Increased Risk Of Type 2 Diabetes Research Articles

Plasma ferritin, C-reactive protein, and risk of incident type 2 diabetes in Singapore Chinese men and women.

Ferritin is postulated to be involved in diabetogenesis as a marker of iron stores. We prospectively examined the association between ferritin levels and type 2 diabetes (T2D) risk in a Chinese population. Plasma ferritin concentrations were assayed among 485 diabetes cases and 485 controls nested within the Singapore Chinese Health Study. Cases and controls were matched on age, gender, date of blood collection, and dialect group. Participants were free of diagnosed diabetes, cardiovascular disease, and cancer at blood collection (1999-2004). Incident self-reported T2D cases were identified at follow-up II interview (2006-2010). Multivariable conditional logistic regression models were used to compute the odds ratio (OR) and the corresponding 95% confidence intervals (CIs). After adjusting for T2D risk factors, including high-sensitivity C-reactive protein (hs-CRP), adiponectin, triglycerides, HDL cholesterol and alanine aminotransferase, the OR comparing the highest versus lowest quartile of ferritin levels was 1.87 (95% CI 1.10-3.19) (P-trend=0.004). When the analysis was limited to participants with hs-CRP<1.5mg/L (below median; n=482), the OR comparing extreme quartiles of ferritin levels was 1.16 (95% CI 0.62-2.16; P-trend=0.63); while the corresponding OR was 2.51 (95% CI 1.31-4.79; P-trend<0.001) when confined to those with hs-CRP≥1.5mg/L (n=488; P-interaction=0.022). Compared to participants with both ferritin and hs-CRP levels below median, those with both levels above median had markedly increased T2D risk (P-interaction for multiplicative scale=0.037). The elevation of blood ferritin levels, in the presence of raised hs-CRP, was significantly associated with increased risk of T2D.

Abstract P055: Cooking Methods for Meats and Risk of Type 2 Diabetes: Results From Three Prospective Cohort Studies

Importance: The role of high-temperature cooking methods (broiling, barbequing, or roasting) on the association of meat consumption with risk of type 2 diabetes (T2D) is unknown. Objective: To examine cooking methods for meats (chicken, fish, and red meat) in relation to T2D risk among men and women who consumed meats regularly (≥2 servings/week). Design, Setting, and Participants: The prospective studies included 52,720 women from the Nurses’ Health Study (NHS 1996-2012), 60,809 women from the Nurses’ Health Study II (NHS II 2001-2013), and 24,679 men from the Health Professionals Follow-Up Study (HPFS 1996-2012) who were free of diabetes, cardiovascular disease, and cancer at baseline. Main Outcomes and Measures: Incident cases of T2D were identified through self-report and confirmed by validated supplementary questionnaires. Results: We documented 7,893 incident T2D cases during 1.74 million person-years of follow up. After multivariate adjustment of demographics, lifestyle factors, and total intake of chicken, fish, and red meat, a higher frequency of high-temperature cooking of meats was independently associated with an increased T2D risk. When comparing &gt;15 times/month with &lt;4 times/month, the hazard ratios (HRs) and 95% confidence intervals (CIs) of T2D were 1.36 (1.22, 1.52; P trend&lt;0.001) in NHS, 1.82 (1.56, 2.12; P trend&lt;0.001) in NHS II, and 1.10 (0.90, 1.36; P trend=0.78) in HPFS; and the pooled HR was 1.43 (1.32, 1.56; P trend &lt;0.001). The results remained significant when analyzing by source of meats; and the pooled HRs (95% CI) were 1.64 (1.49, 1.81; P trend &lt;0.001) for red meat and 1.22 (1.13, 1.32; P trend &lt;0.001) for white meat. In addition, a higher frequency of high-temperature cooking of meats was associated with greater weight gain and higher risk of obesity, especially among women. Mediational analyses showed that the significant associations of high-temperature cooking with T2D risk were partially explained by changes in body mass index (41.6% in NHS and 46.6% in NHS II) in women. Conclusions and Relevance: Our results suggest that, independent of meat consumption, high-temperature cooking methods may further increase diabetes risk, especially in women.

Fatty acid consumption and incident type 2 diabetes: an 18-year follow-up in the female E3N (Etude Epidémiologique auprès des femmes de la Mutuelle Générale de l'Education Nationale) prospective cohort study.

We evaluated the association between dietary estimates of fatty acid (FA) consumption and type 2 diabetes (T2D) risk in the French E3N (Etude Epidémiologique auprès des femmes de la Mutuelle Générale de l'Education Nationale) cohort. In total, 71 334 women without diabetes at baseline were followed up from 1993 to 2011. Diabetes was identified using questionnaires and drug-reimbursement claims, and incident cases were validated. FA consumption in 1993 was estimated from a validated dietary questionnaire. Cox regression estimated hazard ratios (HR) and 95 % CI of diabetes risk, comparing the upper tertile group with the lowest. High n-3 PUFA consumption was associated with T2D even after adjustment for confounders, including other FA and BMI (HR 1·26; 95 % CI 1·13, 1·41; upper tertile compared with lowest). Upon stratification by overweight (BMI≥25 kg/m2)/non-overweight, a positive association between total PUFA consumption and T2D was observed, but it was restricted to non-overweight women (HR 1·22; 95 % CI 1·05, 1·42), whereas n-3 PUFA consumption was associated with increased T2D risk in both BMI strata (BMI<25 kg/m2: HR 1·19; 95 % CI 1·01, 1·40 and BMI≥25 kg/m2: HR 1·38; 95 % CI 1·20, 1·59). Within the n-3 PUFA, high DPA (HR 1·41; 95 % CI 1·23, 1·63) and α-linolenic acid (ALA) intakes were associated with increased T2D risk, but the effects of ALA were restricted to overweight women (HR 1·17; 95 % CI 1·01, 1·36). Within the n-6 PUFA, only arachidonic acid (AA) intake was associated with T2D risk (HR 1·49; 95 % CI 1·33, 1·66). The associations with DPA and AA persisted even after adjustment of their principal source in this cohort, the consumption of meat. The effects of PUFA are heterogeneous within the FA group. Intake of DPA and AA may contribute to T2D development.

Association between liver enzymes and incident type 2 diabetes in Singapore Chinese men and women.

AimsTo assess the association between liver enzymes and the risk of type 2 diabetes (T2D) in a Chinese population.MethodsA nested case–control study comprising 571 T2D cases and 571 matched controls was conducted within the Singapore Chinese Health Study. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) were quantified in baseline plasma collected from them, while γ-glutamyltransferase (GGT) was assayed among 255 T2D cases with baseline hemoglobin A1c <6.5% and 255 matched controls. Participants were free of diagnosed diabetes, cardiovascular disease, and cancer at blood collections (1999–2004). Incident self-reported T2D cases were identified at follow-up II interview (2006–2010). Controls were matched to cases on age, sex, dialect group, and date of blood collection.ResultsHigher levels of ALT and GGT were significantly associated with increased risk of T2D (p for trend <0.001 for ALT, p for trend=0.03 for GGT), and the ORs (95% CIs) comparing highest versus lowest tertiles of ALT and GGT were 2.00 (1.01 to 3.96) and 2.38 (1.21 to 4.66), respectively. A null association was observed for AST, ALP, and LDH with T2D risk. Adding GGT (<23 vs ≥23 IU/L) or ALT (<21 vs ≥21 IU/L) to a prediction model resulted in significant gain in net reclassification improvement and integrated discrimination improvement of T2D prediction (all p<0.001).ConclusionsHigher levels of GGT and ALT are associated with increased T2D risk. GGT ≥23 IU/L and ALT ≥21 IU/L may identify people at higher risk of developing T2D in this Chinese population.

PAX4 R192H and P321H polymorphisms in type 2 diabetes and their functional defects.

We have previously identified PAX4 mutations causing MODY9 and a recent genome-wide association study reported a susceptibility locus of type 2 diabetes (T2D) near PAX4. In this study, we aim to investigate the association between PAX4 polymorphisms and T2D in Thai patients and examine functions of PAX4 variant proteins. PAX4 rs2233580 (R192H) and rs712701 (P321H) were genotyped in 746 patients with T2D and 562 healthy normal control subjects by PCR and restriction-fragment length polymorphism method. PAX4 variant proteins were investigated for repressor function on human insulin and glucagon promoters and for cell viability and apoptosis upon high glucose exposure. Genotype and allele frequencies of PAX4 rs2233580 were more frequent in patients with T2D than in control subjects (P=0.001 and 0.0006, respectively) with odds ratio of 1.66 (P=0.001; 95% confidence interval, 1.22-2.27). PAX4 rs712701 was not associated with T2D but it was in linkage disequilibrium with rs2233580. The 192H/321H (A/A) haplotype was more frequent in T2D patients than in controls (9.5% vs 6.6%; P=0.009). PAX4 R192H, but not PAX4 P321H, impaired repression activities on insulin and glucagon promoters and decreased transcript levels of genes required to maintain β-cell function, proliferation and survival. Viability of β-cell was reduced under glucotoxic stress condition for the cells overexpressing either PAX4 R192H or PAX4 P321H or both. Thus these PAX4 polymorphisms may increase T2D risk by defective transcription regulation of target genes and/or decreased β-cell survival in high glucose condition.

Reproductive factors and risk of type 2 diabetes in an occupational cohort of Chinese women

AimsHormonal milieu has long been known to play an important role in the development of type 2 diabetes (T2D). The aims of this study are to investigate the roles of menstrual and reproductive factors in relation to T2D risk in an occupational cohort of Chinese women; and to explore the role of endogenous estrogen in T2D development. MethodsWe conducted a cross-sectional analysis of baseline data from 16114 women (11051 premenopausal and 5063 postmenopausal) aged ≥20years who participated in the ongoing prospective occupational cohort study. Multivariable logistic regressions were modeled to evaluate the associations of reproductive factors with T2D risk. ResultsEarly menarche at age (≤12 versus 15–16 years) was associated with increased T2D risk (odds ratio [OR]: 1.60, 95% confidence interval [CI]: 1.16–2.22). After multiple adjustment including age, BMI and occupation, postmenopausal status was positively associated with T2D risk (OR: 1.54, 95% CI: 1.10–2.14). Reproductive life span was significantly associated with T2D risk (P=0.02), albeit displaying a U-shape relationship. Similarly, age at menopause was also associated with T2D risk in the same U-shaped as with reproductive life span (P=0.03). Further, years since menopause (P=0.003), but not history of cycle regularity and hormone use, was associated with increased T2D risk. ConclusionReproductive factors were associated with T2D supporting the notion that either a short or prolonged exposure to endogenous estrogen affects T2D risk in Chinese women. Reproductive factors should be added to risk stratification when counseling women about their risk of developing diabetes.

Impact of Common Diabetes Risk Variant in MTNR1B on Sleep, Circadian, and Melatonin Physiology.

The risk of type 2 diabetes (T2D) is increased by abnormalities in sleep quantity and quality, circadian alignment, and melatonin regulation. A common genetic variant in a receptor for the circadian-regulated hormone melatonin (MTNR1B) is associated with increased fasting blood glucose and risk of T2D, but whether sleep or circadian disruption mediates this risk is unknown. We aimed to test if MTNR1B diabetes risk variant rs10830963 associates with measures of sleep or circadian physiology in intensive in-laboratory protocols (n = 58–96) or cross-sectional studies with sleep quantity and quality and timing measures from self-report (n = 4,307–10,332), actigraphy (n = 1,513), or polysomnography (n = 3,021). In the in-laboratory studies, we found a significant association with a substantially longer duration of elevated melatonin levels (41 min) and delayed circadian phase of dim-light melatonin offset (1.37 h), partially mediated through delayed offset of melatonin synthesis. Furthermore, increased T2D risk in MTNR1B risk allele carriers was more pronounced in early risers versus late risers as determined by 7 days of actigraphy. Our results provide the surprising insight that the MTNR1B risk allele influences dynamics of melatonin secretion, generating a novel hypothesis that the MTNR1B risk allele may extend the duration of endogenous melatonin production later into the morning and that early waking may magnify the diabetes risk conferred by the risk allele.

Enteroviruses and Type 1 Diabetes: Candidate Genes Linked With Innate Immune Response

In addition to HLA associated genetic predisposition, the role of exogenous factors in the development of type 1 diabetes (T1D) is well admitted. Since many decades, accumulating evidence strongly has supported an association between enteroviruses (EV) and T1D (Hober and Sauter, 2010). Moreover, the potential mechanisms underlying this enteroviral pathogenesis are getting better understood, and may also be linked to background susceptibility.

Can we ever really tackle diabetes in ethnic minorities?

Can we ever really tackle diabetes in ethnic minorities?

ADCY5 gene expression in adipose tissue is related to obesity in men and mice.

Genome wide association studies revealed an association of the single nucleotide polymorphism rs11708067 within the ADCY5 gene—encoding adenylate cyclase 5—with increased type 2 diabetes (T2D) risk and higher fasting glucose. However, it remains unclear whether the association between ADCY5 variants and glycemic traits may involve adipose tissue (AT) related mechanisms. We therefore tested the hypothesis that ADCY5 mRNA expression in human and mouse AT is related to obesity, fat distribution, T2D in humans and high fat diet (HFD) in mice. We measured ADCY5 mRNA expression in paired samples of visceral and subcutaneous adipose tissue from 244 individuals with a wide range of body weight and parameters of hyperglycemia, which have been genotyped for rs11708067. In addition, AT ADCY5 mRNA was assessed in C57BL/6NTac which underwent a 10 weeks standard chow (n = 6) or high fat diet (HFD, n = 6). In humans, visceral ADCY5 expression is significantly higher in obese compared to lean individuals. ADCY5 expression correlates with BMI, body fat mass, circulating leptin, fat distribution, waist and hip circumference, but not with fasting plasma glucose and HbA1c. Adcy5 expression in mouse AT is significantly higher after a HFD compared to chow (p<0.05). Importantly, rs11708067 is not associated with ADCY5 mRNA expression levels in either fat depot in any of the genetic models tested. Our results suggest that changes in AT ADCY5 expression are related to obesity and fat distribution, but not with impaired glucose metabolism and T2D. However, altered ADCY5 expression in AT does not seem to be the mechanism underlying the association between rs11708067 and increased T2D risk.

Daycare attendance, breastfeeding, and the development of type 1 diabetes: the diabetes autoimmunity study in the young.

Background. The hygiene hypothesis attributes the increased incidence of type 1 diabetes (T1D) to a decrease of immune system stimuli from infections. We evaluated this prospectively in the Diabetes Autoimmunity Study in the Young (DAISY) by examining daycare attendance during the first two years of life (as a proxy for infections) and the risk of T1D. Methods. DAISY is a prospective cohort of children at increased T1D risk. Analyses were limited to 1783 children with complete daycare and breastfeeding data from birth to 2 years of age; 58 children developed T1D. Daycare was defined as supervised time with at least one other child at least 3 times a week. Breastfeeding duration was evaluated as a modifier of the effect of daycare. Cox proportional hazards regression was used for analyses. Results. Attending daycare before the age of 2 years was not associated with T1D risk (HR: 0.89; CI: 0.54–1.47) after adjusting for HLA, first degree relative with T1D, ethnicity, and breastfeeding duration. Breastfeeding duration modified this association, where daycare attendance was associated with increased T1D risk in nonbreastfed children and a decreasing T1D risk with increasing breastfeeding duration (interaction P value = 0.02). Conclusions. These preliminary data suggest breastfeeding may modify the effect of daycare on T1D risk.

Statin-Induced Insulin Resistance Through Inflammasome Activation: Sailing Between Scylla and Charybdis

Elevated LDL cholesterol is an independent risk factor for cardiovascular disease (CVD), and current clinical guidelines recommend aggressive reduction as the preferred course of treatment (1). Type 2 diabetes (T2D) also is a major and independent risk factor for development of CVD (2). A plethora of clinical data exists substantiating the beneficial effects of treatment with inhibitors of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductases—commonly known as statins—on cardiovascular morbidity and mortality in both nondiabetic people and those with T2D (3). While statin therapy clearly reduces cardiovascular events, accumulating evidence indicates that statins also may confer increased risk for T2D (4). Recent analyses of both clinical trials and population-based cohort studies suggest that the cardiovascular benefits of statin therapy outweigh the risk of developing T2D (5,6). Nevertheless, findings that suggest increased incidence of T2D in some high-risk patients (e.g., those with elevated fasting glucose [5]) or in certain populations (e.g., postmenopausal women [7]) may call for greater caution in statin use, particularly at a time when its over-the-counter availability is being considered (8). Given the overwhelming consensus from both meta-analyses and prospective studies that statin treatment can result in an increased risk of developing T2D, it is critical to identify the underlying causes of this unfavorable side effect. It has been suggested that statins increase T2D risk by impairing β-cell insulin secretion and promoting insulin resistance (9), but the precise molecular mechanisms are still unknown. Numerous studies have demonstrated intimate involvement of the innate immune system in both obesity and the pathogenesis of T2D (10,11). In recent years, pattern recognition receptors of the innate immune system, such as Toll-like receptors and Nod-like receptors (NLRs), have been increasingly recognized as links between immune function and metabolism (12,13). The NLR family, pyrin domain containing 3 …

Abstract 593: ApoB-Lipoprotein Association With Insulin Resistance and Hyperinsulinemia: is Activation of the IL-1ß System Involved?

INTRODUCTION: Elevated apoB-lipoproteins is reported to predict type 2 diabetes (T2D) development in postmenopausal women. Low insulin sensitivity (IS) and compensatory hyperinsulinemia is believed to lead to β-cell exhaustion and increase T2D risk. Also, activation of the interleukin-1β (IL-1β) system, a novel inflammatory pathway, is known to predict the development of T2D. We thus aimed to investigate whether plasma apoB associates with low IS and hyperinsulinemia and whether this is via an activation of the IL-1β system. METHODOLOGY: 47 non-diabetic overweight and obese postmenopausal women and 28 men, aged 45 to 74 years old, underwent a modified Botnia clamp, in which 1 st and 2 nd phase insulin secretion were measured during a 1 hour intravenous glucose tolerance test (IVGTT). Following that, a 3 hour hyperinsulinemic-euglycemic clamp (HEIC, insulin infusion rate of 75 mU/m 2 /min) was conducted to measure IS during the last 30 minutes (steady state). IS was expressed as steady state glucose infusion rate (GIR) alone or divided over steady state plasma insulin (M/I). RESULTS: In women, fasting plasma apoB correlated positively with 2 nd phase (r=0.202), total insulin secretion (r=0.168) and with total C-peptide secretion (r=0.204) and negatively with IS (r: GIR= -0.299 and M/I =-0.180) independent of adiposity. Similar to plasma apoB, fasting plasma IL-Ra (indicator of activated IL-1β system) correlated positively with 2 nd phase and total insulin secretion and with total C-peptide secretion (r=0.217; r=0.154; r=0.198 respectively) and negatively with IS (GIR r=-0.304; M/I r=-0.214). Fasting plasma IL-Ra also correlated with apoB r=0.352). Once corrected for IL-1Ra, all associations between apoB and the indexes of IS and insulin secretion were lost. Plasma apoB did not correlate with any indices of insulin secretion or IS in men. The strongest correlate of insulin secretion and IS was adiposity, particularly central. CONCLUSION: ApoB is associated with hyperinsulinemia and low IS in non-diabetic overweight and obese women, which may be mediated through activation of the IL-1β system. Gender differences may need to be considered in exploring the pathophysiology of T2D in humans.

Chlorinated Persistent Organic Pollutants, Obesity, and Type 2 Diabetes

Persistent organic pollutants (POPs) are lipophilic compounds that travel with lipids and accumulate mainly in adipose tissue. Recent human evidence links low-dose POPs to an increased risk of type 2 diabetes (T2D). Because humans are contaminated by POP mixtures and POPs possibly have nonmonotonic dose-response relations with T2D, critical methodological issues arise in evaluating human findings. This review summarizes epidemiological results on chlorinated POPs and T2D, and relevant experimental evidence. It also discusses how features of POPs can affect inferences in humans. The evidence as a whole suggests that, rather than a few individual POPs, background exposure to POP mixtures-including organochlorine pesticides and polychlorinated biphenyls-can increase T2D risk in humans. Inconsistent statistical significance for individual POPs may arise due to distributional differences in POP mixtures among populations. Differences in the observed shape of the dose-response curves among human studies may reflect an inverted U-shaped association secondary to mitochondrial dysfunction or endocrine disruption. Finally, we examine the relationship between POPs and obesity. There is evidence in animal studies that low-dose POP mixtures are obesogenic. However, relationships between POPs and obesity in humans have been inconsistent. Adipose tissue plays a dual role of promoting T2D and providing a relatively safe place to store POPs. Large prospective studies with serial measurements of a broad range of POPs, adiposity, and clinically relevant biomarkers are needed to disentangle the interrelationships among POPs, obesity, and the development of T2D. Also needed are laboratory experiments that more closely mimic real-world POP doses, mixtures, and exposure duration in humans.

The effect of childhood cow's milk intake and HLA-DR genotype on risk of islet autoimmunity and type 1 diabetes: The Diabetes Autoimmunity Study in the Young

Cow's milk intake has been inconsistently associated with islet autoimmunity (IA) and type 1 diabetes (T1D) development. Genetic and environmental factors may modify the effect of cow's milk on IA and T1D risk. The Diabetes Autoimmunity Study in the Young (DAISY) follows children at increased T1D risk of IA (presence of autoantibodies to insulin, GAD65, or IA-2 twice in succession) and T1D development. We examined 1835 DAISY children with data on cow's milk intake: 143 developed IA, 40 subsequently developed T1D. Cow's milk protein and lactose intake were calculated from prospectively collected parent- and self-reported food frequency questionnaires (FFQ). High risk HLA-DR genotype: HLA-DR3/4,DQB1*0302; low/moderate risk: all other genotypes. We examined interactions between cow's milk intake, age at cow's milk introduction, and HLA-DR genotype in IA and T1D development. Interaction models contained the base terms (e.g., cow's milk protein and HLA-DR genotype) and an interaction term (e.g., cow's milk protein*HLA-DR genotype). In survival models adjusted for total calories, FFQ type, T1D family history, and ethnicity, greater cow's milk protein intake was associated with increased IA risk in children with low/moderate risk HLA-DR genotypes [hazard ratio (HR): 1.41, 95% confidence interval (CI): 1.08-1.84], but not in children with high risk HLA-DR genotypes. Cow's milk protein intake was associated with progression to T1D (HR: 1.59, CI: 1.13-2.25) in children with IA. Greater cow's milk intake may increase risk of IA and progression to T1D. Early in the T1D disease process, cow's milk intake may be more influential in children with low/moderate genetic T1D risk.

Evaluating the diet of children at increased risk for type 1 diabetes: first results from the TEENDIAB study.

The development of type 1 diabetes (T1D) is potentially influenced by nutrition. The aim of our study was to assess food and nutrient intakes of children at increased risk of T1D. Dietary intake of the last 4 weeks was assessed using a diet history interview. The daily nutrient and food intakes were compared with the German Dietary Reference Intakes, the Optimized Mixed Diet recommendations and those of a representative sample of children from the EsKiMo study. Children included in the analysis participated in the prospective TEENDIAB study. First-degree relatives of people with T1D (n 268), aged 8-12 years. The TEENDIAB children consumed 52·0 % of their total energy from carbohydrates, 32·6 % from fat and 14·3 % from protein. Compared with the reference values, their intake was lowest for folate at 61·3 % of the reference, for iodine at 58·1 % and for vitamin D at 8·9 %, and exceeded the reference for vitamin K about 5-fold, for Na about 3·5-fold and for protein about 1·5-fold. Their nutrient intakes were similar to those of a control cohort without increased T1D risk. The consumption of non-desirable food groups (meat products, sweets/snacks) was above the recommendations and the consumption of desirable food groups (fruits, vegetables, carbohydrate-rich foods) was below the recommendations. The TEENDIAB children had intakes considerably below the recommendations for vitamin D, iodine, folate and plant-based foods, and intakes above for vitamin K, Na, protein, meat products and sweets/snacks. They showed similar dietary patterns to non-risk children.

Dose response relationship between arsenic exposure from drinking water and Diabetes mellitus in high and low-to-moderate exposed area in Taiwan

Background: Epidemiological studies have shown that high level arsenic exposure is associated with type 2 diabetes (T2D). The association between low-to-moderate arsenic exposure and T2D remains inconclusive. The aim of this study was to examine the association of chronic arsenic exposure from drinking water and T2D across low to high levels in two exposed areas in Taiwan by long-term perspective study. Methods:The southwestern (SW) cohort was recruited from blackfoot disease endemic townships with high arsenic levels in their well water, while the northeastern (NE) cohort was recruited from four townships in the Lanyang Basin with low-to-moderate arsenic level. The status of diabetes for study subjects was ascertained through linkage with the computerized Taiwan National Health Insurance (NHI) database from 1998 to 2009.Cox regression analysis was used to determine the hazard ratios (HRs) and 95% confidence intervals (CIs) for developing newly-diagnosed T2D. Results: A total of 489 and 1,310 newly diagnosed diabetes patients, corresponding to 33.7 and 21.7 per 1000 person-years, were observed in SW and NE cohort, respectively. Significant dose-response relationship between arsenic and T2D was observed in SW cohort. The adjusted hazard ratio were 1.00 (referent), 1.16 (0.85-1.59), 1.31 (0.98-1.76) and 1.88 (1.39-2.53) in relation to cumulative arsenic exposure of 0, 0.1-9.9, 10.0-19.9 and?20.0 mg/L*years, respectively. No significant association was observed in NE cohort. However, among NE cohort with BMI &lt;20, people having consumed water with arsenic &gt;10?g/L had 74%~145% increased T2D risk when compared to those consuming water with arsenic ?10?g/L. Conclusions: Dose-response relationship between arsenic exposure from drinking water and T2D was consistently observed among highly-exposed study cohort. For people with low-to-moderate arsenic exposure, the association was more confined to those with lower BMI.

Consumption of artificially and sugar-sweetened beverages and incident type 2 diabetes in the Etude Epidémiologique auprès des femmes de la Mutuelle Générale de l’Education Nationale–European Prospective Investigation into Cancer and Nutrition cohort

It has been extensively shown, mainly in US populations, that sugar-sweetened beverages (SSBs) are associated with increased risk of type 2 diabetes (T2D), but less is known about the effects of artificially sweetened beverages (ASBs). We evaluated the association between self-reported SSB, ASB, and 100% fruit juice consumption and T2D risk over 14 y of follow-up in the French prospective Etude Epidémiologique auprès des femmes de la Mutuelle Générale de l'Education Nationale-European Prospective Investigation into Cancer and Nutrition cohort. A total of 66,118 women were followed from 1993, and 1369 incident cases of T2D were diagnosed during the follow-up. Cox regression models were used to estimate HRs and 95% CIs for T2D risk. The average consumption of sweetened beverages in consumers was 328 and 568 mL/wk for SSBs and ASBs, respectively. Compared with nonconsumers, women in the highest quartiles of SSB and ASB consumers were at increased risk of T2D with HRs (95% CIs) of 1.34 (1.05, 1.71) and 2.21 (1.56, 3.14) for women who consumed >359 and >603 mL/wk of SSBs and ASBs, respectively. Strong positive trends in T2D risk were also observed across quartiles of consumption for both types of beverage (P = 0.0088 and P < 0.0001, respectively). In sensitivity analyses, associations were partly mediated by BMI, although there was still a strong significant independent effect. No association was observed for 100% fruit juice consumption. Both SSB consumption and ASB consumption were associated with increased T2D risk. We cannot rule out that factors other than ASB consumption that we did not control for are responsible for the association with diabetes, and randomized trials are required to prove a causal link between ASB consumption and T2D.

What Is the Contribution of Two Genetic Variants Regulating VEGF Levels to Type 2 Diabetes Risk and to Microvascular Complications?

Vascular endothelial growth factor (VEGF) is a key chemokine involved in tissue growth and organ repair processes, particularly angiogenesis. Elevated circulating VEGF levels are believed to play a role in type 2 diabetes (T2D) microvascular complications, especially diabetic retinopathy. Recently, a genome-wide association study identified two common single nucleotide polymorphisms (SNPs; rs6921438 and rs10738760) explaining nearly half of the variance in circulating VEGF levels. Considering the putative contribution of VEGF to T2D and its complications, we aimed to assess the effect of these VEGF-related SNPs on the risk of T2D, nephropathy and retinopathy, as well as on variation in related traits.SNPs were genotyped in several case-control studies: French and Danish T2D studies (Ncases = 6,920-Ncontrols = 3,875 and Ncases = 3,561-Ncontrols = 2,623; respectively), two French studies one for diabetic nephropathy (Ncases = 1,242-Ncontrols = 860) and the other for diabetic retinopathy (Ncases = 1,336-Ncontrols = 1,231). The effects of each SNP on quantitative traits were analyzed in a French general population-based cohort (N = 4,760) and two French T2D studies (N = 3,480). SNP associations were assessed using logistic or linear regressions.In the French population, we found an association between the G-allele of rs6921438, shown to increase circulating VEGF levels, and increased T2D risk (OR = 1.15; P = 3.7×10−5). Furthermore, the same allele was associated with higher glycated hemoglobin levels (β = 0.02%; P = 9.2×10−3). However, these findings were not confirmed in the Danes. Conversely, the SNP rs10738760 was not associated with T2D in the French or Danish populations. Despite having adequate statistical power, we did not find any significant effects of rs6921438 or rs10738760 on diabetic microvascular complications or the variation in related traits in T2D patients.In spite of their impact on the variance in circulating VEGF, we did not find any association between SNPs rs6921438 and rs10738760, and the risk of T2D, diabetic nephropathy or retinopathy. The link between VEGF and T2D and its complications might be indirect and more complex than expected.

Systematic identification of interaction effects between genome- and environment-wide associations in type 2 diabetes mellitus

Diseases such as type 2 diabetes (T2D) result from environmental and genetic factors, and risk varies considerably in the population. T2D-related genetic loci discovered to date explain only a small portion of the T2D heritability. Some heritability may be due to gene–environment interactions. However, documenting these interactions has been difficult due to low availability of concurrent genetic and environmental measures, selection bias, and challenges in controlling for multiple hypothesis testing. Through genome-wide association studies (GWAS), investigators have identified over 90 single nucleotide polymorphisms (SNPs) associated to T2D. Using a method analogous to GWAS [environment-wide association study (EWAS)], we found five environmental factors associated with the disease. By focusing on risk factors that emerge from GWAS and EWAS, it is possible to overcome difficulties in uncovering gene–environment interactions. Using data from the National Health and Nutrition Examination Survey (NHANES), we screened 18 SNPs and 5 serum-based environmental factors for interaction in association to T2D. We controlled for multiple hypotheses using false discovery rate (FDR) and Bonferroni correction and found four interactions with FDR <20 %. The interaction between rs13266634 (SLC30A8) and trans-β-carotene withstood Bonferroni correction (corrected p = 0.006, FDR <1.5 %). The per-risk-allele effect sizes in subjects with low levels of trans-β-carotene were 40 % greater than the marginal effect size [odds ratio (OR) 1.8, 95 % CI 1.3–2.6]. We hypothesize that impaired function driven by rs13266634 increases T2D risk when combined with serum levels of nutrients. Unbiased consideration of environmental and genetic factors may help identify larger and more relevant effect sizes for disease associations.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-012-1258-z) contains supplementary material, which is available to authorized users.