Perfluoroalkyl substances (PFAS) have drawn much attention due to bioaccumulation potential and their current omnipresence in human blood. We assessed whether plasma PFAS, suspected to induce ...endocrine-disrupting effects, were prospectively associated with clinical type 2 diabetes (T2D) risk.
We established a nested case-control study within the Swedish prospective population-based Västerbotten Intervention Programme cohort. Several PFAS were measured in plasma from a subset of 124 case-control pairs at baseline (during 1990–2003) and at 10-year follow-up. T2D cases were matched (1:1) according to gender, age and sample date with participants without T2D (controls).
Conditional logistic regressions were used to prospectively assess risk of T2D by baseline PFAS plasma concentrations. Associations between long-term PFAS plasma levels (mean of baseline and follow-up) and insulin resistance (HOMA2-IR) and beta-cell function (HOMA2-B%) at follow-up were prospectively explored among 178 and 181 controls, respectively, by multivariable linear regressions.
After adjusting for gender, age, sample year, diet and body mass index, the odds ratio of T2D for the sum of PFAS (Σ z-score PFAS) was 0.52 (95% confidence interval, CI: 0.20, 1.36), comparing third with first tertile; and 0.92 (95% CI: 0.84, 1.00) per one standard deviation increment of sum of log-transformed PFAS. Among the controls, the adjusted β of HOMA2-IR and HOMA-B% for the sum of PFAS were −0.26 (95% CI: −0.52, −0.01) and −9.61 (95% CI: −22.60, 3.39) respectively comparing third with first tertile.
This prospective nested case-control study yielded overall inverse associations between individual PFAS and risk of T2D, although mostly non-significant. Among participants without T2D, long-term PFAS exposure was prospectively associated with lower insulin resistance.
•PFAS have endocrine-disrupting properties, activate PPARs and may affect T2D risk•We observed weak indications of PFAS-associated lower T2D risk.•Long-term PFAS were inversely associated with insulin resistance in non-diabetics•Confounding from dietary sources of PFAS may explain overall conflicting results•Further research to tease out the true impact of PFAS in human T2D is warranted
How acute hyperglycaemia affects memory functions and functional brain responses in individuals with and without type 2 diabetes is unclear. Our aim was to study the association between acute ...hyperglycaemia and working, semantic, and episodic memory in participants with type 2 diabetes compared to a sex- and age-matched control group. We also assessed the effect of hyperglycaemia on working memory-related brain activity. A total of 36 participants with type 2 diabetes and 34 controls (mean age, 66 years) underwent hyperglycaemic clamp or placebo clamp in a blinded and randomised order. Working, episodic, and semantic memory were tested. Overall, the control group had higher working memory (mean z-score 33.15 ± 0.45) than the group with type 2 diabetes (mean z-score 31.8 ± 0.44, p = 0.042) considering both the placebo and hyperglycaemic clamps. Acute hyperglycaemia did not influence episodic, semantic, or working memory performance in either group. Twenty-two of the participants (10 cases, 12 controls, mean age 69 years) were randomly invited to undergo the same clamp procedures to challenge working memory, using 1-, 2-, and 3-back, while monitoring brain activity by blood oxygen level-dependent functional magnetic resonance imaging (fMRI). The participants with type 2 diabetes had reduced working memory during the 1- and 2-back tests. fMRI during placebo clamp revealed increased BOLD signal in the left lateral frontal cortex and the anterior cingulate cortex as a function of working memory load in both groups (3>2>1). During hyperglycaemia, controls showed a similar load-dependent fMRI response, whereas the type 2 diabetes group showed decreased BOLD response from 2- to 3-back. These results suggest that impaired glucose metabolism in the brain affects working memory, possibly by reducing activity in important frontal brain areas in persons with type 2 diabetes.
Type 2 diabetes mellitus is characterized by a low-grade inflammation; however, mechanisms leading to this inflammation in specific tissues are not well understood. The eye can be affected by ...diabetes; thus, we hypothesized that inflammatory changes in the eye may parallel the inflammation that develops with diabetes. Here, we developed a non-invasive means to monitor the status of inflammatory dendritic cell (DC) subsets in the corneal epithelium as a potential biomarker for the onset of inflammation in type 2 diabetes. In an age-matched cohort of 81 individuals with normal and impaired glucose tolerance and type 2 diabetes, DCs were quantified from wide-area maps of the corneal epithelial sub-basal plexus, obtained using clinical in vivo confocal microscopy (IVCM). With the onset of diabetes, the proportion of mature, antigen-presenting DCs increased and became organized in clusters. Out of 92 plasma proteins analysed in the cohort, tumor necrosis factor receptor super family member 9 (TNFRSF9) was associated with the observed maturation of DCs from an immature to mature antigen-presenting phenotype. A low-grade ocular surface inflammation observed in this study, where resident immature dendritic cells are transformed into mature antigen-presenting cells in the corneal epithelium, is a process putatively associated with TNFRSF9 signalling and may occur early in the development of type 2 diabetes. IVCM enables this process to be monitored non-invasively in the eye.
Studies have indicated that moderate alcohol consumption is associated with lower incidence of diabetes in women. However, not only the amount but also the drinking pattern could be of importance ...when assessing the longitudinal relation between alcohol and glucose. Also, there is a lack of studies on alcohol use beginning in adolescence on adult glucose levels. The aim was to examine the association between total alcohol consumption and binge drinking between ages 16 and 43 and fasting plasma glucose at age 43.
Data were retrieved from a 27-year prospective cohort study, the Northern Swedish Cohort. In 1981, all 9th grade students (n = 1083) within a municipality in Sweden were invited to participate. There were re-assessments at ages 18, 21, 30 and 43. This particular study sample consisted of 897 participants (82.8%). Fasting plasma glucose (mmol/L) was measured at a health examination at age 43. Total alcohol consumption (in grams) and binge drinking were calculated from alcohol consumption data obtained from questionnaires.
Descriptive analyses showed that men had higher levels of fasting plasma glucose as compared to women. Men also reported higher levels of alcohol consumption and binge drinking behavior. Linear regressions showed that total alcohol consumption in combination with binge drinking between ages 16 and 43 was associated with elevated fasting plasma glucose at age 43 in women (beta = 0.14, p = 0.003) but not in men after adjustment for BMI, hypertension and smoking at age 43.
Our findings indicate that reducing binge drinking and alcohol consumption among young and middle-aged women with the highest consumption might be metabolically favorable for their future glucose metabolism.
Aims/hypothesis
Non-Western immigrants to Europe are at high risk for type 2 diabetes. In this nationwide study including incident cases of type 2 diabetes, the aim was to compare all-cause mortality ...(ACM) and cause-specific mortality (CSM) rates in first- and second-generation immigrants with native Swedes.
Methods
People living in Sweden diagnosed with new-onset pharmacologically treated type 2 diabetes between 2006 and 2012 were identified through the Swedish Prescribed Drug Register. They were followed until 31 December 2016 for ACM and until 31 December 2012 for CSM. Analyses were adjusted for age at diagnosis, sex, socioeconomic status, education, treatment and region. Associations were assessed using Cox regression analysis.
Results
In total, 138,085 individuals were diagnosed with type 2 diabetes between 2006 and 2012 and fulfilled inclusion criteria. Of these, 102,163 (74.0%) were native Swedes, 28,819 (20.9%) were first-generation immigrants and 7103 (5.1%) were second-generation immigrants with either one or both parents born outside Sweden. First-generation immigrants had lower ACM rate (HR 0.80 95% CI 0.76, 0.84) compared with native Swedes. The mortality rates were particularly low in people born in non-Western regions (0.46 0.42, 0.50; the Middle East, 0.41 0.36, 0.47; Asia, 0.53 0.43, 0.66; Africa, 0.47 0.38, 0.59; and Latin America, 0.53 0.42, 0.68). ACM rates decreased with older age at migration and shorter stay in Sweden. Compared with native Swedes, first-generation immigrants with ≤ 24 years in Sweden (0.55 0.51, 0.60) displayed lower ACM rates than those spending >24 years in Sweden (0.92 0.87, 0.97). Second-generation immigrants did not have better survival rates than native Swedes but rather displayed higher ACM rates for people with both parents born abroad (1.28 1.05, 1.56).
Conclusions/interpretation
In people with type 2 diabetes, the lower mortality rate in first-generation non-Western immigrants compared with native Swedes was reduced over time and was equalised in second-generation immigrants. These findings suggest that acculturation to Western culture may impact ACM and CSM in immigrants with type 2 diabetes but further investigation is needed.
Graphical abstract
Application of metabolite profiling could expand the etiological knowledge of type 2 diabetes mellitus (T2D). However, few prospective studies apply broad untargeted metabolite profiling to reveal ...the comprehensive metabolic alterations preceding the onset of T2D.
We applied untargeted metabolite profiling in serum samples obtained from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort comprising 300 individuals who developed T2D after a median follow-up time of 6 years and 300 matched controls. For that purpose, we used ultraperformance LC-MS with a protocol specifically designed for large-scale metabolomics studies with regard to robustness and repeatability. After multivariate classification to select metabolites with the strongest contribution to disease classification, we applied multivariable-adjusted conditional logistic regression to assess the association of these metabolites with T2D.
Among several alterations in lipid metabolism, there was an inverse association with T2D for metabolites chemically annotated as lysophosphatidylcholine(dm16:0) and phosphatidylcholine(O-20:0/O-20:0). Hexose sugars were positively associated with T2D, whereas higher concentrations of a sugar alcohol and a deoxyhexose sugar reduced the odds of diabetes by approximately 60% and 70%, respectively. Furthermore, there was suggestive evidence for a positive association of the circulating purine nucleotide isopentenyladenosine-5'-monophosphate with incident T2D.
This study constitutes one of the largest metabolite profiling approaches of T2D biomarkers in a prospective study population. The findings might help generate new hypotheses about diabetes etiology and develop further targeted studies of a smaller number of potentially important metabolites.
•PFAS may impact Type 2 Diabetes (T2D) development, but findings are inconsistent.•We found PFAS-related metabolites from untargeted metabolomics using random forest.•PFAS correlated positively with ...diacylglycerols and glycerophospholipids.•These two metabolite groups showed opposite associations with T2D risk.•The findings may help to explain the conflicting results found for PFAS and T2D.
Perfluoroalkyl substances (PFAS) are widespread persistent environmental pollutants. There is evidence that PFAS induce metabolic perturbations in humans, but underlying mechanisms are still unknown. In this exploratory study, we investigated PFAS-related plasma metabolites for their associations with type 2 diabetes (T2D) to gain potential mechanistic insight in these perturbations.
We used untargeted LC-MS metabolomics to find metabolites related to PFAS exposures in a case-control study on T2D (n = 187 matched pairs) nested within the Västerbotten Intervention Programme cohort. Following principal component analysis (PCA), six PFAS measured in plasma appeared in two groups: 1) perfluorononanoic acid, perfluorodecanoic acid and perfluoroundecanoic acid and 2) perfluorohexane sulfonic acid, perfluorooctane sulfonic acid and perfluorooctanoic acid. Using a random forest algorithm, we discovered metabolite features associated with individual PFAS and PFAS exposure groups which were subsequently investigated for associations with risk of T2D.
PFAS levels correlated with 171 metabolite features (0.16 ≤ |r| ≤ 0.37, false discovery rate (FDR) adjusted p < 0.05). Out of these, 35 associated with T2D (p < 0.05), with 7 remaining after multiple testing adjustment (FDR < 0.05). PCA of the 35 PFAS- and T2D-related metabolite features revealed two patterns, dominated by glycerophospholipids and diacylglycerols, with opposite T2D associations. The glycerophospholipids correlated positively with PFAS and associated inversely with risk for T2D (Odds Ratio (OR) per 1 standard deviation (1-SD) increase in metabolite PCA pattern score = 0.2; 95% Confidence Interval (CI) = 0.1–0.4). The diacylglycerols also correlated positively with PFAS, but they associated with increased risk for T2D (OR per 1-SD = 1.9; 95% CI = 1.3–2.7). These results suggest that PFAS associate with two groups of lipid species with opposite relations to T2D risk.
Objective A population-based point-prevalence study was conducted to determine the prevalence of peripheral arterial disease (PAD) in Sweden, with special attention to critical limb ischemia and sex ...differences. Methods An age-standardized randomly selected population sample of 8000 women and men, aged 60 to 90 years, from four different regions in Sweden was invited to participate. The sample had the same age and gender distribution as the Swedish population in this age group. Participating subjects completed questionnaires on medical history, present medication, and symptoms, and their ankle-brachial index (ABI) was measured. Subjects were analyzed for presence of PAD according to reported symptoms and an ABI <0.9. Results A total of 5080 subjects were included, giving a participation rate of 64%. The prevalence of any PAD, asymptomatic PAD, intermittent claudication, and severe limb ischemia was, respectively, 18% (95% confidence interval CI, 16% to 20%) 11% (9% to 13%), 7% (6.5 to 7%) and 1.2% (1% to 1.5%). Women had a higher prevalence than men when PAD was diagnosed with ABI only; that is, asymptomatic PAD (12.6% vs 9.4%, P = .03) and severe limb ischemia (1.5% vs 0.8%, P < .008). The prevalence of any PAD was 7.9% in the age group 60 to 65 years and increased to 47.2% among the age group 85 to 90 years. Severe limb ischemia occurred in 0.3% in the youngest age group, was highest in the age group 80 to 84 years at 3.3%, and declined to 2.5% among the oldest. The prevalence of PAD differed between regions ( P < .0001). Conclusions PAD is common in Sweden, and almost a fifth of all elderly individuals have some stage of this disease. Women are more often afflicted than men. The prevalence of severe ischemia, as a measure of critical limb ischemia, is about 1% the population.
Recent genome-wide association studies (GWAS) have identified multiple risk loci for common obesity (FTO, MC4R, TMEM18, GNPDA2, SH2B1, KCTD15, MTCH2, NEGR1 and PCSK1). Here we extend those studies by ...examining associations with adiposity and type 2 diabetes in Swedish adults. The nine single nucleotide polymorphisms (SNPs) were genotyped in 3885 non-diabetic and 1038 diabetic individuals with available measures of height, weight and body mass index (BMI). Adipose mass and distribution were objectively assessed using dual-energy X-ray absorptiometry in a sub-group of non-diabetics (n = 2206). In models with adipose mass traits, BMI or obesity as outcomes, the most strongly associated SNP was FTO rs1121980 (P < 0.001). Five other SNPs (SH2B1 rs7498665, MTCH2 rs4752856, MC4R rs17782313, NEGR1 rs2815752 and GNPDA2 rs10938397) were significantly associated with obesity. To summarize the overall genetic burden, a weighted risk score comprising a subset of SNPs was constructed; those in the top quintile of the score were heavier (+2.6 kg) and had more total (+2.4 kg), gynoid (+191 g) and abdominal (+136 g) adipose tissue than those in the lowest quintile (all P < 0.001). The genetic burden score significantly increased diabetes risk, with those in the highest quintile (n = 193/594 cases/controls) being at 1.55-fold (95% CI 1.21–1.99; P < 0.0001) greater risk of type 2 diabetes than those in the lowest quintile (n = 130/655 cases/controls). In summary, we have statistically replicated six of the previously associated obese-risk loci and our results suggest that the weight-inducing effects of these variants are explained largely by increased adipose accumulation.
There is conflicting evidence regarding the association between fish intake and type 2 diabetes (T2D) incidence, possibly owing to measurement errors in self-reported intake and coexposure to ...persistent organic pollutants (POPs) present in fish.
The aim of this study was to identify plasma metabolites associated with fish intake and to assess their association with T2D risk, independently of POPs, in Swedish adults.
In a case-control study nested in the Swedish Västerbotten Intervention Programme, fasting plasma samples from 421 matched T2D case-control pairs of men and women aged 30–60 y at baseline and 10-y follow-up samples from a subset of 149 pairs were analyzed using untargeted metabolomics. Moreover, 16 plasma POPs were analyzed for the 149 pairs who had repeated samples available. Fish-related plasma metabolites were identified using multivariate modelling and partial correlation analysis. Reproducibility of metabolites and metabolite patterns, derived via principal component analysis (PCA), was assessed by intraclass correlation. A unique component of metabolites unrelated to POPs was dissected by integrating metabolites and POPs using 2-way orthogonal partial least squares regression. ORs of T2D were estimated using conditional logistic regression.
We identified 31 metabolites associated with fish intake that had poor to good reproducibility. A PCA-derived metabolite pattern strongly correlated with fish intake (ρ = 0.37, P < 0.001) but showed no association with T2D risk. Integrating fish-related metabolites and POPs led to a unique metabolite component independent of POPs, which tended to be inversely associated with T2D risk (OR: 0.75; 95% CI: 0.54, 1.02, P = 0.07). This component mainly consisted of metabolites reflecting fatty fish intake.
Our results suggest that fatty fish intake may be beneficial for T2D prevention, after removing the counteractive effects of coexposure to POPs in Swedish adults. Integrating metabolite markers and POP exposures appears a promising approach to advance the understanding of associations between fish intake and T2D incidence.
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