The fraction of lung cancer attributable to smoking in the Norwegian Women and Cancer (NOWAC) Study.

BACKGROUND: We examined the association between active and passive smoking and lung cancer risk and the population attributable fraction (PAF) of lung cancer due to active smoking, in the Norwegian Women and Cancer Study, a nationally representative prospective cohort study. METHODS: We followed 142,508 women, aged 31-70 years, who completed a baseline questionnaire between 1991 and 2007, through linkages to national registries through December 2015. We used Cox proportional hazards models, to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). We calculated PAF to indicate what proportion of lung cancer cases could have been prevented in the absence of smoking. RESULTS: During the more than 2.3 million person-years of observation, we ascertained 1507 lung cancer cases. Compared with never smokers, current (HR 13.88, 95% CI 10.18-18.91) smokers had significantly increased risk of lung cancer. Female never smokers exposed to passive smoking had a 1.3-fold (HR 1.34, 95% CI 0.89-2.01) non- significantly increased risk of lung cancer, compared with never smokers. The PAF of lung cancer was 85.3% (95% CI 80.0-89.2). CONCLUSION: More than 8 in 10 lung cancer cases could have been avoided in Norway, if the women did not smoke.

Risk of lung cancer and physical activity by smoking status and body mass index, the Norwegian Women and Cancer Study.

We aimed to investigate physical activity (PA) and risk of different histological subtypes of lung cancer according to smoking status and body mass index using repeated measurements in a large cohort of women in Norway. The study sample for the multiple imputation analyses consisted of 86,499 and for the complete-case analysis 80,802 women. Repeated measurements of PA level, smoking habits, weight, and height were available for 54,691 women (63.2%), who were included in repeated measurement analyses combined with multiple imputation to address attrition. Cox proportional hazards regression models were used to calculate hazard ratios with 95% confidence intervals. During a median follow-up of 12.9 years, 866 cases of primary lung cancer were identified. We found an inverse association between PA and lung cancer overall. The results were consistent from multiple imputed data analysis to complete-case analysis of PA and possible confounders. We observed a similar trend for adenocarcinoma, but not for squamous cell or small cell carcinomas. Our findings suggest a more pronounced association between lung cancer overall and PA levels in current and former smokers, and in normal-weight and overweight participants with increasing PA levels. The potential of a modifiable lifestyle factor as PA to reduce the risk of lung cancer independently of smoking status is important in public health.

Sex Differences in Risk of Smoking-Associated Lung Cancer: Results From a Cohort of 600,000 Norwegians.

Whether women are more susceptible than men to smoking-related lung cancer has been a topic of controversy. To address this question, we compared risks of lung cancer associated with smoking by sex. Altogether, 585,583 participants from 3 Norwegian cohorts (Norwegian Counties Study, 40 Years Study, and Cohort of Norway (CONOR) Study) were followed until December 31, 2013, through linkage of data to national registries. We used Cox proportional hazards models and 95% confidence intervals to estimate risks. During nearly 12 million person-years of follow-up, 6,534 participants (43% women) were diagnosed with lung cancer. More men than women were heavier smokers. Compared with never smokers, male and female current smokers with ≥16 pack-years of smoking had hazard ratios for lung cancer of 27.24 (95% confidence interval (CI): 22.42, 33.09) and 23.90 (95% CI: 20.57, 27.76), respectively (P for heterogeneity = 0.30). In contrast, for current smokers, in a model with pack-years measured continuously, men had a hazard ratio of 1.43 (95% CI: 1.39, 1.48) and women a hazard ratio of 1.64 (95% CI: 1.57, 1.71) for each 10-pack-year increment of smoking (P for heterogeneity < 0.01). Our results suggest that women have an increased susceptibility to lung cancer compared with men, given the same lifetime smoking exposure.

Macrophage Area Content and Phenotype in Hepatic and Adipose Tissue in Patients with Obesity Undergoing Roux-en-Y Gastric Bypass.

OBJECTIVE: To investigate hepatic and adipose tissue macrophage content in subjects with obesity and the role of adipose tissue macrophages in weight loss-induced improved insulin sensitivity (IS). METHODS: A cross-sectional and a longitudinal study were combined to investigate the role of macrophages in subcutaneous (SAT) and visceral (VAT) adipose tissue and the liver in obesity-induced impaired IS and improvements with weight loss. Macrophage markers (CD68, CD163, and CD206) in SAT, VAT, and the liver from patients with obesity were investigated. The same macrophage markers were investigated in SAT from 18 patients with obesity before and ∼18 months after a diet- and Roux-en-Y gastric bypass-induced weight loss. RESULTS: SAT macrophage markers did not decrease with weight loss, but macrophage concentration may have increased, concomitant with improved IS. Hepatic macrophage markers did not correlate to VAT mass or macrophage markers, but they were higher in patients with obesity compared with patients without obesity. Hepatic anti-inflammatory macrophage markers correlated positively with hepatic IS. VAT and SAT macrophage markers did not correlate. CONCLUSIONS: The results indicate that decreased SAT macrophage content is not a primary driver for weight loss-induced IS improvements, but a better hepatic CD163 and CD206 macrophage profile may contribute to improved glycemic control. SAT macrophage markers were not predictive for VAT macrophage markers.

The Effect of Preoperative Type 2 Diabetes and Physical Fitness on Mental Health and Health-Related Quality of Life after Roux-en-Y Gastric Bypass.

Objective. To investigate the predictive value of type 2 diabetes and lack of physical activity for mental health and health-related quality of life after Roux-en-Y gastric bypass. Method. Forty severely obese patients undergoing Roux-en-Y gastric bypass were included in the GASMITO study. Information about physiological and psychological factors was prospectively assessed at four time points, two times prior to surgery and two times after surgery. Measures included oral and intravenous glucose tolerance tests, VO2max test, Symptoms Checklist (SCL-90), Short Form Health Survey 36 (SF-36), Body Image Questionnaire, and a questionnaire assessing sociodemographic factors and medical status. Results. Mean % excess weight loss was 65% (±12) at 18-month follow-up and 50% of the participants with diabetes experienced total remission. Also, significant improvements were observed with regard to physical fitness, mental distress, health-related quality of life, and weight-related body image (p < 0.05). The interaction between follow-up time and type 2 diabetes at baseline significantly predicted six of the thirteen psychological subscales (p < 0.05) and, across the follow-ups, physical fitness level made modest contributions to variations in mental symptoms and HRQOL but not weight-related body image. Conclusion. The results suggest that baseline difference in mental symptoms and physical HRQOL between diabetic and nondiabetic patients declines across follow-ups and resolves around the time of surgery.

Hepatic mitochondrial oxidative phosphorylation is normal in obese patients with and without type 2 diabetes.

KEY POINTS: Hepatic insulin resistance in patients with obesity or type 2 diabetes has been suggested to result from hepatic mitochondrial dysfunction. High-resolution respirometry (HRR) can be used to assess oxidative phosphorylation by measuring the mitochondrial oxygen consumption rate in the individual complexes of the mitochondria. By using HRR, the present study demonstrates no difference in hepatic mitochondrial oxidative phosphorylation among subjects with obesity with or without type 2 diabetes and non-obese controls. Furthermore, the amount of mitochondria, assessed by the citrate synthase activity, is not different between the three groups. Together the present findings indicate that hepatic mitochondrial oxidative phosphorylation capacity is not impaired in patients with obesity or type 2 diabetes. ABSTRACT: Obese patients with type 2 diabetes (T2DM) and without type 2 diabetes (OB) are characterized by high hepatic lipid content and hepatic insulin resistance. This may be linked to impaired hepatic mitochondrial oxidative phosphorylation (OXPHOS) capacity. The aim of the present study was to investigate and compare hepatic mitochondrial OXPHOS capacity in T2DM, OB and non-obese controls (CON). Seventeen obese patients (nine OB and eight T2DM) and six CON patients had perioperative liver biopsies taken. Samples were divided into three parts to measure (1) complex I, II and IV linked respiration, (2) citrate synthase (CS) activity and (3) lipid droplet (LD) size and area (% of total tissue area filled by LDs). State 3 respiration of complex I, II and IV and the CS activity did not differ in OB, T2DM and CON. LD size was significantly higher in T2DM compared with CON, and LD area tended (P = 0.10) to be higher in T2DM and OB compared with CON. The present findings indicate that hepatic OXPHOS capacity is not different in patients with markedly different weight and glycaemic control. Furthermore, the results do not support impaired hepatic mitochondrial respiratory capacity playing a major role in the development of obesity-induced type 2 diabetes.

The effects of diet- and RYGB-induced weight loss on insulin sensitivity in obese patients with and without type 2 diabetes.

AIMS: The impact of diet-induced weight loss and weight loss due to RYGB in patients with (T2DM, N = 16) and without (OB, N = 27) type 2 diabetes was studied. METHODS: At inclusion (A), after diet-induced weight loss (B), 4 months post-surgery (C) and 18 months post-surgery (D) body composition, hepatic glucose production (HGP), insulin-mediated glucose uptake (GIR), respiratory exchange ratio, hepatic insulin sensitivity and clearance were determined. GLUT4, intramuscular triglycerides (IMTG) and glycogen content were measured in skeletal muscle. RESULTS: Weight loss was 35-40 kg, and approximately one-third of the total improvement in GIR in T2DM was observed after the diet-induced weight loss of only ~6 kg (B). Insulin clearance, visceral fat and fasting plasma insulin also improved significantly after the diet (P < 0.05). Throughout the study, HGP, GLUT4 and glycogen content did not change significantly, but IMTG decreased significantly consistent with significant increases in GIR. Metabolic flexibility and hepatic insulin sensitivity improved after RYGB. CONCLUSIONS: Metabolic improvements of RYGB are present already after the diet-induced weight loss prior to surgery. GLUT4 content in skeletal muscle cannot and IMTG content can only partly explain increases in GIR after RYGB.

Adipose tissue mitochondrial respiration and lipolysis before and after a weight loss by diet and RYGB.

OBJECTIVE: To study adipose tissue mitochondrial respiration and lipolysis following a massive weight loss. METHODS: High resolution respirometry of adipose tissue biopsies and tracer determined whole body lipolysis. Sixteen obese patients with type 2 diabetes (T2DM) and 27 without (OB) were studied following a massive weight loss by diet and Roux-en-Y gastric bypass (RYGB). RESULTS: The mitochondrial respiratory rates were similar in OB and T2DM, and the mass-specific oxygen flux increased significantly 4 and 18 months post-surgery (P < 0.05). With normalization to mitochondrial content, no differences in oxidative capacity after RYGB were seen. The ratio between the oxidative phosphorylation system capacity (P) and the capacity of the electron transfer system (E) increased 18 months after RYGB in both groups (P < 0.05). Lipolysis per fat mass was similar in the two groups and was increased (P < 0.05) and lipid oxidation during hyperinsulinemia decreased 4 months post-surgery. In T2DM, visceral fat mass was always higher relative to the body fat mass (%) compared to OB. CONCLUSIONS: Adipose tissue mitochondrial respiratory capacity increases with RYGB. Adipocytes adapt to massive weight loss by increasing the phosphorylation system ratio (P/E), suggesting an increased ability to oxidize substrates after RYGB. Lipolysis increases in the short term post-surgery, and insulin sensitivity for suppression of lipolysis increases with RYGB.

Preoperative ß-cell function in patients with type 2 diabetes is important for the outcome of Roux-en-Y gastric bypass surgery.

The majority of the patients with type 2 diabetes (T2DM) show remission after Roux-en-Y gastric bypass (RYGB). This is the result of increased postoperative insulin sensitivity and ß-cell secretion. The aim of the present study was to elucidate the importance of the preoperative ß-cell function in T2DM for the chance of remission after RYGB. Fifteen patients with and 18 without T2DM had 25 g oral (OGTT) and intravenous (IVGTT) glucose tolerance tests performed at inclusion, after a diet-induced weight loss, and 4 and 18 months after RYGB. Postoperative first phase insulin secretion rate (ISR) during the IVGTT and ß-cell glucose sensitivity during the OGTT increased in T2DM. Postoperative insulin sensitivity and the disposition index (DI) markedly increased in both groups. By stratifying the T2DM into two groups according to highest (T2DMhigh ) and lowest (T2DMlow ) baseline DI, a restoration of first phase ISR and ß-cell glucose sensitivity were seen only in T2DMhigh . Remission of type 2 diabetes was 71 and 38% in T2DMhigh and T2DMlow , respectively. Postoperative postprandial GLP-1 concentrations increased markedly, but did not differ between the groups. Our findings emphasize the importance of the preoperative of ß-cell function for remission of diabetes after RYGB.

The effect of metformin on glucose homeostasis during moderate exercise.

OBJECTIVE: We investigated the role of metformin on glucose kinetics during moderate exercise. RESEARCH DESIGN AND METHODS: Before, during, and after a 45-min bout of exercise at 60% VO2max, glucose kinetics were determined by isotope tracer technique in patients with type 2 diabetes mellitus with metformin treatment (DM2+Met) or without metformin treatment (DM2) and in healthy control subjects (CON) matched for BMI and age. Glucoregulatory hormones and metabolites were measured throughout the study. RESULTS: Plasma glucose concentration was unchanged during exercise in CON but decreased in DM2. No significant change was found in DM2+Met. Hormones and metabolites showed no differences among the groups except for elevated exercise-induced concentrations of lactate in DM2 (area under the curve [AUC] 31 ± 1% vs. CON) and glucagon in DM2 (AUC 5 ± 1% vs. DM2+Met). Free fatty acid levels were lower in DM2+Met than in DM2 (AUC -14 ± 1%). Absolute values of the baseline glucose rate of appearance (Ra) were elevated in DM2 and DM2+Met, but the increase in glucose Ra relative to baseline was blunted in DM2 (19 ± 1%) and DM2+Met (18 ± 4%) compared with CON (46 ± 4%). Glucose rate of disappearance relative to baseline increased more in CON (31 ± 3%) than in DM2 (6 ± 1%) and DM2+Met (21 ± 2%), showing a small increase caused by metformin. Glucose metabolic clearance rate relative to baseline was similar during exercise in DM2 (33 ± 1%) and CON (35 ± 3%) but was improved in DM2+Met (37 ± 3%) compared with DM2. CONCLUSIONS: Metformin has a positive effect on glucose homeostasis during exercise.

The psychological profile of bariatric patients with and without type 2 diabetes: baseline results of the longitudinal GASMITO-PSYC study.

BACKGROUND: Some bariatric patients are referred for surgery with a diagnosis of type 2 diabetes while others are referred without co-morbid diabetes, but psychological differences between patients with and without type 2 diabetes undergoing bariatric surgery have not yet been investigated. The objective of this study was to present the baseline results of the longitudinal GASMITO-PSYC study, and to evaluate the psychological differences between bariatric patients with and without type 2 diabetes. METHODS: A total of 129 Roux-en- Y gastric bypass patients were recruited from the bariatric clinic at a hospital in the suburban Copenhagen area. Participants answered questionnaires concerning personality, mental symptoms, health-related quality of life (HRQOL), body image, lifestyle, and physical health including diabetes status on average 11 weeks before surgery. Questionnaires were either sent to the participant's home address or administered at the University of Copenhagen. RESULTS: Patients with type 2 diabetes scored higher on 'physical function' (P = .001), 'physical role' (P = .014), 'physical pain' (P = .021), and 'vitality' (P = .007) than nondiabetic patients after controlling for sex and age. The total study sample differed significantly from Danish test norms reporting higher neuroticism (P = .000), more mental symptoms (P = .000), lower HRQOL (P = .000), and less positive weight-related body image (P = .000). CONCLUSION: Patients with type 2 diabetes had better physical HRQOL than nondiabetic patients. This study highlights the importance of investigating whether these differences affect surgical outcomes.