Obesity-associated diabetes (“diabesity”) in mouse strains is characterized by severe insulin resistance, hyperglycaemia and progressive failure, and loss of beta cells. This condition is observed in ...inbred obese mouse strains such as the New Zealand Obese (NZO/HlLt and NZO/HlBomDife) or the TALLYHO/JngJ mouse. In lean strains such as C57BLKS/J, BTBR T+tf/J or DBA/2 J carrying diabetes susceptibility genes (“diabetes susceptible” background), it can be induced by introgression of the obesity-causing mutations Lep (ob) or Lepr (db). Outcross populations of these models have been employed in the genome-wide search for mouse diabetes genes, and have led to positional cloning of the strong candidates Pctp, Tbc1d1, Zfp69, and Ifi202b (NZO-derived obesity) and Sorcs1, Lisch-like, Tomosyn-2, App, Tsc2, and Ube2l6 (obesity caused by the ob or db mutation). Some of these genes have been shown to play a role in the regulation of the human glucose or lipid metabolism. Thus, dissection of the genetic basis of obesity and diabetes in mouse models can identify regulatory mechanisms that are relevant for the human disease.
Recently, epidemiological studies have suggested that fluoride is a human developmental neurotoxicant that reduces measures of intelligence in children, placing it into the same category as toxic ...metals (lead, methylmercury, arsenic) and polychlorinated biphenyls. If true, this assessment would be highly relevant considering the widespread fluoridation of drinking water and the worldwide use of fluoride in oral hygiene products such as toothpaste. To gain a deeper understanding of these assertions, we reviewed the levels of human exposure, as well as results from animal experiments, particularly focusing on developmental toxicity, and the molecular mechanisms by which fluoride can cause adverse effects. Moreover, in vitro studies investigating fluoride in neuronal cells and precursor/stem cells were analyzed, and 23 epidemiological studies published since 2012 were considered. The results show that the margin of exposure (MoE) between no observed adverse effect levels (NOAELs) in animal studies and the current adequate intake (AI) of fluoride (50 µg/kg b.w./day) in humans ranges between 50 and 210, depending on the specific animal experiment used as reference. Even for unusually high fluoride exposure levels, an MoE of at least ten was obtained. Furthermore, concentrations of fluoride in human plasma are much lower than fluoride concentrations, causing effects in cell cultures. In contrast, 21 of 23 recent epidemiological studies report an association between high fluoride exposure and reduced intelligence. The discrepancy between experimental and epidemiological evidence may be reconciled with deficiencies inherent in most of these epidemiological studies on a putative association between fluoride and intelligence, especially with respect to adequate consideration of potential confounding factors, e.g., socioeconomic status, residence, breast feeding, low birth weight, maternal intelligence, and exposure to other neurotoxic chemicals. In conclusion, based on the totality of currently available scientific evidence, the present review does not support the presumption that fluoride should be assessed as a human developmental neurotoxicant at the current exposure levels in Europe.
Nitrate is a natural constituent of the human diet and an approved food additive. It can be partially converted to nitrogen monoxide, which induces vasodilation and thereby decreases blood pressure. ...This effect is associated with a reduced risk regarding cardiovascular disease, myocardial infarction, and stroke. Moreover, dietary nitrate has been associated with beneficial effects in patients with gastric ulcer, renal failure, or metabolic syndrome. Recent studies indicate that such beneficial health effects due to dietary nitrate may be achievable at intake levels resulting from the daily consumption of nitrate‐rich vegetables. N‐nitroso compounds are endogenously formed in humans. However, their relevance for human health has not been adequately explored up to now. Nitrate and nitrite are per se not carcinogenic, but under conditions that result in endogenous nitrosation, it cannot be excluded that ingested nitrate and nitrite may lead to an increased cancer risk and may probably be carcinogenic to humans. In this review, the known beneficial and detrimental health effects related to dietary nitrate/nitrite intake are described and the identified gaps in knowledge as well as the research needs required to perform a reliable benefit/risk assessment in terms of long‐term human health consequences due to dietary nitrate/nitrite intake are presented.
The Senate Commission on Food Safety (SKLM) of the German Research Foundation (DFG) has reviewed the currently available data in order to assess the health risks associated with the use of ...acetaldehyde as a flavoring substance in foods. Acetaldehyde is genotoxic in vitro. Following oral intake of ethanol or inhalation exposure to acetaldehyde, systemic genotoxic effects of acetaldehyde in vivo cannot be ruled out (induction of DNA adducts and micronuclei). At present, the key question of whether acetaldehyde is genotoxic and mutagenic in vivo after oral exposure cannot be answered conclusively. There is also insufficient data on human exposure. Consequently, it is currently not possible to reliably assess the health risk associated with the use of acetaldehyde as a flavoring substance. However, considering the genotoxic potential of acetaldehyde as well as numerous data gaps that need to be filled to allow a comprehensive risk assessment, the SKLM considers that the use of acetaldehyde as a flavoring may pose a safety concern. For reasons of precautionary consumer protection, the SKLM recommends that the scientific base for approval of the intentional addition of acetaldehyde to foods as a flavoring substance should be reassessed.
Available data are reviewed in order to assess the health risks associated with the use of acetaldehyde as a flavoring substance in foods. Acetaldehyde is genotoxic in vitro but it is unclear whether it is genotoxic in vivo after oral exposure. Directly exposed tissues may be particularly affected. The exposure to acetaldehyde remains unclear. Considering the data gaps, it is concluded that use of acetaldehyde as a flavoring substance may pose a safety concern and should be re‐evaluated.
Type 2 diabetes (T2D) can be prevented in pre‐diabetic individuals with impaired glucose tolerance (IGT). Here, we have used a metabolomics approach to identify candidate biomarkers of pre‐diabetes. ...We quantified 140 metabolites for 4297 fasting serum samples in the population‐based Cooperative Health Research in the Region of Augsburg (KORA) cohort. Our study revealed significant metabolic variation in pre‐diabetic individuals that are distinct from known diabetes risk indicators, such as glycosylated hemoglobin levels, fasting glucose and insulin. We identified three metabolites (glycine, lysophosphatidylcholine (LPC) (18:2) and acetylcarnitine) that had significantly altered levels in IGT individuals as compared to those with normal glucose tolerance, with P‐values ranging from 2.4 × 10−4 to 2.1 × 10−13. Lower levels of glycine and LPC were found to be predictors not only for IGT but also for T2D, and were independently confirmed in the European Prospective Investigation into Cancer and Nutrition (EPIC)‐Potsdam cohort. Using metabolite–protein network analysis, we identified seven T2D‐related genes that are associated with these three IGT‐specific metabolites by multiple interactions with four enzymes. The expression levels of these enzymes correlate with changes in the metabolite concentrations linked to diabetes. Our results may help developing novel strategies to prevent T2D.
A targeted metabolomics approach was used to identify candidate biomarkers of pre‐diabetes. The relevance of the identified metabolites is further corroborated with a protein‐metabolite interaction network and gene expression data.
Synopsis
A targeted metabolomics approach was used to identify candidate biomarkers of pre‐diabetes. The relevance of the identified metabolites is further corroborated with a protein‐metabolite interaction network and gene expression data.
Three metabolites (glycine, lysophosphatidylcholine (LPC) (18:2) and acetylcarnitine C2) were found with significantly altered levels in pre‐diabetic individuals compared with normal controls.
Lower levels of glycine and LPC (18:2) were found to predict risks for pre‐diabetes and type 2 diabetes (T2D).
Seven T2D‐related genes (PPARG, TCF7L2, HNF1A, GCK, IGF1, IRS1 and IDE) are functionally associated with the three identified metabolites.
The unique combination of methodologies, including prospective population‐based and nested case–control, as well as cross‐sectional studies, was essential for the identification of the reported biomarkers.
Caloric restriction and intermittent fasting are known to improve glucose homeostasis and insulin resistance in several species including humans. The aim of this study was to unravel potential ...mechanisms by which these interventions improve insulin sensitivity and protect from type 2 diabetes. Diabetes-susceptible New Zealand Obese mice were either 10% calorie restricted (CR) or fasted every other day (IF), and compared to ad libitum (AL) fed control mice. AL mice showed a diabetes prevalence of 43%, whereas mice under CR and IF were completely protected against hyperglycemia. Proteomic analysis of hepatic lipid droplets revealed significantly higher levels of PSMD9 (co-activator Bridge-1), MIF (macrophage migration inhibitor factor), TCEB2 (transcription elongation factor B (SIII), polypeptide 2), ACY1 (aminoacylase 1) and FABP5 (fatty acid binding protein 5), and a marked reduction of GSTA3 (glutathione S-transferase alpha 3) in samples of CR and IF mice. In addition, accumulation of diacylglycerols (DAGs) was significantly reduced in livers of IF mice (P=0.045) while CR mice showed a similar tendency (P=0.062). In particular, 9 DAG species were significantly reduced in response to IF, of which DAG-40:4 and DAG-40:7 also showed significant effects after CR. This was associated with a decreased PKCε activation and might explain the improved insulin sensitivity. In conclusion, our data indicate that protection against diabetes upon caloric restriction and intermittent fasting associates with a modulation of lipid droplet protein composition and reduction of intracellular DAG species.
•Caloric restriction and intermittent fasting prevent hyperglycemia in NZO mice.•Proteomics of hepatic LDs found 22 proteins to be affected by food restriction.•Food restriction reduces hepatic diacylglycerol levels and PKCε activation.•Fatty acid oxidation is elevated in glycolytic muscles of intermittent fasted mice.•Caloric restriction and intermittent fasting enhance metabolic flexibility.
Purpose
To examine the association of red meat and whole-grain bread consumption with plasma levels of biomarkers related to glucose metabolism, oxidative stress, inflammation and obesity.
Methods
...Our cross-sectional study was based on 2,198 men and women who were selected as a sub-cohort for an investigation of biological predictors of diabetes and cardiovascular diseases from the European Prospective Investigation into Cancer and Nutrition-Potsdam study. Circulating levels of glycated hemoglobin, adiponectin, hs-CRP, gamma-glutamyltransferase, alanine-aminotransferase, fetuin-A, HDL-cholesterol and triglycerides were measured from random blood samples. Diet and lifestyle data were assessed by questionnaires, and anthropometric data were measured.
Results
After multivariable adjustment, higher consumption of whole-grain bread was significantly (
P
trend <0.05) associated with lower levels of GGT, ALT and hs-CRP, whereas higher consumption of red meat was significantly associated with higher levels of GGT and hs-CRP when adjusted for potential confounding factors related to lifestyle and diet. Further adjustment for body mass index and waist circumference attenuated the association between red meat and hs-CRP (
P
= 0.19).
Conclusions
The results of this study suggest that high consumption of whole-grain bread is related to lower levels of GGT, ALT and hs-CRP, whereas high consumption of red meat is associated with higher circulating levels of GGT and hs-CRP.
Plasma Fetuin-A Levels and the Risk of Type 2 Diabetes
Norbert Stefan 1 ,
Andreas Fritsche 1 ,
Cornelia Weikert 2 ,
Heiner Boeing 2 ,
Hans-Georg Joost 3 ,
Hans-Ulrich Häring 1 and
Matthias B. Schulze ...2 4
1 Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Disease and Clinical Chemistry,
University of Tübingen, Tübingen, Germany
2 Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
3 Department of Pharmacology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
4 Public Health Nutrition Unit, Technische Universität München, Freising, Germany
Corresponding author: Matthias B. Schulze, matthias.schulze{at}wzw.tum.de
Abstract
OBJECTIVE— The liver-secreted protein fetuin-A induces insulin resistance in animals, and circulating fetuin-A is elevated in insulin
resistance and fatty liver in humans. We investigated whether plasma fetuin-A levels predict the incidence of type 2 diabetes
in a large prospective, population-based study.
RESEARCH DESIGN AND METHODS— A case-cohort study within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study comprising
27,548 subjects was designed. We randomly selected a subcohort of 2,500 individuals of whom 2,164 were diabetes free at baseline
and had anamnestic, anthropometrical, and metabolic data for analysis. Of the 849 incident diabetic case subjects identified
in the full cohort during 7 years of follow-up, 703 remained for analyses after similar exclusions.
RESULTS— Plasma fetuin-A levels were positively associated with diabetes risk after adjustment for age (relative risk RR for extreme
quintiles 1.75 95% CI 1.32–2.31; RR for 10 μg/ml 1.04 1.03–1.06). The association remained significant after adjustment
for sex, BMI, waist circumference, and lifestyle risk factors (RR for 10 μg/ml 1.03 1.01–1.06). Adjustment for glucose,
triglycerides, HDL cholesterol, A1C, γ-glutamyltransferase, or high-sensitivity C-reactive protein or mutual adjustment for
these biomarkers did not appreciably change this result (RR for 10 μg/ml full adjusted model 1.05 1.02–1.07). Furthermore,
fetuin-A was associated with increased diabetes risk particularly in individuals with elevated plasma glucose.
CONCLUSIONS— Our data suggest that fetuin-A is an independent risk factor of type 2 diabetes.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 15 July 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted June 30, 2008.
Received April 22, 2008.
DIABETES
Fetuin-A, a protein almost exclusively secreted by the liver, induces insulin resistance and subclinical inflammation in rodents. Circulating fetuin-A levels are elevated in humans with metabolic ...syndrome and insulin resistance, conditions that are associated with increased risk of cardiovascular disease.
We investigated the association between fetuin-A levels and the risk of future myocardial infarction (MI) and ischemic stroke (IS) in a case-cohort study based on the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study comprising 27 548 middle-aged subjects of the general population. Fetuin-A levels were measured in plasma of 227 individuals who developed MI, in 168 who developed IS, and in 2198 individuals who remained free of cardiovascular events during a mean follow-up of 8.2+/-2.2 years. Individuals in the highest compared with the lowest quintile of plasma fetuin-A had significantly increased risks of MI (relative risk, 3.80; 95% confidence interval, 2.37 to 6.10; P for trend <0.0001) and IS (relative risk, 3.93; 95% confidence interval, 2.17 to 7.12; P for trend <0.0001) after adjustment for sex and age. Additional adjustment for smoking status, body mass index, waist circumference, alcohol consumption, educational attainment, physical activity, hypertension, diabetes mellitus, total and high-density lipoprotein cholesterol, and C-reactive protein only moderately attenuated these risks (MI: relative risk, 3.25; 95% confidence interval, 2.01 to 5.28; P for trend <0.0001; IS: relative risk, 3.78; 95% confidence interval, 2.06 to 6.94; P for trend <0.0001).
Our data provide evidence for a link between high plasma fetuin-A levels and an increased risk of MI and IS. Therefore, more research is warranted to determine the role of fetuin-A in the pathophysiology of cardiovascular disease.
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