query: Diabetes as a Disease of Fat Toxicity

positive: A Twenty-First Century Cancer Epidemic Caused by Obesity: The Involvement of Insulin, Diabetes, and Insulin-Like Growth Factors Obesity has reached epidemic proportions in the developed world. The progression from obesity to diabetes mellitus type 2, via metabolic syndrome, is recognised, and the significant associated increase in the risk of major human cancers acknowledged. We review the molecular basis of the involvement of morbidly high concentrations of endogenous or therapeutic insulin and of insulin-like growth factors in the progression from obesity to diabetes and finally to cancer. Epidemiological and biochemical studies establish the role of insulin and hyperinsulinaemia in cancer risk and progression. Insulin-like growth factors, IGF-1 and IGF-2, secreted by visceral or mammary adipose tissue have significant paracrine and endocrine effects. These effects can be exacerbated by increased steroid hormone production. Structural studies elucidate how each of the three ligands, insulin, IGF-1, and IGF-2, interacts differently with isoforms A and B of the insulin receptor and with type I IGF receptor and explain how these protagonists contribute to diabetes-associated cancer. The above should inform appropriate treatment of cancers that arise in obese individuals and in those with diabetes mellitus type 2. Novel drugs that target the insulin and insulin-like growth factor signal transduction pathways are in clinical trial and should be effective if appropriate biomarker-informed patient stratification is implemented.

positive: Pathogenesis of type 2 diabetes: tracing the reverse route from cure to cause. The metabolic abnormalities of type 2 diabetes can be reversed reproducibly by bariatric surgery. By quantifying the major pathophysiological abnormalities in insulin secretion and insulin action after surgery, the sequence of events leading to restoration of normal metabolism can be defined. Liver fat levels fall within days and normal hepatic insulin sensitivity is restored. Simultaneously, plasma glucose levels return towards normal. Insulin sensitivity of muscle remains abnormal, at least over the weeks and months after bariatric surgery. The effect of the surgery is explicable solely in terms of energy restriction. By combining this information with prospective observation of the changes immediately preceding the onset of type 2 diabetes, a clear picture emerges. Insulin resistance in muscle, caused by inherited and environmental factors, facilitates the development of fatty liver during positive energy balance. Once established, the increased insulin secretion required to maintain plasma glucose levels will further increase liver fat deposition. Fatty liver causes resistance to insulin suppression of hepatic glucose output as well as raised plasma triacylglycerol. Exposure of beta cells to increased levels of fatty acids, derived from circulating and locally deposited triacylglycerol, suppresses glucose-mediated insulin secretion. This is reversible initially, but eventually becomes permanent. The essential time sequence of the pathogenesis of type 2 diabetes is now evident. Muscle insulin resistance determines the rate at which fatty liver progresses, and ectopic fat deposition in liver and islet underlies the related dynamic defects of hepatic insulin resistance and beta cell dysfunction. These defects are capable of dramatic reversal under hypoenergetic feeding conditions, completely in early diabetes and to a worthwhile extent in more established disease.

positive: Banting Memorial Lecture 2012 Reversing the twin cycles of Type 2 diabetes It has become widely accepted that Type 2 diabetes is inevitably life-long, with irreversible and progressive beta cell damage. However, the restoration of normal glucose metabolism within days after bariatric surgery in the majority of people with Type 2 diabetes disproves this concept. There is now no doubt that this reversal of diabetes depends upon the sudden and profound decrease in food intake, and does not relate to any direct surgical effect. The Counterpoint study demonstrated that normal glucose levels and normal beta cell function could be restored by a very low calorie diet alone. Novel magnetic resonance methods were applied to measure intra-organ fat. The results showed two different time courses: a) resolution of hepatic insulin sensitivity within days along with a rapid fall in liver fat and normalisation of fasting glucose levels; and b) return of normal beta cell insulin secretion over weeks in step with a fall in pancreas fat. Now that it has been possible to observe the pathophysiological events during reversal of Type 2 diabetes, the reverse time course of events which determine the onset of the condition can be identified. The twin cycle hypothesis postulates that chronic calorie excess leads to accumulation of liver fat with eventual spill over into the pancreas. These self-reinforcing cycles between liver and pancreas eventually cause metabolic inhibition of insulin secretion after meals and onset of hyperglycaemia. It is now clear that Type 2 diabetes is a reversible condition of intra-organ fat excess to which some people are more susceptible than others.

positive: Relationship of dietary fat to glucose metabolism. The relationship between dietary fat and glucose metabolism has been recognized for at least 60 years. In experimental animals, high fat diets result in impaired glucose tolerance. This impairment is associated with decreased basal and insulin-stimulated glucose metabolism. Impaired insulin binding and/or glucose transporters has been related to changes in the fatty acid composition of the membrane induced by dietary fat modification. In humans, high-fat diets, independent of fatty acid profile, have been reported to result in decreased insulin sensitivity. Saturated fat, relative to monounsaturated and polyunsaturated fat, appears to be more deleterious with respect to fat-induced insulin insensitivity. Some of the adverse effects induced by fat feeding can be ameliorated with omega-3 fatty acid. Epidemiological data in humans suggest that subjects with higher intakes of fat are more prone to develop disturbances in glucose metabolism, type 2 diabetes or impaired glucose tolerance, than subjects with lower intakes of fat. Inconsistencies in the data may be attributable to clustering of high intakes of dietary fat (especially animal fat) with obesity and inactivity. Metabolic studies suggest that higher-fat diets containing a higher proportion of unsaturated fat result in better measures of glucose metabolism than high-carbohydrate diet. Clearly, the area of dietary fat and glucose metabolism has yet to be fully elucidated.

positive: Free fatty acids and skeletal muscle insulin resistance. PURPOSE OF REVIEW: Acute exposure to fatty acids causes insulin resistance in muscle, and excess dietary lipid and obesity are also strongly associated with muscle insulin resistance. Relevant mechanisms, however, are still not fully elucidated. Here we examine the latest evidence as to why lipids might accumulate in muscle and the possible mechanisms for lipid-induced insulin resistance. RECENT FINDINGS: Muscle lipid metabolites such as long chain fatty acid coenzyme As, diacylglycerol and ceramides may impair insulin signalling directly. Crosstalk between inflammatory signalling pathways and insulin signalling pathways, mitochondrial dysfunction and oxidative stress have also been put forward as major contributors to the development or maintenance of lipid-induced insulin resistance in muscle. Several animal models with gene deletions in pathways of fatty acid synthesis and storage also show increased metabolic rate, reduced intramuscular lipid storage and improved insulin action when challenged with a high lipid load. SUMMARY: Studies in genetic and dietary obese animal models, genetically modified animals and humans with obesity or type 2 diabetes suggest plausible mechanisms for effects of fatty acids, lipid metabolites, inflammatory pathways and mitochondrial dysfunction on insulin action in muscle. Many of these mechanisms, however, have been demonstrated in situations in which lipid accumulation (obesity) already exists. Whether the initial events leading to muscle insulin resistance are direct effects of fatty acids in muscle or are secondary to lipid accumulation in adipose tissue or liver remains to be clarified.

positive: Prediabetes: A high-risk state for developing diabetes Summary Prediabetes (or “intermediate hyperglycaemia”), based on glycaemic parameters above normal but below diabetes thresholds is a high risk state for diabetes with an annualized conversion rate of 5%–10%; with similar proportion converting back to normoglycaemia. The prevalence of prediabetes is increasing worldwide and it is projected that >470 million people will have prediabetes in 2030. Prediabetes is associated with the simultaneous presence of insulin resistance and β-cell dysfunction, abnormalities that start before glucose changes are detectable. Observational evidence shows associations of prediabetes with early forms of nephropathy, chronic kidney disease, small fibre neuropathy, diabetic retinopathy, and increased risk of macrovascular disease. Multifactorial risk scores could optimize the estimation of diabetes risk using non-invasive parameters and blood-based metabolic traits in addition to glycaemic values. For prediabetic individuals, lifestyle modification is the cornerstone of diabetes prevention with evidence of a 40%–70% relative risk reduction. Accumulating data also suggests potential benefits from pharmacotherapy.

positive: Consumption of whole grain reduces risk of deteriorating glucose tolerance, including progression to prediabetes. BACKGROUND: High whole-grain intake has been reportedly associated with reduced risk of developing type 2 diabetes (T2D), which is an effect possibly subject to genetic effect modification. Confirmation in prospective studies and investigations on the impact on prediabetes is needed. OBJECTIVES: In a prospective population-based study, we investigated whether a higher intake of whole grain protects against the development of prediabetes and T2D and tested for modulation by polymorphisms of the TCF7L2 gene. DESIGN: We examined the 8-10-y incidence of prediabetes (impaired glucose tolerance, impaired fasting glucose, or the combination of both) and T2D in relation to the intake of whole grain. Baseline data were available for 3180 women and 2297 men aged 35-56 y. RESULTS: A higher intake of whole grain (>59.1 compared with <30.6 g/d) was associated with a 34% lower risk to deteriorate in glucose tolerance (to prediabetes or T2D; women and men combined). The association remained after adjustments for age, family history of diabetes, BMI, physical activity, smoking, education, and blood pressure (OR: 0.78; 95% CI: 0.63, 0.96). Risk reduction was significant in men (OR: 0.65; 95% CI: 0.49, 0.85) but not in women. Associations were significant for prediabetes per se (all, OR: 0.73; 95% CI: 0.56, 0.94; men, OR: 0.57; 95% CI: 0.40, 0.80). The intake of whole grain correlated inversely with insulin resistance (HOMA-IR). The impact of whole-grain intake was undetectable in men who harbored diabetogenic polymorphisms of the TCF7L2 gene. CONCLUSIONS: A higher intake of whole grain is associated with decreased risk of deteriorating glucose tolerance including progression from normal glucose tolerance to prediabetes by mechanisms likely tied to effects on insulin sensitivity. Effect modifications by TCF7L2 genetic polymorphisms are supported.

positive: The early treatment of type 2 diabetes. The growing epidemic of type 2 diabetes is one of the leading causes of premature morbidity and mortality worldwide, mainly due to the micro- and macrovascular complications associated with the disease. A growing body of evidence suggests that although the risk of developing complications is greater with glucose levels beyond the established threshold for diagnosis--increasing in parallel with rising hyperglycemia-individuals with glucose levels in the prediabetic range are already at increased risk. Early intervention, ideally as soon as abnormalities in glucose homeostasis are detected, is of great importance to minimize the burden of the disease. However, as the early stages of the disease are asymptomatic, diagnosing prediabetes and early overt type 2 diabetes is challenging. The aim of this article is to discuss these challenges, the benefits of early intervention--with emphasis on the prevention trials showing that progression to type 2 diabetes can be delayed by addressing prediabetes--and the existing evidence-based guidelines that have been drawn to optimize the standards of care at the prediabetes and overt type 2 diabetes stages. Copyright © 2013. Published by Elsevier Inc.

positive: Crossing the Quality Chasm: A New Health System for the 21st Century Excerpt Second in a series of publications from the Institute of Medicine's Quality of Health Care in America project Today's health care providers have more research findings and more technology available to them than ever before. Yet recent reports have raised serious doubts about the quality of health care in America. Crossing the Quality Chasm makes an urgent call for fundamental change to close the quality gap. This book recommends a sweeping redesign of the American health care system and provides overarching principles for specific direction for policymakers, health care leaders, clinicians, regulators, purchasers, and others. In this comprehensive volume the committee offers: A set of performance expectations for the 21st century health care system. A set of 10 new rules to guide patient-clinician relationships. A suggested organizing framework to better align the incentives inherent in payment and accountability with improvements in quality. Key steps to promote evidence-based practice and strengthen clinical information systems. Analyzing health care organizations as complex systems, Crossing the Quality Chasm also documents the causes of the quality gap, identifies current practices that impede quality care, and explores how systems approaches can be used to implement change. Copyright 2001 by the National Academy of Sciences. All rights reserved.

positive: Daily flaxseed consumption improves glycemic control in obese men and women with pre-diabetes: a randomized study. The study hypothesis was that fasting glucose, insulin, fructosamine, C-reactive protein, and interleukin-6 decrease and adiponectin increases with daily flaxseed consumption in overweight or obese individuals with pre-diabetes. In this randomized, cross-over study overweight or obese men and postmenopausal women (n = 25) with pre-diabetes consumed 0, 13, or 26 g ground flaxseed for 12 weeks. Glucose, insulin, homeostatic model assessment (HOMA-IR), and normalized percent of α-linolenic fatty acid (ALA) were significantly different by treatment (multiple analysis of variance, P = .036, P = .013, P = .008, P = .024 respectively). Paired t tests showed glucose decreased on the 13 g intervention compared to the 0 g period [13 g = -2.10 ± 1.66 mg/L (mean ± SEM), 0 g = 9.22 ± 4.44 mg/L, P = .036]. Insulin decreased on the 13 g intervention but not the 26 g (P = .021) and 0 g (P = .013) periods (13 g = -2.12 ± 1.00 mU/L, 26 g = 0.67 ± 0.84 mU/L, 0 g = 1.20 ± 1.16 mU/L). HOMA-IR decreased on the 13 g period but not on the 26 g (P = .012) and 0 g (P = .008) periods (13 g = -0.71 ± 0.31, 26 g = 0.27 ± 0.24, 0 g = 0.51 ± 0.35). The α-linolenic fatty acid decrease for the 0 g period was different than the 13 g (P = .024) and 26 g (P = .000) periods (13 g = 0.20 ± 0.04, 26 g = 0.35 ± 0.07, 0 g = -0.01 ± 0.07). Fructosamine, high sensitivity C-reactive protein, adiponectin, and high-sensitivity interleukin-6 had no significant differences. Flaxseed intake decreased glucose and insulin and improved insulin sensitivity as part of a habitual diet in overweight or obese individuals with pre-diabetes. Copyright © 2013 Elsevier Inc. All rights reserved.

positive: Environmental contaminants as risk factors for developing diabetes. The contribution of exposure to persistent organic pollutants (POPs) to the incidence of diabetes has received little attention until recently. A number of reports have emerged, however, concerning elevated diabetes in persons occupationally exposed to dioxin. United States (US) Air Force personnel in Vietnam who sprayed Agent Orange containing dioxin as a contaminant had elevated rates of diabetes, leading to US government compensation for diabetes in these veterans. Recent studies in populations exposed to polychlorinated biphenyls (PCBs) and chlorinated pesticides found a dose-dependent elevated risk of diabetes. An elevation in risk of diabetes in relation to levels of several POPs has been demonstrated by two different groups using the National Health and Nutrition Examination Survey (NHANES), a random sampling of US citizens. The strong associations seen in quite different studies suggest the possibility that exposure to POPs could cause diabetes. One striking observation is that obese persons that do not have elevated POPs are not at elevated risk of diabetes, suggesting that the POPs rather than the obesity per se is responsible for the association. Although a specific mechanism is not known, most POPs induce a great number and variety of genes, including several that alter insulin action. Because diabetes is a dangerous disease that is increasing in frequency throughout the world, further study of the possibility that exposure to POPs contributes to the etiology of diabetes is critical.

positive: Fish and Marine Omega-3 Polyunsatured Fatty Acid Consumption and Incidence of Type 2 Diabetes: A Systematic Review and Meta-Analysis Objective. To examine the association between fish and marine long-chain omega-3 polyunsaturated fatty acid (LC n-3 PUFA) consumption and incidence of type 2 diabetes (T2D) in prospective cohort studies. Methods. Meta-analytic procedures were used to estimate the relative risk (RR) using random effects or fixed effects generic inverse variance model. Publication bias and study heterogeneity were assessed using Egger's test and I2 statistic. Results. We found no significant association between the intake of fish/seafood (pooled RR: 1.04; P = 0.63, 95% CI: 0.9 to 1.2, 549, 955 participants) or marine LC n-3 PUFA (pooled RR: 1.08, P = 0.39, 95% CI: 0.90 to 1.30, 346, 710 participants) and T2D risk. Significant study heterogeneity was observed in fish/seafood and marine LC n-3 PUFA studies (P < 0.00001). Subgroup analysis revealed no obvious sources for high heterogeneity. We also found a significant protective effect of oily fish intake on T2D risk (pooled RR = 0.89, P = 0.005, 95% CI: 0.82 to 0.96). Dose-response analysis suggested that every 80 g per day intake of oily fish may reduce 20% risk of T2D. Conclusion. We found no significant effect of fish/seafood or marine LC n-3 PUFA intake on risk of T2D but a significant effect of oily fish intake on risk of T2D.

positive: Public health concern behind the exposure to persistent organic pollutants and the risk of metabolic diseases Background Persistent organic pollutants (POPs) are hazardous chemicals omnipresent in our food chain, which have been internationally regulated to ensure public health. Initially described for their potency to affect reproduction and promote cancer, recent studies have highlighted an unexpected implication of POPs in the development of metabolic diseases like type 2 diabetes and obesity. Based on this novel knowledge, this article aims at stimulating discussion and evaluating the effectiveness of current POP legislation to protect humans against the risk of metabolic diseases. Furthermore, the regulation of POPs in animal food products in the European Union (EU) is addressed, with a special focus on marine food since it may represent a major source of POP exposure to humans. Discussion There is mounting scientific evidence showing that current POP risk assessment and regulation cannot effectively protect humans against metabolic disorders. Better regulatory control of POPs in dietary products should be of high public health priority. Summary The general population is exposed to sufficient POPs, both in term of concentration and diversity, to induce metabolic disorders. This situation should attract the greatest attention from the public health and governmental authorities.

positive: Fish Consumption, Dietary Long-Chain n-3 Fatty Acids, and Risk of Type 2 Diabetes OBJECTIVE The evidence on the association between fish consumption, dietary long-chain n-3 fatty acids, and risk of type 2 diabetes is inconsistent. We therefore performed a systematic review and meta-analysis of the available prospective evidence. RESEARCH DESIGN AND METHODS Studies were identified by searching the PubMed and EMBASE databases through 15 December 2011 and by reviewing the reference lists of retrieved articles. Prospective studies were included if they reported relative risk (RR) estimates with 95% CIs for the association between fish consumption and/or dietary long-chain n-3 fatty acids and incidence of type 2 diabetes. A dose-response random-effects model was used to combine study-specific RRs. Potential sources of heterogeneity were explored by prespecified stratifications. RESULTS Sixteen studies involving 527,441 participants and 24,082 diabetes cases were included. Considerable statistical heterogeneity in the overall summary estimates was partly explained by geographical differences. For each serving per week increment in fish consumption, the RRs (95% CIs) of type 2 diabetes were 1.05 (1.02–1.09), 1.03 (0.96–1.11), and 0.98 (0.97–1.00) combining U.S., European, and Asian/Australian studies, respectively. For each 0.30 g per day increment in long-chain n-3 fatty acids, the corresponding summary estimates were 1.17 (1.09–1.26), 0.98 (0.70–1.37), and 0.90 (0.82–0.98). CONCLUSIONS Results from this meta-analysis indicate differences between geographical regions in observed associations of fish consumption and dietary intake of long-chain n-3 fatty acids with risk of type 2 diabetes. In consideration of the heterogeneous results, the relationship warrants further investigation. Meanwhile, current public health recommendations on fish consumption should be upheld unchanged.

positive: Marine N-3 Polyunsaturated Fatty Acids Are Inversely Associated with Risk of Type 2 Diabetes in Asians: A Systematic Review and Meta-Analysis Background Prospective cohort studies in relation to the associations between n-3 polyunsaturated fatty acids (PUFA) and risk of type 2 diabetes (T2D) were inconsistent. Differences in tissue n-3 PUFA compositions in subjects with and without T2D were also inconsistent in both cohort and case-control studies. We conducted a systematic review and meta-analysis of prospective cohort studies to examine the associations of fish and n-3 PUFA intake with T2D risk. The differences in tissue n-3 PUFA compositions in subjects with and without T2D were investigated based on cohort and case-control studies. Methods and Findings PubMed, Embase, Cochrane library, China National Knowledge Infrastructure (CNKI) and Chinese VIP database up to January 2012 was used to identify relevant studies, and reference lists from retrieved studies were reviewed. Two authors independently extracted the data. Random-effects models were used to pool the summary relative risk (RR). Twenty-four studies including 24,509 T2D patients and 545,275 participants were identified. For cohort studies, the summary RR of T2D for the highest vs lowest categories of total fish, marine n-3 PUFA and alpha-linolenic acid intake was 1.07 (95% CI: 0.91, 1.25), 1.07 (95% CI: 0.95, 1.20) and 0.93 (95% CI: 0.81, 1.07), respectively. Subgroup analyses indicated that summary RR (highest vs lowest category) of T2D for fish and marine n-3 PUFA intake was 0.89 (95% CI: 0.81, 0.98) and 0.87 (95% CI: 0.79, 0.96) for Asian populations, and 1.20 (95% CI: 1.01, 1.44) and 1.16 (95% CI: 1.04, 1.28) for Western populations. Asian subjects with T2D had significantly lower tissue compositions of C22∶6n-3 (SMD: −1.43; 95% CI: −1.75, −1.12) and total n-3 PUFA (SMD: −1.41; 95% CI: −2.23, −0.59) compared with those without T2D. Conclusion This systematic review and meta-analysis provides evidence that marine n-3 PUFA have beneficial effects on the prevention of T2D in Asian populations.

positive: Fish consumption, insulin sensitivity and beta-cell function in the Insulin Resistance Atherosclerosis Study (IRAS) Background and aims Previous research on the association between fish consumption and incident type 2 diabetes has been inconclusive. In addition, few studies have investigated how fish consumption may be related to the metabolic abnormalities underlying diabetes. Therefore, we examined the association of fish consumption with measures of insulin sensitivity and beta-cell function in a multi-ethnic population. Methods and results We examined the cross-sectional association between fish consumption and measures of insulin sensitivity and secretion in 951 non-diabetic participants in the Insulin Resistance Atherosclerosis Study (IRAS). Fish consumption, categorized as <2 vs. ≥2 portions/week, was measured using a validated food frequency questionnaire. Insulin sensitivity (SI) and acute insulin response (AIR) were determined from frequently sampled intravenous glucose tolerance tests. Higher fish consumption was independently associated with lower SI-adjusted AIR (β=−0.13 [−0.25, −0.016], p=0.03, comparing ≥ 2 vs. <2 portions/week). Fish consumption was positively associated with intact and split proinsulin/C-peptide ratios, however, these associations were confounded by ethnicity (multivariable-adjusted β=0.073 [−0.014, 0.16] for intact proinsulin/C-peptide ratio, β=0.031 [−0.065, 0.13] for split proinsulin/C-peptide ratio). We also observed a significant positive association between fish consumption and fasting blood glucose (multivariable-adjusted β=2.27 [0.68, 3.86], p=0.005). We found no association between fish consumption and SI (multivariable-adjusted β= −0.015 [−0.083, 0.053]) or fasting insulin (multivariable-adjusted β=0.016 [−0.066, 0.10]). Conclusions Fish consumption was not associated with measures of insulin sensitivity in the multi-ethnic IRAS cohort. However, higher fish consumption may be associated with pancreatic beta-cell dysfunction.

positive: Omega-3 Fatty Acids and incident Type 2 Diabetes: A Systematic Review and Meta-Analysis The relationship between omega-3 polyunsaturated fatty acids (n-3 PUFA) from seafood (eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA) or plant (alpha-linolenic acid, ALA) sources and risk of type 2 diabetes mellitus (DM) remains unclear. We systematically searched multiple literature databases through June 2011 to identify prospective studies examining relations of dietary n-3 PUFA, dietary fish and/or seafood, and circulating n-3 PUFA biomarkers with incidence of DM. Data were independently extracted in duplicate by 2 investigators, including multivariate-adjusted relative risk (RR) estimates and corresponding 95% CIs. Generalized least-squares trend estimation was used to assess dose-response relationships, with pooled summary estimates calculated by both fixed-effect and random-effect models. From 288 identified abstracts, 16 studies met inclusion criteria, including 18 separate cohorts comprising 540,184 individuals and 25,670 cases of incident DM. Consumption of fish and/or seafood was not significantly associated with DM (n=13 studies; RR per 100g/d=1.12, 95% CI=0.94, 1.34); nor were consumption of EPA+DHA (n=16 cohorts; RR per 250mg/d=1.04, 95% CI=0.97, 1.10) or circulating levels of EPA+DHA biomarkers (n=5 cohorts; RR per 3% of total fatty acids=0.94, 95% CI=0.75, 1.17). Both dietary ALA (n=7 studies; RR per 0.5g/d=0.93, 95% CI=0.83, 1.04) and circulating ALA biomarker levels (n=6 studies; RR per 0.1% of total fatty acid=0.90, 95% CI=0.80, 1.00, P=0.06) were associated with non-significant trend towards lower risk of DM. Substantial heterogeneity (I2~80%) was observed among studies of fish/seafood or EPA+DHA and DM; moderate heterogeneity (<55%) was seen for dietary and biomarker ALA and DM. In unadjusted meta-regressions, study location (Asia vs. North America/Europe), mean BMI, and duration of follow-up each modified the association between fish/seafood and EPA+DHA consumption and DM risk (P-Interaction ≤ 0.02 each). We had limited statistical power to determine the independent effect of these sources of heterogeneity due to their high collinearity. The overall pooled findings do not support either major harms or benefits of fish/seafood or EPA+DHA on development of DM, and suggest that ALA may be associated with modestly lower risk. Reasons for potential heterogeneity of effects, which could include true biologic heterogeneity, publication bias, or chance, deserve further investigation.

positive: Fish oil supplementation in type 2 diabetes: a quantitative systematic review. OBJECTIVE: To determine the effects of fish oil supplementation on lipid levels and glycemic control in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A comprehensive search of Medline, Embase, Lilacs, the Cochrane Clinical Trials Registry bibliographies of relevant papers, and expert input updated through September 1998 was undertaken. All randomized placebo-controlled trials were included in which fish oil supplementation was the only intervention in subjects with type 2 diabetes. Three investigators performed data extraction and quality scoring independently with discrepancies resolved by consensus. Eighteen trials including 823 subjects followed for a mean of 12 weeks were included. Doses of fish oil used ranged from 3 to 18 g/day The outcomes studied were glycemic control and lipid levels. RESULTS: Meta-analysis of pooled data demonstrated a statistically significant effect of fish oil on lowering triglycerides (-0.56 mmol/l [95% CI -0.71 to -0.41]) and raising LDL cholesterol (0.21 mmol/l [0.02 to 0.41]). No statistically significant effect was observed for fasting glucose. HbA1c total cholesterol, or HDL cholesterol. The triglyceride-lowering effect and the elevation in LDL cholesterol were most marked in those trials that recruited hypertriglyceridemic subjects and used higher doses of fish oil. Heterogeneity was observed and explained by the recruitment of subjects with baseline hypertriglyceridemia in some studies. CONCLUSIONS: Fish oil supplementation in type 2 diabetes lowers triglycerides, raises LDL cholesterol, and has no statistically significant effect on glycemic control. Trials with hard clinical end points are needed.

positive: Association of fish and n-3 fatty acid intake with the risk of type 2 diabetes: a meta-analysis of prospective studies. Results from observational studies on the association of fish and n-3 fatty acid consumption with type 2 diabetes mellitus (T2DM) risk are conflicting. Hence, a meta-analysis was performed to investigate this association from cohort studies. A comprehensive search was then conducted to identify cohort studies on the association of fish and/or n-3 fatty acid intake with T2DM risk. In the highest v. lowest categorical analyses, the fixed or random-effect model was selected based on the homogeneity test among studies. Linear and non-linear dose-response relationships were also assessed by univariate and bivariate random-effect meta-regression with restricted maximum likelihood estimation. In the highest v. lowest categorical analyses, the pooled relative risk (RR) of T2DM for intake of fish and n-3 fatty acid was 1·146 (95 % CI 0·975, 1·346) and 1·076 (95 % CI 0·955, 1·213), respectively. In the linear dose-response relationship, the pooled RR for an increment of one time (about 105 g)/week of fish intake (four times/month) and of 0·1 g/d of n-3 fatty acid intake was 1·042 (95 % CI 1·026, 1·058) and 1·057 (95 % CI 1·042, 1·073), respectively. The significant non-linear dose-response associations of fish and n-3 fatty acid intake with T2DM risk were not observed. The present evidence from observational studies suggests that the intake of both fish and n-3 fatty acids might be weakly positively associated with the T2DM risk. Further studies are needed to confirm these results.

positive: Egg consumption and the risk of type 2 diabetes mellitus: a case-control study. OBJECTIVE: Type 2 diabetes mellitus appears to involve an interaction between susceptible genetic backgrounds and environmental factors including highly calorific diets. As it is important to identify modifiable risk factors that may help reduce the risk of type 2 diabetes mellitus, the aim of the present study was to determine the association between egg consumption and the risk of type 2 diabetes mellitus. DESIGN: A specifically designed questionnaire was used to collect information on possible risk factors of type 2 diabetes mellitus. The odds ratios and 95 % confidence intervals for type 2 diabetes mellitus were calculated by conditional logistic regression. SETTING: A case-control study in a Lithuanian out-patient clinic was performed in 2001. SUBJECTS: A total of 234 cases with a newly confirmed diagnosis of type 2 diabetes mellitus and 468 controls free of the disease. RESULTS: Variables such as BMI, family history of diabetes, cigarette smoking, education, morning exercise and plasma TAG level were retained in multivariate logistic regression models as confounders because their inclusion changed the value of the odds ratio by more than 10 % in any exposure category. After adjustment for possible confounders more than twofold increased risk of type 2 diabetes mellitus was determined for individuals consuming 3-4·9 eggs/week (OR = 2·60; 95 % CI 1·34, 5·08) and threefold increased risk of the disease was determined for individuals consuming ≥5 eggs/week (OR = 3·02; 95 % CI 1·14, 7·98) compared with those eating <1 egg/week. CONCLUSIONS: Our data support a possible relationship of egg consumption and increased risk of type 2 diabetes mellitus.

positive: Egg Consumption and Cardiovascular Disease and Mortality The Physicians' Health Study Background Reduction in dietary cholesterol is recommended to prevent cardiovascular disease (CVD). Although eggs are important sources of cholesterol and other nutrients, limited and inconsistent data are available on the effects of egg consumption on the risk of CVD and mortality. Objectives To examine the association between egg consumption and the risk of CVD and mortality. Design Prospective cohort study of 21,327 participants from the Physicians' Health Study I. Egg consumption was assessed using a simple abbreviated food questionnaire. We used Cox regression to estimate relative risks. Results After an average follow up of 20 years, a total of 1,550 new myocardial infarction (MI), 1,342 incident strokes, and 5,169 deaths occurred in this cohort. Egg consumption was not associated with incident MI or stroke in a multivariable Cox regression. In contrast, adjusted hazard ratios (95% CI) for mortality were 1.0 (reference), 0.94 (0.87-1.02), 1.03 (0.95-1.11), 1.05 (0.93-1.19), and 1.23 (1.11-1.36) for egg consumption of <1, 1, 2-4, 5-6, and 7+ per week, respectively, (p for trend <0.0001). This association was stronger among diabetic subjects with a 2-fold increased risk of death comparing the highest to the lowest category of egg consumption than non-diabetic subjects (HR: 1.22 (1.09-1.35) (p for interaction 0.09). Conclusions Our data suggest that infrequent egg consumption does not influence the risk of CVD and only confers a modest increased risk for total mortality in male physicians. In addition, egg consumption was positively related to mortality and such relation was stronger among diabetic subjects in this selective population.

positive: Egg consumption and the risk of diabetes in adults, Jiangsu, China. BACKGROUND: Although egg consumption has been associated with elevated plasma levels of cholesterol and triglyceride and with risk of cardiovascular disease in some populations, epidemiologic studies on egg consumption and the risk of diabetes are extremely sparse, particularly in the Chinese population. METHOD: Data from a household survey in the year 2002 among 2849 adults aged ≥20 y from a nationally representative sample in Jiangsu Province, China, were used. Dietary information was assessed by a validated food frequency questionnaire and 3 d weighed food records. Fasting blood specimens were collected. RESULTS: After the adjustment for age, total calorie intake, education, smoking, family history of diabetes, and sedentary activity, egg consumption was significantly and positively associated with diabetes risk, particularly in women. The odds ratios (OR) (95% CI) of diabetes associated with egg consumption <2/wk, 2-6/wk, and ≥1/d in the total sample were 1.00, 1.75, 2.28 (1.14-4.54), respectively (P for trend 0.029). Corresponding ORs (95% CI) in women were 1.00, 1.66, and 3.01 (1.12, 8.12), respectively (P for trend 0.022). Additional adjustment of body mass index attenuated the association, but it remained significant. There was a similar, however, not statistically significant association in men. In addition, plasma triglyceride and total cholesterol levels were significantly higher in women who consumed ≥2 eggs/wk than those who consumed eggs less often. CONCLUSION: Egg consumption was positively associated with the risk of diabetes among the Chinese, particularly in women. Copyright Â© 2011 Elsevier Inc. All rights reserved.

positive: Egg consumption and risk of type 2 diabetes in older adults Background: Type 2 diabetes (T2D) remains an important public health issue in the United States. There are limited and inconsistent data on the association between egg consumption and fasting glucose or incident diabetes. Objectives: We assessed the association between egg intake and incident diabetes in older adults. Design: In this prospective study of 3898 men and women from the Cardiovascular Health Study (1989–2007), we assessed egg consumption by using a picture-sorted food questionnaire and ascertained incident T2D annually by using information on hypoglycemic agents and plasma glucose. We used Cox proportional hazards models to estimate adjusted relative risks. Results: During a mean follow-up of 11.3 y, 313 new cases of T2D occurred. Crude incidence rates of T2D were 7.39, 6.83, 7.00, 6.72, and 12.20 per 1000 person-years in people who reported egg consumption of never, <1 egg/mo, 1–3 eggs/mo, 1–4 eggs/wk, and almost daily, respectively. In multivariable-adjusted models, there was no association between egg consumption and increased risk of T2D in either sex and overall. In a secondary analysis, dietary cholesterol was not associated with incident diabetes (P for trend = 0.47). In addition, egg consumption was not associated with clinically meaningful differences in fasting glucose, fasting insulin, or measures of insulin resistance despite small absolute analytic differences that were significant. Conclusion: In this cohort of older adults with limited egg intake, there was no association between egg consumption or dietary cholesterol and increased risk of incident T2D.

positive: Egg Consumption and Risk of Type 2 Diabetes in Men and Women OBJECTIVE—Whereas limited and inconsistent findings have been reported on the relation between dietary cholesterol or egg consumption and fasting glucose, no previous study has examined the association between egg consumption and type 2 diabetes. This project sought to examine the relation between egg intake and the risk of type 2 diabetes in two large prospective cohorts. RESEARCH DESIGN AND METHODS—In this prospective study, we used data from two completed randomized trials: 20,703 men from the Physicians' Health Study I (1982–2007) and 36,295 women from the Women's Health Study (1992–2007). Egg consumption was ascertained using questionnaires, and we used the Cox proportional hazard model to estimate relative risks of type 2 diabetes. RESULTS—During mean follow-up of 20.0 years in men and 11.7 years in women, 1,921 men and 2,112 women developed type 2 diabetes. Compared with no egg consumption, multivariable adjusted hazard ratios for type 2 diabetes were 1.09 (95% CI 0.87–1.37), 1.09 (0.88–1.34), 1.18 (0.95–1.45), 1.46 (1.14–1.86), and 1.58 (1.25–2.01) for consumption of <1, 1, 2–4, 5–6, and ≥7 eggs/week, respectively, in men (P for trend <0.0001). Corresponding multivariable hazard ratios for women were 1.06 (0.92–1.22), 0.97 (0.83–1.12), 1.19 (1.03–1.38), 1.18 (0.88–1.58), and 1.77 (1.28–2.43), respectively (P for trend <0.0001). CONCLUSIONS—These data suggest that high levels of egg consumption (daily) are associated with an increased risk of type 2 diabetes in men and women. Confirmation of these findings in other populations is warranted.

positive: High intakes of protein and processed meat associate with increased incidence of type 2 diabetes. Diets high in protein have shown positive effects on short-term weight reduction and glycaemic control. However, the understanding of how dietary macronutrient composition relates to long-term risk of type 2 diabetes is limited. The aim of the present study was to examine intakes of macronutrients, fibre and protein sources in relation to incident type 2 diabetes. In total, 27 140 individuals, aged 45-74 years, from the population-based Malmö Diet and Cancer cohort, were included. Dietary data were collected with a modified diet history method, including registration of cooked meals. During 12 years of follow-up, 1709 incident type 2 diabetes cases were identified. High protein intake was associated with increased risk of type 2 diabetes (hazard ratio (HR) 1.27 for highest compared with lowest quintile; 95 % CI 1.08, 1.49; P for trend = 0.01). When protein consumption increased by 5 % of energy at the expense of carbohydrates (HR 1.20; 95 % CI 1.09, 1.33) or fat (HR 1.21; 95 % CI 1.09, 1.33), increased diabetes risk was observed. Intakes in the highest quintiles of processed meat (HR 1.16; 95 % CI 1.00, 1.36; P for trend = 0.01) and eggs (HR 1.21; 95 % CI 1.04, 1.41; P for trend = 0.02) were associated with increased risk. Intake of fibre-rich bread and cereals was inversely associated with type 2 diabetes (HR 0.84; 95 % CI 0.73, 0.98; P for trend = 0.004). In conclusion, results from the present large population-based prospective study indicate that high protein intake is associated with increased risk of type 2 diabetes. Replacing protein with carbohydrates may be favourable, especially if fibre-rich breads and cereals are chosen as carbohydrate sources.

positive: Flaxseed supplementation improved insulin resistance in obese glucose intolerant people: a randomized crossover design Background Obesity leads to an increase in inflammation and insulin resistance. This study determined antioxidant activity of flaxseed and its role in inflammation and insulin resistance in obese glucose intolerant people. Methods Using a randomized crossover design, nine obese glucose intolerant people consumed 40 g ground flaxseed or 40 g wheat bran daily for 12 weeks with a 4-week washout period. Plasma inflammation biomarkers (CRP, TNF-α, and IL-6), glucose, insulin, and thiobaribituric acid reactive substance (TBARS) were measured before and after of each supplementation. Results Flaxseed supplementation decreased TBARS (p = 0.0215) and HOMA-IR (p = 0.0382). Flaxseed or wheat bran supplementation did not change plasma inflammatory biomarkers. A positive relationship was found between TBARS and HOMA-IR (r = 0.62, p = 0.0003). Conclusions The results of the study weakly support that decreased insulin resistance might have been secondary to antioxidant activity of flaxseed. However, the mechanism(s) of decreased insulin resistance by flaxseed should be further determined using flaxseed lignan.

positive: High alpha-linolenic acid flaxseed (Linum usitatissimum): some nutritional properties in humans. Although high alpha-linolenic acid flaxseed (Linum usitatissimum) is one of the richest dietary sources of alpha-linolenic acid and is also a good source of soluble fibre mucilage, it is relatively unstudied in human nutrition. Healthy female volunteers consumed 50 g ground, raw flaxseed/d for 4 weeks which provided 12-13% of energy intake (24-25 g/100 g total fat). Flaxseed raised alpha-linolenic acid and long-chain n-3 fatty acids in both plasma and erythrocyte lipids, as well as raising urinary thiocyanate excretion 2.2-fold. Flaxseed also lowered serum total cholesterol by 9% and low-density-lipoprotein-cholesterol by 18%. Changes in plasma alpha-linolenic acid were equivalent when 12 g alpha-linolenic acid/d was provided as raw flaxseed flour (50 g/d) or flaxseed oil (20 g/d) suggesting high bioavailability of alpha-linolenic acid from ground flaxseed. Test meals containing 50 g carbohydrate from flaxseed or 25 g flaxseed mucilage each significantly decreased postprandial blood glucose responses by 27%. Malondialdehyde levels in muffins containing 15 g flaxseed oil or flour/kg were similar to those in wheat-flour muffins. Cyanogenic glycosides (linamarin, linustatin, neolinustatin) were highest in extracted flaxseed mucilage but were not detected in baked muffins containing 150 g flaxseed/kg. We conclude that up to 50 g high-alpha-linolenic acid flaxseed/d is palatable, safe and may be nutritionally beneficial in humans by raising n-3 fatty acids in plasma and erythrocytes and by decreasing postprandial glucose responses.

positive: Dietary milled flaxseed and flaxseed oil improve N-3 fatty acid status and do not affect glycemic control in individuals with well-controlled type ... OBJECTIVE: To determine the effects of dietary consumption of milled flaxseed or flaxseed oil on glycemic control, n-3 fatty acid status, anthropometrics, and adipokines in individuals with type 2 diabetes. DESIGN: Thirty-four participants were randomized into a parallel, controlled trial. SUBJECTS: The participants were adults with type 2 diabetes (age 52.4 +/- 1.5 years, body mass index 32.4 +/- 1.0 kg/m(2), n = 17 men and 17 women). INTERVENTIONS: Participants consumed a selection of bakery products containing no flax (control group [CTL], n = 9), milled flaxseed (FXS, n = 13; 32 g/d), or flaxseed oil (FXO, n = 12; 13 g/d) daily for 12 weeks. The FXS and FXO groups received equivalent amounts of alpha-linolenic acid (ALA; 7.4 g/day). MEASURES OF OUTCOME: The primary outcome measures were fasting plasma hemoglobin A(1c), glucose, insulin, and phospholipid fatty acid composition. The secondary outcome measures were fasting circulating leptin and adiponectin, as well as body weight, body mass index, and waist circumference. Dietary intake assessment and calculations for homeostasis model assessment for insulin resistance and quantified insulin sensitivity check were also completed. RESULTS: The FXS and FXO groups had increases in plasma phospholipid n-3 fatty acids (ALA, eicosapentaenoic acid [EPA], or decosapentaenoic acid [DPA], but not docosahexaenoic acid), and the FXO group had more EPA and DPA in plasma phospholipids compared to the FXS group. All groups had similar caloric intakes; however, the CTL group experienced a 4% weight gain compared to baseline (p < 0.05), while both flax groups had constant body weights during the study period. All other parameters, including glycemic control, were unchanged by dietary treatment. CONCLUSIONS: Milled FXS and FXO intake does not affect glycemic control in adults with well-controlled type 2 diabetes. Possible prevention of weight gain by flax consumption warrants further investigation.

positive: An open-label study on the effect of flax seed powder (Linum usitatissimum) supplementation in the management of diabetes mellitus. Diabetes mellitus is characterized by hyperglycemia and associated with aberrations in the metabolism of carbohydrate, protein, and lipid that result in development of secondary complications. Extensive studies have indicated that nutritional therapy plays a pivotal role in the controlling or postponing of development of these secondary complications. Several functional foods have been shown to possess hypoglycemic and hypolipidemic properties. Flax seed (FS) is a functional food that is rich in omega 3 fatty acids and antioxidants and is low in carbohydrates. In exploratory studies, FS was incorporated in recipes, which resulted in a reduction in the glycemic index of the food items. These observations prompted us to investigate the efficacy of FS supplementation in type 2 diabetics (n = 29). Subjects were assigned to the experimental (n = 18) or the control group (n = 11) on the basis of their desire to participate in the study. The experimental group's diet was supplemented daily with 10 g of FS powder for a period of 1 month. The control group received no supplementation or placebo. During the study, diet and drug intake of the subjects remained unaltered. The efficacy of supplementation with FS was evaluated through a battery of clinico-biochemical parameters. Supplementation with FS reduced fasting blood glucose by 19.7% and glycated hemoglobin by 15.6%. A favorable reduction in total cholesterol (14.3%), triglycerides (17.5%), low-density lipoprotein cholesterol (21.8%), and apolipoprotein B and an increase in high-density lipoprotein cholesterol (11.9%) were also noticed. These observations suggest the therapeutic potential of FS in the management of diabetes mellitus.

positive: Antitumour effects of Phyllanthus emblica L.: induction of cancer cell apoptosis and inhibition of in vivo tumour promotion and in vitro invasion o... Phyllanthus emblica Linn. (PE) is a medicinal fruit used in many Asian traditional medicine systems for the treatment of various diseases including cancer. The present study tested the potential anticancer effects of aqueous extract of PE in four ways: (1) against cancer cell lines, (2) in vitro apoptosis, (3) mouse skin tumourigenesis and (4) in vitro invasiveness. The PE extract at 50-100 microg/mL significantly inhibited cell growth of six human cancer cell lines, A549 (lung), HepG2 (liver), HeLa (cervical), MDA-MB-231 (breast), SK-OV3 (ovarian) and SW620 (colorectal). However, the extract was not toxic against MRC5 (normal lung fibroblast). Apoptosis in HeLa cells was also observed as PE extract caused DNA fragmentation and increased activity of caspase-3/7 and caspase-8, but not caspase-9, and up-regulation of the Fas protein indicating a death receptor-mediated mechanism of apoptosis. Treatment of PE extract on mouse skin resulted in over 50% reduction of tumour numbers and volumes in animals treated with DMBA/TPA. Lastly, 25 and 50 microg/mL of PE extract inhibited invasiveness of MDA-MB-231 cells in the in vitro Matrigel invasion assay. These results suggest P. emblica exhibits anticancer activity against selected cancer cells, and warrants further study as a possible chemopreventive and antiinvasive agent. Copyright 2010 John Wiley & Sons, Ltd.

positive: Effect of Amla fruit (Emblica officinalis Gaertn.) on blood glucose and lipid profile of normal subjects and type 2 diabetic patients. The present study evaluated the anti-hyperglycemic and lipid-lowering properties of Emblica officinalis Gaertn. fruit in normal and diabetic human volunteers. The results indicated a significant decrease (P <  0.05) in fasting and 2-h post-prandial blood glucose levels on the 21st day in both normal and diabetic subjects receiving 1, 2 or 3 g E. officinalis powder per day as compared with their baseline values. Significant (P <  0.05) decreases were also observed in total cholesterol and triglycerides in both normal and diabetic volunteers on day 21 that were given either 2 or 3 g E. officinalis powder per day. However, diabetic volunteers receiving only 3 g E. officinalis powder exhibited a significant (P <  0.05) decrease in total lipids on day 21. Both normal and diabetic volunteers receiving 2 or 3 g E. officinalis powder significantly (P <  0.05) improved high-density lipoprotein-cholesterol and lowered low-density lipoprotein-cholesterol levels.

negative: High Fat Intake Leads to Acute Postprandial Exposure to Circulating Endotoxin in Type 2 Diabetic Subjects OBJECTIVE To evaluate the changes in circulating endotoxin after a high–saturated fat meal to determine whether these effects depend on metabolic disease state. RESEARCH DESIGN AND METHODS Subjects (n = 54) were given a high-fat meal (75 g fat, 5 g carbohydrate, 6 g protein) after an overnight fast (nonobese control [NOC]: age 39.9 ± 11.8 years [mean ± SD], BMI 24.9 ± 3.2 kg/m2, n = 9; obese: age 43.8 ± 9.5 years, BMI 33.3 ± 2.5 kg/m2, n = 15; impaired glucose tolerance [IGT]: age 41.7 ± 11.3 years, BMI 32.0 ± 4.5 kg/m2, n = 12; type 2 diabetic: age 45.4 ± 10.1 years, BMI 30.3 ± 4.5 kg/m2, n = 18). Blood was collected before (0 h) and after the meal (1–4 h) for analysis. RESULTS Baseline endotoxin was significantly higher in the type 2 diabetic and IGT subjects than in NOC subjects, with baseline circulating endotoxin levels 60.6% higher in type 2 diabetic subjects than in NOC subjects (P < 0.05). Ingestion of a high-fat meal led to a significant rise in endotoxin levels in type 2 diabetic, IGT, and obese subjects over the 4-h time period (P < 0.05). These findings also showed that, at 4 h after a meal, type 2 diabetic subjects had higher circulating endotoxin levels (125.4%↑) than NOC subjects (P < 0.05). CONCLUSIONS These studies have highlighted that exposure to a high-fat meal elevates circulating endotoxin irrespective of metabolic state, as early as 1 h after a meal. However, this increase is substantial in IGT and type 2 diabetic subjects, suggesting that metabolic endotoxinemia is exacerbated after high fat intake. In conclusion, our data suggest that, in a compromised metabolic state such as type 2 diabetes, a continual snacking routine will cumulatively promote their condition more rapidly than in other individuals because of the greater exposure to endotoxin.

negative: Dietary Fat and Cholesterol and Risk of Cardiovascular Disease in Older Adults: the Health ABC Study BACKGROUND AND AIMS Although dietary fats and cholesterol have previously been associated with risk of cardiovascular disease (CVD) in middle aged populations, less is known among older adults. The purpose of this study was to determine the association between dietary fats, cholesterol, and eggs and CVD risk among community-dwelling adults aged 70–79 in the Health, Aging and Body Composition Study. METHODS AND RESULTS Diet was assessed using an interviewer-administered 108-item food frequency questionnaire (n=1,941). CVD events were defined as a confirmed myocardial infarction, coronary death, or stroke. Relative rates of CVD over 9 years of follow-up were estimated using Cox proportional hazards models. During follow-up, there were 203 incident cases of CVD. There were no significant associations between dietary fats and CVD risk. Dietary cholesterol (HR (95% CI): 1.47 (0.93, 2.32) for the upper vs. lower tertile; P for trend, 0.10) and egg consumption (HR (95% CI): 1.68 (1.12, 2.51) for 3+/week vs. <1/week); P for trend, 0.01) were associated with increased CVD risk. However, in subgroup analyses, dietary cholesterol and egg consumption were associated with increased CVD risk only among older adults with type 2 diabetes (HR (95% CI): 3.66 (1.09, 12.29) and 5.02 (1.63, 15.52), respectively, for the upper vs. lower tertile/group). CONCLUSIONS Dietary cholesterol and egg consumption were associated with increased CVD risk among older, community-dwelling adults with type 2 diabetes. Further research on the biological mechanism(s) for the increased CVD risk with higher dietary cholesterol and frequent egg consumption among older adults with diabetes is warranted.

negative: Laboratory, Epidemiological, and Human Intervention Studies Show That Tea (Camellia sinensis) May Be Useful in the Prevention of Obesity Tea (Camellia sinensis, Theaceae) and tea polyphenols have been studied for the prevention of chronic diseases, including obesity. Obesity currently affects >20% of adults in the United States and is a risk factor for chronic diseases such as type II diabetes, cardiovascular disease, and cancer. Given this increasing public health concern, the use of dietary agents for the prevention of obesity would be of tremendous benefit. Whereas many laboratory studies have demonstrated the potential efficacy of green or black tea for the prevention of obesity, the underlying mechanisms remain unclear. The results of human intervention studies are mixed and the role of caffeine has not been clearly established. Finally, there is emerging evidence that high doses of tea polyphenols may have adverse side effects. Given that the results of scientific studies on dietary components, including tea polyphenols, are often translated into dietary supplements, understanding the potential toxicities of the tea polyphenols is critical to understanding their potential usefulness in preventing obesity. In this review, we will critically evaluate the evidence for the prevention of obesity by tea, discuss the relevance of proposed mechanisms in light of tea polyphenol bioavailability, and review the reports concerning the toxic effects of high doses of tea polyphenols and the implication that this has for the potential use of tea for the prevention of obesity. We hope that this review will expose areas for further study and encourage research on this important public health issue.

negative: Can noncommunicable diseases be prevented? Lessons from studies of populations and individuals. Noncommunicable diseases (NCDs)--mainly cancers, cardiovascular diseases, diabetes, and chronic respiratory diseases--are responsible for about two-thirds of deaths worldwide, mostly in low- and middle-income countries. There is an urgent need for policies and strategies that prevent NCDs by reducing their major risk factors. Effective approaches for large-scale NCD prevention include comprehensive tobacco and alcohol control through taxes and regulation of sales and advertising; reducing dietary salt, unhealthy fats, and sugars through regulation and well-designed public education; increasing the consumption of fresh fruits and vegetables, healthy fats, and whole grains by lowering prices and improving availability; and implementing a universal, effective, and equitable primary-care system that reduces NCD risk factors, including cardiometabolic risk factors and infections that are precursors to NCDs, through clinical interventions.

negative: Diet and cell growth modulation by ammonia. Fiber is not digested by endogenous enzymes but is fermented by microbes principally in the large intestine. With fermentable energy available, microbes synthesize protein by using ammonia released by their enzymes from urea and other nitrogenous substances in ingesta and intestinal secretions. Fibber fermentation also yields fatty acids that lower the concentration of free ammonia by lowering pH. Fiber increases bulk and water of intestinal contents, shortens transit time, and decreases the concentration of toxic substances in contact with the intestinal mucosa. These processes decrease duration and intensity of exposure of the intestinal mucosa to free ammonia, the form of nitrogen that is most toxic and most readily absorbed by cells. At concentrations found in the lower bowel on usual Western diets, ammonia destroys cells, alters nucleic acid synthesis, increases intestinal mucosal cell mass, increases virus infections, favors growth of cancerous cells over noncancerous cells in tissue culture, and increases virus infections. Ammonia in the bowel increases as protein intake increases. The attributes of ammonia and the epidemiological evidence comparing populations that maintain low intakes of unrefined carbohydrate with those that consume high intakes of protein, fat, and refined carbohydrates implicate ammonia in carcinogenesis and other disease processes.

negative: Hibiscus sabdariffa L. in the treatment of hypertension and hyperlipidemia: a comprehensive review of animal and human studies The effectiveness of Hibiscus sabdariffa L. (HS) in the treatment of risk factors associated with cardiovascular disease is assessed in this review by taking a comprehensive approach to interpreting the randomized clinical trial (RCT) results in the context of the available ethnomedical, phytochemical, pharmacological, and safety and toxicity information. HS decoctions and infusions of calyxes, and on occasion leaves, are used in at least 10 countries worldwide in the treatment of hypertension and hyperlipidemia with no reported adverse events or side effects. HS extracts have a low degree of toxicity with a LD50 ranging from 2,000 to over 5,000 mg/kg/day. There is no evidence of hepatic or renal toxicity as the result of HS extract consumption, except for possible adverse hepatic effects at high doses. There is evidence that HS acts as a diuretic, however in most cases the extract did not significantly influence electrolyte levels. Animal studies have consistently shown that consumption of HS extract reduces blood pressure in a dose dependent manner. In RCTs, the daily consumption of a tea or extract produced from HS calyxes significantly lowered systolic blood pressure (SBP) and diastolic blood pressure (DBP) in adults with pre to moderate essential hypertension and type 2 diabetes. In addition, HS tea was as effective at lowering blood pressure as the commonly used blood pressure medication Captropril, but less effective than Lisinopril. Total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides were lowered in the majority of normolipidemic, hypolipidemic, and diabetic animal models, whereas high-density lipoprotein cholesterol (HDL-C) was generally not affected by the consumption of HS extract. Over half of the RCTs showed that daily consumption of HS tea or extracts had favorable influence on lipid profiles including reduced total cholesterol, LDL-C, triglycerides, as well as increased HDL-C. Anthocyanins found in abundance in HS calyxes are generally considered the phytochemicals responsible for the antihypertensive and hypocholesterolemic effects, however evidence has also been provided for the role of polyphenols and hibiscus acid. A number of potential mechanisms have been proposed to explain the hypotensive and anticholesterol effects, but the most common explanation is the antioxidant effects of the anthocyanins inhibition of LDL-C oxidation, which impedes atherosclerosis, an important cardiovascular risk factor. This comprehensive body of evidence suggests that extracts of HS are promising as a treatment of hypertension and hyperlipidemia, however more high quality animal and human studies informed by actual therapeutic practices are needed to provide recommendations for use that have the potential for widespread public health benefit.

negative: Vegetarian and vegan diets in type 2 diabetes management. Vegetarian and vegan diets offer significant benefits for diabetes management. In observational studies, individuals following vegetarian diets are about half as likely to develop diabetes, compared with non-vegetarians. In clinical trials in individuals with type 2 diabetes, low-fat vegan diets improve glycemic control to a greater extent than conventional diabetes diets. Although this effect is primarily attributable to greater weight loss, evidence also suggests that reduced intake of saturated fats and high-glycemic-index foods, increased intake of dietary fiber and vegetable protein, reduced intramyocellular lipid concentrations, and decreased iron stores mediate the influence of plant-based diets on glycemia. Vegetarian and vegan diets also improve plasma lipid concentrations and have been shown to reverse atherosclerosis progression. In clinical studies, the reported acceptability of vegetarian and vegan diets is comparable to other therapeutic regimens. The presently available literature indicates that vegetarian and vegan diets present potential advantages for the management of type 2 diabetes.

negative: Energy and Fructose From Beverages Sweetened With Sugar or High-Fructose Corn Syrup Pose a Health Risk for Some People Sugar intake in the United States has increased by >40 fold since the American Revolution. The health concerns that have been raised about the amounts of sugar that are in the current diet, primarily as beverages, are the subject of this review. Just less than 50% of the added sugars (sugar and high-fructose corn syrup) are found in soft drinks and fruit drinks. The intake of soft drinks has increased 5-fold between 1950 and 2000. Most meta-analyses have shown that the risk of obesity, diabetes, cardiovascular disease, and metabolic syndrome are related to consumption of beverages sweetened with sugar or high-fructose corn syrup. Calorically sweetened beverage intake has also been related to the risk of nonalcoholic fatty liver disease, and, in men, gout. Calorically sweetened beverages contribute to obesity through their caloric load, and the intake of beverages does not produce a corresponding reduction in the intake of other food, suggesting that beverage calories are “add-on” calories. The increase in plasma triglyceride concentrations by sugar-sweetened beverages can be attributed to fructose rather than glucose in sugar. Several randomized trials of sugar-containing soft drinks versus low-calorie or calorie-free beverages show that either sugar, 50% of which is fructose, or fructose alone increases triglycerides, body weight, visceral adipose tissue, muscle fat, and liver fat. Fructose is metabolized primarily in the liver. When it is taken up by the liver, ATP decreases rapidly as the phosphate is transferred to fructose in a form that makes it easy to convert to lipid precursors. Fructose intake enhances lipogenesis and the production of uric acid. By worsening blood lipids, contributing to obesity, diabetes, fatty liver, and gout, fructose in the amounts currently consumed is hazardous to the health of some people.

negative: Relevance of protein fermentation to gut health. It is generally accepted that carbohydrate fermentation results in beneficial effects for the host because of the generation of short chain fatty acids, whereas protein fermentation is considered detrimental for the host's health. Protein fermentation mainly occurs in the distal colon, when carbohydrates get depleted and results in the production of potentially toxic metabolites such as ammonia, amines, phenols and sulfides. However, the effectivity of these metabolites has been established mainly in in vitro studies. In addition, some important bowel diseases such as colorectal cancer (CRC) and ulcerative colitis appear most often in the distal colon, which is the primary site of protein fermentation. Finally, epidemiological studies revealed that diets rich in meat are associated with the prevalence of CRC, as is the case in Western society. Importantly, meat intake not only increases fermentation of proteins but also induces increased intake of fat, heme and heterocyclic amines, which may also play a role in the development of CRC. Despite these indications, the relationship between gut health and protein fermentation has not been thoroughly investigated. In this review, the existing evidence about the potential toxicity of protein fermentation from in vitro animal and human studies will be summarized. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

negative: A low-fat vegan diet and a conventional diabetes diet in the treatment of type 2 diabetes: a randomized, controlled, 74-wk clinical trial Background: Low-fat vegetarian and vegan diets are associated with weight loss, increased insulin sensitivity, and improved cardiovascular health. Objective: We compared the effects of a low-fat vegan diet and conventional diabetes diet recommendations on glycemia, weight, and plasma lipids. Design: Free-living individuals with type 2 diabetes were randomly assigned to a low-fat vegan diet (n = 49) or a diet following 2003 American Diabetes Association guidelines (conventional, n = 50) for 74 wk. Glycated hemoglobin (Hb A1c) and plasma lipids were assessed at weeks 0, 11, 22, 35, 48, 61, and 74. Weight was measured at weeks 0, 22, and 74. Results: Weight loss was significant within each diet group but not significantly different between groups (−4.4 kg in the vegan group and −3.0 kg in the conventional diet group, P = 0.25) and related significantly to Hb A1c changes (r = 0.50, P = 0.001). Hb A1c changes from baseline to 74 wk or last available values were −0.34 and −0.14 for vegan and conventional diets, respectively (P = 0.43). Hb A1c changes from baseline to last available value or last value before any medication adjustment were −0.40 and 0.01 for vegan and conventional diets, respectively (P = 0.03). In analyses before alterations in lipid-lowering medications, total cholesterol decreased by 20.4 and 6.8 mg/dL in the vegan and conventional diet groups, respectively (P = 0.01); LDL cholesterol decreased by 13.5 and 3.4 mg/dL in the vegan and conventional groups, respectively (P = 0.03). Conclusions: Both diets were associated with sustained reductions in weight and plasma lipid concentrations. In an analysis controlling for medication changes, a low-fat vegan diet appeared to improve glycemia and plasma lipids more than did conventional diabetes diet recommendations. Whether the observed differences provide clinical benefit for the macro- or microvascular complications of diabetes remains to be established. This trial was registered at clinicaltrials.gov as NCT00276939.

negative: Curcumin in inflammatory diseases. Curcumin (diferuloylmethane), a yellow coloring agent extracted from turmeric is also used as a remedy for the treatment and prevention of inflammatory diseases. Acute and chronic inflammation is a major factor in the progression of obesity, type II diabetes, arthritis, pancreatitis, cardiovascular, neurodegenerative and metabolic diseases, as well as certain types of cancer. Turmeric has a long history of use in Ayurvedic medicine for the treatment of inflammatory disorders. Recent studies on the efficacy and therapeutic applicability of turmeric have suggested that the active ingredient of tumeric is curcumin. Further, compelling evidence has shown that curcumin has the ability to inhibit inflammatory cell proliferation, invasion, and angiogenesis through multiple molecular targets and mechanisms of action. Curcumin is safe, non-toxic, and mediates its anti-inflammatory effects through the down-regulation of inflammatory transcription factors, cytokines, redox status, protein kinases, and enzymes that all promote inflammation. In addition, curcumin induces apoptosis through mitochondrial and receptor-mediated pathways, as well as activation of caspase cascades. In the current study, the anti-inflammatory effects of curcumin were evaluated relative to various chronic inflammatory diseases. Based on the available pharmacological data obtained from in vitro and in vivo research, as well as clinical trials, an opportunity exists to translate curcumin into clinics for the prevention of inflammatory diseases in the near future. Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc.

negative: Effects of a high-fat meal on pulmonary function in healthy subjects. Obesity has important health consequences, including elevating risk for heart disease, diabetes, and cancer. A high-fat diet is known to contribute to obesity. Little is known regarding the effect of a high-fat diet on pulmonary function, despite the dramatic increase in the prevalence of respiratory ailments (e.g., asthma). The purpose of our study was to determine whether a high-fat meal (HFM) would increase airway inflammation and decrease pulmonary function in healthy subjects. Pulmonary function tests (PFT) (forced expiratory volume in 1-s, forced vital capacity, forced expiratory flow at 25-75% of vital capacity) and exhaled nitric oxide (eNO; airway inflammation) were performed in 20 healthy (10 men, 10 women), inactive subjects (age 21.9 +/- 0.4 years) pre and 2 h post HFM (1 g fat/1 kg body weight; 74.2 +/- 4.1 g fat). Total cholesterol, triglycerides, and C-reactive protein (CRP; systemic inflammation) were determined via a venous blood sample pre and post HFM. Body composition was measured via dual energy X-ray absorptiometry. The HFM significantly increased total cholesterol by 4 +/- 1%, and triglycerides by 93 +/- 3%. ENO also increased (p < 0.05) due to the HFM by 19 +/- 1% (pre 17.2 +/- 1.6; post 20.6 +/- 1.7 ppb). ENO and triglycerides were significantly related at baseline and post-HFM (r = 0.82, 0.72 respectively). Despite the increased eNO, PFT or CRP did not change (p > 0.05) with the HFM. These results demonstrate that a HFM, which leads to significant increases in total cholesterol, and especially triglycerides, increases exhaled NO. This suggests that a high-fat diet may contribute to chronic inflammatory diseases of the airway and lung.

negative: Differential effect of oleic and palmitic acid on lipid accumulation and apoptosis in cultured hepatocytes. BACKGROUND AND AIM: Studies have shown monounsaturated oleic acid to be less toxic than palmitic acid and to prevent/attenuate palmitic acid hepatocites toxicity in steatosis models in vitro. However, to what degree these effects are mediated by steatosis extent is unknown. METHODS: We evaluated whether steatosis per se is associated with hepatocytes apoptosis and determined the role of oleic and palmitic acid, the most abundant fatty acids in western diets, on triglyceride accumulation and apoptosis in an in vitro model of steatosis induced in three hepatocytic cell lines (HepG2, HuH7, WRL68). The impact of incubation for 24 h with oleic (0.66 and 1.32 mM) and palmitic acid (0.33 and 0.66 mM), alone or combined (molar ratio 2 : 1) on steatosis, apoptosis, and insulin signalling, was evaluated. RESULTS: Concurrent with PPARgamma and SREBP-1 gene activation, steatosis extent was larger when cells were treated with oleic than with palmitic acid; the latter fatty acid was associated with increased PPARalpha expression. Cell apoptosis was inversely proportional to steatosis deposition. Moreover, palmitic, but not oleic acid, impaired insulin signalling. Despite the higher amount of fat resulting from incubation of the two fatty acids combined, the apoptosis rate and impaired insulin signalling were lower than in cells treated with palmitic acid alone, indicating a protective effect of oleic acid. CONCLUSIONS: Oleic acid is more steatogenic but less apoptotic than palmitic acid in hepatocityc cell cultures. These data may provide a biological basis for clinical findings on dietary patterns and pathogenetic models of nonalcoholic fatty liver disease.

negative: Vegetarian diet improves insulin resistance and oxidative stress markers more than conventional diet in subjects with Type 2 diabetes Aims The aim of this study was to compare the effects of calorie-restricted vegetarian and conventional diabetic diets alone and in combination with exercise on insulin resistance, visceral fat and oxidative stress markers in subjects with Type 2 diabetes. Methods A 24-week, randomized, open, parallel design was used. Seventy-four patients with Type 2 diabetes were randomly assigned to either the experimental group (n = 37), which received a vegetarian diet, or the control group (n = 37), which received a conventional diabetic diet. Both diets were isocaloric, calorie restricted (-500 kcal/day). All meals during the study were provided. The second 12 weeks of the diet were combined with aerobic exercise. Participants were examined at baseline, 12 weeks and 24 weeks. Primary outcomes were: insulin sensitivity measured by hyperinsulinaemic isoglycaemic clamp; volume of visceral and subcutaneous fat measured by magnetic resonance imaging; and oxidative stress measured by thiobarbituric acid reactive substances. Analyses were by intention to treat. Results Forty-three per cent of participants in the experimental group and 5% of participants in the control group reduced diabetes medication (P < 0.001). Body weight decreased more in the experimental group than in the control group [–6.2 kg (95% CI –6.6 to –5.3) vs. –3.2 kg (95% CI –3.7 to –2.5); interaction group × time P = 0.001]. An increase in insulin sensitivity was significantly greater in the experimental group than in the control group [30% (95% CI 24.5–39) vs. 20% (95% CI 14–25), P = 0.04]. A reduction in both visceral and subcutaneous fat was greater in the experimental group than in the control group (P = 0.007 and P = 0.02, respectively). Plasma adiponectin increased (P = 0.02) and leptin decreased (P = 0.02) in the experimental group, with no change in the control group. Vitamin C, superoxide dismutase and reduced glutathione increased in the experimental group (P = 0.002, P < 0.001 and P = 0.02, respectively). Differences between groups were greater after the addition of exercise training. Changes in insulin sensitivity and enzymatic oxidative stress markers correlated with changes in visceral fat. Conclusions A calorie-restricted vegetarian diet had greater capacity to improve insulin sensitivity compared with a conventional diabetic diet over 24 weeks. The greater loss of visceral fat and improvements in plasma concentrations of adipokines and oxidative stress markers with this diet may be responsible for the reduction of insulin resistance. The addition of exercise training further augmented the improved outcomes with the vegetarian diet.

negative: The risks of copper toxicity contributing to cognitive decline in the aging population and to Alzheimer's disease. It is a pleasure and an honor to contribute a paper to a special issue of the Journal of the American College of Nutrition honoring Stanley Wallach and Pearl Small. In this brief review I advance the hypothesis that copper toxicity is the major cause of the epidemic of mild cognitive impairment and Alzheimer's disease engulfing our aging population. This epidemic is recent, exploding in the last 50-60 years. The disease was virtually unknown 100 years ago. And it involves only developed countries that use copper plumbing. Something in our environment associated with development is poisoning the minds of our aged. The epidemic is associated with the use of copper plumbing, and the taking of copper in multi-mineral supplements. Food copper (organic copper) is processed by the liver and is transported and sequestered in a safe manner. Inorganic copper, such as that in drinking water and copper supplements, largely bypasses the liver and enters the free copper pool of the blood directly. This copper is potentially toxic because it may penetrate the blood/brain barrier. I review a web of animal and human data that tightens the noose around the hypothesis that copper toxicity is causing the epidemic of Alzeimer's disease and loss of cognition in our aging population.

negative: Synergistic toxicity of the environmental neurotoxins methylmercury and β-N-methylamino-L-alanine. Determination of the environmental factors involved in neurodegenerative diseases has been elusive. Methylmercury and β-N-methylamino-L-alanine (BMAA) have both been implicated in this role. Exposure of primary cortical cultures to these compounds independently induced concentration-dependent neurotoxicity. Importantly, concentrations of BMAA (10-100 μM) that caused no toxicity alone potentiated methylmercury (3 μM) toxicity. In addition, concentrations of BMAA and methylmercury that had no effect by themselves on the main cellular antioxidant glutathione together decreased glutathione levels. Furthermore, the combined toxicity of methylmercury and BMAA was attenuated by the cell permeant form of glutathione, glutathione monoethyl ester. The results indicate a synergistic toxic effect of the environmental neurotoxins BMAA and methylmercury, and that the interaction is at the level of glutathione depletion.

negative: Effect of the vegetarian diet on non-communicable diseases. A vegetarian diet generally includes plenty of vegetables and fruits, which are rich in phytochemicals, antioxidants, fiber, magnesium, vitamins C and E, Fe³⁺, folic acid and n-6 polyunsaturated fatty acid (PUFA), and is low in cholesterol, total fat and saturated fatty acid, sodium, Fe²⁺, zinc, vitamin A, B₁₂ and D, and especially n-3 PUFA. Mortality from all-cause, ischemic heart disease, and circulatory and cerebrovascular diseases was significantly lower in vegetarians than in omnivorous populations. Compared with omnivores, the incidence of cancer and type 2 diabetes was also significantly lower in vegetarians. However, vegetarians have a number of increased risk factors for non-communicable diseases such as increased plasma homocysteine, mean platelet volume and platelet aggregability compared with omnivores, which are associated with low intake of vitamin B₁₂ and n-3 PUFA. Based on the present data, it would seem appropriate for vegetarians to carefully design their diet, specifically focusing on increasing their intake of vitamin B₁₂ and n-3 PUFA to further reduce already low mortality and morbidity from non-communicable diseases. © 2013 Society of Chemical Industry.

negative: Incident Heart Failure Is Associated with Lower Whole-Grain Intake and Greater High-Fat Dairy and Egg Intake in the Atherosclerosis Risk in Communities (ARIC) Study Background Prospective studies evaluating associations between food intake and risk of heart failure (HF) in diverse populations are needed. Objectives Relationships between incident HF (death or hospitalization) and intake of seven food categories (whole grains, fruits/vegetables, fish, nuts, high-fat dairy, eggs, red meat) were investigated in an observational cohort of 14,153 African-American and white adults, age 45 to 64 years, sampled from four US communities. Methods Between baseline (1987–1989) and Exam 3 (1993–1995), dietary intake was based on responses to a 66-item food frequency questionnaire administered at baseline; thereafter, intake was based on averaged baseline and Exam 3 responses. Hazard ratios (HR [95% CI]) for HF were calculated per 1–daily serving difference in food group intake. Results During a mean of 13 years, 1,140 HF hospitalizations were identified. After multivariable adjustment (energy intake, demographics, lifestyle factors, prevalent cardiovascular disease, diabetes, hypertension), HF risk was lower with greater whole-grain intake (0.93 [0.87, 0.99]), but HF risk was higher with greater intake of eggs (1.23 [1.08, 1.41]) and high-fat dairy (1.08 [1.01, 1.16]). These associations remained significant independent of intakes of the five other food categories, which were not associated with HF. Conclusions In this large, population-based sample of African-American and white adults, whole-grain intake was associated with lower HF risk, whereas intake of eggs and high-fat dairy were associated with greater HF risk after adjustment for several confounders.

negative: Evolution of the human diet: linking our ancestral diet to modern functional foods as a means of chronic disease prevention. The evolution of the human diet over the past 10,000 years from a Paleolithic diet to our current modern pattern of intake has resulted in profound changes in feeding behavior. Shifts have occurred from diets high in fruits, vegetables, lean meats, and seafood to processed foods high in sodium and hydrogenated fats and low in fiber. These dietary changes have adversely affected dietary parameters known to be related to health, resulting in an increase in obesity and chronic disease, including cardiovascular disease (CVD), diabetes, and cancer. Some intervention trials using Paleolithic dietary patterns have shown promising results with favorable changes in CVD and diabetes risk factors. However, such benefits may be offset by disadvantages of the Paleolithic diet, which is low in vitamin D and calcium and high in fish potentially containing environmental toxins. More advantageous would be promotion of foods and food ingredients from our ancestral era that have been shown to possess health benefits in the form of functional foods. Many studies have investigated the health benefits of various functional food ingredients, including omega-3 fatty acids, polyphenols, fiber, and plant sterols. These bioactive compounds may help to prevent and reduce incidence of chronic diseases, which in turn could lead to health cost savings ranging from $2 to $3 billion per year as estimated by case studies using omega-3 and plant sterols as examples. Thus, public health benefits should result from promotion of the positive components of Paleolithic diets as functional foods.

negative: The safety of rosiglitazone in the treatment of type 2 diabetes. BACKGROUND: Cardiovascular disease is the leading cause of mortality among adults with Type 2 diabetes. The thiazolidinediones including rosiglitazone are approved for the treatment of Type 2 diabetes on the basis of their ability to lower blood sugar and surrogate markers of cardiovascular disease. OBJECTIVES: To ascertain the cardiovascular, skeletal and hematologic safety profile of rosiglitazone. METHODS: Synthesis of evidence from recent trials, systematic reviews, meta-analysis, regulatory documents and clinical trials registries of manufacturers. CONCLUSION: Rosiglitazone increases the risk of heart failure, myocardial infarction and fractures (in women) with Type 2 diabetes.

negative: Dietary manganese intake and type of lipid do not affect clinical or neuropsychological measures in healthy young women. Because manganese (Mn) is potentially toxic, and because dietary fat type may affect Mn absorption, the objectives of the current study were to determine whether diets containing very low or very high amounts of Mn and enriched in either saturated or unsaturated fats affected measures of neuropsychological and basic metabolic function. Healthy young women were fed for 8 wk each, in a crossover design, diets that provided 0.8 or 20 mg of Mn/d. One half of the subjects received 15% of energy as cocoa butter, and one half received 15% of energy as corn oil. A meal containing (54)Mn was fed after 4 wk, and subjects underwent whole-body counting for the next 21 d. Blood draws and neuropsychological tests were administered at regular intervals during the dietary periods. When subjects consumed the diets low in Mn, compared with the high Mn diets, they absorbed a significantly higher percentage of (54)Mn, but had a significantly longer biological half-life of the absorbed (54)Mn. Manganese intake did not affect any neurological measures and only minimally affected psychologic variables. These data show that efficient mechanisms operate to maintain Mn homeostasis over the range of intakes that may be encountered in a mixed Western diet. Thus, dietary intakes of Mn from 0.8 to 20 mg for 8 wk likely do not result in Mn deficiency or toxicity signs in healthy adults.

negative: Chocolate/cocoa and human health: a review. Chocolate/cocoa has been known for its good taste and proposed health effects for centuries. Earlier, chocolate used to be criticised for its fat content and its consumption was a sin rather than a remedy, associated with acne, caries, obesity, high blood pressure, coronary artery disease and diabetes. Therefore, many physicians tended to warn patients about the potential health hazards of consuming large amounts of chocolate. However, the recent discovery of biologically active phenolic compounds in cocoa has changed this perception and stimulated research on its effects in ageing, oxidative stress, blood pressure regulation, and atherosclerosis. Today, chocolate is lauded for its tremendous antioxidant potential. However, in many studies, contradictory results and concerns about methodological issues have made it hard for health professionals and the public to understand the available evidence on chocolate's effects on health. The purpose of this review is to interpret research done in the last decade on the benefits and risks of chocolate consumption.

negative: Dioxin May Promote Inflammation-Related Development of Endometriosis Laboratory and population-based studies suggest that exposure to environmental toxicants may be one of several triggers for the development of endometriosis. We discuss evidence that modulation of the endometrial endocrine-immune interface could mechanistically link toxicant exposure to the development of this disease. Capsule Summary: Environmental toxicant exposure induces an inflammatory-like endometrial response that may promote the development of endometriosis.

negative: Diet, lifestyle, and the etiology of coronary artery disease: the Cornell China study. Investigators collected and analyzed mortality data for >50 diseases, including 7 different cancers, from 65 counties and 130 villages in rural mainland China. Blood, urine, food samples, and detailed dietary data were collected from 50 adults in each village and analyzed for a variety of nutritional, viral, hormonal, and toxic chemical factors. In rural China, fat intake was less than half that in the United States, and fiber intake was 3 times higher. Animal protein intake was very low, only about 10% of the US intake. Mean serum total cholesterol was 127 mg/dL in rural China versus 203 mg/dL for adults aged 20-74 years in the United States. Coronary artery disease mortality was 16.7-fold greater for US men and 5.6-fold greater for US women than for their Chinese counterparts. The combined coronary artery disease mortality rates for both genders in rural China were inversely associated with the frequency of intake of green vegetables and plasma erythrocyte monounsaturated fatty acids, but positively associated with a combined index of salt intake plus urinary sodium and plasma apolipoprotein B. These apolipoproteins, in turn, are positively associated with animal protein intake and the frequency of meat intake and inversely associated with plant protein, legume, and light-colored vegetable intake. Rates of other diseases were also correlated with dietary factors. There was no evidence of a threshold beyond which further benefits did not accrue with increasing proportions of plant-based foods in the diet.

negative: Studies of fish consumption as source of methylmercury should consider fish-meal-fed farmed fish and other animal foods. The co-occurrence of fish MeHg and omega-3 fatty acids in wild species can indeed be optimized by choosing certain species. Farmed finfish and shellfish that are fed fish-meal, however, can bioconcentrate both MeHg (in muscle) and organohalogen pollutants passed on in the fat components [Dorea, J.G., 2006. Fish meal in animal feed and human exposure to persistent bioaccumulative and toxic substances. J. Food Prot. 69, 2777-2785); when fish-meal is used to feed farm animals it may offer the worst of both worlds: saturated fat (with organohalogen pollutants) and MeHg. It is time to address the dietary sources of Hg derived from animals raised on fish-meal that may contribute to increase tissue Hg concentrations.

negative: Sensitivity-related illness: the escalating pandemic of allergy, food intolerance and chemical sensitivity. The prevalence of allergic-related diseases, food intolerance, and chemical sensitivities in both the pediatric and adult population has increased dramatically over the last two decades, with escalating rates of associated morbidity. Conditions of acquired allergy, food intolerance and chemical hypersensitivity are frequently the direct sequelae of a toxicant induced loss of tolerance (TILT) in response to a significant initiating toxic exposure. Following the primary toxicant insult, the individuals become sensitive to low levels of diverse and unrelated triggers in their environment such as commonly encountered chemical, inhalant or food antigens. Among sensitized individuals, exposure to assorted inciting stimuli may precipitate diverse clinical and/or immune sequelae as may be evidenced by clinical symptoms as well as varied lymphocyte, antibody, or cytokine responses in some cases. Recently recognized as a mechanism of disease development, TILT and resultant sensitivity-related illness (SRI) may involve various organ systems and evoke wide-ranging physical or neuropsychological manifestations. With escalating rates of toxicant exposure and bioaccumulation in the population-at-large, an increasing proportion of contemporary illness is the direct result of TILT and ensuing SRI. Avoidance of triggers will preclude symptoms, and desensitization immunotherapy or immune suppression may ameliorate symptomatology in some cases. Resolution of SRI generally occurs on a gradual basis following the elimination of bioaccumulated toxicity and avoidance of further initiating adverse environmental exposures. As has usually been the case throughout medical history whenever new evidence regarding disease mechanisms emerges, resistance to the translation of knowledge abounds. Copyright © 2010 Elsevier B.V. All rights reserved.

negative: Plasma adiponectin concentrations are associated with body composition and plant-based dietary factors in female twins. Circulating adiponectin is emerging as an important link between obesity, type 2 diabetes, and cardiovascular disease (CVD). However, the spectrum of lifestyle factors that modulate the adiponectin concentration remains to be elucidated, particularly among women. We conducted a cross-sectional study of 877 female twin pairs from the TwinsUK adult twin registry. Using a co-twin design, we examined dietary and body composition influences on adiponectin by conducting matched, within-pair analyses to eliminate confounding. Following multivariable adjustment within-twin pairs, significant influences on adiponectin (log-transformed, percent change per SD of the dietary/body composition variable) were observed for nonstarch polysaccharides (3.25%; 95% CI: 0.06, 6.54; P < 0.05) and magnesium intake (3.80%; 95%CI: 0.17, 7.57; P < 0.05), with a trend toward an association for fruit and vegetable (F&V) intakes (2.55%; 95% CI: -0.26, 5.45; P = 0.08). These modest positive associations cannot be explained by confounding through other lifestyle factors shared by the twins. A significant relationship between adiponectin and 3 derived dietary patterns (F&V, dieting, traditional English), carbohydrate, protein, trans fat, and alcohol intake was also observed. Strong inverse associations with adiponectin were observed for BMI (-10.72%; 95% CI: -13.78, -7.55), total (-6.89%: 95% CI: -10.34, -3.30; P < 0.05), and central fat mass (-12.50%; 95% CI: -15.82, -9.05; P < 0.05); these relationships were significant both when twins were analyzed as individuals and when characteristics were contrasted within-twin pairs, suggesting a direct effect. We observed modest associations between dietary factors and adiponectin in female twins, independent of adiposity, and report strong inverse associations with body composition. These data reinforce the importance of weight maintenance and increasing consumption of diets rich in plant-based foods to prevent CVD and type 2 diabetes.

negative: Effect of a Daily Supplement of Soy Protein on Body Composition and Insulin Secretion in Postmenopausal Women Objective: To determine if a supplement of soy protein improves body composition, body fat distribution, and glucose and insulin metabolism in non-diabetic postmenopausal women compared to an isocaloric casein placebo. Design: Randomized, double-blind, placebo-controlled 3-month trial Setting: Clinical Research Center Patients: 15 postmenopausal women Interventions: CT scans at L4/L5, dual energy x-ray absorptiometry (DXA), hyperglycemic clamps Main outcome measures: Total fat, total abdominal fat, visceral fat, subcutaneous abdominal fat, and insulin secretion. Results: Weight by DXA did not change between groups (+1.38 ± 2.02 kg for placebo vs. +0.756 ± 1.32 kg for soy, p=0.48, means ± S.D.). Total and subcutaneous abdominal fat increased more in the placebo compared to the soy group (for differences between groups in total abdominal fat: +38.62 ± 22.84 cm2 for placebo vs. −11.86 ± 31.48 cm2 for soy, p=0.005; subcutaneous abdominal fat: +22.91 ± 28.58 cm2 for placebo vs. −14.73 ± 22.26 cm2 for soy, p=0.013). Insulin secretion, visceral fat, total body fat, and lean mass did not differ between groups. Isoflavone levels increased more in the soy group. Conclusion: A daily supplement of soy protein prevents the increase in subcutaneous and total abdominal fat observed with an isocaloric casein placebo in postmenopausal women.

negative: Dietary lipids modulate methylmercury toxicity in Atlantic salmon. This experiment aimed to study the molecular toxicity of methylmercury (MeHg) in liver, brain and white muscle of Atlantic salmon fed a diet based on fish oil (FO, high dietary n-3/n-6 ratio) compared to an alternative diet mainly based on vegetable oil (VO, low dietary n-3/n-6 ratio). Juvenile salmon were fed decontaminated diets or the FO and VO diets enriched with 5 mg Hg/kg (added as MeHg) for three months. The dietary lipid composition affected the fatty acid composition in the tissues, especially in liver and white muscle. After 84 days of exposure, the liver accumulated three times as much MeHg as the brain and white muscle. Vitamin C content and heme oxygenase, tubulin alpha (TUBA) and Cpt1 transcriptional levels all showed significant effects of MeHg exposure in the liver. TBARS, α-tocopherol, γ-tocopherol, and the transcriptional levels of thioredoxin, heme oxygenase, TUBA, PPARB1, D5D and D6D showed an effect of dietary lipid composition in liver tissue. Effects of dietary lipids were observed in brain tissue for MT-A, HIF1, Bcl-X and TUBA. Interaction effects between MeHg exposure and dietary lipid composition were observed in all tissues. Our data suggest that dietary fats have modulating effects on MeHg toxicity in Atlantic salmon. Copyright © 2011 Elsevier Ltd. All rights reserved.

negative: Blood Harmane, Blood Lead, and Severity of Hand Tremor: Evidence of Additive Effects Background Tremor is a widespread phenomenon in human populations. Environmental factors are likely to play an etiological role. Harmane (1-methyl-9H-pyrido[3,4-β]indole) is a potent tremor-producing β-carboline alkaloid. Lead is another tremor-producing neurotoxicant. The effects of harmane and lead with respect to tremor have been studied in isolation. Objectives We tested the hypothesis that tremor would be particularly severe among individuals who had high blood concentrations of both of these toxicants. Methods Blood concentrations of harmane and lead were each quantified in 257 individuals (106 essential tremor cases and 151 controls) enrolled in an environmental epidemiological study. Total tremor score (range = 0 – 36) was a clinical measure of tremor severity. Results The total tremor score ranged from 0 – 36, indicating that a full spectrum of tremor severities was captured in our sample. Blood harmane concentration correlated with total tremor score (p = 0.007), as did blood lead concentration (p = 0.045). The total tremor score was lowest in participants with both low blood harmane and lead concentrations (8.4 ± 8.2), intermediate in participants with high concentrations of either toxicant (10.5 ± 9.8), and highest in participants with high concentrations of both toxicants (13.7 ± 10.4)(p = 0.01). Conclusions Blood harmane and lead concentrations separately correlated with total tremor scores. Participants with high blood concentrations of both toxicants had the highest tremor scores, suggesting an additive effect of these toxicants on tremor severity. Given the very high population prevalence of tremor disorders, identifying environmental determinants is important for primary disease prevention.

negative: Safety considerations and potential interactions of vitamins: should vitamins be considered drugs? OBJECTIVE: To examine adverse effects, adverse events, and potential interactions of vitamins in light of their current prevalence of use, and to discuss whether vitamins should be considered over-the-counter drugs or natural health products/dietary supplements. DATA SOURCES: We performed a MEDLINE/PubMed search, explored 4 online databases (Medline Plus, Drug Digest, Natural Medicine Comprehensive Database, and the database of the University of Maryland), and examined reference lists of included studies published from 1966 through October 2009. STUDY SELECTION AND DATA EXTRACTION: The studies were reviewed, with an emphasis on randomized controlled clinical trials. We included articles with the most clinically important information with regard to adverse events and interactions. DATA SYNTHESIS: Vitamins are used by over one third of the North American population. Vitamins have documented adverse effects and toxicities, and most have documented interactions with drugs. While some vitamins (biotin, pantothenic acid, riboflavin, thiamine, vitamin B(12), vitamin K) have minor and reversible adverse effects, others, such as fat-soluble vitamins (A, E, D), can cause serious adverse events. Two water-soluble vitamins, folic acid and niacin, can also have significant toxicities and adverse events. CONCLUSIONS: Our recommendation is that vitamins A, E, D, folic acid, and niacin should be categorized as over-the-counter medications. Labeling of vitamins, especially those intended for children and other vulnerable groups, should include information on possible toxicities, dosing, recommended upper intake limits, and concurrent use with other products. Vitamin A should be excluded from multivitamin supplements and food fortificants.

negative: Reducing the staggering costs of environmental disease in children, estimated at $76.6 billion in 2008. A 2002 analysis documented $54.9 billion in annual costs of environmentally mediated diseases in US children. However, few important changes in federal policy have been implemented to prevent exposures to toxic chemicals. We therefore updated and expanded the previous analysis and found that the costs of lead poisoning, prenatal methylmercury exposure, childhood cancer, asthma, intellectual disability, autism, and attention deficit hyperactivity disorder were $76.6 billion in 2008. To prevent further increases in these costs, efforts are needed to institute premarket testing of new chemicals; conduct toxicity testing on chemicals already in use; reduce lead-based paint hazards; and curb mercury emissions from coal-fired power plants.