The unexplored role of sedentary time and physical activity in glucose and lipid metabolism-related placental mRNAs in pregnant women who are obese: the DALI lifestyle randomised controlled trial.

OBJECTIVE: We aimed to explore: (i) the association of sedentary time (ST) and physical activity (PA) during pregnancy with the placental expression of genes related to glucose and lipid metabolism in pregnant women who are obese; (ii) maternal metabolic factors mediating changes in these placental transcripts; and (iii) cord blood markers related to the mRNAs mediating neonatal adiposity. DESIGN: Multicentre randomised controlled trial. SETTING: Hospitals in nine European countries. POPULATION: A cohort of 112 pregnant women with placental tissue. METHODS: Both ST and moderate-to-vigorous PA (MVPA) levels were measured objectively using accelerometry at three time periods during pregnancy. MAIN OUTCOME MEASURES: Placental mRNAs (FATP2, FATP3, FABP4, GLUT1 and PPAR-γ) were measured with NanoString technology. Maternal and fetal metabolic markers and neonatal adiposity were assessed. RESULTS: Longer periods of ST, especially in early to middle pregnancy, was associated with lower placental FATP2 and FATP3 expression (P < 0.05), whereas MVPA at baseline was inversely associated with GLUT1 mRNA (P = 0.02). Although placental FATP2 and FATP3 expression were regulated by the insulin-glucose axis (P < 0.05), no maternal metabolic marker mediated the association of ST/MVPA with placental mRNAs (P > 0.05). Additionally, placental FATP2 expression was inversely associated with cord blood triglycerides and free fatty acids (FFAs; P < 0.01). No cord blood marker mediated neonatal adiposity except for cord blood leptin, which mediated the effects of PPAR-γ on neonatal sum of skinfolds (P < 0.05). CONCLUSIONS: In early to middle pregnancy, ST is associated with the expression of placental genes linked to lipid transport. PA is hardly related to transporter mRNAs. Strategies aimed at reducing sedentary behaviour during pregnancy could modulate placental gene expression, which may help to prevent unfavourable fetal and maternal pregnancy outcomes. TWEETABLE ABSTRACT: Reducing sedentary behaviour in pregnancy might modulate placental expression of genes related to lipid metabolism in women who are obese.

Effect of metformin and insulin vs. placebo and insulin on whole body composition in overweight patients with type 2 diabetes: a randomized placebo-controlled trial.

Some studies indicate potential beneficial effects of metformin on body composition and bone. This trial compared metformin + insulin vs placebo + insulin. Metformin treatment had a small but positive effect on bone quality in the peripheral skeleton, reduced weight gain, and resulted in a more beneficial body composition compared with placebo in insulin-treated patients with type 2 diabetes. INTRODUCTION: Glucose-lowering medications affect body composition. We assessed the long-term effects of metformin compared with placebo on whole body bone and body composition measures in patients with type 2 diabetes mellitus. METHODS: This was a sub-study of the Copenhagen Insulin and Metformin Therapy trial, which was a double-blinded randomized placebo-controlled trial assessing 18-month treatment with metformin compared with placebo, in combination with different insulin regimens in patients with type 2 diabetes mellitus (T2DM). The sub-study evaluates the effects on bone mineral content (BMC), density (BMD), and body composition from whole body dual-energy X-ray absorptiometry (DXA) scans which were assessed at baseline and after 18 months. RESULTS: Metformin had a small, but positive, (p < 0.05) effect on subtotal, appendicular, and legs BMC and BMD compared with placebo. After adjustment for sex, age, vitamin D, smoking, BMI, T2DM duration, HbA1c, and insulin dose, the effects on appendicular BMC and BMD persisted (p < 0.05 for both). The changes in appendicular BMC and BMD corresponded approximately to a 0.7% and 0.5% increase in the metformin group and 0.4% and 0.4% decrease in the placebo group, respectively. These effects were mostly driven by an increase in BMC and BMD in the legs and a loss of BMC and BMD in the arms. During 18 months, all participants increased in weight, fat mass (FM), FM%, and lean mass (LM), but decreased in LM%. The metformin group increased less in weight (subtotal weight (weight-head) - 2.4 [- 3.5, - 1.4] kg, p value < 0.001) and FM (- 1.5 [- 2.3, - 0.8] kg, p value < 0.001) and decreased less in LM% (0.6 [0.2, 1.1] %, p value < 0.001) compared with the placebo group. CONCLUSION: Metformin treatment had a small positive effect on BMC and BMD in the peripheral skeleton and reduced weight gain compared with placebo in insulin-treated patients with T2DM.

Metabolic phenotypes of early gestational diabetes mellitus and their association with adverse pregnancy outcomes.

AIMS: To describe the metabolic phenotypes of early gestational diabetes mellitus and their association with adverse pregnancy outcomes. METHODS: We performed a post hoc analysis using data from the Vitamin D And Lifestyle Intervention for gestational diabetes prevention (DALI) trial conducted across nine European countries (2012-2014). In women with a BMI ≥29 kg/m2 , insulin resistance and secretion were estimated from the oral glucose tolerance test values performed before 20 weeks, using homeostatic model assessment of insulin resistance and Stumvoll first-phase indices, respectively. Women with early gestational diabetes, defined by the International Association of Diabetes and Pregnancy Study Groups criteria, were classified into three groups: GDM-R (above-median insulin resistance alone), GDM-S (below-median insulin secretion alone), and GDM-B (combination of both) and the few remaining women were excluded. RESULTS: Compared with women in the normal glucose tolerance group (n = 651), women in the GDM-R group (n = 143) had higher fasting and post-load glucose values and insulin levels, with a greater risk of having large-for-gestational age babies [adjusted odds ratio 3.30 (95% CI 1.50-7.50)] and caesarean section [adjusted odds ratio 2.30 (95% CI 1.20-4.40)]. Women in the GDM-S (n = 37) and GDM-B (n = 56) groups had comparable pregnancy outcomes with those in the normal glucose tolerance group. CONCLUSIONS: In overweight and obese women with early gestational diabetes, higher degree of insulin resistance alone was more likely to be associated with adverse pregnancy outcomes than lower insulin secretion alone or a combination of both.

The effect of metformin versus placebo in combination with insulin analogues on bone mineral density and trabecular bone score in patients with type 2 diabetes mellitus: a randomized placebo-controlled trial.

Some antihyperglycemic medications have been found to affect bone metabolism. We assessed the long-term effects of metformin compared with placebo on bone mineral density (BMD) and trabecular bone score (TBS) in patients with type 2 diabetes. Metformin had no significant effect on BMD in the spine and hip or TBS compared with a placebo. INTRODUCTION: Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fractures despite a high bone mass. Some antihyperglycemic medications have been found to affect bone metabolism. We assessed the long-term effects of metformin compared with placebo on bone mineral density (BMD) and trabecular bone score (TBS). METHODS: This was a sub-study of a multicenter, randomized, 18-month placebo-controlled, double-blinded trial with metformin vs. placebo in combination with different insulin regimens (the Copenhagen Insulin and Metformin Therapy trial) in patients with T2DM. BMD in the spine and hip and TBS in the spine were assessed by dual-energy X-ray absorptiometry at baseline and after 18 months follow-up. RESULTS: Four hundred seven patients were included in this sub-study. There were no between-group differences in BMD or TBS. From baseline to 18 months, TBS decreased significantly in both groups (metformin group, - 0.041 [- 0.055, - 0.027]; placebo group - 0.046 [- 0.058, - 0.034]; both p < 0.001). BMD in the spine and total hip did not change significantly from baseline to 18 months. After adjustments for gender, age, vitamin D, smoking, BMI, duration of T2DM, HbA1c, and insulin dose, the TBS between-group differences increased but remained non-significant. HbA1c was negatively associated with TBS (p = 0.009) as was longer duration of diabetes, with the femoral neck BMD (p = 0.003). Body mass index had a positive effect on the hip and femoral neck BMD (p < 0.001, p = 0.045, respectively). CONCLUSIONS: Eighteen months of treatment with metformin had no significant effect on BMD in the spine and hip or TBS in patients with T2DM compared with a placebo. TBS decreased significantly in both groups. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00657943).

Repeated measurements of carotid atherosclerosis and future risk of venous thromboembolism: the Tromsø Study.

Essentials The relationship between atherosclerosis and venous thromboembolism (VTE) is controversial. In total, 10 426 participants recruited from the general population were included. Carotid intima media thickness and total plaque area was not associated with VTE. There was no association between plaque initiation or plaque progression and subsequent VTE. SUMMARY: Background Whether a relationship between atherosclerosis and subsequent venous thromboembolism (VTE) exists is controversial. Objective To investigate the association between carotid atherosclerosis and VTE by using repeated measurements of intima media thickness (IMT) and total plaque area (TPA) in participants recruited from the general population. Methods Participants were recruited from the fourth (1994-1995), fifth (2001-2002) and sixth (2007-2008) surveys of the Tromsø Study. In total, 10 426 participants attended, for whom measurements of carotid IMT and TPA and potential confounders were updated at each available survey. Time-varying Cox regression models were used to calculate hazard ratios (HRs) of VTE across various levels of IMT and TPA adjusted for age, sex, and body mass index. Results There were 368 incident VTE events during a median follow-up of 10.8 years. Participants with increasing IMT were, on average, older and had a less favorable cardiovascular risk profile. There was no association between tertiles of increasing TPA and the risk of VTE in the time-varying model, and increasing IMT was not associated with an increased risk of VTE (HR 0.96, 95% confidence interval [CI] 0.86-1.07). Neither plaque formation nor plaque progression was associated with the risk of VTE (respectively: HR 1.00, 95% CI 0.98-1.02; and HR 0.96, 95% CI 0.84-1.11). Conclusion Carotid IMT and TPA were not associated with an increased risk of VTE in time-varying analyses. Furthermore, there was no association between plaque initiation or plaque progression and subsequent VTE.

Atrial fibrillation is associated with cognitive decline in stroke-free subjects: the Tromsø Study.

BACKGROUND AND PURPOSE: Previous studies have shown associations between atrial fibrillation (AF) and cognitive decline. We investigated this association in a prospective population study, focusing on whether stroke risk factors modulated this association in stroke-free women and men. METHODS: We included 4983 participants (57% women) from the fifth survey of the Tromsø Study (Tromsø 5, 2001), of whom 2491 also participated in the sixth survey (Tromsø 6, 2007-2008). Information about age, education, blood pressure, body mass index, lipids, smoking, coffee consumption, physical activity, depression, coronary and valvular heart disease, heart failure and diabetes was obtained at baseline. AF status was based on hospital records. The outcome was change in cognitive score from Tromsø 5 to Tromsø 6, measured by the verbal memory test, the digit-symbol coding test and the tapping test. RESULTS: Mean age at baseline was 65.4 years. The mean reduction in the tapping test scores was significantly larger in participants with AF (5.3 taps/10 s; 95% CI: 3.9, 6.7) compared with those without AF (3.8 taps/10 s; 95% CI: 3.5, 4.1). These estimates were unchanged when adjusted for other risk factors and were similar for both sexes. AF was not associated with change in the digit-symbol coding or the verbal memory tests. CONCLUSION: Atrial fibrillation in stroke-free participants was independently associated with cognitive decline as measured with the tapping test.

C-reactive protein, obesity, and the risk of arterial and venous thrombosis.

UNLABELLED: Essentials We performed repeated measurements of C-reactive protein (CRP) and obesity in a cohort study. CRP was associated with risk of myocardial infarction and venous thromboembolism. CRP was a mediator for risk of myocardial infarction in obese men and women. CRP was a partial mediator for risk of venous thromboembolism in obese women, but not in men. SUMMARY: Background Low-grade inflammation in obesity may be a shared pathway for the risk of venous thromboembolism (VTE) and myocardial infarction (MI). Objectives To investigate the associations between repeated measurements of C-reactive protein (CRP) and the risks of MI and VTE, and to explore whether CRP mediated these risks in obese subjects. Methods CRP and obesity measures were collected from 15 134 subjects who participated in one or more surveys of the Tromsø study in 1994-1995, 2001-2002, or 2007-2008. Incident VTEs and MIs were registered until 1 January 2011. Time-varying Cox regression models were used to calculate hazard ratios of MI and VTE according to categories of CRP and obesity measures. Results There were 291 VTEs and 920 MIs during follow-up. High levels of CRP (≥ 3 mg L(-1) versus < 1 mg L(-1) ) were associated with increased risks of MI (hazard ratio [HR] 1.73; 95% confidence interval [CI] 1.32-2.26) and VTE (HR 1.84; 95% CI 1.22-2.78) in women, but only with MI in men (HR 1.93; 95% CI 1.53-2.44). All obesity measures showed stronger associations with CRP in women than in men. In obese women (body mass index [BMI] of ≥ 30 kg m(-2) versus < 25 kg m(-2) ), adjustment for CRP attenuated the risk estimate for VTE by 22%, whereas the incidence rates of VTE increased with combined categories of higher BMI and CRP. No association was found in men. Conclusions Our findings suggest that low-grade inflammation, assessed by measurement of CRP, is associated with the risks of MI and VTE, and may be a shared pathway for MI and VTE in obesity.

Impact of incident myocardial infarction on the risk of venous thromboembolism: the Tromsø Study.

UNLABELLED: Essentials Registry-based studies indicate a link between arterial- and venous thromboembolism (VTE). We studied this association in a cohort with confounder information and validated outcomes. Myocardial infarction (MI) was associated with a 4.8-fold increased short-term risk of VTE. MI was associated with a transient increased risk of VTE, and pulmonary embolism in particular. SUMMARY: Background Recent studies have demonstrated an association between venous thromboembolism (VTE) and arterial thrombotic diseases. Objectives To study the association between incident myocardial infarction (MI) and VTE in a prospective population-based cohort. Methods Study participants (n = 29 506) were recruited from three surveys of the Tromsø Study (conducted in 1994-1995, 2001-2002, and 2007-2008) and followed up to 2010. All incident MI and VTE events during follow-up were recorded. Cox regression models with age as the time scale and MI as a time-dependent variable were used to calculate hazard ratios (HRs) of VTE adjusted for sex, body mass index, blood pressure, diabetes mellitus, HDL cholesterol, smoking, physical activity, and education level. Results During a median follow-up of 15.7 years, 1853 participants experienced an MI and 699 experienced a VTE. MI was associated with a 51% increased risk of VTE (HR 1.51; 95% confidence interval [CI] 1.08-2.10) and a 72% increased risk of pulmonary embolism (PE) (HR 1.72; 95% CI 1.07-2.75), but not significantly associated with the risk of deep vein thrombosis (DVT) (HR 1.36; 95% CI 0.86-2.15). The highest risk estimates for PE were observed during the first 6 months after the MI (HR 8.49; 95% CI 4.00-18.77). MI explained 6.2% of the PEs in the population (population attributable risk) and 78.5% of the PE risk in MI patients (attributable risk). Conclusions Our findings indicate that MI is associated with a transient increased VTE risk, independently of traditional atherosclerotic risk factors. The risk estimates were particularly high for PE.

HbA1c levels in non-diabetic older adults - No J-shaped associations with primary cardiovascular events, cardiovascular and all-cause mortality after adjustment for confounders in a meta-analysis of individual participant data from six cohort studies.

BACKGROUND: To determine the shape of the associations of HbA1c with mortality and cardiovascular outcomes in non-diabetic individuals and explore potential explanations. METHODS: The associations of HbA1c with all-cause mortality, cardiovascular mortality and primary cardiovascular events (myocardial infarction or stroke) were assessed in non-diabetic subjects ≥50 years from six population-based cohort studies from Europe and the USA and meta-analyzed. Very low, low, intermediate and increased HbA1c were defined as <5.0, 5.0 to <5.5, 5.5 to <6.0 and 6.0 to <6.5% (equals <31, 31 to <37, 37 to <42 and 42 to <48 mmol/mol), respectively, and low HbA1c was used as reference in Cox proportional hazards models. RESULTS: Overall, 6,769 of 28,681 study participants died during a mean follow-up of 10.7 years, of whom 2,648 died of cardiovascular disease. Furthermore, 2,493 experienced a primary cardiovascular event. A linear association with primary cardiovascular events was observed. Adjustment for cardiovascular risk factors explained about 50% of the excess risk and attenuated hazard ratios (95 confidence interval) for increased HbA1c to 1.14 (1.03-1.27), 1.17 (1.00-1.37) and 1.19 (1.04-1.37) for all-cause mortality, cardiovascular mortality and cardiovascular events, respectively. The six cohorts yielded inconsistent results for the association of very low HbA1c levels with the mortality outcomes and the pooled effect estimates were not statistically significant. In one cohort with a pronounced J-shaped association of HbA1c levels with all-cause and cardiovascular mortality (NHANES), the following confounders of the association of very low HbA1c levels with mortality outcomes were identified: race/ethnicity; alcohol consumption; BMI; as well as biomarkers of iron deficiency anemia and liver function. Associations for very low HbA1c levels lost statistical significance in this cohort after adjusting for these confounders. CONCLUSIONS: A linear association of HbA1c levels with primary cardiovascular events was observed. For cardiovascular and all-cause mortality, the observed small effect sizes at both the lower and upper end of HbA1c distribution do not support the notion of a J-shaped association of HbA1c levels because a certain degree of residual confounding needs to be considered in the interpretation of the results.

Mental health in early pregnancy is associated with pregnancy outcome in women with pregestational diabetes.

AIM: To explore the role of early pregnancy health-related quality of life, anxiety, depression and locus of control for pregnancy outcome in women with pregestational diabetes. METHODS: This was a cohort study of 148 pregnant women with pregestational diabetes (118 with Type 1 diabetes and 30 with Type 2 diabetes), who completed three internationally validated questionnaires: the 36-item Short-Form Health Survey, the Hospital Anxiety and Depression Scale and the Multidimensional Health Locus of Control survey at 8 weeks. Selected pregnancy outcomes were preterm delivery (< 37 weeks) and large for gestational age infants (birth weight > 90(th) percentile). Differences between groups in the questionnaires were analysed using an unpaired t-test. RESULTS: Women with preterm deliveries (n = 28) had lower (i.e. worse) mean (sd) quality-of-life scores for the two 36-item Short-Form Health Survey scales, Role-Emotional [58.3 (38.1) vs. 82.9 (31.3); P = 0.0005] and Mental Health [67.7 (20.4) vs. 75.2 (15.8), P = 0.04], and a lower score for the 36-item Short-Form Health Survey scale Mental Component Summary (42.8 (13.1) vs. 48.8 (9.7), P = 0.03) in early pregnancy, compared with women with term deliveries. Depression symptoms (Hospital Anxiety and Depression Scale depression score ≥ 8) were more frequent in women with preterm vs. term deliveries (seven (25%) vs. six women (5%); P = 0.003), while levels of anxiety and locus of control were similar in these two groups. No difference in early pregnancy scores for health-related quality of life, anxiety, depression and locus of control were seen in women delivering large or appropriate for gestational age infants. CONCLUSIONS: Poor mental quality of life and the presence of depressive symptoms in early pregnancy were associated with preterm delivery in women with pregestational diabetes.

Atrial fibrillation and future risk of venous thromboembolism:the Tromsø study.

AIMS: Whether atrial fibrillation is related to risk of venous thromboembolism (VTE) has not been extensively studied. Therefore, we investigated the association between atrial fibrillation and future risk of VTE in a population-based cohort. METHODS: In total, 29,975 subjects were recruited from three surveys of the Tromsø study and followed from enrollment (1994-1995, 2001-2002 and 2007-2008) up to 2010. Incident events of atrial fibrillation and VTE during follow-up were recorded. Information on potential confounders was obtained at baseline. Cox-regression models with atrial fibrillation as time-dependent variable were used to calculate hazard ratios (HRs) for VTE with 95% confidence intervals (CIs). RESULTS: During 16 years of median follow-up, 1604 subjects were diagnosed with atrial fibrillation and 614 with incident VTE. The risk of VTE was substantially increased during the first 6 months after diagnosis of atrial fibrillation (HR, 8.44; 95% CI, 5.61-12.69), and remained increased throughout the study period (HR, 1.43; 95% CI, 1.43-1.99) compared with those without atrial fibrillation. Atrial fibrillation displayed higher risk estimates for pulmonary embolism (HR, 11.84; 95% CI, 6.80-20.63) than for deep vein thrombosis (HR, 6.20; 95% CI, 3.37-11.39) during the first 6 months, and was still associated with pulmonary embolism (HR, 1.96; 95% CI, 1.24-3.10) but not with deep vein thrombosis (HR, 1.08; 95% CI, 0.66-1.75) more than 6 months after diagnosis. CONCLUSION: Atrial fibrillation was associated with increased risk of VTE, and pulmonary embolism in particular. Our findings support the concept that isolated pulmonary embolism may originate from right atrial thrombi due to atrial fibrillation.

Fetal growth in relation to gestational weight gain in women with type 2 diabetes: an observational study.

AIMS: To evaluate fetal growth in relation to gestational weight gain in women with Type 2 diabetes. METHODS: A retrospective cohort study of 142 consecutive pregnancies in 28 women of normal weight, 39 overweight women and 75 obese women with Type 2 diabetes (pre-pregnancy BMI < 25, 25-29.9, ≥ 30 kg/m2, respectively). Gestational weight gain was categorized as excessive (exceeding the US Institute of Medicine recommendations) or as non-excessive (within or below the Institute of Medicine recommendations). RESULTS: Excessive and non-excessive gestational weight gain were seen in 61 (43%) and 81 women (57%) with a median (range) gestational weight gain of 14.3 (9-32) vs. 7.0 (-5-16) kg (P < 0.001), respectively. Infants of women with excessive gestational weight gain were characterized by higher birth weight (3712 vs. 3258 g; P = 0.001), birth weight z-score (1.14 vs. -0.01, P = 0.001) and prevalence of large-for-gestational-age infants (48 vs. 20%; P < 0.001). In normal weight, overweight and obese women with non-excessive gestational weight gain, the median weight gain in the first half of pregnancy was 371, 114 and 81 g/week, and in the second half of pregnancy 483, 427 and 439 g/week, respectively. In multiple linear regression analysis, gestational weight gain was associated with a higher infant birth weight z-score independent of pre-pregnancy BMI, smoking, HbA1c and insulin dose at last visit, ethnicity and parity [ß=0.1 (95% CI 0.06-0.14), P < 0.001]. CONCLUSIONS: Infant birth weight was almost 0.5 kg higher in women with Type 2 diabetes and excessive gestational weight gain than in women with Type 2 diabetes and non-excessive weight gain.

Single-nucleotide polymorphism, rs1799941 in the Sex Hormone-Binding Globulin (SHBG) gene, related to both serum testosterone and SHBG levels and the risk of myocardial infarction, type 2 diabetes, cancer and mortality in men: the Tromsø Study.

Low testosterone levels are associated with metabolic and cardiovascular disease risk factor, and have been shown to predict type 2 diabetes mellitus (T2DM), myocardial infarction (MI) and all-cause mortality. It is not known if these associations are causal or not. Recently, it has been shown that the serum testosterone levels are associated with single-nucleotide polymorphisms (SNPs), and we therefore studied the associations between one of these SNPs, rs1799941 on the Sex Hormone-Binding Globulin (SHBG) gene, and MI, T2DM, cancer and death. DNA was prepared from men who participated in the fourth survey of the Tromsø Study in 1994-1995 and who were registered with the endpoints MI, T2DM, cancer or death and a randomly selected control group. For mortality, the observation time was set from 1994, and for the other endpoints from birth. The endpoint data were completed up to 2010-2013. Genetic analyses were successfully performed in 5309 men, of whom 1454 were registered with MI, 638 with T2DM, 1534 with cancer and in 2226 who had died. Men with the minor homozygote genotype had significantly higher levels of total testosterone (14.7%) and SHBG (24.7%) compared with men with the major homozygote genotype, whereas free testosterone levels did not differ significantly between the genotypes. The SNP rs1799941 was not significantly associated with MI, T2DM, cancer or mortality. Thus, our result does not support a causal relationship between total testosterone and SHBG and MI, T2DM, cancer or mortality, suggesting that low testosterone more likely is a marker of poor health.

Real-time continuous glucose monitoring as a tool to prevent severe hypoglycaemia in selected pregnant women with Type 1 diabetes - an observational study.

AIMS: Among women with Type 1 diabetes who have had severe hypoglycaemia the year before pregnancy, 70% also experience this complication in pregnancy, and particularly in the first half of pregnancy. We evaluated whether routine use of real-time continuous glucose monitoring from early pregnancy onwards could prevent severe hypoglycaemia in these women. METHODS: All 136 consecutive pregnant women with Type 1 diabetes referred to our centre were asked about severe hypoglycaemic events in the year before pregnancy and early in pregnancy at their first antenatal visit. Women with a relevant recent history were informed about their additional high risk of severe hypoglycaemia, their treatment was focused on restricted insulin doses during the first 16 gestational weeks, and they were offered real-time continuous glucose monitoring on top of self-monitored plasma glucose measurements. RESULTS: Among 28 women with a recent history of severe hypoglycaemia, 12 (43%) used real-time continuous glucose monitoring from a median (range) of 10 (7-13) gestational weeks for 10 (1-32) weeks. Among these 12 women, eight had experienced a total of 34 (range 1-11) severe hypoglycaemic events in the year before pregnancy and nine had experienced 23 (range 1-10) events early in pregnancy. After initiation of real-time continuous glucose monitoring, two (17%) women experienced one event each. The incidence rates of severe hypoglycaemia were 2.8,17.5 and 0.3 events/patient-year. Among the 16 women in the high risk group not using real-time continuous glucose monitoring, the corresponding figures were 1.6, 5.0 and 0.1 events/patient-year. CONCLUSIONS: Further evaluation is required to determine whether continuous real-time continuous glucose monitoring from early pregnancy onwards in highly selected women may reduce the risk of severe hypoglycaemia. Other elements of focused intervention probably also contribute to the risk reduction.

La obesidad abdominal es esencial para el riesgo de tromboembolismo venoso en el síndrome metabólico: el estudio de tromso / Abdominal obesity is essential for the risk of venous thromboembolism in the metabolic syndrome: the thrombus study

ANTECEDENTES: el síndrome metabólico es un conjunto de factoresde riesgo cardiovascular, como la obesidad abdominal, hipertensión, dislipidemia y resistenciaa la insulina, asociado con un mayor riesgo de enfermedades cardiovasculares y mortalidad porcualquier causa. OBJETIVOS: el propósito del estudio fue evaluar el impacto del síndrome metabólico y sus componentes individuales, sobre el riesgo de tromboembolismo venoso (TEV) en un estudio poblacional prospectivo. MÉTODOS: Los componentes individuales del síndrome metabólico se registraron en 6170 sujetos de 25 a84 años en el Estudio de Tromsø en 1994-1995, y por primera vez los eventos de TEV se registraron hasta el 1 de septiembre de 2007...

Cognitive function, drusen, and age-related macular degeneration: a cross-sectional study.

PURPOSE: To examine the cross-sectional relationship between drusen, late age-related macular degeneration (AMD), and cognitive function. METHODS; We included 2149 stroke-free participants from the population-based Tromsø Study in Norway. Retinal photographs were graded for presence of drusen and AMD. Cognitive function was assessed using the verbal memory test (short verbal memory), digit-symbol coding test (processing speed), and the tapping test (psychomotor tempo). We assessed the relationship between drusen, late AMD, and cognitive test scores, adjusted for potential confounders. RESULTS: Late AMD was associated with decreased performance in the verbal memory test (standardized ß=-0.23, 95% confidence interval (CI): -0.51 to -0.01). Intermediate and large drusen were associated with decreased performance in the digit-symbol coding test (standardized ß=-0.14 and -0.19, 95% CIs: -0.23 to -0.05 and -0.29 to -0.09, respectively). Participants with large drusen were more likely to have test scores in the lowest quartile of the digit-symbol coding test (odds ratio (OR)=1.9, 95% CI: 1.1-3.5) and the tapping test (OR=1.6, 95% CI: 1.0-2.6), but not in the verbal memory test (OR=1.0, 95% CI: 0.6-1.6). CONCLUSIONS: The findings suggest a relationship between drusen deposition and reduced cognitive function. Although the relationships between drusen, late AMD, and the cognitive test results varied in strength and significance across the types of cognitive test, and may partly have been caused by residual confounding, it is not unlikely that a genuine but weaker relationship exists between drusen deposition and cognitive decline.

The incidence of severe hypoglycaemia in pregnant women with type 1 diabetes mellitus can be reduced with unchanged HbA1c levels and pregnancy outcomes in a routine care setting.

AIMS: To investigate whether the incidence of severe hypoglycaemia in pregnant women with type 1 diabetes can be reduced without deteriorating HbA1c levels or pregnancy outcomes in a routine care setting. METHODS: Two cohorts (2004-2006; n=108 and 2009-2011; n=104) were compared. In between the cohorts a focused intervention including education of caregivers and patients in preventing hypoglycaemia was implemented. Women were included at median 8 (range 5-13) weeks. Severe hypoglycaemia (requiring assistance from others) was prospectively reported in structured interviews. RESULTS: In the first vs. second cohort, severe hypoglycaemia during pregnancy occurred in 45% vs. 23%, p=0.0006, corresponding to incidences of 2.5 vs. 1.6 events/patient-year, p=0.04. Unconsciousness and/or convulsions occurred at 24% vs. 8% of events. Glucagon and/or glucose injections were given at 15% vs. 5% of events. At inclusion HbA1c was comparable between the cohorts while in the second cohort fewer women reported impaired hypoglycaemia awareness (56% vs. 36%, p=0.0006), insulin dose in women on multiple daily injections was lower (0.77 IU/kg (0.4-1.7) vs. 0.65 (0.2-1.4), p=0.0006) and more women were on insulin analogues (rapid-acting 44% vs. 97%, p<0.0001; long-acting 6% vs. 76%, p<0.0001) and insulin pumps (5% vs. 23%, p<0.0001). Pregnancy outcomes were similar in the two cohorts. CONCLUSIONS: A 36% reduction in the incidence of severe hypoglycaemia in pregnancy with unchanged HbA1c levels and pregnancy outcomes was observed after implementation of focused intervention against severe hypoglycaemia in a routine care setting. Improved insulin treatment, increased health professional education and fewer women with impaired hypoglycaemia awareness may contribute.

Real-time continuous glucose monitoring during labour and delivery in women with Type 1 diabetes - observations from a randomized controlled trial.

AIMS: To explore whether real-time continuous glucose monitoring during labour and delivery supplementary to hourly self-monitored plasma glucose in women with Type 1 diabetes reduces the prevalence of neonatal hypoglycaemia. METHODS: Women with Type 1 diabetes participating in a randomized controlled trial on the effect of real-time continuous glucose monitoring in pregnancy were included in this study. Twenty-seven of 60 (45%) women in the intervention arm used real-time continuous glucose monitoring during labour and delivery, supplementary to hourly self-monitored plasma glucose. Real-time continuous glucose monitoring glucose data covering the last 8 h prior to delivery were retrospectively evaluated, and maternal hypo- and hyperglycaemia were defined as glucose values ≤ 3.9 mmol/l and > 7.0 mmol/l, respectively. Women in the control arm (n = 59) solely used self-monitored plasma glucose. Neonatal hypoglycaemia was defined as a 2-h plasma glucose < 2.5 mmol/l. RESULTS: In infants of women using real-time continuous glucose monitoring during labour and delivery, 10 (37%) developed neonatal hypoglycaemia vs. 27 (46%) infants in the control arm (P = 0.45). Among 10 infants with and 17 infants without neonatal hypoglycaemia within the real-time continuous glucose monitoring arm, median maternal self-monitored plasma glucose was 6.2 (range 4.2-7.8) vs. 5.6 (3.3-8.5) mmol/l (P = 0.26) during labour and delivery, with maternal hyperglycaemia present in 17 (0-94) vs. 4 (0-46)% of the time (P = 0.02), and birthweight was 4040 (3102-4322) vs. 3500 (1829-4320) g (P = 0.04). Maternal hypoglycaemia up to delivery was relatively rare. CONCLUSIONS: The prevalence of neonatal hypoglycaemia was comparable between infants of women using real-time continuous glucose monitoring supplementary to self-monitored plasma glucose during labour and delivery and infants of women solely using self-monitored plasma glucose.

Common carotid intima-media thickness does not add to Framingham risk score in individuals with diabetes mellitus: the USE-IMT initiative.

AIMS/HYPOTHESIS: The aim of this work was to investigate whether measurement of the mean common carotid intima-media thickness (CIMT) improves cardiovascular risk prediction in individuals with diabetes. METHODS: We performed a subanalysis among 4,220 individuals with diabetes in a large ongoing individual participant data meta-analysis involving 56,194 subjects from 17 population-based cohorts worldwide. We first refitted the risk factors of the Framingham heart risk score on the individuals without previous cardiovascular disease (baseline model) and then expanded this model with the mean common CIMT (CIMT model). The absolute 10 year risk for developing a myocardial infarction or stroke was estimated from both models. In individuals with diabetes we compared discrimination and calibration of the two models. Reclassification of individuals with diabetes was based on allocation to another cardiovascular risk category when mean common CIMT was added. RESULTS: During a median follow-up of 8.7 years, 684 first-time cardiovascular events occurred among the population with diabetes. The C statistic was 0.67 for the Framingham model and 0.68 for the CIMT model. The absolute 10 year risk for developing a myocardial infarction or stroke was 16% in both models. There was no net reclassification improvement with the addition of mean common CIMT (1.7%; 95% CI -1.8, 3.8). There were no differences in the results between men and women. CONCLUSIONS/INTERPRETATION: There is no improvement in risk prediction in individuals with diabetes when measurement of the mean common CIMT is added to the Framingham risk score. Therefore, this measurement is not recommended for improving individual cardiovascular risk stratification in individuals with diabetes.

Carotid artery plaque progression and cognitive decline: the Tromsø Study 1994-2008.

BACKGROUND: Carotid atherosclerosis is a risk factor for stroke and cognitive decline, but knowledge on how progression of carotid atherosclerosis affects cognitive function in stroke-free individuals is scarce. METHODS: In the population-based Tromsø study, we calculated the change in ultrasound-assessed carotid plaque number and total plaque area from baseline (survey 4) to follow-up 7 years later (survey 5) in 4274 middle-aged stroke-free subjects. Cognitive function was assessed at follow-up by the verbal memory test, the digit-symbol coding test, and the tapping test and repeated after an additional 6 years in a subgroup of 2042 subjects (survey 6). Associations between the average of survey 4 and survey 5 plaque scores and the progression of plaque scores and cognitive test scores were assessed in regression analyses adjusted for baseline age, sex, education, depression, and cardiovascular risk factors. RESULTS: Progression of total plaque area was associated with lower scores in the digit-symbol coding test (multivariable adjusted standardized ß, -0.03; 95% CI, -0.05 to -0.00; P = 0.04) and the tapping test (ß, -0.03; 95% CI, -0.06 to -0.00; P = 0.03). Similar results were seen for progression of plaque number. The average plaque scores were associated with lower scores in all cognitive tests (P-values ≤ 0.01). No association was found between plaque scores and cognitive decline. CONCLUSIONS: The average plaque scores were associated with lower scores in all cognitive tests. Progression of plaque scores was associated with lower scores in the digit-symbol coding test and the tapping test, but not with the verbal memory test or with cognitive decline.