Diet-dependent acid load and type 2 diabetes: pooled results from three prospective cohort studies

Aims/hypothesis

Studies suggest a potential link between low-grade metabolic acidosis and type 2 diabetes. A western dietary pattern increases daily acid load but the association between diet-dependent acid load and type 2 diabetes is still unclear. This study aimed to assess whether diet-dependent acid load is associated with the risk of type 2 diabetes.

Methods

We examined the association between energy-adjusted net endogenous acid production (NEAP), potential renal acid load (PRAL) and animal protein-to-potassium ratio (A:P) on incident type 2 diabetes in 67,433 women from the Nurses’ Health Study, 84,310 women from the Nurses’ Health Study II and 35,743 men from the Health Professionals’ Follow-up Study who were free from type 2 diabetes, cardiovascular disease and cancer at baseline. Study-specific HRs were estimated using Cox proportional hazards models with time-varying covariates and were pooled using a random effects meta-analysis.

Results

We documented 15,305 cases of type 2 diabetes during 4,025,131 person-years of follow-up. After adjustment for diabetes risk factors, dietary NEAP, PRAL and A:P were positively associated with type 2 diabetes (pooled HR [95% CI] for highest (Q5) vs lowest quintile (Q1): 1.29 [1.22, 1.37], p _trend <0.0001; 1.29 [1.22, 1.36], p _trend <0.0001 and 1.32 [1.24, 1.40], p _trend <0.0001 for NEAP, PRAL and A:P, respectively). These results were not fully explained by other dietary factors including glycaemic load and dietary quality (HR [95% CI] for Q5 vs Q1: 1.21 [1.09, 1.33], p _trend <0.0001; 1.19 [1.08, 1.30] and 1.26 [1.17, 1.36], p _trend <0.0001 for NEAP, PRAL and A:P, respectively).

Conclusions/interpretation

This study suggests that higher diet-dependent acid load is associated with an increased risk of type 2 diabetes. This association is not fully explained by diabetes risk factors and overall diet quality.

     

Dietary acid load,insulin sensitivity and risk of type 2 diabetes in community-dwelling older men

Aims/hypothesis

We tested the hypothesis that dietary acid load may increase the risk of type 2 diabetes, and studied the association between acid load and insulin sensitivity as a possible mechanism involved.

Methods

An observational survey with prospective follow-up including 911 non-diabetic Swedish men aged 70–71 years was carried out. The gold standard euglycaemic–hyperinsulinaemic clamp technique and the OGTT were used to determine insulin sensitivity and beta cell function, respectively. Diabetes incidence was assessed during 18 years of follow-up. Renal function was estimated from serum cystatin C concentrations. Dietary acid load was calculated as potential renal acid load (PRAL) and net endogenous acid production (NEAP) algorithms from 7 day food records. Adequate dietary reporters were identified by Goldberg cut-offs.

Results

PRAL and NEAP were not associated with insulin sensitivity or beta cell function. Underlying kidney function or consideration of dietary adequate reporters did not modify these null findings. During follow-up, 115 new cases of diabetes were validated. Neither PRAL nor NEAP was associated with diabetes incidence.

Conclusions/interpretation

Our results do not support the hypothesis that dietary acid load influences insulin sensitivity, beta cell function or diabetes risk. Interventional studies modifying acid–base dietary intake are needed to further elucidate a possible role of acid load in the development of type 2 diabetes.     

Dietary dairy product intake and incident type 2 diabetes: a prospective study using dietary data from a 7-day food diary

Aim/hypothesis

The aim of this study was to investigate the association between total and types of dairy product intake and risk of developing incident type 2 diabetes, using a food diary.

Methods

A nested case-cohort within the EPIC-Norfolk Study was examined, including a random subcohort (n?=?4,000) and cases of incident diabetes (n?=?892, including 143 cases in the subcohort) followed-up for 11 years. Diet was assessed using a prospective 7-day food diary. Total dairy intake (g/day) was estimated and categorised into high-fat (≥3.9%) and low-fat (<3.9% fat) dairy, and by subtype into yoghurt, cheese and milk. Combined fermented dairy product intake (yoghurt, cheese, sour cream) was estimated and categorised into high- and low-fat. Prentice-weighted Cox regression HRs were calculated.

Results

Total dairy, high-fat dairy, milk, cheese and high-fat fermented dairy product intakes were not associated with the development of incident diabetes. Low-fat dairy intake was inversely associated with diabetes in age- and sex-adjusted analyses (tertile [T] 3 vs T1, HR 0.81 [95% CI 0.66, 0.98]), but further adjustment for anthropometric, dietary and diabetes risk factors attenuated this association. In addition, an inverse association was found between diabetes and low-fat fermented dairy product intake (T3 vs T1, HR 0.76 [95% CI 0.60, 0.99]; p _trend?=?0.049) and specifically with yoghurt intake (HR 0.72 [95% CI 0.55, 0.95]; p _trend?=?0.017) in multivariable adjusted analyses.

Conclusions/interpretation

Greater low-fat fermented dairy product intake, largely driven by yoghurt intake, was associated with a decreased risk of type 2 diabetes development in prospective analyses. These findings suggest that the consumption of specific dairy types may be beneficial for the prevention of diabetes, highlighting the importance of food group subtypes for public health messages.     

Circulating prolactin concentrations and risk of type 2 diabetes in US women

Aims/hypothesis

Prolactin, a multifunctional hormone, is involved in regulating insulin sensitivity and glucose homeostasis in experimental studies. However, whether circulating concentrations of prolactin are associated with risk of type 2 diabetes remains uncertain.

Methods

We analysed the prospective relationship between circulating prolactin concentrations and type 2 diabetes risk in the Nurses’ Health Study (NHS) and NHSII with up to 22 years of follow-up. Total plasma prolactin was measured using immunoassay in 8615 women free of type 2 diabetes and cardiovascular disease at baseline blood collection (NHS 1989–1990; NHSII 1996–1999) and a subset of 998 NHS women providing a second blood sample during 2000–2002. Baseline bioactive prolactin was measured in a subset of 2478 women using the Nb2 bioassay. HRs were estimated using Cox regression.

Results

A total of 699 incident type 2 diabetes cases were documented during 156,140 person-years of follow-up. Total plasma prolactin levels were inversely associated with type 2 diabetes risk; the multivariable HR comparing the highest with the lowest quartile was 0.73 (95% CI 0.55, 0.95; p_trend?=?0.02). The associations were similar by menopausal status and other risk factors (p_interaction?>?0.70). Additional adjustment for sex and growth hormones, adiponectin, and inflammatory and insulin markers did not significantly alter the results. The association of plasma bioactive prolactin with type 2 diabetes risk was non-significantly stronger than that of total prolactin (HR comparing extreme quartiles, 0.53 vs 0.81 among the subset of 2478 women, p_difference?=?0.11). The inverse association of total prolactin with type 2 diabetes was significant during the first 9 years after blood draw but waned linearly with time, whereas for bioactive prolactin, the inverse relationship persisted for a longer follow-up time after blood draw.

Conclusions/interpretation

A normally high circulating total prolactin concentration was associated with a lower type 2 diabetes risk within 9–10 years of follow-up since blood draw in US women. Our findings are consistent with experimental evidence, suggesting that among healthy women, prolactin within the biologically normal range may play a protective role in the pathogenesis of type 2 diabetes.

     

Impact of diabetes and glycaemic control on peripheral artery disease in Japanese patients with end-stage renal disease: long-term follow-up study from the beginning of haemodialysis

Aims/hypothesis

End-stage renal disease (ESRD) patients with diabetes have been regarded as being at the highest risk of cardiovascular disease. We therefore investigated the relationship between diabetes and the incidence of peripheral artery disease (PAD) in new haemodialysis patients.

Methods

We enrolled 1,513 ESRD patients who had just begun haemodialysis therapy. They were divided into two groups: those with (n?=?739) and those without diabetes (n?=?774). The endpoint was the development of PAD, defined as ankle brachial pressure index ≤0.9 or toe brachial pressure index <0.7 in patients with an ankle brachial pressure index >0.9.

Results

According to the Kaplan–Meier method, the 10?year event-free rate for development of PAD and lower limb amputation was significantly lower in the diabetes group than in the non-diabetes group (60.3% vs 82.8%, HR 2.99, 95% CI 2.27, 3.92, p?p?=?0.0005 for PAD and lower limb amputation, respectively). In patients with diabetes, quartile analysis of HbA_1c levels showed that the highest quartile group (≥6.8% [51?mmol/mol]) had significant development of PAD and lower limb amputation compared with lower quartile groups (PAD HR 1.63, 95% CI 1.17, 2.28, p?=?0.0038; lower limb amputation HR 2.99, 95% CI 1.17, 7.70, p?=?0.023).

Conclusions/interpretation

Diabetes was a strong predictor of PAD after initiation of haemodialysis therapy in patients with ESRD. In addition, higher HbA_1c levels were associated with increased risk of developing PAD and requiring limb amputation in such diabetic populations.     

HbA1c variability is associated with an increased risk of retinopathy requiring laser treatment in type 1 diabetes

Aims/hypothesis

This study aimed to investigate whether variation in long-term glycaemia in type 1 diabetes as measured by HbA_1c variability is associated with the cumulative incidence and risk of retinopathy requiring laser treatment.

Methods

The effect of HbA_1c variability was assessed in 2,019 Finnish Diabetic Nephropathy (FinnDiane) study patients. The patients were studied in two partially overlapping subcohorts with either verified first laser treatment (n?=?1,459) or retinopathy severity graded from ophthalmic records with the Early Treatment of Diabetic Retinopathy Study (ETDRS) scale (n?=?1,346). The ratio of intrapersonal SD and mean of serially measured HbA_1c was considered an estimate of HbA_1c variability.

Results

A subcohort of 1,459 patients did not have laser treatment prior to the first FinnDiane visit and 174 of these patients were treated during a mean follow-up period of 5.2?±?2.2 years. The 5 year cumulative incidence of laser treatment was 19% (95% CI 15, 24) in the highest quartile of HbA_1c variability and 10% (95% CI 7, 12) in the lowest quartile (p?<?0.001, Gray’s test) with a corresponding HR of 1.6 (95% CI 1.1, 2.5; p?=?0.02) adjusted for renal status, diabetes duration, mean HbA_1c, blood pressure, sex and number of HbA_1c measurements. In a subcohort of 1,346 patients, 434 patients had proliferative diabetic retinopathy (PDR). Patients in the highest quartile of HbA_1c variability had an increased risk of PDR compared with the lowest quartile (HR 1.7 [95% CI 1.3, 2.2]; p?<?0.001]).

Conclusions/interpretation

HbA_1c variability was associated with an increased cumulative incidence and risk of retinopathy requiring laser treatment in type 1 diabetes.     

Mediterranean diet and glycaemic load in relation to incidence of type 2 diabetes: results from the Greek cohort of the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)

Aims/hypothesis

The role of diet in the prevention of diabetes remains uncertain. The aim of this study was to investigate two different dietary aspects, i.e. adherence to the Mediterranean diet and glycaemic load (GL), in relation to diabetes occurrence.

Methods

We analysed data from the Greek cohort of the population-based European Prospective Investigation into Cancer and Nutrition (EPIC). From a total of 22,295 participants, actively followed for a median of 11.34 years, 2,330 cases of incident type 2 diabetes were recorded. All participants completed a validated, interviewer-administered semi-quantitative food frequency questionnaire at enrolment. From this information, we calculated a ten point Mediterranean diet score (MDS), reflecting adherence to the traditional Mediterranean diet, as well as the dietary GL. We estimated HRs and the corresponding 95% CIs of diabetes using Cox proportional hazards regression models adjusted for potential confounders.

Results

A higher MDS was inversely associated with diabetes risk (HR 0.88 [95% CI 0.78, 0.99] for MDS ≥6 vs MDS ≤3). GL was positively associated with diabetes (HR 1.21 [95% CI 1.05, 1.40] for the highest vs the lowest GL quartile). A significant protection of about 20% was found for a diet with a high MDS and a low GL.

Conclusions/interpretation

A low GL diet that also adequately adheres to the principles of the traditional Mediterranean diet may reduce the incidence of type 2 diabetes.     

Erythrocyte trans-fatty acids, type 2 diabetes and cardiovascular risk factors in middle-aged and older Chinese individuals

Aims/hypothesis

Few data are available about intakes and food sources of trans-fatty acids (TFAs) or their associations with cardiometabolic outcomes in Asian people who consume a prudent diet but are experiencing rapid nutritional transitions. We aimed to investigate the relationships between TFA biomarkers and type 2 diabetes and cardiovascular risk factors in Chinese individuals.

Methods

Erythrocyte fatty acids were measured by gas chromatography among 3,107 men and women (50–70?years) recruited from urban and rural areas in Beijing and Shanghai, China.

Results

Total trans-18:1 and two trans-18:2 isomers were detected and accounted for 0.37% of the total fatty acids in the erythrocytes. Concentrations of TFAs were higher in women than men, and in urban than rural residents. Of the TFAs, trans-18:1, but not trans-18:2, showed a modest association with dairy consumption (β?=?0.27), but not with other foods. After adjustment for BMI, social-demographic, lifestyle and dietary factors and other TFAs, erythrocyte trans-18:1 was shown to be associated with a lower risk of type 2 diabetes (OR comparing extreme [first and fourth] quartiles 0.68, 95% CI 0.48, 0.97, p _trend?=?0.02), as well as 20–50% lower odds of central obesity, dyslipidaemia, hyperglycaemia, insulin resistance and chronic inflammation. In contrast, trans-18:2 fatty acids were positively associated with high triacylglycerol (p _trend?p _trend?=?0.03) levels, but not with diabetes and other cardiometabolic risk factors.

Conclusions/interpretation

Among middle-aged and older Chinese individuals with overall low erythrocyte TFAs levels, trans-18:1 might serve as a marker of dairy intake. Higher trans-18:1 levels were associated with a lower risk of type 2 diabetes, whereas higher trans-18:2 levels were associated with dyslipidaemia.     

Association of the pattern recognition molecule H-ficolin with incident microalbuminuria in an inception cohort of newly diagnosed type 1 diabetic patients: an 18 year follow-up study

Aims/hypothesis

Increasing evidence links complement activation through the lectin pathway to diabetic nephropathy. Adverse complement recognition of proteins modified by glycation has been suggested to trigger complement auto-attack in diabetes. H-ficolin (also known as ficolin-3) is a pattern recognition molecule that activates the complement cascade on binding to glycated surfaces, but the role of H-ficolin in diabetic nephropathy is unknown. We aimed to investigate the association between circulating H-ficolin levels and the incidence of microalbuminuria in type 1 diabetes.

Methods

We measured baseline H-ficolin levels and tracked the development of persistent micro- and macroalbuminuria in a prospective 18 year observational follow-up study of an inception cohort of 270 patients with newly diagnosed type 1 diabetes.

Results

Patients were followed for a median of 18 years (range 1–22 years). During follow-up, 75 patients developed microalbuminuria, defined as a persistent urinary albumin excretion rate (UAER) above 30 mg/24 h. When H-ficolin levels were divided into quartile groups an unadjusted Cox proportional hazards regression model showed a significant association with risk of incident microalbuminuria during follow-up (HR, fourth vs first quartile, 2.45; 95% CI 1.24, 4.85) (p?=?0.01). This remained significant after adjusting for HbA_1c, systolic blood pressure, smoking and baseline UAER (HR 2.09; 95% CI 1.03, 4.25) (p?=?0.04).

Conclusions/interpretation

Our data suggest that high levels of the complement activating molecule H-ficolin are associated with an increased risk of future progression to microalbuminuria in patients with newly diagnosed type 1 diabetes.     

The link between family history and risk of type 2 diabetes is not explained by anthropometric, lifestyle or genetic risk factors: the EPIC-InterAct study

Aims/hypothesis

Although a family history of type 2 diabetes is a strong risk factor for the disease, the factors mediating this excess risk are poorly understood. In the InterAct case-cohort study, we investigated the association between a family history of diabetes among different family members and the incidence of type 2 diabetes, as well as the extent to which genetic, anthropometric and lifestyle risk factors mediated this association.

Methods

A total of 13,869 individuals (including 6,168 incident cases of type 2 diabetes) had family history data available, and 6,887 individuals had complete data on all mediators. Country-specific Prentice-weighted Cox models were fitted within country, and HRs were combined using random effects meta-analysis. Lifestyle and anthropometric measurements were performed at baseline, and a genetic risk score comprising 35 polymorphisms associated with type 2 diabetes was created.

Results

A family history of type 2 diabetes was associated with a higher incidence of the condition (HR 2.72, 95% CI 2.48, 2.99). Adjustment for established risk factors including BMI and waist circumference only modestly attenuated this association (HR 2.44, 95% CI 2.03, 2.95); the genetic score alone explained only 2% of the family history-associated risk of type 2 diabetes. The greatest risk of type 2 diabetes was observed in those with a biparental history of type 2 diabetes (HR 5.14, 95% CI 3.74, 7.07) and those whose parents had been diagnosed with diabetes at a younger age (<50 years; HR 4.69, 95% CI 3.35, 6.58), an effect largely confined to a maternal family history.

Conclusions/interpretation

Prominent lifestyle, anthropometric and genetic risk factors explained only a marginal proportion of the excess risk associated with family history, highlighting the fact that family history remains a strong, independent and easily assessed risk factor for type 2 diabetes. Discovering factors that will explain the association of family history with type 2 diabetes risk will provide important insight into the aetiology of type 2 diabetes.     

Erythrocyte membrane docosapentaenoic acid levels are associated with islet autoimmunity: the Diabetes Autoimmunity Study in the Young

Aims/hypotheses

We previously reported that lower n-3 fatty acid intake and levels in erythrocyte membranes were associated with increased risk of islet autoimmunity (IA) but not progression to type 1 diabetes in children at increased risk for diabetes. We hypothesise that specific n-3 fatty acids and genetic markers contribute synergistically to this increased risk of IA in the Diabetes Autoimmunity Study in the Young (DAISY).

Methods

DAISY is following 2,547 children at increased risk for type 1 diabetes for the development of IA, defined as being positive for glutamic acid decarboxylase (GAD)₆₅, IA-2 or insulin autoantibodies on two consecutive visits. Using a case-cohort design, erythrocyte membrane fatty acids and dietary intake were measured prospectively in 58 IA-positive children and 299 IA-negative children.

Results

Lower membrane levels of the n-3 fatty acid, docosapentaenoic acid (DPA), were predictive of IA (HR 0.23; 95% CI 0.09, 0.55), while α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not, adjusting for HLA and diabetes family history. We examined whether the effect of dietary intake of the n-3 fatty acid ALA on IA risk was modified by fatty acid elongation and desaturation genes. Adjusting for HLA, diabetes family history, ethnicity, energy intake and questionnaire type, ALA intake was significantly more protective for IA in the presence of an increasing number of minor alleles at FADS1 rs174556 (p_interaction?=?0.017), at FADS2 rs174570 (p_interaction?=?0.016) and at FADS2 rs174583 (p_interaction?=?0.045).

Conclusions/interpretation

The putative protective effect of n-3 fatty acids on IA may result from a complex interaction between intake and genetically controlled fatty acid desaturation.     

Association between dietary meat consumption and incident type 2 diabetes: the EPIC-InterAct study

Aims/hypothesis

A diet rich in meat has been reported to contribute to the risk of type 2 diabetes. The present study aims to investigate the association between meat consumption and incident type 2 diabetes in the EPIC-InterAct study, a large prospective case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

Methods

During 11.7 years of follow-up, 12,403 incident cases of type 2 diabetes were identified among 340,234 adults from eight European countries. A centre-stratified random subsample of 16,835 individuals was selected in order to perform a case-cohort design. Prentice-weighted Cox regression analyses were used to estimate HR and 95% CI for incident diabetes according to meat consumption.

Results

Overall, multivariate analyses showed significant positive associations with incident type 2 diabetes for increasing consumption of total meat (50 g increments: HR 1.08; 95% CI 1.05, 1.12), red meat (HR 1.08; 95% CI 1.03, 1.13) and processed meat (HR 1.12; 95% CI 1.05, 1.19), and a borderline positive association with meat iron intake. Effect modifications by sex and class of BMI were observed. In men, the results of the overall analyses were confirmed. In women, the association with total and red meat persisted, although attenuated, while an association with poultry consumption also emerged (HR 1.20; 95% CI 1.07, 1.34). These associations were not evident among obese participants.

Conclusions/interpretation

This prospective study confirms a positive association between high consumption of total and red meat and incident type 2 diabetes in a large cohort of European adults.     

Decreased insulin secretion and increased risk of type 2 diabetes associated with allelic variations of the WFS1 gene: the Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study

Aims/hypothesis

We investigated associations of allelic variations in the WFS1 gene with insulin secretion and risk of type 2 diabetes in a general population prospective study.

Methods

We studied 5,110 unrelated French men and women who participated in the prospective Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study. Additional cross-sectional analyses were performed on 4,472 French individuals with type 2 diabetes and 3,065 controls. Three single nucleotide polymorphisms (SNPs) were genotyped: rs10010131, rs1801213/rs7672995 and rs734312.

Results

We observed statistically significant associations between the major alleles of the three variants and prevalent type 2 diabetes in the DESIR cohort at baseline. Cox analyses showed an association between the G-allele of rs10010131 and incident type 2 diabetes (HR 1.34, 95% CI 1.08?C1.70, p?=?0.007). Similar results were observed for the G-allele of rs1801213 and the A-allele of rs734312. The GGA haplotype was associated with an increased risk of diabetes as compared with the ACG haplotype (HR 1.26, 95% CI 1.04?C1.42, p?=?0.02). We also observed statistically significant associations of the three SNPs with plasma glucose, HbA_1c levels and insulin secretion at baseline and throughout the study in individuals with type 2 diabetes or at risk of developing diabetes. However, no association was observed in those who remained normoglycaemic at the end of the follow-up. Associations between the three variants and type 2 diabetes were replicated in cross-sectional studies of type 2 diabetic patients in comparison with a non-diabetic control group.

Conclusions/interpretation

The most frequent haplotype at the haplotype block containing the WFS1 gene modulated insulin secretion and was associated with an increased risk of type 2 diabetes.     

Shared genetic influence of BMI, physical activity and type 2 diabetes: a twin study

Aims/hypothesis

The aim of this study was to examine the long-term associations of BMI and physical activity with type 2 diabetes, and to estimate shared genetic components of these traits.

Methods

We used data from the Swedish Twin Registry on 23,539 twins born 1886–1958 who answered questionnaires between 1967 and 1972 and were followed up until 1998. The risk of type 2 diabetes in relation to BMI and physical activity was assessed by Cox regression. Structural equation models were used to estimate genetic and environmental variance components and genetic correlations.

Results

The risk of type 2 diabetes increased with BMI (HR 1.32 [95% CI 1.29, 1.35] per kg/m²) and decreased with physical activity (HR 0.56 [95% CI 0.39, 0.80] for high vs low). Heritability was estimated to be 77% (95% CI 54%, 83%) for type 2 diabetes, 65% (95% CI 58%, 73%) for BMI, and 57% (95% CI 47%, 67%) for physical activity. The genetic correlation with type 2 diabetes was 0.43 (95% CI 0.31, 0.58) for BMI and ?0.23 (95% CI ?0.46, 0.02) for physical activity, implying that 18% (95% CI 9%, 34%) of the genetic influence on type 2 diabetes is shared with BMI and 5% (95% CI 0%, 20%) with physical activity.

Conclusions/interpretation

Indications of shared genetic effects are found for BMI and type 2 diabetes, which suggests that these traits are partly influenced by the same genetic factors. In contrast, our findings suggest that the genes related to physical activity are essentially different from those associated with type 2 diabetes.     

Association of non-HDL-C/HDL-C ratio and its dynamic changes with incident type 2 diabetes mellitus: The Rural Chinese Cohort Study

BackgroundWe aimed to evaluate the association of the ratio of non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol (non-HDL-C/HDL-C) and its dynamic changes with incident type 2 diabetes mellitus (T2DM).MethodsA total of 11,487 nondiabetic participants ≥18 years old in rural China were recruited in 2007–2008 and followed up in 2013–2014. A Cox proportional-hazards model was used to assess the risk of incident T2DM by quartiles of baseline non-HDL-C/HDL-C ratio and dynamic absolute and relative changes in non-HDL-C/HDL-C ratio, estimating hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsRisk of incident T2DM was increased with quartiles 2, 3, and 4 versus quartile 1 of baseline non-HDL-C/HDL-C ratio (HR 1.46 [95% CI 1.08–1.98], 1.51 [1.12–2.03], and 2.16 [1.62–2.88], P_trend < 0.001). As compared with stable non-HDL-C/HDL-C ratio during follow-up, an absolute gain in non-HDL-C/HDL-C ratio was associated with increased risk of T2DM (HR 1.67 [95% CI 1.25–2.24] for quartile 3 and 2.00 [1.52–2.61] for quartile 4). A relative increase in non-HDL-C/HDL-C ratio was also associated with increased risk of T2DM (HR 1.56 [95% CI 1.19–2.04] for quartile 3 and 1.97 [1.49–2.60] for quartile 4). Subgroup analyses showed that the association of non-HDL-C/HDL-C ratio with T2DM risk remained consistent.ConclusionsIncreased non-HDL-C/HDL-C ratio is associated with increased risk of incident T2DM among rural Chinese adults, so the index may be an important indicator for identifying individuals at T2DM risk.     

Intensive glucose control and macrovascular outcomes in type 2 diabetes

Aims/hypothesis

Improved glucose control in type 2 diabetes is known to reduce the risk of microvascular events. There is, however, continuing uncertainty about its impact on macrovascular disease. The aim of these analyses was to generate more precise estimates of the effects of more-intensive, compared with less-intensive, glucose control on the risk of major cardiovascular events amongst patients with type 2 diabetes.

Methods

A prospectively planned group-level meta-analysis in which characteristics of trials to be included, outcomes of interest, analyses and subgroup definitions were all pre-specified.

Results

A total of 27,049 participants and 2,370 major vascular events contributed to the meta-analyses. Allocation to more-intensive, compared with less-intensive, glucose control reduced the risk of major cardiovascular events by 9% (HR 0.91, 95% CI 0.84–0.99), primarily because of a 15% reduced risk of myocardial infarction (HR 0.85, 95% CI 0.76–0.94). Mortality was not decreased, with non-significant HRs of 1.04 for all-cause mortality (95% CI 0.90–1.20) and 1.10 for cardiovascular death (95% CI 0.84–1.42). Intensively treated participants had significantly more major hypoglycaemic events (HR 2.48, 95% CI 1.91–3.21). Exploratory subgroup analyses suggested the possibility of a differential effect for major cardiovascular events in participants with and without macrovascular disease (HR 1.00, 95% CI 0.89–1.13, vs HR 0.84, 95% CI 0.74–0.94, respectively; interaction p?=?0.04).

Conclusions/interpretation

Targeting more-intensive glucose lowering modestly reduced major macrovascular events and increased major hypoglycaemia over 4.4 years in persons with type 2 diabetes. The analyses suggest that glucose-lowering regimens should be tailored to the individual.     

Long-term exposure to traffic-related air pollution and diabetes-associated mortality: a cohort study

Aims/hypothesis

The aim of this study was to investigate whether air pollution from traffic at a residence is associated with mortality related to type 1 or type 2 diabetes.

Methods

We followed up 52,061 participants in the Danish Diet, Cancer and Health cohort for diabetes-related mortality in the nationwide Register of Causes of Death, from baseline in 1993–1997 up to the end of 2009, and traced their residential addresses since 1971 in the Central Population Registry. We used dispersion-modelled concentration of nitrogen dioxide (NO₂) since 1971 and amount of traffic at the baseline residence as indicators of traffic-related air pollution and used Cox regression models to estimate mortality-rate ratios (MRRs) with adjustment for potential confounders.

Results

Mean levels of NO₂ at the residence since 1971 were significantly associated with mortality from diabetes. Exposure above 19.4 μg/m³ (upper quartile) was associated with a MRR of 2.15 (95% CI 1.21, 3.83) when compared with below 13.6 μg/m³ (lower quartile), corresponding to an MRR of 1.31 (95% CI 0.98, 1.76) per 10 μg/m³ NO₂ after adjustment for potential confounders.

Conclusions/interpretation

This study suggests that traffic-related air pollution is associated with mortality from diabetes. If confirmed, reduction in population exposure to traffic-related air pollution could be an additional strategy against the global public health burden of diabetes.     

Pleiotropic effects of HNF1A rs1183910 in a population-based study of 60,283 individuals

Aims/hypothesis

According to genome-wide association studies (GWAS) a locus in the HNF1A gene has pleiotropic effects on several metabolic traits. In a large single-centre study we used the intronic variant rs1183910 located in a region with no or low recombination rate as an instrument for the HNF1A locus to evaluate pleiotropic effects of this locus on the risk of developing type 2 diabetes, as well as on body composition and levels of non-fasting glucose, lipids, acute-phase reactants, and biomarkers of liver and pancreas function.

Methods

We investigated 60,283 individuals from the Danish general population who were all examined in the same laboratory, comprising the Copenhagen General Population Study.

Results

We confirm previous GWAS findings, namely that the minor rs1183910 A allele is associated with an increased risk of developing type 2 diabetes (p _trend?=?0.003), decreased levels of C-reactive protein (CRP; p _trend?=?6?×?10^?76) and γ-glutamyltransferase (p _trend?=?4?×?10^?48), and increased levels of total cholesterol (p _trend?=?3?×?10^?10) and LDL-cholesterol (p _trend?=?3?×?10^?11). For the first time, we report that the minor rs1183910 A allele is associated with increased levels of non-fasting plasma glucose (p _trend?=?3?×?10^?5), apolipoprotein B (ApoB; p _trend?=?1?×?10^?4) and alkaline phosphatase (p _trend?=?5?×?10^?14), and decreased levels of bilirubin (p _trend?=?3?×?10^?5). Our results suggest that the association with increased risk of type 2 diabetes is driven by high non-fasting glucose levels.

Conclusions/interpretation

The minor rs1183910 A allele prompts a potential adverse metabolic profile with increased levels of non-fasting glucose, total cholesterol, LDL-cholesterol, ApoB, and alkaline phosphatase, but simultaneously has potential beneficial effects through decreased levels of CRP, γ-glutamyltransferase and bilirubin.     

Breast-feeding and maternal risk of type 2 diabetes: a prospective study and meta-analysis

Aims/hypothesis

We aimed to examine the association between breast-feeding and maternal risk of type 2 diabetes and to investigate whether this association is mediated by anthropometric and biochemical factors.

Methods

A case–cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study between 1994 and 2005 including 1,262 childbearing women (1,059 in a random sub-cohort and 203 incident cases) mainly aged between 35 and 64 years at baseline was applied. Self-reported lifetime duration of breast-feeding was assessed by questionnaire. Blood samples were used for biomarker measurement (HDL-cholesterol, triacylglycerols, C-reactive protein, fetuin-A, γ-glutamyltransferase, adiponectin). A systematic literature search and meta-analysis was conducted of prospective cohort studies investigating breast-feeding and risk of type 2 diabetes.

Results

The HR for each additional 6 months of breast-feeding was 0.73 (95% CI 0.56, 0.94) in EPIC-Potsdam. Meta-analysis of three previous prospective studies and the current study revealed an inverse association between breast-feeding duration and risk of diabetes (pooled HR for lifetime breast-feeding duration of 6–11 months compared with no breast-feeding 0.89; 95% CI 0.82, 0.97). Adjustment for BMI and waist circumference attenuated the association (HR per six additional months in EPIC-Potsdam 0.80; 95% CI 0.61, 1.04). Further controlling for potentially mediating biomarkers largely explained this association (HR 0.89; 95% CI 0.68, 1.16).

Conclusions/interpretation

Longer duration of breast-feeding may be related to a lower risk of diabetes. This potentially protective effect seems to be reflected by a more favourable metabolic profile; however, the role of body weight as a mediator or confounder remains uncertain.