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Aims/hypothesis: We assessed whether the risk of developing type 2 diabetes and the age of onset varied with the age at diabetes diagnosis of affected family members., Methods: We performed a national register-based open cohort study of individuals living in Denmark between 1995 and 2012. The population under study consisted of all individuals aged 30 years or older without diagnosed diabetes at the start date of the cohort (1 January 1995) and who had information about their parents' identity. Individuals who turned 30 years of age during the observation period and had available parental identity information were also added to the cohort from that date (open cohort design). These criteria restricted the study population mostly to people born between 1960 and 1982. Multivariable Poisson regression models adjusted for current age and highest educational attainment were used to estimate incidence rate ratios (IRRs) of type 2 diabetes., Results: We followed 2,000,552 individuals for a median of 14 years (24,034,059 person-years) and observed 76,633 new cases of type 2 diabetes. Compared with individuals of the same age and sex who did not have a parent or full sibling with diabetes, the highest risk of developing type 2 diabetes was observed in individuals with family members diagnosed at an early age. The IRR was progressively lower with a higher age at diabetes diagnosis in family members: 3.9 vs 1.4 for those with a parental age at diagnosis of 50 or 80 years, respectively; and 3.3 vs 2.0 for those with a full sibling's age at diagnosis of 30 or 60 years, respectively., Conclusions/interpretation: People with a family member diagnosed with diabetes at an earlier age are more likely to develop diabetes and also to develop it at an earlier age than those with a family member diagnosed in later life. This finding highlights the importance of expanding our understanding of the interplay between genetic diabetes determinants and the social, behavioural and environmental diabetes determinants that track in families across generations. Accurate registration of age at diagnosis should form an integral part of recording a diabetes family history, as it provides easily obtainable and highly relevant detail that may improve identification of individuals at increased risk of younger onset of type 2 diabetes. In particular, these individuals may benefit from closer risk factor assessment and follow-up, as well as prevention strategies that may involve the family.

Aims/hypothesis: Reversion from prediabetes to normoglycaemia is accompanied by an improvement in cardiovascular risk factors, but it is unclear whether this translates into a reduction in risk of cardiovascular disease (CVD) events or death. Hence, we studied the probability of reversion from prediabetes to normoglycaemia and the associated risk of future CVD and death using data from the Whitehall II observational cohort study., Methods: Three glycaemic criteria for prediabetes (fasting plasma glucose [FPG] 5.6-6.9 mmol/l, 2 h plasma glucose [2hPG] 7.8-11.0 mmol/l, and HbA 1c 39-47 mmol/mol [5.7-6.4%]) were assessed in 2002-2004 and 2007-2009 for 5193 participants free of known diabetes at enrolment. Among participants with prediabetes in the first examination, we calculated the probability of reversion to normoglycaemia by re-examination according to each glycaemic criterion. Poisson regression analysis was used to estimate and compare incidence rates of a composite endpoint of a CVD event or death in participants with prediabetes who did vs did not revert to normoglycaemia. Analyses were adjusted for age, sex, ethnicity and previous CVD., Results: Based on the FPG criterion, 820 participants had prediabetes and 365 (45%) of them had reverted to normoglycaemia in 5 years. The corresponding numbers were 324 and 120 (37%) for the 2hPG criterion and 1709 and 297 (17%) for the HbA 1c criterion. During a median follow-up of 6.7 (interquartile range 6.3-7.2) years, 668 events of non-fatal CVD or death occurred among the 5193 participants. Reverting from 2hPG-defined prediabetes to normoglycaemia vs remaining prediabetic or progressing to diabetes was associated with a halving in event rate (12.7 vs 29.1 per 1000 person-years, p = 0.020). No association with event rate was observed for reverting from FPG-defined (18.6 vs 18.2 per 1000 person-years, p = 0.910) or HbA 1c -defined prediabetes to normoglycaemia (24.5 vs 22.9 per 1000 person-years, p = 0.962)., Conclusions/interpretation: Most people with HbA 1c -defined prediabetes remained prediabetic or progressed to diabetes during 5 years of follow-up. In contrast, reversion to normoglycaemia was frequent among people with FPG- or 2hPG-defined prediabetes. Only reversion from 2hPG-defined prediabetes to normoglycaemia was associated with a reduction in future risk of CVD and death.

Aims/hypothesis: The role of burden and duration of multiple microvascular complications on mortality rate has not been explored in detail in type 1 diabetes. Taking complication burden and time-updated duration into account we aimed to quantify mortality rate in individuals with and without microvascular complications., Methods: This observational clinical cohort included 3828 individuals with type 1 diabetes attending the Steno Diabetes Center Copenhagen in 2001-2013. We used information on mortality and detailed clinical measures of microvascular complications from electronic patient records. Poisson models were used to model mortality rates according to complication burden., Results: During 26,665 person-years of follow-up, 503 deaths occurred. Compared with individuals without microvascular complications, the mortality rate ratio was 2.20 (95% CI 1.79, 2.69) for individuals with diabetic kidney disease, 1.72 (95% CI 1.39, 2.12) for individuals with neuropathy and 1.02 (95% CI 0.77, 1.37) for individuals with retinopathy, all adjusted for calendar time (year/month/day), age, duration of diabetes, sex, HbA 1c , LDL-cholesterol, BMI, smoking status, systolic blood pressure, use of antihypertensive and lipid-lowering medication, and cardiovascular disease status. In individuals with two complications or more, the risk of mortality did not exceed the combined risk from each individual complication. Mortality rate ratios increased immediately after diagnosis of neuropathy and diabetic kidney disease. Mortality rate ratios were independent of the duration of neuropathy and retinopathy, while the mortality rate associated with diabetic kidney disease reached a stable level after approximately 3 years., Conclusions/interpretation: Neuropathy and diabetic kidney disease are strong and independent risk markers of mortality in type 1 diabetes, whereas no evidence of higher mortality rate was found for retinopathy. We found no indication that the mortality risk with multiple complications exceeds the risk conferred by each complication separately. The duration spent with microvascular complications had only a marginal effect on mortality.

Aims/hypothesis: In the UK, more than one million people have undiagnosed diabetes and an additional five million are at high risk of developing the disease. Given that early identification of these people is key for both primary and secondary prevention, new screening approaches are needed. Since spouses resemble each other in cardiometabolic risk factors related to type 2 diabetes, we aimed to investigate whether diabetes and cardiometabolic risk factors in one spouse can be used as an indicator of incident type 2 diabetes in the other spouse., Methods: We analysed data from 3649 men and 3478 women from the English Longitudinal Study of Ageing with information on their own and their spouse's diabetes status and cardiometabolic risk factors. We modelled incidence rates and incidence rate ratios with Poisson regression, using spousal diabetes status or cardiometabolic risk factors (i.e. BMI, waist circumference, systolic and diastolic BP, HDL- and LDL-cholesterol and triacylglycerols) as exposures and type 2 diabetes incidence in the index individual as the outcome. Models were adjusted for two nested sets of covariates., Results: Spousal BMI and waist circumference were associated with incident type 2 diabetes, but with different patterns for men and women. A man's risk of type 2 diabetes increased more steeply with his wife's obesity level, and the association remained statistically significant even after adjustment for the man's own obesity level. Having a wife with a 5 kg/m 2 higher BMI (30 kg/m 2 vs 25 kg/m 2 ) was associated with a 21% (95% CI 11%, 33%) increased risk of type 2 diabetes. In contrast, the association between incident type 2 diabetes in a woman and her husband's BMI was attenuated after adjusting for the woman's own obesity level. Findings for waist circumference were similar to those for BMI. Regarding other risk factors, we found a statistically significant association only between the risk of type 2 diabetes in women and their husbands' triacylglycerol levels., Conclusions/interpretation: The main finding of this study is the sex-specific effect of spousal obesity on the risk of type 2 diabetes. Having an obese spouse increases an individual's risk of type 2 diabetes over and above the effect of the individual's own obesity level among men, but not among women. Our results suggest that a couples-focused approach may be beneficial for the early detection of type 2 diabetes and individuals at high risk of developing type 2 diabetes, especially in men, who are less likely than women to attend health checks., Data Availability: Data were accessed via the UK Data Service under the data-sharing agreement no. 91400 ( https://discover.ukdataservice.ac.uk/catalogue/?sn=5050&type=Data%20catalogue ).

Aims/hypothesis: The secretion of glucagon is controlled by blood glucose and inappropriate secretion of glucagon contributes to hyperglycaemia in diabetes. Besides its role in glucose regulation, glucagon regulates amino acid metabolism in hepatocytes by increasing ureagenesis. Disruption of this mechanism causes hyperaminoacidaemia, which in turn increases glucagon secretion. We hypothesised that hepatic insulin resistance (secondary to hepatic steatosis) via defective glucagon signalling/glucagon resistance would lead to impaired ureagenesis and, hence, increased plasma concentrations of glucagonotropic amino acids and, subsequently, glucagon., Methods: To examine the association between glucagon and amino acids, and to explore whether this relationship was modified by hepatic insulin resistance, we studied a well-characterised cohort of 1408 individuals with normal and impaired glucose regulation. In this cohort, we have previously reported insulin resistance to be accompanied by increased plasma concentrations of glucagon. We now measure plasma levels of amino acids in the same cohort. HOMA-IR was calculated as a marker of hepatic insulin resistance., Results: Fasting levels of glucagonotropic amino acids and glucagon were significantly and inversely associated in linear regression models (persisting after adjustment for age, sex and BMI). Increasing levels of hepatic, but not peripheral insulin resistance (p > 0.166) attenuated the association between glucagon and circulating levels of alanine, glutamine and tyrosine, and was significantly associated with hyperaminoacidaemia and hyperglucagonaemia. A doubling of the calculated glucagon-alanine index was significantly associated with a 30% increase in hepatic insulin resistance, a 7% increase in plasma alanine aminotransferase levels, and a 14% increase in plasma γ-glutamyltransferase levels., Conclusions/interpretation: This cross-sectional study supports the existence of a liver-alpha cell axis in humans: glucagon regulates plasma levels of amino acids, which in turn feedback to regulate the secretion of glucagon. With hepatic insulin resistance, reflecting hepatic steatosis, the feedback cycle is disrupted, leading to hyperaminoacidaemia and hyperglucagonaemia. The glucagon-alanine index is suggested as a relevant marker for hepatic glucagon signalling.

The authors have discovered a coding error in the statistical analysis syntax file used for the mixed-effect model analyses in this paper. The error has led to differences (first decimal) in the estimates for the main results.

Aims/hypothesis: In addition to blood glucose concentrations measured in the fasting state and 2 h after an OGTT, intermediate measures during an OGTT may provide additional information regarding a person's risk of future diabetes and cardiovascular disease (CVD). First, we aimed to characterise heterogeneity of glycaemic patterns based on three time points during an OGTT. Second, we compared the incidences of diabetes and CVD and all-cause mortality rates among those with different patterns., Methods: Our cohort study included 5861 participants without diabetes at baseline from the Danish Inter99 study. At baseline, all participants underwent an OGTT with measurements of plasma glucose levels at 0, 30 and 120 min. Latent class mixed-effects models were fitted to identify distinct patterns of glycaemic response during the OGTT. Information regarding incident diabetes, CVD and all-cause mortality rates during a median follow-up time of 11, 12 and 13 years, respectively, was extracted from national registers. Cox proportional hazard models with adjustment for several cardiometabolic risk factors were used to compare the risk of diabetes, CVD and all-cause mortality among individuals in the different latent classes., Results: Four distinct glucose patterns during the OGTT were identified. One pattern was characterised by high 30 min but low 2 h glucose values. Participants with this pattern had an increased risk of developing diabetes compared with participants with lower 30 min and 2 h glucose levels (HR 4.1 [95% CI 2.2, 7.6]) and participants with higher 2 h but lower 30 min glucose levels (HR 1.5 [95% CI 1.0, 2.2]). Furthermore, the all-cause mortality rate differed between the groups with significantly higher rates in the two groups with elevated 30 min glucose. Only small non-significant differences in risk of future CVD were observed across latent classes after confounder adjustment., Conclusions/interpretation: Elevated 30 min glucose is associated with increased risk of diabetes and all-cause mortality rate independent of fasting and 2 h glucose levels. Therefore, subgroups at high risk may not be revealed when considering only fasting and 2 h glucose levels during an OGTT.

Aims/hypothesis: Health check programmes for chronic disease have been introduced in a number of countries. However, there are few trials assessing the benefits and harms of these screening programmes at the population level. In a post hoc analysis, we evaluated the effect of population-based screening for type 2 diabetes and cardiovascular risk factors on mortality rates and cardiovascular events., Methods: This register-based, non-randomised, controlled trial included men and women aged 40-69 years without known diabetes who were registered with a general practice in Denmark (n = 1,912,392). Between 2001 and 2006, 153,107 individuals registered with 181 practices participating in the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION)-Denmark study were sent a diabetes risk score questionnaire. Individuals at moderate-to-high risk were invited to visit their GP for assessment of diabetes status and cardiovascular risk (screening group). The 1,759,285 individuals registered with all other general practices in Denmark constituted the retrospectively constructed no-screening (control) group. Outcomes were mortality rate and cardiovascular events (cardiovascular disease death, non-fatal ischaemic heart disease or stroke). The analysis was performed according to the intention-to-screen principle., Results: Among the screening group, 27,177 (18%) individuals attended for assessment of diabetes status and cardiovascular risk. Of these, 1,533 were diagnosed with diabetes. During a median follow-up of 9.5 years, there were 11,826 deaths in the screening group and 141,719 in the no-screening group (HR 0.99 [95% CI 0.96, 1.02], p = 0.66). There were 17,941 cardiovascular events in the screening group and 208,476 in the no-screening group (HR 0.99 [0.96, 1.02], p = 0.49)., Conclusions/interpretation: A population-based stepwise screening programme for type 2 diabetes and cardiovascular risk factors among all middle-aged adults in Denmark was not associated with a reduction in rate of mortality or cardiovascular events between 2001 and 2012.

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/hypothesis: Within a trial of intensive treatment of people with screen-detected diabetes, we aimed to assess a potential spillover effect of the trial intervention on incident cardiovascular disease (CVD) and all-cause mortality among people who screened positive on a diabetes risk questionnaire but who were normoglycaemic., Methods: In the Anglo-Danish-Dutch Study of Intensive Treatment In People with Screen-Detected Diabetes in Primary Care (ADDITION)-Denmark trial, 175 general practices were cluster-randomised into: (1) screening plus routine care of individuals with screen-detected diabetes (control group); or (2) screening plus training and support in intensive multifactorial treatment of individuals with screen-detected diabetes (intervention group). We identified all individuals who screened positive on a diabetes risk questionnaire in ADDITION-Denmark but were normoglycaemic following biochemical testing for use in this secondary analysis. After a median 8.9 years follow-up, we used data from national registers to compare rates of first CVD events and all-cause mortality in individuals in the routine care group with those in the intensive treatment group., Results: In total, 21,513 individuals screened positive for high risk of diabetes but were normoglycaemic on biochemical testing in ADDITION-Denmark practices between 2001 and 2006 (10,289 in the routine care group and 11,224 in the intensive treatment group). During 9 years of follow-up, there were 3784 first CVD events and 1748 deaths. The incidence of CVD was lower among the intensive treatment group compared with the routine care group (HR 0.92 [95% CI 0.85, 0.99]). This association was stronger among individuals at highest CVD risk (heart SCORE ≥ 10; HR 0.85 [95% CI 0.75, 0.96]). There was no difference in mortality between the two treatment groups (HR 1.02 [95% CI 0.92, 1.14])., Conclusions/interpretation: Training of general practitioners to provide target-driven intensive management of blood glucose levels and other cardiovascular risk factors showed some evidence of a spillover effect on the risk of CVD over a 9 year period among individuals at high risk of diabetes. The effect was particularly pronounced among those at highest risk of CVD. There was no effect on mortality., Trial Registration: ClinicalTrials.gov NCT00237549.

Aims/hypothesis: Fasting plasma levels of branched-chain amino acids (BCAAs) are associated with insulin resistance, but it remains unclear whether there is a causal relation between the two. We aimed to disentangle the causal relations by performing a Mendelian randomisation study using genetic variants associated with circulating BCAA levels and insulin resistance as instrumental variables., Methods: We measured circulating BCAA levels in blood plasma by NMR spectroscopy in 1,321 individuals from the ADDITION-PRO cohort. We complemented our analyses by using previously published genome-wide association study (GWAS) results from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) (n = 46,186) and from a GWAS of serum BCAA levels (n = 24,925). We used a genetic risk score (GRS), calculated using ten established fasting serum insulin associated variants, as an instrumental variable for insulin resistance. A GRS of three variants increasing circulating BCAA levels was used as an instrumental variable for circulating BCAA levels., Results: Fasting plasma BCAA levels were associated with higher HOMA-IR in ADDITION-PRO (β 0.137 [95% CI 0.08, 0.19] p = 6 × 10 -7 ). However, the GRS for circulating BCAA levels was not associated with fasting insulin levels or HOMA-IR in ADDITION-PRO (β -0.011 [95% CI -0.053, 0.032] p = 0.6 and β -0.011 [95% CI -0.054, 0.031] p = 0.6, respectively) or in GWAS results for HOMA-IR from MAGIC (β for valine-increasing GRS -0.012 [95% CI -0.069, 0.045] p = 0.7). By contrast, the insulin-resistance-increasing GRS was significantly associated with increased BCAA levels in ADDITION-PRO (β 0.027 [95% CI 0.005, 0.048] p = 0.01) and in GWAS results for serum BCAA levels (β 1.22 [95% CI 0.71, 1.73] p = 4 × 10 -6 , β 0.96 [95% CI 0.45, 1.47] p = 3 × 10 -4 , and β 0.67 [95% CI 0.16, 1.18] p = 0.01 for isoleucine, leucine and valine levels, respectively) and instrumental variable analyses in ADDITION-PRO indicated that HOMA-IR is causally related to higher circulating fasting BCAA levels (β 0.73 [95% CI 0.26, 1.19] p = 0.002)., Conclusions/interpretation: Our results suggest that higher BCAA levels do not have a causal effect on insulin resistance while increased insulin resistance drives higher circulating fasting BCAA levels.

Aim/hypothesis: Our aim was to investigate the association between the macrophage-activation marker soluble CD163 (sCD163), adiponectin, C-reactive protein (CRP) and changes in glycaemia, insulin resistance and insulin secretion in individuals at high risk of type 2 diabetes mellitus., Methods: This prospective study included 1014 individuals at high risk of type 2 diabetes mellitus participating in the Danish arm of the Anglo-Danish-Dutch study of Intensive Treatment In PeOple with ScreeN-detected Diabetes in Primary Care (ADDITION-Europe trial) baseline examination in 2001-2006 and follow-up examination (ADDITION-Progression [ADDITION-PRO]) in 2009-2011. Baseline serum samples were analysed for sCD163, adiponectin and CRP. The associations between sCD163, adiponectin and CRP per doubling of concentration, and changes per year in HbA1c, fasting plasma glucose, 2 h glucose, fasting insulin, HOMA-IR and HOMA-β were assessed using a mixed-effects model., Results: A doubling of sCD163 concentration was positively associated with changes in fasting insulin (β = 1.078 per year, 95% CI 0.454, 1.702) and HOMA-β (β = 1.313 per year, 95% CI 0.537, 2.089), and a doubling of CRP concentration was positively associated with HbA 1c (β = 0.004 per year, 95% CI 0.001, 0.007) and fasting insulin (β = 0.267 per year, 95% CI 0.029, 0.504) after adjustment for age and sex. A doubling of adiponectin was inversely associated with changes in fasting glucose (β = −0.017 per year, 95% CI −0.028, −0.005), 2 h glucose (β = −0.063 per year, 95% CI −0.107, −0.019), fasting insulin (β = −1.558 per year, 95% CI −2.020, −1.096), HOMA-IR (β = −0.040 per year, 95% CI −0.062, −0.019) and HOMA-β (β = −1.009 per year, 95% CI −1.589, −0.429) after adjustment for age and sex. The associations were robust to adjustment for baseline waist circumference and smoking. Adjustment for CRP did not change the associations for sCD163 or adiponectin., Conclusions/interpretation: Our findings indicate that mechanisms related to inflammation, including macrophage activation and adipocyte metabolism, may play a role in changes in glucose homeostasis in individuals at high risk of type 2 diabetes mellitus.

Aims/hypothesis: Screening programmes for type 2 diabetes inevitably find more people at high risk of developing diabetes than people with undiagnosed prevalent diabetes. We describe the incidence of diabetes for risk groups according to advancement in a screening process., Methods: In 2001-2006, a diabetes screening programme based on the Danish diabetes risk score and measures of HbA1c and glucose was carried out in Danish general practices. The present study includes 13,249 individuals with low diabetes risk scores and 22,726 with high diabetes risk scores but no diabetes according to WHO 1999 criteria. Seven incremental levels of diabetes risk were defined and followed for incident diabetes recorded in the Danish National Diabetes Register until December 2012. For each group, cumulative diabetes incidence was calculated. Incidence rates and rate ratios were estimated by Poisson regression analyses., Results: After 10 years of follow-up 1,164 new diabetes cases were registered. Incidence rates were 1.0, 4.2, 14.5, 28.8 and 52.6 per 1,000 person-years in individuals at low risk and in those with normal glucose tolerance, impaired fasting glucose, impaired glucose tolerance and one diabetic glucose value, respectively. For each step in the screening algorithm, the risk of developing diabetes was higher than in the previous step., Conclusions/interpretation: The risk of developing clinical diabetes in people who screen negative for diabetes depends on the level of risk stratification at screening, even at lower risk levels. This risk increases markedly in the presence of impaired glucose regulation. These results can inform policy recommendations concerning prevention strategies following screening.

Aim/hypothesis: Little is known about the relative roles of physical activity energy expenditure (PAEE) and cardiorespiratory fitness (CRF) as determinants of glucose regulation. The aim of this study was to examine the associations of PAEE and CRF with markers of glucose metabolism, and to test the hypothesis that CRF modifies the association between PAEE and glucose metabolism., Methods: We analysed cross-sectional data from 755 adults from the Danish ADDITION-PRO study. On the basis of OGTT results, participants without known diabetes were classified as having normal glucose tolerance, isolated impaired fasting glycaemia (i-IFG), isolated impaired glucose tolerance (i-IGT), combined IFG + IGT or screen-detected diabetes mellitus. Markers of insulin sensitivity and beta cell function were determined. PAEE was measured using a combined heart rate and movement sensor. CRF (maximal oxygen uptake) was estimated using a submaximal 8 min step test. The associations were examined by linear regression analysis. Results were adjusted for relevant confounders., Results: PAEE and CRF were reduced in individuals with i-IGT, combined IFG + IGT and screen-detected diabetes mellitus, but were not significantly different in individuals with i-IFG compared with those with normal glucose tolerance. When adjusting CRF for PAEE and vice versa, PAEE and CRF were both associated with lower fasting and 2 h insulin and higher peripheral insulin sensitivity. CRF was additionally associated with lower fasting and 2 h glucose and higher insulin sensitivity and beta cell function. There was no interaction between CRF and PAEE for any markers of glucose metabolism., Conclusions/interpretation: Only CRF, not PAEE, appears to be independently associated with plasma glucose levels and beta cell function, suggesting that CRF may be particularly important for glycaemic control.

Aims: Methylglyoxal (MG) has been implicated in the development of micro- and macrovascular diabetic complications, but it remains unclear how current treatments of type 2 diabetes affect its circulating levels., Methods: In the Danish arm of the ADDITION trial, we (a) described serum MG levels at baseline and at 6-year follow-up among individuals with screen-detected type 2 diabetes, (b) examined the effect of intensive multifactorial treatment compared with routine care on MG, (c) examined the associations between MG and risk factors at baseline and at follow-up and (d) examined the associations between changes in MG and changes in risk factors., Results: Patients in both treatment arms experienced a significant decline in MG from baseline to follow-up, with no effect of allocation to intensive treatment. In cohort analyses, MG was associated with smoking and fasting glucose at baseline and smoking and LDL cholesterol at follow-up. Compared with patients receiving no lipid-lowering treatment, patients receiving lipid-lowering treatment had higher MG at follow-up, and those initiating lipid-lowering treatment experienced a less pronounced decline in MG., Conclusions: Further studies are required to explore any possible effects of the observed decrease in MG in type 2 diabetes patients as well as the potential interplay between MG, lipids, lipid-lowering treatment and smoking.

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.

Understanding early determinants of type 2 diabetes is essential for refining disease prevention strategies. Proteomic technology may provide a useful approach to identify novel protein patterns potentially related to pathophysiological changes that lead up to diabetes. In this study, we sought to identify protein signals that are associated with diabetes incidence in a middle-aged population. Serum samples from 519 participants in a nested case-control selection (167 cases and 352 age-, sex- and BMI-matched normoglycemic control subjects, median follow-up 14.0 years) within the Whitehall-II cohort were analyzed by linear matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Nine protein peaks were found to be associated with incident diabetes. Rate ratios for high peak intensity ranged between 0.4 (95% CI, 0.2-0.8) and 4.0 (95% CI, 1.7-9.2) and were robust to adjustment for main potential confounders, including obesity, lipids and C-reactive protein. The proteins associated with these peaks may reflect diabetes pathogenesis. Our study exemplifies the utility of an approach that combines proteomic and epidemiological data.