Frontiers | The Porphyromonas gingivalis/host interactome shows enrichment in GWASdb genes related to Alzheimer’s disease, diabetes and cardiovascular diseases | Frontiers in Aging Neuroscience

Periodontal disease is of established aetiology in which polymicrobial
synergistic ecology has become dysbiotic under the influence of
Porphyromonas gingivalis. Following breakdown of the host’s protective
oral tissue barriers, P. gingivalis migrates to developing inflammatory
pathologies that associate with Alzheimer’s disease (AD). Periodontal
disease is a risk factor for cardiovascular disorders (CVD), type II
diabetes mellitus (T2DM), AD and other chronic diseases, whilst T2DM
exacerbates periodontitis. This study analysed the relationship between
the P. gingivalis/host interactome and the genes identified in
genome-wide association studies (GWAS) for the aforementioned conditions
using data from GWASdb (P<1E-03) and, in some cases, from the
NCBI/EBI GWAS database (P< 1E-05). Gene expression data from
periodontitis or P. gingivalis microarray was compared to microarray
datasets from the AD hippocampus and/or from carotid artery plaques. The
results demonstrated that the host genes of the P. gingivalis
interactome were significantly enriched in genes deposited in GWASdb
genes related to cognitive disorders, AD and dementia, and its co-morbid
conditions T2DM, obesity, and CVD. The P. gingivalis/host interactome
was also enriched in GWAS genes from the more stringent NCBI-EBI
database for AD, atherosclerosis and T2DM. The misregulated genes in
periodontitis tissue or P. gingivalis infected macrophages also matched
those in the AD hippocampus or atherosclerotic plaques. Together, these
data suggest important gene/environment interactions between P.
gingivalis and susceptibility genes or gene expression changes in
conditions where periodontal disease is a contributory factor.

Nonnutritive sweeteners and cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials and prospective cohort studies

 BACKGROUND Nonnutritive sweeteners, such as aspartame, sucralose and stevioside, are widely consumed, yet their long-term health impact is uncertain. We synthesized evidence from prospective studies to determine whether routine consumption of non-nutritive sweeteners was associated with long-term adverse cardiometabolic effects. 

METHODS We searched MEDLINE, Embase and Cochrane Library (inception to January 2016) for randomized controlled trials (RCTs) that evaluated interventions for nonnutritive sweeteners and prospective cohort studies that reported on consumption of non-nutritive sweeteners among adults and adolescents. The primary outcome was body mass index (BMI). Secondary outcomes included weight, obesity and other cardiometabolic end points.

 RESULTS From 11 774 citations, we included 7 trials (1003 participants; median follow-up 6 mo) and 30 cohort studies (405 907 participants; median follow-up 10 yr). In the included RCTs, nonnutritive sweeteners had no significant effect on BMI (mean difference −0.37 kg/m2; 95% confidence interval [CI] −1.10 to 0.36; I2 9%; 242 participants). In the included cohort studies, consumption of nonnutritive sweeteners was associated with a modest increase in BMI (mean correlation 0.05, 95% CI 0.03 to 0.06; I2 0%; 21 256 participants). Data from RCTs showed no consistent effects of nonnutritive sweeteners on other measures of body composition and reported no further secondary outcomes. In the cohort studies, consumption of nonnutritive sweeteners was associated with increases in weight and waist circumference, and higher incidence of obesity, hypertension, metabolic syndrome, type 2 diabetes and cardiovascular events. Publication bias was indicated for studies with diabetes as an outcome.

 INTERPRETATION Evidence from RCTs does not clearly support the intended benefits of nonnutritive sweeteners for weight management, and observational data suggest that routine intake of nonnutritive sweeteners may be associated with increased BMI and cardiometabolic risk. Further research is needed to fully characterize the long-term risks and benefits of nonnutritive sweeteners. Protocol registration: PROSPERO-CRD42015019749"



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The association between total phthalate concentration and non-communicable diseases and chronic inflammation in South Australian urban dwelling men - ScienceDirect

 Objective
To investigate associations between urinary total phthalate concentration, chronic low-grade inflammation and non-communicable diseases in a cohort of South Australian men.
Methods
1504 men aged 39–84 years who provided a urinary sample at the follow-up visit of the Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) study, a randomly-selected group of urban-dwelling, community-based men from Adelaide, Australia (n = 2038; study participation rate: 78.1%). Total phthalate concentration was quantified in fasting morning urine samples. Chronic diseases were assessed through self-report questionnaire or directly measured using standardised clinical and laboratory procedures. Inflammatory biomarkers were assayed by ELISA or spectroscopy. Multivariable linear and logistic regression models were applied to determine associations of log-transformed urinary phthalate concentration with inflammation and chronic disease.
Results
Total phthalates were detected in 99.6% of urinary samples; geometric mean (95% CI) was 114.1 (109.5–118.9) µg/g creatinine. Higher total phthalate levels were associated with higher levels of hs-CRP, IL-6 (all p < 0.05) and TNF-α but not MPO. Urinary total phthalate concentrations were positively associated with cardiovascular disease, type-2-diabetes and hypertension. Comparing extreme quartiles of total phthalate, prevalence ratios were 1.78 (95% CI 1.17 – 2.71, p-trend = 0.001) for cardiovascular disease and 1.84 (95%CI 1.34 – 2.51, p-trend = 0.001) for type-2-diabetes and 1.14 (95%CI 1.01 – 1.29, p-trend = 0.013) for hypertension. Total phthalates and asthma and depression were not significantly associated.
Conclusion
A positive association between total phthalates and cardiovascular disease, type-2-diabetes, hypertension and increased levels of chronic low-grade inflammatory biomarkers was observed in urban-dwelling Australian men."



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Intestinal virome changes precede autoimmunity in type I diabetes-susceptible children

 "Viruses have long been considered potential triggers of autoimmune diseases. Here we defined the intestinal virome from birth to the development of autoimmunity in children at risk for type 1 diabetes (T1D). A total of 220 virus-enriched preparations from serially collected fecal samples from 11 children (cases) who developed serum autoantibodies associated with T1D (of whom five developed clinical T1D) were compared with samples from controls. Intestinal viromes of case subjects were less diverse than those of controls. Among eukaryotic viruses, we identified significant enrichment of Circoviridae-related sequences in samples from controls in comparison with cases. Enterovirus, kobuvirus, parechovirus, parvovirus, and rotavirus sequences were frequently detected but were not associated with autoimmunity. For bacteriophages, we found higher Shannon diversity and richness in controls compared with cases and observed that changes in the intestinal virome over time differed between cases and controls. Using Random Forests analysis, we identified disease-associated viral bacteriophage contigs after subtraction of age-associated contigs. These disease-associated contigs were statistically linked to specific components of the bacterial microbiome. Thus, changes in the intestinal virome preceded autoimmunity in this cohort. Specific components of the virome were both directly and inversely associated with the development of human autoimmune disease."



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Cholesterol—Good for the brain, bad for the heart

 Healthy brains need plenty of cholesterol for nerve cells to grow and work properly, but diabetes can reduce the amount of cholesterol in the brain, as a Joslin Diabetes Center team has demonstrated. Joslin researchers and their colleagues now have gone on to show that mice that are genetically modified to suppress cholesterol production in the brain show dramatic symptoms of neurological impairment . This finding may help to explain why the risk of developing Alzheimer's disease increases in diabetes, says Heather Ferris, M.D., Ph.D., a Joslin research associate and lead author on a paper about the work published in PNAS. 

Loss of astrocyte cholesterol synthesis disrupts neuronal function and alters whole-body metabolism PNAS

Scientists provide first evidence that carbamates can upset circadian rhythms

 The current research focuses on two chemicals, carbaryl, the third most widely used insecticide in the U.S. but which is illegal in several countries, and carbofuran, the most toxic carbamate insecticide, which has been banned for applications on food crops for human consumption since 2009. It is still used in many countries, including Mexico and traces persist in food, plants and wildlife.
"We found that both insecticides are structurally similar to melatonin and that both showed affinity for the melatonin, MT2 receptors, that can potentially affect glucose homeostasis and insulin secretion," said Marina Popovska-Gorevski, co-author, now a scientist with Boehringer Ingelheim Pharmaceuticals, who worked in Dubocovich's lab while earning her master's degree at UB. "That means that exposure to them could put people at higher risk for diabetes and also affect sleeping patterns.""

Aspartame may prevent, not promote, weight loss by blocking intestinal enzyme's activity: Study identifies possible mechanism behind sugar substitute's lack of effectiveness -- ScienceDaily

A team of Massachusetts General Hospital (MGH) investigators has found a possible mechanism explaining why use of the sugar substitute aspartame might not promote weight loss. In their report published online in Applied Physiology, Nutrition and Metabolism, the researchers show how the aspartame breakdown product phenylalanine interferes with the action of an enzyme previously shown to prevent metabolic syndrome -- a group of symptoms associated with type 2 diabetes and cardiovascular disease. They also showed that mice receiving aspartame in their drinking water gained more weight and developed other symptoms of metabolic syndrome than animals fed similar diets lacking aspartame.

Aspartame blocks a gut enzyme called intestinal alkaline phosphatase (IAP) that we previously showed can prevent obesity, diabetes and metabolic syndrome; so we think that aspartame might not work because, even as it is substituting for sugar, it blocks the beneficial aspects of IAP

Community water fluoridation predicts increase in age-adjusted incidence and prevalence of diabetes in 22 states from 2005 and 2010

Community water fluoridation is considered a significant public health achievement of the 20th century. In this paper, the hypothesis that added water fluoridation has contributed to diabetes incidence and prevalence in the United States was investigated. Panel data from publicly available sources was used with population-averaged models to test the associations of added and natural fluoride on the outcomes at the county level in 22 states in the years 2005 and 2010. The findings suggest that a 1 mg increase in the county mean added fluoride significantly positively predicts a 0.23 per 1,000 person increase in age-adjusted diabetes incidence (P < 0.001) and a 0.17% increase in age-adjusted diabetes prevalence percent (P < 0.001), while natural fluoride concentration is significantly protective. For counties using fluorosilicic acid as the chemical additive, both outcomes were lower: by 0.45 per 1,000 persons (P < 0.001) and 0.33% (P < 0.001), respectively. These findings are adjusted for county-level and time-varying changes in per capita tap water consumption, poverty, year, population density, age-adjusted obesity and physical inactivity and mean number of years since water fluoridation started. Sensitivity analyses revealed robust effects for both types of fluoride. Community water fluoridation is associated with epidemiological outcomes for diabetes."

Related articles

• Chemical exposure linked to rising diabetes, obesity risk

Artificial sweeteners induce glucose intolerance by altering the gut microbiota : Nature : Nature Publishing Group

Non-caloric artificial sweeteners (NAS) are among the most widely used food additives worldwide, regularly consumed by lean and obese individuals alike. NAS consumption is considered safe and beneficial owing to their low caloric content, yet supporting scientific data remain sparse and controversial. Here we demonstrate that consumption of commonly used NAS formulations drives the development of glucose intolerance through induction of compositional and functional alterations to the intestinal microbiota. These NAS-mediated deleterious metabolic effects are abrogated by antibiotic treatment, and are fully transferrable to germ-free mice upon faecal transplantation of microbiota configurations from NAS-consuming mice, or of microbiota anaerobically incubated in the presence of NAS. We identify NAS-altered microbial metabolic pathways that are linked to host susceptibility to metabolic disease, and demonstrate similar NAS-induced dysbiosis and glucose intolerance in healthy human subjects. Collectively, our results link NAS consumption, dysbiosis and metabolic abnormalities, thereby calling for a reassessment of massive NAS usage.

Burden of disease and costs of exposure to endocrine disrupting chemicals in the European Union: an updated analysis. - PubMed - NCBI

A previous report documented that endocrine disrupting chemicals contribute substantially to certain forms of disease and disability. In the present analysis, our main objective was to update a range of health and economic costs that can be reasonably attributed to endocrine disrupting chemical exposures in the European Union, leveraging new burden and disease cost estimates of female reproductive conditions from accompanying report. Expert panels evaluated the epidemiologic evidence, using adapted criteria from the WHO Grading of Recommendations Assessment, Development and Evaluation Working Group, and evaluated laboratory and animal evidence of endocrine disruption using definitions recently promulgated by the Danish Environmental Protection Agency. The Delphi method was used to make decisions on the strength of the data. Expert panels consensus was achieved for probable (>20%) endocrine disrupting chemical causation for IQ loss and associated intellectual disability; autism; attention deficit hyperactivity disorder; endometriosis; fibroids; childhood obesity; adult obesity; adult diabetes; cryptorchidism; male infertility, and mortality associated with reduced testosterone. Accounting for probability of causation, and using the midpoint of each range for probability of causation, Monte Carlo simulations produced a median annual cost of €163 billion (1.28% of EU Gross Domestic Product) across 1000 simulations. We conclude that endocrine disrupting chemical exposures in the EU are likely to contribute substantially to disease and dysfunction across the life course with costs in the hundreds of billions of Euros per year. These estimates represent only those endocrine disrupting chemicals with the highest probability of causation; a broader analysis would have produced greater estimates of burden of disease and costs.



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Epigenetic germline inheritance of diet-induced obesity and insulin resistance : Nature Genetics : Nature Publishing Group

"There is considerable controversy regarding epigenetic inheritance in mammalian gametes. Using in vitro fertilization to ensure exclusive inheritance via the gametes, we show that a parental high-fat diet renders offspring more susceptible to developing obesity and diabetes in a sex- and parent of origin–specific mode. The epigenetic inheritance of acquired metabolic disorders may contribute to the current obesity and diabetes pandemic."



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Common mechanisms involved in Alzheimer's disease and type 2 diabetes: a key role of chronic bacterial infection and inflammation. - PubMed - NCBI

Strong epidemiologic evidence and common molecular mechanisms support an association betweenAlzheimer's disease (AD) and type 2-diabetes. Local inflammation and amyloidosis occur in both diseases and are associated with periodontitis and various infectious agents. This article reviews the evidence for the presence of local inflammation and bacteria in type 2 diabetes and discusses host pathogen interactions in chronic inflammatory disorders. Chlamydophyla pneumoniae, Helicobacter pylori and spirochetes are demonstrated in association with dementia and brain lesions in AD and islet lesions in type 2 diabetes. The presence of pathogens in host tissues activates immune responses through Toll-like receptor signaling pathways. Evasion of pathogens from complement-mediated attack results in persistent infection, inflammation and amyloidosis. Amyloid beta and the pancreatic amyloid called amylin bind to lipid bilayers and produce Ca(2+) influx and bacteriolysis. Similarly to AD, accumulation of amylin deposits in type 2 diabetes may result from an innate immune response to chronic bacterial infections, which are known to be associated with amyloidosis. Further research based on an infectious origin of both AD and type 2 diabetes may lead to novel treatment strategies.

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Beyond the brain: disrupted in schizophrenia 1 regulates pancreatic β-cell function via glycogen synthase kinase-3β

"Individuals with schizophrenia and their first-degree relatives have higher rates of type 2 diabetes (T2D) than the general population (18–30 vs. 1.2–6.3%), independent of body mass index and antipsychotic medication, suggesting shared genetic components may contribute to both diseases. The cause of this association remains unknown. Mutations in disrupted in schizophrenia 1 (DISC1) increase the risk of developing psychiatric disorders [logarithm (base 10) of odds = 7.1]. Here, we identified DISC1 as a major player controlling pancreatic β-cell proliferation and insulin secretion via regulation of glycogen synthase kinase-3β (GSK3β). DISC1 expression was enriched in developing mouse and human pancreas and adult β- and ductal cells. Loss of DISC1 function, through siRNA-mediated depletion or expression of a dominant-negative truncation that models the chromosomal translocation of human DISC1 in schizophrenia, resulted in decreased β-cell proliferation (3 vs. 1%; P < 0.01), increased apoptosis (0.1 vs. 0.6%; P < 0.01), and glucose intolerance in transgenic mice. Insulin secretion was reduced (0.5 vs. 0.1 ng/ml; P < 0.05), and critical β-cell transcription factors Pdx1 and Nkx6.1 were significantly decreased. Impaired DISC1 allowed inappropriate activation of GSK3β in β cells, and antagonizing GSK3β (SB216763; IC50 = 34.3 nM) rescued the β-cell defects. These results uncover an unexpected role for DISC1 in normal β-cell physiology and suggest that DISC1 dysregulation contributes to T2D independently of its importance for cognition.



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Chemical exposure linked to rising diabetes, obesity risk

Chemical exposure linked to rising diabetes, obesity risk: "Emerging evidence ties endocrine-disrupting chemical exposure to two of the biggest public health threats facing society - diabetes and obesity, according to the executive summary of an upcoming Scientific Statement issued today by the Endocrine Society."

New research exposes the health risks of fructose and sugary drinks

"There is compelling evidence that drinking too many sugar-sweetened beverages, which contain added sugars in the form of high fructose corn syrup or table sugar (sucrose), can lead to excess weight gain and a greater risk of developing type 2 diabetes and cardiovascular disease, according to a new review paper published today in the Journal of the American College of Cardiology."



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Chemical exposure linked to rising diabetes, obesity risk

Emerging evidence ties endocrine-disrupting chemical (EDC) exposure to two of the biggest public health threats facing society - diabetes and obesity, according to the executive summary of an upcoming Scientific Statement issued today by the Endocrine Society.

EDCs contribute to health problems by mimicking, blocking or otherwise interfering with the body's natural hormones. By hijacking the body's chemical messengers, EDCs can alter the way cells develop and grow.

Known EDCs include bisphenol A (BPA) found in food can linings and cash register receipts, phthalates found in plastics and cosmetics, flame retardants and pesticides. The chemicals are so common that nearly every person on Earth has been exposed to one or more. An economic analysis published in The Journal of Clinical Endocrinology and Metabolism in March estimated that EDC exposure likely costs the European Union €157 billion ($209 billion) a year in actual health care expenses and lost earning potential.

Analysis of 21 studies shows exposure to pesticides is associated with increased risk of developing diabetes -- ScienceDaily

A meta-analysis of 21 studies presented at this year's annual meeting the European Association for the Study of Diabetes (EASD) shows that exposure to pesticides is associated with increased risk of developing diabetes by 61%, with different types of pesticides showing varying levels of risk. The study is by Giorgos Ntritsos, University of Ioannina, Greece, and Dr Ioanna Tzoulaki and Dr Evangelos Evangelou, Imperial College London, UK, and colleagues.

Study links brain tangles and diabetes independently of Alzheimer's - Medical News Today

The study was based on data from the US Alzheimer's Disease Neuroimaging Initiative. It looked at the relationship between type 2 diabetes and the loss of brain cells and their connections, the levels of beta-amyloid and tangles of protein in the spinal fluid of the participants.

On average, those in the study with diabetes had 16 picograms per milliliter greater levels of the tau protein in the spinal and brain fluid regardless of whether they had been diagnosed with dementia. It is these tangles, according to Dr. Srikanth, that may eventually contribute to the development of dementia.

Bacteria (Staph aureus )may cause type 2 diabetes -- ScienceDaily

The research team led by Patrick Schlievert, PhD, professor and DEO of
microbiology at the UI Carver College of Medicine, found that prolonged
exposure to a toxin produced by Staphylococcus aureus (staph)
bacteria causes rabbits to develop the hallmark symptoms of Type 2
diabetes, including insulin resistance, glucose intolerance, and
systemic inflammation.

The zoonotic potential of Mycobacterium avium ssp. paratuberculosis: a systematic review and meta-analyses of the evidence.

This systematic review-meta-analysis appraises and summarizes all the
available research (128 papers) on the zoonotic potential of
Mycobacterium avium ssp. paratuberculosis. The latter has been debated
for a century due to pathogenic and clinical similarities between
Johne's disease in ruminants and Crohn's disease (108 studies) in humans
and recently for involvement in other human diseases; human
immunodeficiency virus (HIV) infection (2), sarcoidosis (3), diabetes
mellitus type 1 (T1DM) (7) and type 2 (3), multiple sclerosis (5) and
Hashimoto's thyroiditis (2). Meta-analytical results indicated a
significant positive association, consistently across different
laboratory methods for Crohn's disease [odds ratio (OR) range
4·26-8·44], T1DM (OR range 2·91-9·95) and multiple sclerosis (OR range
6·5-7·99). The latter two and the thyroiditis hypothesis require further
investigation to confirm the association. Meta-regression of Crohn's
disease studies using DNA detection methods indicated that choice of
primers and sampling frame (e.g. general population vs. hospital-based
sample) explained a significant proportion of heterogeneity. Other
epidemiological studies demonstrated a lack of association between
high-risk occupations and development of Crohn's disease. Due to
knowledge gaps in understanding the role of M. paratuberculosis in the
development or progression of human disease, the evidence at present is
not strong enough to inform the potential public health impact of M.
paratuberculosis exposure.