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Objective: The role of adiponectin in the natural history of diabetes is not well characterized. We set out to characterize prediagnosis trajectories of adiponectin in individuals who develop type 2 diabetes.Research Design and Methods: In a case-cohort study (335 incident diabetes case and 2,474 noncase subjects) nested in the Whitehall II study, serum adiponectin was measured up to three times per participant (1991-1993, 1997-1999, and 2003-2004). Multilevel models adjusted for age and ethnicity were fitted to assess 13-year trajectories of log-transformed adiponectin preceding diabetes diagnosis or a randomly selected time point during follow-up (year(0)) based on 755/5,095 (case/noncase) person-examinations.Results: Adiponectin levels were lower in diabetes case than in noncase subjects (median 7,141 [interquartile range 5,187-10,304] vs. 8,818 [6,535-12,369] ng/mL at baseline, P < 0.0001). Control subjects showed a modest decline in adiponectin throughout follow-up (0.3% per year, P < 0.0001) at higher levels in women than in men (difference at year(0): 5,358 ng/mL, P < 0.0001). Female case and early-onset case (age at diagnosis <52 years) subjects had a steeper decline than control subjects (slope difference -1.1% per year, P = 0.001 in females, -1.6% per year in early-onset case subjects, P = 0.034). In men, adiponectin slopes for case and noncase subjects were parallel. The slope differences by diabetes onset were largely attenuated after adjustment for changes in obesity, whereas the sex-specific slope differences were independent of obesity.Conclusions: Lower adiponectin levels were observed already a decade before the diagnosis of diabetes. The marked sex difference in trajectories suggests that sex-specific mechanisms affect the association between adiponectin levels and diabetes development. [ABSTRACT FROM AUTHOR]

Objective: In the general, nondiabetic population, fasting glucose increases only slightly over time, whereas 2-h postload glucose shows a much steeper age-related rise. The reasons underlying these different age trajectories are unknown. We investigated whether common genetic variants associated with fasting and 2-h glucose contribute to age-related changes of these traits.Research Design and Methods: We studied 5,196 nondiabetic participants of the Whitehall II cohort (aged 40-78 years) attending up to four 5-yearly oral glucose tolerance tests. A genetic score was calculated separately for fasting and 2-h glucose, including 16 and 5 single nucleotide polymorphisms, respectively. Longitudinal modeling with age centered at 55 years was used to study the effects of each genotype and genetic score on fasting and 2-h glucose and their interactions with age, adjusting for sex and time-varying BMI.Results: The fasting glucose genetic score was significantly associated with fasting glucose with a 0.029 mmol/L (95% CI 0.023-0.034) difference (P = 2.76 × 10(-21)) per genetic score point, an association that remained constant over time (age interaction P = 0.17). Two-hour glucose levels differed by 0.076 mmol/L (0.047-0.105) per genetic score point (P = 3.1 × 10(-7)); notably, this effect became stronger with increasing age by 0.006 mmol/L (0.003-0.009) per genetic score point per year (age interaction P = 3.0 × 10(-5)), resulting in diverging age trajectories by genetic score.Conclusions: Common genetic variants contribute to the age-related rise of 2-h glucose levels, whereas associations of variants for fasting glucose are constant over time, in line with stable age trajectories of fasting glucose. [ABSTRACT FROM AUTHOR]

Objective: To examine antidepressant use before and after the diagnosis of diabetes.Research Design and Methods: This study was a longitudinal analysis of diabetic and nondiabetic groups selected from a prospective cohort study of 151,618 men and women in Finland (the Finnish Public Sector Study, 1995-2005). We analyzed the use of antidepressants in those 493 individuals who developed type 2 diabetes and their 2,450 matched nondiabetic control subjects for each year during a period covering 4 years before and 4 years after the diagnosis. For comparison, we undertook a corresponding analysis on 748 individuals who developed cancer and their 3,730 matched control subjects.Results: In multilevel longitudinal models, the odds ratio for antidepressant use in those who developed diabetes was 2.00 (95% CI 1.57-2.55) times greater than that in nondiabetic subjects. The relative difference in antidepressant use between these groups was similar before and after the diabetes diagnosis except for a temporary peak in antidepressant use at the year of the diagnosis (OR 2.66 [95% CI 1.94-3.65]). In incident cancer case subjects, antidepressant use substantially increased after the cancer diagnosis, demonstrating that our analysis was sensitive for detecting long-term changes in antidepressant trajectories when they existed.Conclusions: Awareness of the diagnosis of type 2 diabetes may temporarily increase the risk of depressive symptoms. Further research is needed to determine whether more prevalent use of antidepressants noted before the diagnosis of diabetes relates to effects of depression, side effects of antidepressant use, or a common causal pathway for depression and diabetes. [ABSTRACT FROM AUTHOR]

Objective: Although interleukin-1 receptor antagonist (IL-1Ra) treatment is associated with improved beta-cell function and glycemic control in patients with type 2 diabetes, its role in the development of type 2 diabetes remains unclear. We used repeated measurements to characterize IL-1Ra trajectories in individuals who developed type 2 diabetes.Research Design and Methods: This case-cohort study, nested within the Whitehall II cohort, was based on 335 incident type 2 diabetes cases and 2,475 noncases. We measured serum IL-1Ra levels at up to three time points per individual and estimated retrospective trajectories of IL-1Ra before diabetes diagnosis (case subjects) or end of follow-up (control subjects) using multilevel analysis. Models were adjusted for age, sex, and ethnicity.Results: IL-1Ra levels were already higher in the case than control subjects 13 years before diabetes diagnosis/end of follow-up (mean [95% CI] 302 [290-314] vs. 244 [238-249] pg/ml). In control subjects, IL-1Ra levels showed a modest linear increase throughout the study period. In case subjects, IL-1Ra trajectories were parallel to those in control subjects until 6 years (95% CI 7.5-4.5) before diagnosis and then rose steeply to 399 (379-420) pg/ml at the time of diagnosis (P < 0.0001 for slope difference). Adjustment for BMI and waist circumference as time-varying covariates had little impact on these trajectories.Conclusions: We show elevated IL-1Ra levels for 13 years and an accelerated increase during the last 6 years before type 2 diabetes diagnosis, indicating the presence of an anti-inflammatory response that may act to counterbalance the metabolic and immunologic disturbances that precede type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: Interleukin-1 receptor antagonist (IL-1Ra), a natural inhibitor of interleukin-1 beta, has been shown to improve beta-cell function and glycemic control in patients with type 2 diabetes. The aim of this study was to investigate whether baseline systemic levels of IL-1Ra are associated with incident type 2 diabetes during more than 10 years of follow-up.Research Design and Methods: We measured serum IL-1Ra concentrations in a nested case-control study (181 case and 376 age-, sex-, and BMI-matched normoglycemic control subjects) within the Whitehall II cohort (U.K.).Results: IL-1Ra concentrations were higher in case subjects (P = 0.0006) and associated with incident type 2 diabetes (odds ratio for a 1-SD increase of IL-1Ra 1.48 [95% CI 1.21-1.80]). This association remained significant after adjustment for multiple potential confounders but was attenuated by adjusting for 2-h glucose.Conclusions: Our findings indicate that individuals who will develop type 2 diabetes are characterized by a complex immune activation that also includes upregulation of the anti-inflammatory cytokine IL-1Ra. [ABSTRACT FROM AUTHOR]

Aims: To estimate prevalence of diagnosed (dDM) and undiagnosed diabetes (uDM) in Hungary and investigate determinants of uDM., Methods: Data was obtained from the nationally representative H-UNCOVER study. As laboratory measurements were available for 11/19 Hungarian counties, n = 5,974/17,787 people were eligible. After exclusions, 5,673 (representing 4,976,097 people) were included. dDM was defined by self-reporting, while uDM as negative self-reporting and elevated fasting glucose (≥7 mmol/l) and/or HbA1c (≥48 mmol/mol). Logistic regression for complex samples was used to calculate comparisons between dDM and uDM adjusted for age and BMI., Results: Diabetes prevalence was 12.0 %/11.9 % (women/men, 95 %CI:10.7-13.4 %/10.7-13.2 %), while 2.2 %/2.8 % (1.7-2.8 %/2.2-3.6 %) of women/men were uDM. While the proportion of uDM vs. dDM was similar for women ≥ 40, men in their forties had the highest odds for uDM. Neither unemployment (women/men OR:0.58 [0.14-2.45]/0.50 [0.13-1.92]), nor education level (tertiary vs. primary; women/men OR: 1.16 [0.53-2.56]/ 0.53 [0.24-1.18]) were associated with uDM. The risk of uDM was lower in both sexes with chronic morbidities., Conclusions: We report higher prevalence of diabetes and undiagnosed diabetes than previous Hungarian estimates. The finding that socioeconomic factors are not associated to uDM suggests that universal health care could provide equitable access to diabetes diagnosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Significant regional variability in lifespan in Europe is influenced by environmental factors and lifestyle behaviors, including diet. This study investigates the impact of geographical region on the lifespan of European rulers spanning from the fourteenth century to the present day. By analyzing historical records and literature, we aim to identify region-specific dietary patterns and lifestyle factors that may have contributed to longer lifespans among rulers. The hypothesis to be tested is that rulers from Southern European countries, where the traditional Mediterranean diet is consumed by the local people, may exhibit longer lifespans compared to rulers from other regions, due to the well-documented health benefits associated with this dietary pattern. We extracted comprehensive information for each ruler, encompassing their sex, birth and death dates, age, age of enthronement, duration of rulership, country, and cause of death (natural vs. non-natural). To determine their nationality, we coded rulers based on their hypothetical present-day residence (2023). Utilizing the EuroVoc Geographical classification, we categorized the countries into four regions: Northern, Western, Southern, Central and Eastern Europe. While Cox regression models did not find significant differences in survival rates among regions, further analysis stratified by time periods revealed intriguing trends. Contrary to our initial predictions, the Northern region displayed better survival rates compared to the Southern region between 1354 and 1499, whereas survival rates were similar across regions from 1500 to 1749. However, after 1750, all regions, except the Southern region, exhibited significantly improved survival rates, suggesting advancements in healthcare and lifestyle factors. These findings underscore the dynamic influence of both region and time period on health and longevity. Interestingly, despite the prevalence of the Mediterranean diet in the Southern region of Europe, rulers from this region did not demonstrate longer lifespans compared to their counterparts in other regions. This suggests that additional lifestyle factors may have played a more prominent role in their longevity. In conclusion, our study sheds light on the intricate relationship between region, time period, and lifespan among European rulers. Although the Mediterranean diet is often associated with health benefits, our findings indicate that it alone may not account for differences in ruler longevity across regions. Further research is warranted to explore the impact of other lifestyle factors on the health and lifespan of European rulers throughout history., (© 2023. The Author(s).)

The high mortality of patients with coronavirus disease 2019 (COVID-19) is effectively reduced by vaccination. However, the effect of vaccination on mortality among hospitalised patients is under-researched. Thus, we investigated the effect of a full primary or an additional booster vaccination on in-hospital mortality among patients hospitalised with COVID-19 during the delta wave of the pandemic. This retrospective cohort included all patients (n = 430) admitted with COVID-19 at Semmelweis University Department of Medicine and Oncology in 01/OCT/2021-15/DEC/2021. Logistic regression models were built with COVID-19-associated in-hospital/30 day-mortality as outcome with hierarchical entry of predictors of vaccination, vaccination status, measures of disease severity, and chronic comorbidities. Deceased COVID-19 patients were older and presented more frequently with cardiac complications, chronic kidney disease, and active malignancy, as well as higher levels of inflammatory markers, serum creatinine, and lower albumin compared to surviving patients (all p < 0.05). However, the rates of vaccination were similar (52-55%) in both groups. Based on the fully adjusted model, there was a linear decrease of mortality from no/incomplete vaccination (ref) through full primary (OR 0.69, 95% CI: 0.39-1.23) to booster vaccination (OR 0.31, 95% CI 0.13-0.72, p = 0.006). Although unadjusted mortality was similar among vaccinated and unvaccinated patients, this was explained by differences in comorbidities and disease severity. In adjusted models, a full primary and especially a booster vaccination improved survival of patients hospitalised with COVID-19 during the delta wave of the pandemic. Our findings may improve the quality of patient provider discussions at the time of admission., (© 2023. The Author(s).)

The Semmelweis Study is a prospective occupational cohort study that seeks to enroll all employees of Semmelweis University (Budapest, Hungary) aged 25 years and older, with a population of 8866 people, 70.5% of whom are women. The study builds on the successful experiences of the Whitehall II study and aims to investigate the complex relationships between lifestyle, environmental, and occupational risk factors, and the development and progression of chronic age-associated diseases. An important goal of the Semmelweis Study is to identify groups of people who are aging unsuccessfully and therefore have an increased risk of developing age-associated diseases. To achieve this, the study takes a multidisciplinary approach, collecting economic, social, psychological, cognitive, health, and biological data. The Semmelweis Study comprises a baseline data collection with open healthcare data linkage, followed by repeated data collection waves every 5 years. Data are collected through computer-assisted self-completed questionnaires, followed by a physical health examination, physiological measurements, and the assessment of biomarkers. This article provides a comprehensive overview of the Semmelweis Study, including its origin, context, objectives, design, relevance, and expected contributions., (© 2023. The Author(s).)

Introduction: Studies indicate that due to school lockdown during the Coronavirus Disease 2019 (COVID-19) pandemic, screen time increased more steeply than pre-pandemic years. The aim of our study was to examine changes in screen time and its components (screen time spent on videos, games, homework, and other activities) of adolescents affected by COVID-19 school closures compared to controls from pre-pandemic years and to assess the effect of family structure and family communication., Methods: Two sets of ninth-grader boys and girls transitioning into 10th grade were included in the analysis. The 'pre-COVID classes' (controls) completed the baseline survey in February 2018 and the follow-up survey in March 2019. 'COVID classes' (cases) completed the baseline survey in February 2020 (1 month before the COVID-19-related school lockdowns) and the follow-up survey in March 2021. Linear mixed models stratified by sex were built to assess the change in screen time over one year adjusted for family structure and communication., Results: Our study population consisted of 227 controls (128 girls, 99 boys) and 240 cases (118 girls, 122 boys). Without COVID-19, overall screen time did not change significantly for boys, but there was a decrease in screen time for gaming by 0.63 h, which was accompanied by an increase of 1.11 h in screen time for other activities (consisting mainly of social media and communication). Because of the pandemic, all components increased by 1.44-2.24 h in boys. Girls' screen time and its components remained stable without school lockdown, while it increased for videos and homework by 1.66-2.10 h because of school lockdown. Living in a single-parent household was associated with higher, while better family communication resulted in lower screen time., Discussion: Our results indicate that COVID-19-related school lockdowns modified the age-specific increase in screen time for boys and girls as well. This trend, however, may be counterbalanced by improving communication between family members., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Major, Fazekas-Pongor, Pártos, Tabák, Ungvari, Eörsi, Árva and Terebessy.)

This study aims to examine the association between baseline level and change of autonomic nervous function with subsequent development of arterial stiffness. Autonomic nervous function was assessed in 4901 participants of the Whitehall II occupational cohort by heart rate variability (HRV) indices and resting heart rate (rHR) three times between 1997 and 2009, while arterial stiffness was assessed by carotid-femoral pulse wave velocity (PWV) measured twice between 2007 and 2013. First, individual HRV/rHR levels and annual changes were estimated. Then, we modelled the development of PWV by HRV/rHR using linear mixed effect models. First, we adjusted for sex and ethnicity (model 1), and then for socioeconomic and lifestyle factors, various clinical measurements, and medications (model 2). A decrease in HRV and unchanged rHR was associated with subsequent higher levels of PWV, but the effect of a change in HRV was less pronounced at higher ages. A typical individual aged 65 years with a SDNN level of 30 ms and a 2% annual decrease in SDNN had 1.32 (0.95; 1.69) higher PWV compared to one with the same age and SDNN level but with a 1% annual decrease in SDNN. Further adjustment had no major effect on the results. People who experience a steeper decline in autonomic nervous function have higher levels of arterial stiffness. The association was stronger in younger people., (© 2023. The Author(s), under exclusive licence to American Aging Association.)

Introduction: In 1989, the St Vincent declaration aimed to approximate pregnancy outcomes of diabetes to that of healthy pregnancies. We aimed to compare frequency and trends of outcomes of pregnancies affected by type 1 diabetes and controls in 1996-2018., Methods: We used anonymized records of a mandatory nation-wide registry of all deliveries between gestational weeks 24 and 42 in Hungary. We included all singleton births (4,091 type 1 diabetes, 1,879,183 controls) between 1996 and 2018. We compared frequency and trends of pregnancy outcomes between type 1 diabetes and control pregnancies using hierarchical Poisson regression., Results: The frequency of stillbirth, perinatal mortality, large for gestational age, caesarean section, admission to neonatal intensive care unit (NICU), and low Appearance, Pulse, Grimace, Activity, and Respiration (APGAR) score was 2-4 times higher in type 1 diabetes compared to controls, while the risk of congenital malformations was increased by 51% and SGA was decreased by 42% (all p<0.05). These observations remained significant after adjustment for confounders except for low APGAR scores. We found decreasing rate ratios comparing cases and controls over time for caesarean sections, low APGAR scores (p<0.05), and for NICU admissions (p=0.052) in adjusted models. The difference between cases and controls became non-significant after 2009. No linear trends were observed for the other outcomes., Conclusions: Although we found that the rates of SGA, NICU care, and low APGAR score improved in pregnancies complicated by type 1 diabetes, the target of the St Vincent Declaration was only achieved for the occurrence of low APGAR scores., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fazekas-Pongor, Svébis, Major, Pártos, Dósa, Mészáros, Horváth, Domján, Zsirai and Tabák.)

It is well accepted that COVID-19-related mortality shows a strong age dependency. However, temporal changes in the age distribution of excess relative mortality between waves of the pandemic are less frequently investigated. We aimed to assess excess absolute mortality and the age-distribution of all-cause mortality during the second and third waves of the COVID-19 pandemic in Hungary compared to the same periods of non-pandemic years. Rate ratios for excess all-cause mortality with 95% confidence intervals and the number of excess deaths for the second (week 41 of 2020 through week 4 of 2021) and third waves (weeks 7-21 of 2021) of the COVID pandemic for the whole of Hungary compared to the same periods of the pre-pandemic years were estimated for 10-year age strata using Poisson regression. Altogether, 9771 (95% CI: 9554-9988) excess deaths were recorded during the second wave of the pandemic, while it was lower, 8143 (95% CI: 7953-8333) during the third wave. During the second wave, relative mortality peaked for ages 65-74 and 75-84 (RR 1.37, 95%CI 1.33-1.41, RR 1.38, 95%CI 1.34-1.42). Conversely, during the third wave, relative mortality peaked for ages 35-44 (RR 1.43, 95%CI 1.33-1.55), while those ≥65 had substantially lower relative risks compared to the second wave. The reduced relative mortality among the elderly during the third wave is likely a consequence of the rapidly increasing vaccination coverage of the elderly coinciding with the third wave. The hugely increased relative mortality of those 35-44 could point to non-biological causes, such as less stringent adherence to non-pharmaceutical measures in this population., (© 2022. The Author(s), under exclusive licence to American Aging Association.)

Background: It is unclear whether replacing oral glucose tolerance test (OGTT) with hemoglobin A1c (HbA1c) measurement for diagnosing diabetes is justified. We aimed to assess the proportion of OGTT-diagnosed diabetes cases that can be confirmed by HbA1c and to examine whether individuals with OGTT diagnosis but nondiagnostic HbA1c are at higher risk of macrovascular and microvascular disease., Methods: Participants were 5773 men and women from the population-based Whitehall II prospective cohort study in the United Kingdom. New OGTT diabetes cases diagnosed in clinical examinations in 2002 to 2004 and 2007 to 2009 were assessed for HbA1c confirmation (≥6.5%) in these and subsequent clinical examinations in 2012 to 2013 and 2015 to 2016. All participants were followed up for major cardiovascular events through linkage to electronic health records until 2017 and for incident chronic kidney disease (estimated glomerular filtration rate <60 mL·min -1 ·1.73 m -2 ) until the last clinical examination. In analysis of vascular disease risk, new OGTT-diagnosed diabetes cases with and without diagnostic HbA1c and preexisting diabetes cases were compared with diabetes-free participants., Results: Of the 378 (59.3%) participants with OGTT-diagnosed diabetes, 224 were confirmed by HbA1c during 4.1 years (SD, 4.1 years) of follow-up. We recorded 942 cardiovascular events over 12.1 years. After adjustment for nonmodifiable risk factors and compared with the 4997 diabetes-free participants, 371 participants with new HbA1c-confirmed diabetes and 405 participants with preexisting diabetes had increased risk of cardiovascular disease (hazard ratio, 1.53 [95% CI, 1.12-2.10] and 1.85 [95% CI, 1.50-2.28], respectively). The corresponding hazard ratios in the analysis of incident chronic kidney disease (487 cases; follow-up, 6.6 years) were 1.69 (95% CI, 1.09-2.62) for 282 participants with new HbA1c-confirmed diabetes and 1.67 (95% CI, 1.22-2.28) for 276 participants with preexisting diabetes. In both analyses, OGTT cases with nondiagnostic HbA1c (n=149 and 107) had a risk (hazard ratio, 0.99-1.07) similar to that of the diabetes-free population., Conclusions: More than 40% of OGTT-diagnosed diabetes cases were not confirmed by HbA1c during an extended follow-up. However, because these individuals have a risk of cardiovascular disease and chronic kidney disease similar to that of the diabetes-free population, replacement of OGTT with HbA1c-based diagnosis appears justified.

Background: People with diabetic cardiovascular autonomic neuropathy (CAN) have increased cardiovascular mortality. However, the association between distal symmetric polyneuropathy (DSPN) or CAN with all-cause mortality is much less investigated. Thus, we set out to examine the effect of CAN and DSPN on all-cause mortality in a well-phenotyped cohort., Methods: All diabetes cases ( n = 1,347) from the catchment area of a secondary diabetes care centre who had medical examination including neuropathy assessment between 1997 and 2016 were followed up for all-cause mortality in the NHS Hungary reimbursement database until 2018. We investigated the association of CAN (Ewing tests) and DSPN (Neurometer) with all-cause mortality using Cox models stratified by diabetes type., Results: Altogether, n = 131/1,011 persons with type 1/type 2 diabetes were included. Of the participants, 53%/43% were male, mean age was 46 ± 12/64 ± 10 years, diabetes duration was 13 ± 10/7 ± 8 years, 42%/29% had CAN, and 39%/37% had DSPN. During the 9 ± 5/8 ± 5-year follow-up, n = 28/494 participants died. In fully adjusted models, participants with type 1 diabetes patients with versus without DSPN had an increased mortality (HR 2.99, 95% CI 1.4-8.63), while no association with CAN was observed. In type 2 diabetes, both DSPN and CAN independently increased mortality (HR 1.32, 95% CI: 1.07-1.64, and HR 1.44, 95% CI: 1.17-1.76)., Conclusions: Our results are compatible with an increased risk of mortality in people with type 1 diabetes and DSPN. Furthermore, we report a similarly strong association between DSPN and CAN and all-cause mortality in type 2 diabetes mellitus., Competing Interests: The authors declare that that they have no competing interests., (Copyright © 2021 Orsolya E. Vági et al.)

Objective: Higher resting heart rate (rHR) and lower heart rate variability (HRV) are associated with increased risk of cardiovascular disease (CVD) and all-cause mortality in people with and without diabetes. It is unknown whether temporal changes in rHR and HRV may contribute to this risk. We investigated associations between 5-year changes in rHR and HRV and risk of future CVD and death, taking into account participants' baseline glycemic state., Research Design and Methods: In this prospective, population-based cohort study we investigated 4,611 CVD-free civil servants (mean [SD] age, 60 [5.9] years; 70% men). We measured rHR and/or six indices of HRV. Associations of 5-year change in 5-min rHR and HRV with fatal and nonfatal CVD and all-cause mortality or the composite of the two were assessed, with adjustments made for relevant confounders. Effect modification by glycemic state was tested., Results: At baseline, 63% of participants were normoglycemic, 29% had prediabetes, and 8% had diabetes. During a median (interquartile range) follow-up of 11.9 (11.4; 12.3) years, 298 participants (6.5%) experienced a CVD event and 279 (6.1%) died of non-CVD-related causes. We found no association between 5-year changes in rHR and HRV and future events. Only baseline rHR was associated with all-cause mortality. A 10 bpm-higher baseline HR level was associated with an 11.4% higher rate of all-cause mortality (95% CI 1.0-22.9%; P = 0.032). Glycemic state did not modify associations., Conclusions: Changes in rHR and HRV and possibly also baseline values of these measures are not associated with future CVD or death in people with or without dysglycemia., (© 2021 by the American Diabetes Association.)

The state of intermediate hyperglycemia is indicative of elevated risk of developing type 2 diabetes 1 . However, the current definition of prediabetes neither reflects subphenotypes of pathophysiology of type 2 diabetes nor is predictive of future metabolic trajectories. We used partitioning on variables derived from oral glucose tolerance tests, MRI-measured body fat distribution, liver fat content and genetic risk in a cohort of extensively phenotyped individuals who are at increased risk for type 2 diabetes 2,3 to identify six distinct clusters of subphenotypes. Three of the identified subphenotypes have increased glycemia (clusters 3, 5 and 6), but only individuals in clusters 5 and 3 have imminent diabetes risks. By contrast, those in cluster 6 have moderate risk of type 2 diabetes, but an increased risk of kidney disease and all-cause mortality. Findings were replicated in an independent cohort using simple anthropomorphic and glycemic constructs 4 . This proof-of-concept study demonstrates that pathophysiological heterogeneity exists before diagnosis of type 2 diabetes and highlights a group of individuals who have an increased risk of complications without rapid progression to overt type 2 diabetes.

Objective: Monophasic glucose response (MGR) during an oral glucose tolerance test (OGTT) and gestational diabetes mellitus (GDM) are predictors of type 2 diabetes mellitus (T2DM). We investigated the association between current MGR and (1) glucose tolerance during a pregnancy 3 years before and (2) current glucose tolerance status. We also sought (3) other determinants of MGR. Research Design and Methods . We conducted a nested case-control study of GDM ( n = 47 early GDM, diagnosed between 16 and 20 weeks of gestation; n = 40 late GDM, diagnosed between 24 and 28 weeks of gestation) and matched healthy controls ( n = 37, normal glucose tolerance during pregnancy) all free from diabetes at follow-up 3.4 ± 0.6 years after delivery. Glucose tolerance was determined by 2-hour 75 g OGTT. Monophasic and biphasic groups were defined based on serum glucose measurements during OGTT., Results: The biphasic group was younger, had lower triglyceride levels and area under the OGTT glucose curve, and was less frequently diagnosed with early GDM (25 vs. 45%, all p < 0.05). Women with a biphasic response also tended to have lower systolic blood pressure ( p < 0.1). No differences were found in fasting and 2-hour glucose and insulin levels, or BMI. According to multiple logistic regression, MGR was associated with prior early GDM (OR 2.14, 95% CI 0.92-4.99) and elevated triglyceride levels (OR 2.28, 95% CI 1.03-5.03/log (mmol/l))., Conclusions: We found that more severe, early-onset GDM was an independent predictor of monophasic glucose response suggesting that monophasic response may represent an intermediate state between GDM and manifest type 2 diabetes., Competing Interests: The authors declare no conflict of interest (financial disclosure) with the findings of the article., (Copyright © 2020 Timea Tänczer et al.)

Here, we review insulin management options and strategies in nonpregnant adult patients with type 1 diabetes mellitus (T1DM). Most patients with T1DM should follow a regimen of multiple daily injections of basal/bolus insulin, but those not meeting individual glycemic targets or those with frequent or severe hypoglycemia or pronounced dawn phenomenon should consider continuous subcutaneous insulin infusion. The latter treatment modality could also be an alternative based on patient preferences and availability of reimbursement. Continuous glucose monitoring may improve glycemic control irrespective of treatment regimen. A glycemic target of glycated hemoglobin < 7% (53 mmol/mol) is appropriate for most nonpregnant adults. Basal insulin analogues with a reduced peak profile and an extended duration of action with lower intraindividual variability relative to neutral protamine Hagedorn insulin are preferred. The clinical advantages of basal analogues compared with older basal insulins include reduced injection burden, better efficacy, lower risk of hypoglycemic episodes (especially nocturnal), and reduced weight gain. For prandial glycemic control, any rapid-acting prandial analogue (aspart, glulisine, lispro) is preferred over regular human insulin. Faster-acting insulin aspart is a relatively new option with the advantage of better postprandial glucose coverage. Frequent blood glucose measurements along with patient education on insulin dosing based on carbohydrate counting, premeal blood glucose, and anticipated physical activity is paramount, as is education on the management of blood glucose under different circumstances.Plain Language Summary: Plain language summary is available for this article.

Objective: Autonomic nervous system dysfunction is associated with impaired glucose metabolism, but the temporality of this association remains unclear in individuals without diabetes. We investigated the association of autonomic function with 5-year changes in glucose metabolism in individuals without diabetes., Research Design and Methods: Analyses were based on 9,000 person-examinations for 3,631 participants without diabetes in the Whitehall II cohort. Measures of autonomic function included 5-min resting heart rate and six heart rate variability (HRV) indices. Associations between baseline autonomic function measures and 5-year changes in fasting and 2-h plasma glucose, serum insulin concentrations, insulin sensitivity (insulin sensitivity index [ISI 0-120 ] and HOMA of insulin sensitivity), and β-cell function (HOMA of β-cell function) were estimated in models adjusting for age, sex, ethnicity, metabolic factors, and medication., Results: A 10-bpm higher resting heart rate was associated with 5-year changes in fasting and 2-h insulin and ISI 0-120 of 3.3% change (95% CI 1.8; 4.8), P < 0.001; 3.3% change (1.3; 5.3), P = 0.001; and -1.4% change (-2.4; -0.3), P = 0.009, respectively. In models adjusted for age, sex, and ethnicity, higher baseline values of several HRV indices were associated with a 5-year decrease in fasting and 2-h insulin and ISI 0-120 . However, significance was lost by full adjustment. A majority of HRV indices exhibited a trend toward higher values being associated with lower insulin levels and higher insulin sensitivity., Conclusions: Higher resting heart rate in individuals without diabetes is associated with future unfavorable changes in insulin levels and insulin sensitivity. Associations may be mediated via autonomic function; however, results are inconclusive. Resting heart rate may be a risk marker for future pathophysiological changes in glucose metabolism., (© 2019 by the American Diabetes Association.)

Background: Neighbourhood socioeconomic disadvantage has been linked to increased diabetes risk, but little is known about differences in risk factors in childhood and adulthood in those with high and low neighbourhood socioeconomic disadvantage, or about the association between long-term neighbourhood socioeconomic disadvantage and incidence of diabetes in adulthood. We used data from the prospective, population-based Young Finns Study to address these questions., Methods: We did a nationwide population-based cohort study in Finland using data from The Young Finns Study, which included 3467 participants aged 6-18 years followed up for over 30 years via eight repeated biomedical examinations and linkage to electronic health records. Participants were also linked to national grid data on neighbourhood disadvantage via their residential address from age 6-48 years. We used these data to examine differences in ten risk factors (dietary habits, physical activity, daily smoking, body-mass index, systolic blood pressure, fasting HDL cholesterol, fasting triglycerides, fasting plasma glucose, fasting serum insulin, and homoeostasis model assessment insulin sensitivity) from childhood (6-21 years) to adulthood (22-48 years) among individuals with high (>0·5 SD above the national mean) and low (≥0·5 SD below the national mean) neighbourhood socioeconomic disadvantage, and the association of cumulative neighbourhood socioeconomic disadvantage with six cardiometabolic risk factors (obesity, high waist circumference, fatty liver, hypertension, carotid plaque, and left ventricle mass index) and diabetes by middle age (22-48 years). We used logistic and linear regression analyses to assess the effects of neighbourhood disadvantage on cardiometabolic and diabetes risk, controlling for potential confounders (age, sex, and individual socioeconomic disadvantage)., Findings: We included data for 3002 individuals with risk factor assessment in childhood and adulthood. Of whom, 2048 underwent a clinical examination during the last follow-up at age 33-48 years. Differences in risk factors by neighbourhood socioeconomic disadvantage at the beginning of follow-up were small, but large differences emerged over the follow-up. High neighbourhood socioeconomic disadvantage was characterised by decreased fruit and vegetable intake as early as age 6 years, decreased physical activity, and increased prevalence of daily smoking from adolescence (12 years) onwards, and decreased homoeostasis model assessment insulin sensitivity and increased fasting glucose and insulin concentration from early adulthood (27 years; all p<0·03). Individuals consistently exposed to high neighbourhood socioeconomic disadvantage were more likely to be obese (odds ratio [OR] 1·44, 95% CI 1·01-2·06), hypertensive (1·83, 1·14-2·93), have a fatty liver (1·73, 1·11-2·71), and diabetes (3·71, 1·77-7·75), compared with those who were consistently exposed to low neighbourhood socioeconomic disadvantage., Interpretation: Living in socioeconomically disadvantaged areas can shape health in childhood and adulthood. Neighbourhood socioeconomic disadvantage is associated with differences in health risks across the life course, including detrimental lifestyle factors from childhood and adolescence onwards and worse glucose metabolism from early adulthood. By middle age, cumulative neighbourhood socioeconomic disadvantage is associated with increased cardiometabolic risk factors and increased incidence of diabetes., Funding: Academy of Finland, NordForsk, UK Medical Research Council, European Commission, and European Research Council., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Biomarkers of inflammation and adiponectin are associated with cardiovascular autonomic neuropathy (CAN) in cross-sectional studies, but prospective data are scarce. This study aimed to assess the associations of biomarkers of subclinical inflammation and adiponectin with subsequent changes in heart rate (HR) and heart rate variability (HRV) in non-diabetic and diabetic individuals., Methods: Data are based on up to 25,050 person-examinations for 8469 study participants of the Whitehall II cohort study. Measures of CAN included HR and several HRV indices. Associations between baseline serum levels of high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, IL-1 receptor antagonist (IL-1Ra) and adiponectin and 5-year changes in HR and six HRV indices were estimated using mixed-effects models adjusting for age, sex, ethnicity, body mass index (BMI), metabolic covariates and medication. A modifying effect of diabetes was tested., Results: Higher levels of IL-1Ra were associated with higher increases in HR. Additional associations with measures of HRV were observed for hsCRP, IL-6 and IL-1Ra, but these associations were explained by BMI and other confounders. Associations between adiponectin, HR and HRV differed depending on diabetes status. Higher adiponectin levels were associated with more pronounced decreases in HR and increases in three measures of HRV reflecting both sympathetic and vagal activity, but these findings were limited to individuals with type 2 diabetes., Conclusions: Higher IL-1Ra levels appeared as novel risk marker for increases in HR. Higher adiponectin levels were associated with a more favourable development of cardiovascular autonomic function in individuals with type 2 diabetes independently of multiple confounders.

Aims/hypothesis: South Asian individuals have reduced insulin sensitivity and increased risk of type 2 diabetes compared with white individuals. Temporal changes in glycaemic traits during middle age suggest that impaired insulin secretion is a particular feature of diabetes development among South Asians. We therefore aimed to examine ethnic differences in early changes in glucose metabolism prior to incident type 2 diabetes., Methods: In a prospective British occupational cohort, subject to 5 yearly clinical examinations, we examined ethnic differences in trajectories of fasting plasma glucose (FPG), 2 h post-load plasma glucose (2hPG), fasting serum insulin (FSI), 2 h post-load serum insulin (2hSI), HOMA of insulin sensitivity (HOMA2-S) and secretion (HOMA2-B), and the Gutt insulin sensitivity index (ISI 0,120 ) among 120 South Asian and 867 white participants who developed diabetes during follow-up (1991-2013). We fitted cubic mixed-effects models to longitudinal data with adjustment for a wide range of covariates., Results: Compared with white individuals, South Asians had a faster increase in FPG before diagnosis (slope difference 0.22 mmol/l per decade; 95% CI 0.02, 0.42; p = 0.03) and a higher FPG level at diagnosis (0.27 mmol/l; 95% CI 0.06, 0.48; p = 0.01). They also had higher FSI and 2hSI levels before and at diabetes diagnosis. South Asians had a faster decline and lower HOMA2-S (log e -transformed) at diagnosis compared with white individuals (0.33; 95% CI 0.21, 0.46; p < 0.001). HOMA2-B increased in both ethnic groups until 7 years before diagnosis and then declined; the initial increase was faster in white individuals. ISI 0,120 declined steeply in both groups before diagnosis; levels were lower among South Asians before and at diagnosis. There were no ethnic differences in 2hPG trajectories., Conclusions/interpretation: We observed different trajectories of plasma glucose, insulin sensitivity and secretion prior to diabetes diagnosis in South Asian and white individuals. This might be due to ethnic differences in the natural history of diabetes. South Asian individuals experienced a more rapid decrease in insulin sensitivity and faster increases in FPG compared with white individuals. These findings suggest more marked disturbance in beta cell compensation prior to diabetes diagnosis in South Asian individuals.

Aims: To estimate and compare the prevalence of self-reported diabetes based on nationally representative surveys of the Hungarian adult population in 2002 (published data - Hungarostudy) and a survey in 2012., Methods: A cross-sectional computer-assisted telephone interview survey on a stratified representative sample of community-dwelling adults (n=1000) in 2012. To describe self-reported diabetes prevalence and its temporal changes generalized linear models were used and results were compared to figures from Hungarostudy., Results: Age standardized prevalence of self-reported type 2 diabetes was 11.7% (95%CI 10.0-13.8%) without gender or rural-urban differences in 2012. People with self-reported diabetes were older than controls (mean [SE]: 63.9 [0.9] vs. 45.9 [0.3] years, p<0.0001). The prevalence of diabetes sharply increased after 40 years of age and peaked at age 70 (27.7% [2.5], p age*age <0.0001). The prevalence of self-reported diabetes increased by 89% (OR 1.89, 95%CI 1.53-2.32) from 6.2 to 11.7% between the two surveys with the most pronounced increase in the age group 55-64 years (from 11.6 to 24.4%)., Conclusions: We reported an alarming increase in the prevalence of self-reported type 2 diabetes in the last decade that mostly affects working age people. If this trend continues, a major public health crisis in Hungary can be envisaged., (Copyright © 2016 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

We aimed to examine heterogeneity in glucose response curves during an oral glucose tolerance test with multiple measurements and to compare cardiometabolic risk profiles between identified glucose response curve groups. We analyzed data from 1,267 individuals without diabetes from five studies in Denmark, the Netherlands and the USA. Each study included between 5 and 11 measurements at different time points during a 2-h oral glucose tolerance test, resulting in 9,602 plasma glucose measurements. Latent class trajectories with a cubic specification for time were fitted to identify different patterns of plasma glucose change during the oral glucose tolerance test. Cardiometabolic risk factor profiles were compared between the identified groups. Using latent class trajectory analysis, five glucose response curves were identified. Despite similar fasting and 2-h values, glucose peaks and peak times varied greatly between groups, ranging from 7-12 mmol/L, and 35-70 min. The group with the lowest and earliest plasma glucose peak had the lowest estimated cardiovascular risk, while the group with the most delayed plasma glucose peak and the highest 2-h value had the highest estimated risk. One group, with normal fasting and 2-h values, exhibited an unusual profile, with the highest glucose peak and the highest proportion of smokers and men. The heterogeneity in glucose response curves and the distinct cardiometabolic risk profiles may reflect different underlying physiologies. Our results warrant more detailed studies to identify the source of the heterogeneity across the different phenotypes and whether these differences play a role in the development of type 2 diabetes and cardiovascular disease.

Objective: Higher systemic levels of pro-inflammatory biomarkers and low adiponectin are associated with increased risk of type 2 diabetes, but their associations with changes in glycaemic deterioration before onset of diabetes are poorly understood. We aimed to study whether inflammation-related biomarkers are associated with 5-year changes in glucose and insulin, HbA1c, insulin sensitivity and beta-cell function before the diagnosis of type 2 diabetes and whether these associations may be bidirectional., Design and Methods: We used multiple repeat measures (17 891 person-examinations from 7683 non-diabetic participants) from the Whitehall II study to assess whether circulating high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL6), IL1 receptor antagonist (IL1Ra) and adiponectin are associated with subsequent changes in glycaemia, insulin, insulin resistance and beta-cell function (based on oral glucose tolerance tests). We examined bidirectionality by testing if parameters of glucose metabolism at baseline are associated with changes in inflammation-related biomarkers., Results: Higher hsCRP and IL6 were associated with increases in fasting insulin, insulin resistance and, for IL6, with beta-cell function after adjustment for confounders. Higher adiponectin was associated with decreases in fasting glucose, HbA1c, fasting insulin, insulin resistance and beta-cell function. The reverse approach showed that 2-h glucose and insulin sensitivity were associated with changes in IL1Ra. Fasting insulin and insulin resistance showed inverse associations with changes in adiponectin., Conclusions: Subclinical inflammation is associated with development of increased glycaemia, insulin resistance and beta-cell function in non-diabetic individuals. These findings are consistent with the hypothesis that inflammation-related processes may increase insulin resistance and lead to a compensatory upregulation of beta-cell function., (© 2016 European Society of Endocrinology.)

Background: Hypertension is associated with an increased risk of dementia and depression with uncertain longitudinal associations with brain structure., Aims: To examine lifetime blood pressure as a predictor of brain structure in old age., Method: A total of 190 participants (mean age 69.3 years) from the Whitehall II study were screened for hypertension six times (1985-2013). In 2012-2013, participants had a 3T-magnetic resonance imaging (MRI) brain scan. Data from the MRI were analysed using automated and visual measures of global atrophy, hippocampal atrophy and white matter hyperintensities., Results: Longitudinally, higher mean arterial pressure predicted increased automated white matter hyperintensities (P<0.002). Cross-sectionally, hypertensive participants had increased automated white matter hyperintensities and visually rated deep white matter hyperintensities. There was no significant association with global or hippocampal atrophy., Conclusions: Long-term exposure to high blood pressure predicts hyperintensities, particularly in deep white matter. The greatest changes are seen in those with severe forms of hypertension, suggesting a dose-response pattern., (Royal College of Psychiatrists.)

Aims/hypothesis: South Asian individuals have an increased prevalence of type 2 diabetes, but little is known about the development of glycaemic traits in this ethnic group. We compared age-related changes in glycaemic traits between non-diabetic South Asian and white participants., Methods: In a prospective British occupational cohort with 5-yearly clinical examinations (n = 230/5,749 South Asian/white participants, age 39-79 years at baseline), age-related trajectories of fasting glucose (FG) and 2 h post-load glucose (PLG), log-transformed fasting insulin (FINS) and 2 h post-load insulin (PLINS), HOMA insulin sensitivity (HOMA2-%S) and HOMA insulin secretion (HOMA2-%B) were fitted for South Asian and white individuals who remained free of diabetes between 1991 and 2009., Results: In sex-adjusted multilevel models, FG was stable in white participants but increased with age in South Asians (0.12 [SE = 0.04] mmol/l per decade). PLG, FINS and PLINS levels were lower among white participants (by 0.271 [SE = 0.092] mmol/l, 0.306 [SE = 0.046] log pmol/l, 0.707 [SE = 0.059] log pmol/l at age 50, respectively) compared with South Asians, although their age-related trajectories were parallel. HOMA2-%S was higher (0.226 [SE = 0.038] at age 50) and HOMA2-%B lower (by 0.189 [SE = 0.026] at age 50) among white than South Asian participants. The age-related decline in HOMA2-%S was similar in these groups, but the age-related increase in HOMA2-%B was greater in white participants (0.04 [SE = 0.02] per decade). This difference was explained by obesity, lifestyle and social status., Conclusions/interpretation: Findings from a diabetes-free population suggest an inadequate pancreatic beta cell reserve in South Asians, as a significantly steeper age-related increase in FG was observed in this ethnic group compared with white individuals.

Purpose: Classical regression models might give an incomplete picture of the associations between predictors and outcomes. We investigated associations between gestational weight gain (GWG) and birth weight along the entire birth weight distribution with quantile regression and estimated effects of hypothetical prevention strategies., Methods: The GWG-birth weight association was analyzed using quantile and classical regression models on data from a population-based gestational diabetes screening (n = 4760) at the Szent Imre Teaching Hospital in Budapest, Hungary (2002-2005). Birth weight distributions were modeled based on hypothetical GWG changes., Results: At a body mass index of 20 kg/m(2), a 1-kg difference in GWG was associated with a 14.2 g (95% confidence interval, 10.0-20.9) higher birth weight at the fifth percentile of the birth weight distribution and a 29.0 g (21.3-35.6) higher birth weight at the 95th percentile. The coefficient from linear regression was 20.7 (17.5-24.0). Estimates differed modestly between the two regressions at a body mass index of 30 kg/m(2). A population-wide 2-kg decrease in GWG would rather affect the risk of macrosomia (-1.8%) than that of low birth weight (+0.4%). In contrast, a 3-kg decrease in GWG among overweight and obese women would lower macrosomia more modestly (-0.8%)., Conclusions: A population-wide lowering of GWG would lead to greater improvements in the right tail of the birth weight distribution., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Diabetes is an increasingly important public health concern, but little is known about the contribution of psychological factors on diabetes risk. We examined whether personality is associated with risk of incident diabetes and diabetes-related mortality., Method: An individual-participant meta-analysis of 34,913 adults free of diabetes at baseline (average age 53.7 years, 57% women) from 5 prospective cohort studies from the United States and United Kingdom. Personality dimensions included extraversion, neuroticism, agreeableness, conscientiousness, and openness to experience based on the Five Factor Model., Results: During an average follow-up of 5.7 years, 1845 participants became diabetic. Of the 5 personality dimensions, only low conscientiousness was associated with an elevated diabetes risk (OR = 0.87, 95% CI = 0.82-0.91 per 1 standard deviation increment in conscientiousness). This association attenuated by 60% after adjustment for obesity and by 25% after adjustment for physical inactivity. Low conscientiousness was also associated with elevated risk of diabetes mortality (HR = 0.72, CI = 0.53-0.98 per 1 standard deviation increment in conscientiousness). Other personality traits were not consistently associated with diabetes incidence or mortality., Conclusions: Low conscientiousness-a cognitive-behavioral disposition reflecting careless behavior and a lack of self-control and planning-is associated with elevated risk of diabetes and diabetes-related mortality. The underlying mechanisms are likely to involve health behaviors, such as poor weight management, physical inactivity, and adherence to medical management recommendations.

Background: To estimate cardiovascular disease (CVD) mortality in relation to obesity and gender., Methods: Data from 11 prospective cohorts from four European countries including 23 629 men and 21 965 women, aged 24 to 99 years, with a median follow-up of 7.9 years were analyzed. Hazards ratios (HR) for CVD mortality in relation to baseline body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR) and waist-to-height ratio (WHtR) were estimated using Cox proportional hazards models with age as the timescale., Results: Men had higher CVD mortality than women in all four BMI categories (<25.0, 25.0-29.9, 30.0-34.9 and ≥35.0 kg/m(2)). Compared with the lowest BMI category in women, multivariable adjusted HRs (95% confidence intervals) for higher BMI categories are 1.0 (0.8-1.4), 1.6 (1.1-2.1) and 2.8 (2.0-3.8) in women and 2.8 (2.2-3.6), 3.1 (2.5-3.9), 3.8 (2.9-4.9) and 5.4 (3.8-7.7) in men, respectively. Similar findings were observed for abdominal obesity defined by WC, WHR or WHtR. The gender difference was slightly smaller in obese than in non-obese individuals; but the interaction was statistically significant only between gender and WC (p = 0.02), and WHtR (p = 0.01). None of the interaction terms was significant among non-diabetic individuals., Conclusions: Men had higher CVD mortality than women across categories of anthropometric measures of obesity. The gender difference was attenuated in obese individuals, which warrants further investigation.

Background: Secular trends in cardiovascular risk factors have been described, but few studies have examined simultaneously the effects of both ageing and secular trends within the same cohort., Methods: Development of cardiovascular risk factors over the past three decades was analysed using serial measurements from 10 308 participants aged from 35 to 80 years over 25 years of follow-up from five clinical examination phases of the Whitehall II study. Changes of body mass index, waist circumference, blood pressure and total and high-density lipoprotein cholesterol distribution characteristics were analysed with quantile regression models in the 57-61 age group. Age-related trajectories of risk factors were assessed by fitting mixed-effects models with adjustment for year of birth to reveal secular trends., Results: Average body mass index and waist circumference increased faster with age in women than in men, but the unfavourable secular trend was more marked in men. Distributions showed a fattening of the right tail in each consecutive phase, meaning a stronger increase in higher percentiles. Despite the higher obesity levels in younger birth cohorts, total cholesterol decreased markedly in the 57-61 age group along the entire distribution rather than in higher extremes only., Conclusion: The past three decades brought strong and heterogeneous changes in cardiovascular risk factor distributions. Secular trends appear to modify age-related trajectories of cardiovascular risk factors, which may be a source of bias in longitudinal analyses., (© The Author 2014. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Hyperglycemia is a common, but not well-characterized side effect of glucocorticoid treatment., Aim: To study the effect of pulse dexamethasone treatment on carbohydrate metabolism among multiple myeloma patients., Material/subjects and Methods: A randomized crossover observational study in a teaching hospital with nine myeloma patients (one male, two with known type 2 diabetes (KDM), mean age 69.0 ± 6.7 years) were investigated using a standard 75 g Oral Glucose Tolerance Test (patients without KDM) and a 3-day continuous glucose monitoring (CGM--all patients) during and between dexamethasone cycles., Results: During dexamethasone treatment patients had elevated 2-h postload glucose (12.8 ± 4.7 vs. 8.7 ± 3.2 mmol/L, P = 0.024) but similar fasting glucose (6.3 ± 1.4 vs. 5.1 ± 0.5 mmol/L, P = 0.112). Estimated hourly mean interstitial glucose values based on linear mixed models showed an increase of 0.03 [SE 0.01] mmol/L per hour from 5.0 [0.4] in patients without KDM and followed a quadratic curve from 5.0 [0.4] mmol/L at midnight to 7.5 [0.5] mmol/L at 12:00 h in patients with KDM during control periods. During dexamethasone treatment glucose was similar to control periods between 02:00 and 12:00 h in the non-KDM group, where they followed a cubic trajectory from 5.3 [0.4] mmol/L at 04:00 h to 7.3 [0.4] mmol/L at 18:00 h. In contrast, interstitial glucose was increased by at least 7.9 [0.3] mmol/L throughout the day in KDM patients during dexamethasone treatment and increased from 13.6 [0.5] mmol/L at midnight to 17.5 [0.5] mmol/L at 17:00 h., Conclusions: During pulse steroid therapy of myeloma patients without KDM afternoon and evening glucose measurements may be the optimal tools to characterize glucose metabolism.

To examine sex differences in trajectories of glucose and insulin prior to the development of type 2 diabetes. Glucose and insulin levels from oral glucose tolerance tests performed every 5 years in the prospective Whitehall II cohort were analysed using mixed-effects models. Out of 6,712 White participants, 475 men and 177 women developed diabetes during a median follow-up time of 14 years. Men who developed diabetes had higher fasting glucose levels than women over the entire follow-up period (P < 0.001), whereas trajectories of 2-h glucose did not differ between sexes (P = 0.34). Two-hour insulin levels tended to be higher among women than men developing diabetes (P = 0.05), but not after adjustment for height (P = 0.45). Men have higher fasting glucose levels than women many years before the diagnosis of diabetes and at time of diagnosis, indicating that the pathogenesis of diabetes may be different between sexes.

There is a controversy regarding whether depression and type 2 diabetes are causally linked. To assess this issue, we review key findings for the association between depression and diabetes, and its underlying mechanisms. Findings from meta-analyses of cohort studies show a modestly sized bidirectional association between depression and type 2 diabetes (ie, depression predicts diabetes onset and diabetes predicts future depression). However, depression-related biological alterations in the hypothalamic-pituitary-adrenal cortex axis and the sympathetic nervous system, and subclinical inflammation, are not consistently linked with increased diabetes risk. The evidence for an association between depression and glycaemic traits (eg, glucose, insulin, insulin sensitivity, and insulin secretion) is also mixed. Diabetes increases the risk of depression to the same extent as do other chronic disorders (eg, cardiac diseases, osteoarthritis, lung disease, and poor hearing). At present, the available evidence suggests that pathophysiological changes preceding the onset of type 2 diabetes might not cause depression, nor might depression directly increase the risk of developing type 2 diabetes. Despite insufficient robust causal evidence, treating physicians should be aware of the co-occurrence of depression and type 2 diabetes., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Type 2 diabetes increases the risk for dementia, but whether it affects cognition before old age is unclear. We investigated whether duration of diabetes in late midlife and poor glycaemic control were associated with accelerated cognitive decline., Methods: 5653 participants from the Whitehall II cohort study (median age 54.4 years [IQR 50.3-60.3] at first cognitive assessment), were classified into four groups: normoglycaemia, prediabetes, newly diagnosed diabetes, and known diabetes. Tests of memory, reasoning, phonemic and semantic fluency, and a global score that combined all cognitive tests, were assessed three times over 10 years (1997-99, 2002-04, and 2007-09). Mean HbA1c was used to assess glycaemic control during follow-up. Analyses were adjusted for sociodemographic characteristics, health-related behaviours, and chronic diseases., Findings: Compared with normoglycaemic participants, those with known diabetes had a 45% faster decline in memory (10 year difference in decline -0.13 SD, 95% CI -0.26 to -0.00; p=0.046), a 29% faster decline in reasoning (-0.10 SD, -0.19 to -0.01; p=0.026), and a 24% faster decline in the global cognitive score (-0.11 SD, -0.21 to -0.02; p=0.014). Participants with prediabetes or newly diagnosed diabetes had similar rates of decline to those with normoglycaemia. Poorer glycaemic control in participants with known diabetes was associated with a significantly faster decline in memory (-0.12 [-0.22 to -0.01]; p=0.034) and a decline in reasoning that approached significance (-0.07 [-0.15 to 0.00]; p=0.052)., Interpretation: The risk of accelerated cognitive decline in middle-aged patients with type 2 diabetes is dependent on both disease duration and glycaemic control., Funding: US National Institutes of Health, UK Medical Research Council., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Obstructive sleep apnea (OSA) is often accompanied by the metabolic syndrome. Because both conditions are associated with depressed heart rate variability (HRV) separately, our aim was to study whether co-morbid OSA is associated with more reduced HRV in male patients with the metabolic syndrome., Methods: In this cross-sectional study, 35 men (age, 57±11 years) with the metabolic syndrome (according to International Diabetes Federation criteria) were included. OSA severity was defined by the apnea-hypopnea index (AHI). HRV was assessed by 24-hr ambulatory electrocardiographic monitoring. Standard deviation of all normal-to-normal RR intervals (SDNN), the high frequency power (HFP), and the ratio of low- to high-frequency power (LF/HF) were measured., Results: There were 14, 6, and 8 cases of severe (AHI ≥30/hr), moderate (15/hr≤AHI <30/hr), and mild (5/hr ≤AHI <15/hr) OSA, respectively. Seven patients had no OSA. Patients with mild-moderate or severe OSA had reduced SDNN and HFP values compared to those without OSA. Increasing OSA severity was associated significantly with lower daytime LF/HF ratio [standardized β regression coefficient (β)=-0.362, P=0.043] and higher night/day LF/HF ratio (β=0.377, P=0.023) after controlling for age, duration of diabetes, and severity of metabolic syndrome., Conclusions: Co-morbid OSA is associated with decreased overall HRV, parasympathetic loss, and impaired diurnal pattern of sympathovagal balance that may further increase the cardiovascular vulnerability of male patients with the metabolic syndrome. The role of the HRV analysis in the risk assessment of these patients warrants further studies.

Background: Patients with type 2 diabetes vary greatly with respect to degree of obesity at time of diagnosis. To address the heterogeneity of type 2 diabetes, we characterised patterns of change in body mass index (BMI) and other cardiometabolic risk factors before type 2 diabetes diagnosis., Methods and Findings: We studied 6,705 participants from the Whitehall II study, an observational prospective cohort study of civil servants based in London. White men and women, initially free of diabetes, were followed with 5-yearly clinical examinations from 1991-2009 for a median of 14.1 years (interquartile range [IQR]: 8.7-16.2 years). Type 2 diabetes developed in 645 (1,209 person-examinations) and 6,060 remained free of diabetes during follow-up (14,060 person-examinations). Latent class trajectory analysis of incident diabetes cases was used to identify patterns of pre-disease BMI. Associated trajectories of cardiometabolic risk factors were studied using adjusted mixed-effects models. Three patterns of BMI changes were identified. Most participants belonged to the "stable overweight" group (n = 604, 94%) with a relatively constant BMI level within the overweight category throughout follow-up. They experienced slightly worsening of beta cell function and insulin sensitivity from 5 years prior to diagnosis. A small group of "progressive weight gainers" (n = 15) exhibited a pattern of consistent weight gain before diagnosis. Linear increases in blood pressure and an exponential increase in insulin resistance a few years before diagnosis accompanied the weight gain. The "persistently obese" (n = 26) were severely obese throughout the whole 18 years before diabetes diagnosis. They experienced an initial beta cell compensation followed by loss of beta cell function, whereas insulin sensitivity was relatively stable. Since the generalizability of these findings is limited, the results need confirmation in other study populations., Conclusions: Three patterns of obesity changes prior to diabetes diagnosis were accompanied by distinct trajectories of insulin resistance and other cardiometabolic risk factors in a white, British population. While these results should be verified independently, the great majority of patients had modest weight gain prior to diagnosis. These results suggest that strategies focusing on small weight reductions for the entire population may be more beneficial than predominantly focusing on weight loss for high-risk individuals.

Purpose: Static magnetic field (SMF) could improve pain sensation and bone turnover. In a single-center randomized double-blind placebo-controlled study we investigated the effects of SMF exposure on subjective pain and bone turnover., Materials and Methods: Postmenopausal osteoporotic women (aged 50-70 years) with bone deformity and back pain were randomized to 10 weekly visits of 30-min SMF (n = 6) or treatment with non-magnetized pads (n = 5) on the back. Primary and secondary outcomes were changes in pain sensation on a visual analogue scale (VAS) during each visit and over 10 weeks, respectively. Tertiary outcomes were changes in osteocalcin and β-crosslaps. SMF was inhomogeneous with 192 millitesla peak-to-peak value by 19 tesla/meter gradient of the magnetic flux density at 3 mm., Results: Participants randomized to sham had higher VAS at baseline (mean difference: 2.8, 95% confidence interval (CI) 0.47-5.2 cm). Both SMF and sham similarly reduced short term pain (sham-SMF: 0.59, 95% CI - 0.31-1.49 cm, p = 0.195). VAS did not change in SMF, while it decreased in the sham group (between-group difference 0.27, 95% CI 0.04-0.50 cm/visit). Bone turnover markers remained stable., Conclusions: SMF as used in this investigation is not recommended for pain relief in postmenopausal women with vertebral deformity. The finding on long-term pain relief may relate to unbalanced randomization.

Aims: Antihypertensive drug therapy is a major strategy of stroke prevention among hypertensive patients. The aim of this study was to estimate the excess risk of stroke associated with non-adherence to antihypertensive drug therapy among hypertensive patients., Methods and Results: We conducted a population-based study using records from Finnish national registers for 1 January 1995 to 31 December 2007. Of the 73 527 hypertensive patients aged 30 years or older and without pre-existing stroke or cardiovascular disease, 2144 died from stroke and 24 560 were hospitalized due to stroke during the follow-up. At the 2- and 10-year follow-up after the start of continuous antihypertensive medication, non-adherent patients had 3.81 [95% confidence interval (CI) 2.85-5.10] and 3.01 (95% CI: 2.37-3.83) times higher odds of stroke death when compared with the adherent patients. The corresponding odds ratio (OR) for stroke hospitalization was 2.74 (95% CI: 2.35-3.20) at Year 2 and 1.71 (95% CI: 1.49-1.96) at Year 10. In the stroke-event year, the ORs were higher, 5.68 (95% CI: 5.05-6.39) for stroke death and 1.87 (95% CI: 1.72-2.03) for hospitalization. Among those using agents acting on the renin-angiotensin system combined with diuretics or β-blockers, these ORs were 7.49 (95% CI: 5.62-9.98) and 3.91 (95% CI: 3.23-4.75), respectively. The associations between non-adherence and stroke followed a dose-response pattern--the poorer the adherence, the greater the risk of death and hospitalization due to stroke., Conclusion: These data suggest that poor adherence to antihypertensive therapy substantially increases near- and long-term risk of stroke among hypertensive patients.

Background: Most clinicians acknowledge that type 2 diabetes is multifactorial and has heterogeneous characteristics, but neither prevention nor treatment is systematically stratified. To address the heterogeneity of the disease, we examined whether patients diagnosed on the basis of fasting glucose concentrations, those diagnosed on the basis of 2 h concentrations, and those diagnosed on the basis of both criteria differed in terms of pathogenesis or cardiovascular risks., Methods: Retrospectively, we analysed trajectories of cardiometabolic risk factors and 10 year cardiovascular risks in the prospective Whitehall II study cohort by use of multilevel longitudinal modelling. Participants were diagnosed by 75 g oral glucose-tolerance tests. We classified those diagnosed with type 2 diabetes into three subgroups: diagnosed on the basis of fasting glucose concentrations, diagnosed on the basis of 2 h glucose concentrations, and diagnosed on the basis of both concentrations. We also developed a classification tree for identification of individuals who are likely to have high fasting and 2 h glucose concentrations, but for whom only fasting concentrations are available., Results: Median follow-up was 14·2 years with 15,826 person-examinations (1991-2009). Of 10,308 individuals, 6843 were included and 6569 remained diabetes free. 274 cases of type 2 diabetes were identified: 55 had high fasting glucose concentrations only, 148 had high 2 h concentrations only, and 71 had high fasting and 2 h concentrations. At diagnosis, participants with high fasting and 2 h glucose concentrations had higher mean body-mass indices (30·9 kg/m(2) [SD 5·7]) than did those with high fasting concentrations (28·4 kg/m(2) [4·4]; p=0·0009) or 2 h concentrations (27·9 kg/m(2) [4·9]; <0·0001). Mean glycated haemoglobin A1c concentrations were also higher in the fasting and 2 h subgroup (7·4% [1·6]) than in the fasting (5·9% [0·5]; <0·0001) or 2 h (5·9% [0·6]; <0·0001) sugroups. Additionally, the fasting and 2 h subgroup had a higher proportion of individuals with moderate or high risk of cardiovascular disease than did the fasting subgroup (p=0·02). A classic pattern of β-cell decompensation before diagnosis was noted only in the fasting and 2 h subgroup. Additionally, glucose concentrations and insulin resistance accelerated more substantially before diagnosis in the fasting and 2 h subgroup than in the fasting subgroup or the 2 h subgroup., Interpretation: Patients with type 2 diabetes diagnosed on the basis of increased fasting glucose concentrations or 2 h glucose concentrations, or both, have distinct cardiometabolic risk development before diagnosis., Funding: UK Medical Research Council, UK Economic and Social Research Council, British Heart Foundation, UK Health and Safety Executive, UK Department of Health, US National Heart Lung and Blood Institute, US National Institute on Aging, US Agency for Health Care Policy Research, and John D and Catherine T MacArthur Foundation., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: The extent to which abnormal glucose metabolism increases the risk of depression remains unclear. In this study, we investigated prospective associations of levels of fasting glucose and fasting insulin and indices of insulin resistance and secretion with subsequent new-onset depressive symptoms (DepS)., Research Design and Methods: In this prospective cohort study of 3,145 adults from the Whitehall II Study (23.5% women, aged 60.6 ± 5.9 years), baseline examination included fasting glucose and insulin level, the homeostasis model assessment of insulin resistance (HOMA2-%IR), and the homeostasis model assessment of β-cell insulin secretion (HOMA2-%B). DepS (Center for Epidemiologic Studies Depression Scale ≥16 or use of antidepressive drugs) were assessed at baseline and at 5-year follow-up., Results: Over the 5-year follow-up, DepS developed in 142 men and 84 women. Women in the lowest quintile of insulin secretion (HOMA2-%B ≤55.3%) had 2.18 (95% CI 1.25-3.78) times higher odds of developing DepS than those with higher insulin secretion. This association was not accounted for by inflammatory markers, cortisol secretion, or menopausal status and hormone replacement therapy. Fasting insulin measures were not associated with DepS in men, and fasting glucose measures were not associated with new-onset DepS in either sex., Conclusions: Low insulin secretion appears to be a risk factor for DepS in middle-aged women, although further work is required to confirm this finding.

Aims/hypothesis: We aimed to study diurnal variation in glucose regulation by examining the effects of time of day and fasting duration on fasting plasma glucose (FPG), 2 h post-load plasma glucose (2hPG) and HbA(1c) levels., Methods: We analysed data from 5,978 non-diabetic white men and women from the prospective Whitehall II Study. All studied participants fasted for at least 8 h before a clinical examination, which included an OGTT and anthropometric measurements. We fitted mixed-effects models for FPG, 2hPG and HbA(1c) as outcome variables, and time of day and/or fasting duration as explanatory variables. Models were adjusted for age, BMI and study phase., Results: Time of day and fasting duration were associated inversely with FPG and positively with 2hPG. The mean difference between measures at 08:00 and 15:00 hours in men/women was -0.46 (95% CI -0.50, -0.42) mmol/l/-0.39 (95% CI -0.46, -0.31) mmol/l and 1.39 (95% CI 1.25, 1.52) mmol/l/1.19 (95% CI 0.96, 1.42) mmol/l for FPG and 2hPG, respectively. HbA(1c) levels were independent of either time. Time of day and fasting duration were independently associated with 2hPG. In contrast, the effect of fasting duration on FPG was markedly attenuated with adjustment for time of day. Ageing, but not obesity, was associated with increased diurnal variation in glucose tolerance., Conclusions/interpretation: Both time of day and fasting duration should be considered in clinical practice and epidemiological studies, since they have clinically relevant effects on FPG and 2hPG levels. As biochemically expected, HbA(1c) levels are independent of time of blood sampling and fasting duration.