass spectrometry-based serum metabolomics were measured. Associations between THM, clinical markers, metabolites and disease status were evaluated using logistic regressions with Least Absolute Shrinkage and Selection Operator procedure. Results: Low median THM exposures (ng/g, IQR) were measured in both cohorts (cases and controls of HUNT and Lifelines, respectively, 193 (76, 470), 208 (77, 502) and 292 (162, 595), 342 (180, 602). Neither BrTHM (OR = 0.87; 95% CI: 0.67, 1.11 | OR = 1.09; 95% CI: 0.73, 1.61), nor TCM (OR = 1.03; 95% CI: 0.88, 1.2 | OR = 1.03; 95% CI: 0.79, 1.35) were associated with incident or prevalent T2D, respectively. Metabolomics showed 48 metabolites associated with incident T2D after adjusting for sex, age and BMI, whereas a total of 244 metabolites were associated with prevalent T2D. A total of 34 metabolites were associated with the progression of T2D. In data driven logistic regression, novel biomarkers, such as cinnamoylglycine or 1-methylurate, being protective of T2D were identified. The incident T2D risk prediction model (HUNT) predicted well incident Lifelines cases (AUC = 0.845; 95% CI: 0.72, 0.97). Conclusion: Such exposome-based approaches in cohort-nested studies are warranted to better understand the environmental origins of diabetogenesis