Dissecting the relationship between plasma and tissue metabolome in a cohort of women with obesity: Analysis of subcutaneous and visceral adipose, muscle, and liver.

Untargeted metabolomics of blood samples has become widely applied to study metabolic alterations underpinning disease and to identify biomarkers. However, understanding the relevance of a blood metabolite marker can be challenging if it is unknown whether it reflects the concentration in relevant tissues. To explore this field, metabolomic and lipidomic profiles of plasma, four sites of adipose tissues (ATs) from peripheral or central depot, two sites of muscle tissue, and liver tissue from a group of nondiabetic women with obesity who were scheduled to undergo bariatric surgery (n = 21) or other upper GI surgery (n = 5), were measured by liquid chromatography coupled with mass spectrometry. Relationships between plasma and tissue profiles were examined using Pearson correlation analysis subject to Benjamini-Hochberg correction. Plasma metabolites and lipids showed the highest number of significantly positive correlations with their corresponding concentrations in liver tissue, including lipid species of ceramide, mono- and di-hexosylceramide, sphingomyelin, phosphatidylcholine (PC), phosphatidylethanolamine (PE), lysophosphatidylethanolamine, dimethyl phosphatidylethanolamine, ether-linked PC, ether-linked PE, free fatty acid, cholesteryl ester, diacylglycerol and triacylglycerol, and polar metabolites linked to several metabolic functions and gut microbial metabolism. Plasma also showed significantly positive correlations with muscle for several phospholipid species and polar metabolites linked to metabolic functions and gut microbial metabolism, and with AT for several triacylglycerol species. In conclusion, plasma metabolomic and lipidomic profiles were reflective more of the liver profile than any of the muscle or AT sites examined in the present study. Our findings highlighted the importance of taking into consideration the metabolomic relationship of various tissues with plasma when postulating plasma metabolites marker to underlying mechanisms occurring in a specific tissue.

Structure-functional changes in eNAMPT at high concentrations mediate mouse and human beta cell dysfunction in type 2 diabetes.

AIMS/HYPOTHESIS: Progressive decline in functional beta cell mass is central to the development of type 2 diabetes. Elevated serum levels of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) are associated with beta cell failure in type 2 diabetes and eNAMPT immuno-neutralisation improves glucose tolerance in mouse models of diabetes. Despite this, the effects of eNAMPT on functional beta cell mass are poorly elucidated, with some studies having separately reported beta cell-protective effects of eNAMPT. eNAMPT exists in structurally and functionally distinct monomeric and dimeric forms. Dimerisation is essential for the NAD-biosynthetic capacity of NAMPT. Monomeric eNAMPT does not possess NAD-biosynthetic capacity and may exert distinct NAD-independent effects. This study aimed to fully characterise the structure-functional effects of eNAMPT on pancreatic beta cell functional mass and to relate these to beta cell failure in type 2 diabetes. METHODS: CD-1 mice and serum from obese humans who were without diabetes, with impaired fasting glucose (IFG) or with type 2 diabetes (from the Body Fat, Surgery and Hormone [BodyFatS&H] study) or with or at risk of developing type 2 diabetes (from the VaSera trial) were used in this study. We generated recombinant wild-type and monomeric eNAMPT to explore the effects of eNAMPT on functional beta cell mass in isolated mouse and human islets. Beta cell function was determined by static and dynamic insulin secretion and intracellular calcium microfluorimetry. NAD-biosynthetic capacity of eNAMPT was assessed by colorimetric and fluorescent assays and by native mass spectrometry. Islet cell number was determined by immunohistochemical staining for insulin, glucagon and somatostatin, with islet apoptosis determined by caspase 3/7 activity. Markers of inflammation and beta cell identity were determined by quantitative reverse transcription PCR. Total, monomeric and dimeric eNAMPT and nicotinamide mononucleotide (NMN) were evaluated by ELISA, western blot and fluorometric assay using serum from non-diabetic, glucose intolerant and type 2 diabetic individuals. RESULTS: eNAMPT exerts bimodal and concentration- and structure-functional-dependent effects on beta cell functional mass. At low physiological concentrations (~1 ng/ml), as seen in serum from humans without diabetes, eNAMPT enhances beta cell function through NAD-dependent mechanisms, consistent with eNAMPT being present as a dimer. However, as eNAMPT concentrations rise to ~5 ng/ml, as in type 2 diabetes, eNAMPT begins to adopt a monomeric form and mediates beta cell dysfunction, reduced beta cell identity and number, increased alpha cell number and increased apoptosis, through NAD-independent proinflammatory mechanisms. CONCLUSIONS/INTERPRETATION: We have characterised a novel mechanism of beta cell dysfunction in type 2 diabetes. At low physiological levels, eNAMPT exists in dimer form and maintains beta cell function and identity through NAD-dependent mechanisms. However, as eNAMPT levels rise, as in type 2 diabetes, structure-functional changes occur resulting in marked elevation of monomeric eNAMPT, which induces a diabetic phenotype in pancreatic islets. Strategies to selectively target monomeric eNAMPT could represent promising therapeutic strategies for the treatment of type 2 diabetes.

Evidence of enhanced serum amino acid profile but not appetite suppression by dietary glycomacropeptide (GMP): a comparison of dairy whey proteins.

OBJECTIVE: There is evidence that high-protein foods increase satiety and may aid weight loss, yet little is known of differential effects of protein composition. The aim of the study was to compare the acute effects of 4 whey proteins on satiety and food intake and to evaluate possible relationships with postprandial serum amino acid concentrations. METHODS: Isoenergetic high-protein shakes (∼1 MJ) containing 25 g whey protein were given to 18 lean male participants using a crossover design. Three protein fractions identified as satiating in a rat model, glycomacropeptide (GMP), beta-lactoglobulin (ß-lac), and colostrum whey protein concentrate (WPC), were compared with a WPC control. A standardized 2.5MJ breakfast was given at 0830 hours, followed by the preload beverages at 1130 hours. Participants rated appetite sensations using visual analogue scales (VAS) prior to the beverage (baseline, 0 minutes) and then at 15, 30, 45, 60, 90, 150, and 210 minutes. Energy and macronutrient intake was measured by covert weighing of an ad libitum lunch meal at 90 minutes. Repeat blood samples were collected via venous cannulation. RESULTS: Serum amino acid (a.a.) concentrations differed between whey fractions (p=0.012) and were higher following GMP compared to ß-lac (p=0.051) and colostrum WPC (p=0.044) but not the WPC control (p=0.20). There was no difference in VAS-rated hunger, satisfaction, or thoughts of food between whey fractions, but fullness did differ (p=0.032) and was highest following the ß-lac beverage. Energy intake was not suppressed relative to control by any of the 3 whey fractions. CONCLUSIONS: We conclude that total serum a.a. concentration was a poor indicator of satiety, with little evidence of differential satiety between these whey proteins other than a modest enhancement of fullness by ß-lac.

Sensitivity of ad libitum meals to detect changes in hunger. Restricted-item or multi-item testmeals in the design of preload appetite studies.

The aims of the study were to determine whether restricted single-item or multi-item testmeals are better able to detect prior changes in hunger and fullness when assessing ad libitum eating behaviour. Thirty male participants were given a low- (L(E), 0.5 MJ) or high-energy (H(E), 4.0 MJ) breakfast preload designed to induce or suppress hunger, followed 3h later by a restricted-item (R(I)) or multi-item (M(I)) testmeal. The R(I) testmeal comprised pasta+meat sauce, whilst the M(I) testmeal comprised pasta+meat sauce plus bread, chicken, ham, cheese, salad, cake and fruit. The four conditions were (i) L(E)/R(I); (ii) L(E)/M(I); (iii) H(E)/R(I); (iv) H(E)/M(I). Visual analogue scales (VAS) were used to rate appetite sensations and EI was measured at the lunch testmeal. As expected, increasing the energy content of the preload significantly altered VAS ratings and decreased EI at the testmeal. Following both L(E) and H(E) breakfasts, EI was lower at the R(I) (L(E)=4566 kJ, H(E)=3583 kJ) compared with the M(I) (L(E)=6142 kJ, H(E)=5149 kJ) testmeal. However, the compensatory decrease in EI in response to the H(E) breakfast was not significantly greater at the R(I) testmeal (R(I): -983 kJ, 28.1% compensation; M(I): -993 kJ, 28.4% compensation). In preload studies measuring EI, increasing the variety of an ad lib testmeal may not decrease the sensitivity to detect changes in hunger and fullness.

Low-dose whey protein-enriched water beverages alter satiety in a study of overweight women.

AIM: To determine the effect of low-dose whey protein-enriched water beverages on postprandial satiety and energy intake (EI). METHODS: Fifty overweight and mildly obese women were given 500 mL water-based beverages on 4 different occasions in a double blind, cross-over study. The beverages were reasonably matched for colour, flavour, sweetness and contained 0% (water control, 0 g, 8 kJ), 1% (5 g, 93 kJ), 2% (10 g, 178 kJ) and 4% (20 g, 348 kJ) whey protein by weight (ClearProtein8855™). Following a standard evening meal and breakfast, beverages were consumed 120 min before an ad libitum lunch at which EI was measured. Feelings associated with hunger and fullness were also measured using visual analogue scales (VAS). RESULTS: 46 participants completed all 4 beverage conditions. There was a significant effect of beverage preload on hunger (beverage×time; P=0.0074), where each of the 1%, 2% and 4% w/w protein beverages decreased hunger compared to the water control (P<0.05). Suppression of hunger was also maintained for longer following the protein beverages (Friedman test, P=0.013). Fullness (beverage×time; P=0.0020) and satisfaction (beverage×time; P=0.0356) were both increased by the 1% and 4% protein beverages (P<0.05). EI at lunch decreased by up to 8 percent (control vs 4% protein, delta=-247 kJ, Tukey's post hoc, P>0.05) when escalating protein doses were added to the water preload (water control, 3028 kJ; 1%, 3080 kJ; 2%, 2924 kJ; 4%, 2781 kJ), only partial compensation for the added energy. CONCLUSIONS: These low-dose, whey protein-enriched water beverages significantly altered short term postprandial satiety, however the effect was not sufficient to impact on food intake when assessed 2 h after consumption.

No evidence of differential effects of SFA, MUFA or PUFA on post-ingestive satiety and energy intake: a randomised trial of fatty acid saturation.

BACKGROUND: High fat diets have long been associated with weight gain and obesity, and the weak satiety response elicited in response to dietary lipids is likely to play a role. Suppression of appetite and food intake has consistently been shown to be diminished with high fat relative to either high protein or carbohydrate meals. There is however some evidence that the satiating capacity of lipids may be modulated when physicochemical properties are altered, but studies investigating the effect of lipid saturation on appetite have generated inconsistent findings. This study investigated the effects of changes in fatty acid saturation on post-ingestive satiety and energy intake. METHODS: High-fat (HF) test breakfasts (2.0 MJ) containing 26 g lipid were given to 18 healthy, lean men in a 3 treatment randomised cross-over design, each treatment separated by a washout of at least 3 days. The breakfasts were high in saturated (SFA, 65% of total fat), polyunsaturated (PUFA, 76%) or monounsaturated (MUFA, 76%) fatty acids, and comprised 2 savoury muffins. Participants rated appetite sensations using visual analogue scales (VAS) to assess palatability immediately following the meals, and hunger and fullness prior to the HF breakfast and throughout the day. Energy intake was measured by covert weighing of a lunch meal which was served 3.5 h after the breakfast, and from which the participants ate ad libitum. RESULTS: There was no difference in VAS ratings of pleasantness, visual appearance, smell, taste, aftertaste and overall palatability between the 3 high-fat test breakfasts. However, there was also no differential effect of the 3 treatments on ratings of hunger, fullness, satisfaction or prospective food consumption during the 3.5 h following the breakfast meal and over the full 6 h experiment. Energy and macronutrient intake at lunch also did not differ between treatments (mean, sem; SFA: 5275.9 +/- 286.5 kJ; PUFA: 5227.7 +/- 403.9 kJ; MUFA: 5215.6 +/- 329.5 kJ; P > 0.05). The maximum difference in energy intake between treatments was less than 2%. CONCLUSIONS: There was no evidence of a difference in post-ingestion satiety between high fat meals which differed in saturation profile in this group of lean, healthy men.

Predictors Linking Obesity and the Gut Microbiome (the PROMISE Study): Protocol and Recruitment Strategy for a Cross-Sectional Study on Pathways That Affect the Gut Microbiome and Its Impact on Obesity.

BACKGROUND: The prevalence of obesity has increased substantially over recent decades and is associated with considerable health inequalities. Although the causes of obesity are complex, key drivers include overconsumption of highly palatable, energy-dense, and nutrient-poor foods, which have a profound impact on the composition and function of the gut microbiome. Alterations to the microbiome may play a critical role in obesity by affecting energy extraction from food and subsequent energy metabolism and fat storage. OBJECTIVE: We report the study protocol and recruitment strategy of the PRedictors linking Obesity and the gut MIcrobiomE (PROMISE) study, which characterizes the gut microbiome in 2 populations with different metabolic disease risk (Pacific and European women) and different body fat profiles (normal and obese). It investigates (1) the role of gut microbiome composition and functionality in obesity and (2) the interactions between dietary intake; eating behavior; sweet, fat, and bitter taste perception; and sleep and physical activity; and their impact on the gut microbiome, metabolic and endocrine regulation, and body fat profiles. METHODS: Healthy Pacific and New Zealand (NZ) European women aged between 18 and 45 years from the Auckland region were recruited for this cross-sectional study. Participants were recruited such that half in each group had either a normal weight (body mass index [BMI] 18.5-24.9 kg/m2) or were obese (BMI ≥30.0 kg/m2). In addition to anthropometric measurements and assessment of the body fat content using dual-energy x-ray absorptiometry, participants completed sweet, fat, and bitter taste perception tests; food records; and sleep diaries; and they wore accelerometers to assess physical activity and sleep. Fasting blood samples were analyzed for metabolic and endocrine biomarkers and DNA extracted from fecal samples was analyzed by shotgun sequencing. Participants completed questionnaires on dietary intake, eating behavior, sleep, and physical activity. Data were analyzed using descriptive and multivariate regression methods to assess the associations between dietary intake, taste perception, sleep, physical activity, gut microbiome complexity and functionality, and host metabolic and body fat profiles. RESULTS: Of the initial 351 women enrolled, 142 Pacific women and 162 NZ European women completed the study protocol. A partnership with a Pacific primary health and social services provider facilitated the recruitment of Pacific women, involving direct contact methods and networking within the Pacific communities. NZ European women were primarily recruited through Web-based methods and special interest Facebook pages. CONCLUSIONS: This cross-sectional study will provide a wealth of data enabling the identification of distinct roles for diet, taste perception, sleep, and physical activity in women with different body fat profiles in modifying the gut microbiome and its impact on obesity and metabolic health. It will advance our understanding of the etiology of obesity and guide future intervention studies involving specific dietary approaches and microbiota-based therapies. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12618000432213; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370874. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/14529.

Case finding of lifestyle and mental health disorders in primary care: validation of the 'CHAT' tool.

BACKGROUND: Primary care is accessible and ideally placed for case finding of patients with lifestyle and mental health risk factors and subsequent intervention. The short self-administered Case-finding and Help Assessment Tool (CHAT) was developed for lifestyle and mental health assessment of adult patients in primary health care. This tool checks for tobacco use, alcohol and other drug misuse, problem gambling, depression, anxiety and stress, abuse, anger problems, inactivity, and eating disorders. It is well accepted by patients, GPs and nurses. AIM: To assess criterion-based validity of CHAT against a composite gold standard. DESIGN OF STUDY: Conducted according to the Standards for Reporting of Diagnostic Accuracy statement for diagnostic tests. SETTING: Primary care practices in Auckland, New Zealand. METHOD: One thousand consecutive adult patients completed CHAT and a composite gold standard. Sensitivities, specificities, positive and negative predictive values, and likelihood ratios were calculated. RESULTS: Response rates for each item ranged from 79.6 to 99.8%. CHAT was sensitive and specific for almost all issues screened, except exercise and eating disorders. Sensitivity ranged from 96% (95% confidence interval [CI] = 87 to 99%) for major depression to 26% (95% CI = 22 to 30%) for exercise. Specificity ranged from 97% (95% CI = 96 to 98%) for problem gambling and problem drug use to 40% (95% CI = 36 to 45%) for exercise. All had high likelihood ratios (3-30), except exercise and eating disorders. CONCLUSION: CHAT is a valid and acceptable case-finding tool for most common lifestyle and mental health conditions.

Relationships of low serum vitamin D3 with anthropometry and markers of the metabolic syndrome and diabetes in overweight and obesity.

Low serum 25 hydroxyvitamin D3 (vitamin D3) is known to perturb cellular function in many tissues, including the endocrine pancreas, which are involved in obesity and type II diabetes mellitus (TIIDM). Vitamin D3 insufficiency has been linked to obesity, whether obesity is assessed by body mass index (BMI) or waist circumference (waist). Central obesity, using waist as the surrogate, is associated with the metabolic syndrome (MetSyn), insulin resistance, TIIDM and atherosclerotic cardiovascular disease (CVD). We tested how vitamin D3 was related to measures of fat mass, MetSyn markers, haemoglobin A1c (HbA1c) and MetSyn in a cross-sectional sample of 250 overweight and obese adults of different ethnicities. There were modest inverse associations of vitamin D3 with body weight (weight) (r = -0.21, p = 0.0009), BMI (r = -0.18, p = 0.005), waist (r = -0.14, p = 0.03), [but not body fat % (r = -0.08, p = 0.24)], and HbA1c (r = -0.16, p = 0.01). Multivariable regression carried out separately for BMI and waist showed a decrease of 0.74 nmol/L (p = 0.002) in vitamin D3 per 1 kg/m2 increase in BMI and a decrease of 0.29 nmol/L (p = 0.01) per 1 cm increase in waist, with each explaining approximately 3% of the variation in vitamin D3 over and above gender, age, ethnicity and season. The similar relationships of BMI and waist with vitamin D3 may have been due to associations between BMI and waist, or coincidental, where different mechanisms relating hypovitaminosis D3 to obesity occur concurrently. Previously reviewed mechanisms include that 1) low vitamin D3, may impair insulin action, glucose metabolism and various other metabolic processes in adipose and lean tissue 2) fat soluble-vitamin D3 is sequestered in the large adipose compartment, and low in serum, 3) obese people may be sensitive about their body shape, minimising their skin exposure to view and sunlight (not tested). We showed evidence for the first theory but no evidence to support the second. In the current study, serum vitamin D3 was inversely related to weight, BMI and markers of TIIDM (large waist, raised HbA1c) but not to adipose mass nor to MetSyn per se.

Duodenal and ileal glucose infusions differentially alter gastrointestinal peptides, appetite response, and food intake: a tube feeding study.

Background: Activation of the ileal brake through the delivery of nutrients into the distal small intestine to promote satiety and suppress food intake provides a new target for weight loss. Evidence is limited, with support from naso-ileal lipid infusion studies.Objective: The objective of the study was to investigate whether glucose infused into the duodenum and ileum differentially alters appetite response, food intake, and secretion of satiety-related gastrointestinal peptides.Design: Fourteen healthy male participants were randomly assigned to a blinded 4-treatment crossover, with each treatment of single-day duration. On the day before the intervention (day 0), a 380-cm multilumen tube (1.75-mm diameter) with independent port access to the duodenum and ileum was inserted, and position was confirmed by X-ray. Subsequently (days 1-4), a standardized breakfast meal was followed midmorning by a 90-min infusion of isotonic glucose (15 g, 235 kJ) or saline to the duodenum or ileum. Appetite ratings were assessed with the use of visual analog scales (VASs), blood samples collected, and ad libitum energy intake (EI) measured at lunch, afternoon snack, and dinner.Results: Thirteen participants completed the 4 infusion days. There was a significant effect of nutrient infused and site (treatment × time, P < 0.05) such that glucose-to-ileum altered VAS-rated fullness, satisfaction, and thoughts of food compared with saline-to-ileum (Tukey's post hoc, P < 0.05); decreased ad libitum EI at lunch compared with glucose-to-duodenum [-22%, -988 ± 379 kJ (mean ± SEM), Tukey's post hoc, P < 0.05]; and increased glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) compared with all other treatments (Tukey's post hoc, P < 0.05).Conclusions: Macronutrient delivery to the proximal and distal small intestine elicits different outcomes. Glucose infusion to the ileum increased GLP-1 and PYY secretion, suppressed aspects of VAS-rated appetite, and decreased ad libitum EI at a subsequent meal. Although glucose to the duodenum also suppressed appetite ratings, eating behavior was not altered. This trial was registered at www.anzctr.org.au as ACTRN12612000429853.

General practitioners' views on providing nutrition care to patients with chronic disease: a focus group study.

INTRODUCTION Nutrition care refers to practices conducted by health professionals to support patients to improve their dietary intake. General practitioners (GPs) are expected to provide nutrition care to patients for prevention and management of chronic disease. AIM This study explores GPs' opinions regarding nutrition care provision to patients with chronic disease. METHODS An interpretive descriptive approach to qualitative research using seven semi-structured focus groups with 48 GPs in Auckland was used. Focus groups investigated how GPs felt about providing nutrition care; the perceived barriers to and support required for this care; the development of further nutrition knowledge and skills; and possible roles for Practice Nurses. Recorded interviews were transcribed verbatim and analysed using a thematic approach. RESULTS GPs indicated routine provision of basic nutrition care to patients with chronic disease, but perceived their limited consultation time and nutrition competence constrained their capacity to provide nutrition care. GPs felt they needed further information to provide culturally, socially and economically sensitive nutrition care. GPs displayed variable opinions on the benefits of developing their nutrition knowledge and skills, and the idea of Practice Nurses providing nutrition care. CONCLUSIONS Despite perceiving that nutrition care is important for patients with chronic disease and facing barriers to providing nutrition care, GPs appear reluctant to further develop their knowledge and skills and for Practice Nurses to provide this care. Strategies to enhance GPs' nutrition-related self-efficacy, nutrition cultural competence and attitudes towards further training care may be warranted.

Doctors' attitudes and confidence towards providing nutrition care in practice: Comparison of New Zealand medical students, general practice registrars and general practitioners.

INTRODUCTION: Improvements in individuals' nutrition behaviour can improve risk factors and outcomes associated with lifestyle-related chronic diseases. AIM: This study describes and compares New Zealand medical students, general practice registrars and general practitioners' (GPs') attitudes towards incorporating nutrition care into practice, and self-perceived skills in providing nutrition care. METHODS: A total of 183 New Zealand medical students, 51 general practice registrars and 57 GPs completed a 60-item questionnaire investigating attitudes towards incorporating nutrition care into practice and self-perceived skills in providing nutrition care. Items were scored using a 5-point Likert scale. Factor analysis was conducted to group questionnaire items and a generalised linear model compared differences between medical students, general practice registrars and GPs. RESULTS: All groups indicated that incorporating nutrition care into practice is important. GPs displayed more positive attitudes than students towards incorporating nutrition in routine care (p<0.0001) and performing nutrition recommendations (p<0.0001). General practice registrars were more positive than students towards performing nutrition recommendations (p=0.004), specified practices (p=0.037), and eliciting behaviour change (p=0.024). All groups displayed moderate confidence towards providing nutrition care. GPs were more confident than students in areas relating to wellness and disease (p<0.0001); macronutrients (p=0.030); micronutrients (p=0.010); and women, infants and children (p<0.0001). DISCUSSION: New Zealand medical students, general practice registrars and GPs have positive attitudes and moderate confidence towards incorporating nutrition care into practice. It is possible that GPs' experience providing nutrition care contributes to greater confidence. Strategies to facilitate medical students developing confidence in providing nutrition care are warranted.

Increased intake of selected vegetables, herbs and fruit may reduce bone turnover in post-menopausal women.

Increased consumption of vegetables/herbs/fruit may reduce bone turnover and urinary calcium loss in post-menopausal women because of increased intake of polyphenols and potassium, but comparative human studies are lacking. The main aim was to compare bone turnover markers and urinary calcium excretion in two randomised groups (n = 50) of healthy post-menopausal women consuming ≥ 9 servings of different vegetables/herbs/fruit combinations (three months). Group A emphasised a generic range of vegetables/herbs/fruit, whereas Group B emphasised specific vegetables/herbs/fruit with bone resorption-inhibiting properties (Scarborough Fair Diet), with both diets controlled for potential renal acid load (PRAL). Group C consumed their usual diet. Plasma bone markers, urinary electrolytes (24 h) and estimated dietary PRAL were assessed at baseline and 12 weeks. Procollagen type I N propeptide (PINP) decreased (-3.2 µg/L, p < 0.01) in the B group only, as did C-terminal telopeptide of type I collagen (CTX) (-0.065 µg/L, p < 0.01) in women with osteopenia compared to those with normal bone mineral density (BMD) within this group. Intervention Groups A and B had decreased PRAL, increased urine pH and significantly decreased urinary calcium loss. Urinary potassium increased in all groups, reflecting a dietary change. In conclusion, Group B demonstrated positive changes in both turnover markers and calcium conservation.

Causes of metabolic syndrome and obesity-related co-morbidities Part 1: A composite unifying theory review of human-specific co-adaptations to brain energy consumption.

The medical, research and general community is unable to effect significantly decreased rates of central obesity and related type II diabetes mellitus (TIIDM), cardiovascular disease (CVD) and cancer. All conditions seem to be linked by the concept of the metabolic syndrome (MetS), but the underlying causes are not known. MetS markers may have been mistaken for causes, thus many treatments are destined to be suboptimal. The current paper aims to critique current paradigms, give explanations for their persistence, and to return to first principles in an attempt to determine and clarify likely causes of MetS and obesity related comorbidities. A wide literature has been mined, study concepts analysed and the basics of human evolution and new biochemistry reviewed. A plausible, multifaceted composite unifying theory is formulated. The basis of the theory is that the proportionately large, energy-demanding human brain may have driven co-adaptive mechanisms to provide, or conserve, energy for the brain. A 'dual system' is proposed. 1) The enlarged, complex cortico-limbic-striatal system increases dietary energy by developing strong neural self-reward/motivation pathways for the acquisition of energy dense food, and (2) the nuclear factor-erythroid 2-related factor 2 (NRF2) cellular protection system amplifies antioxidant, antitoxicant and repair activity by employing plant chemicals, becoming highly energy efficient in humans. The still-evolving, complex human cortico-limbic-striatal system generates strong behavioural drives for energy dense food procurement, including motivating agricultural technologies and social system development. Addiction to such foods, leading to neglect of nutritious but less appetizing 'common or garden' food, appears to have occurred. Insufficient consumption of food micronutrients prevents optimal human NRF2 function. Inefficient oxidation of excess energy forces central and non-adipose cells to store excess toxic lipid. Oxidative stress and metabolic inflammation, or metaflammation, allow susceptibility to infectious, degenerative atherosclerotic cardiovascular, autoimmune, neurodegenerative and dysplastic diseases. Other relevant human-specific co-adaptations are examined, and encompass the unusual ability to store fat, certain vitamin pathways, the generalised but flexible intestine and microbiota, and slow development and longevity. This theory has significant past and future corollaries, which are explored in a separate article by McGill, A-T, in Archives of Public Health, 72: 31.

Past and future corollaries of theories on causes of metabolic syndrome and obesity related co-morbidities part 2: a composite unifying theory review of human-specific co-adaptations to brain energy consumption.

Metabolic syndrome (MetS) predicts type II diabetes mellitus (TIIDM), cardiovascular disease (CVD) and cancer, and their rates have escalated over the last few decades. Obesity related co-morbidities also overlap the concept of the metabolic syndrome (MetS). However, understanding of the syndrome's underlying causes may have been misapprehended. The current paper follows on from a theory review by McGill, A-T in Archives of Public Health, 72: 30. This accompanying paper utilises research on human evolution and new biochemistry to theorise on why MetS and obesity arise and how they affect the population. The basis of this composite unifying theory is that the proportionately large, energy-demanding human brain may have driven co-adaptive mechanisms to provide, or conserve, energy for the brain. A 'dual system' is proposed. 1) The enlarged, complex cortico-limbic-striatal system increases dietary energy by developing strong neural self-reward/motivation pathways for the acquisition of energy dense food, and (2) the nuclear factor-erythroid 2-related factor 2 (NRF2) cellular protection system amplifies antioxidant, antitoxicant and repair activity by employing plant chemicals. In humans who consume a nutritious diet, the NRF2 system has become highly energy efficient. Other relevant human-specific co-adaptations are explored. In order to 'test' this composite unifying theory it is important to show that the hypothesis and sub-theories pertain throughout the whole of human evolution and history up till the current era. Corollaries of the composite unifying theory of MetS are examined with respect to past under-nutrition and malnutrition since agriculture began 10,000 years ago. The effects of man-made pollutants on degenerative change are examined. Projections are then made from current to future patterns on the state of 'insufficient micronutrient and/or unbalanced high energy malnutrition with central obesity and metabolic dysregulation' or 'malnubesity'. Forecasts on human health are made on positive, proactive strategies using the composite unifying theory, and are extended to the wider human ecology of food production. A comparison is made with the outlook for humans if current assumptions and the status quo on causes and treatments are maintained. Areas of further research are outlined. A table of suggestions for possible public health action is included.

Is the use of cholesterol-lowering drugs for the prevention of cardiovascular complications in type 2 diabetics evidence-based? A systematic review.

Cholesterol-lowering drugs are often prescribed to patients with type 2 diabetes mellitus despite uncertainty about the benefits of this treatment in the prevention of cardiovascular complications. We here systematically review (PRISMA guidelines) the results of high-quality double blind trials testing whether cholesterol-lowering drugs (statins and fibrates) reduce mortality and cardiovascular complications specifically in type 2 diabetics. Trials with premature termination without pertinent medical justification or using nonrandomized subgroups of diabetics were excluded from the review. Only four trials met our predefined inclusion criteria. Among the 3 statin trials, CARDS was discontinued 2 years before the anticipated end and in the absence of significant effect on both overall and cardiovascular mortality, suggesting that the trial should not have been prematurely stopped. The two other statin trials showed no significant effect on the primary endpoint (relative risk 0.92, 95% CI 0.77 to 1.10 in 4D and 0.90, 95% CI 0.73 to 1.12 in ASPEN) and on both cardiovascular and overall mortality. Finally, the fibrate trial (FIELD) showed no significant benefit on the primary endpoint (relative risk 0.89, 95% CI 0.75 to 1.05) and mortality (relative risk 1.11, 95% CI 0.95 to 1.29). Because of a huge medical heterogeneity between patients in the selected trials, it was consensually decided to stop the analysis at this stage. This review does not support the use of cholesterol-lowering drugs (such as statin and fibrate) to reduce mortality and cardiovascular complications in type 2 diabetics. Official guidelines should be re-examined and reformulated by experts independent from the pharmaceutical industry.

Influence of tail versus cardiac sampling on blood glucose and lipid profiles in mice.

Blood is collected during animal experimentation to measure haematological and metabolic parameters. It cannot be assumed that circulating blood has the same composition irrespective of its location, and indeed, differences in the composition of blood sampled from the arterial and venous compartments have been reported. Here we investigated whether blood collected by cardiac puncture (CP) versus that collected following removal of the distal 1 mm of the tail tip (TT) differs with respect to glucose and lipid profiles in male C57BL/6J mice at 4, 7, 20 and 28 weeks of age. Blood was first collected from the TT of unanaesthetized mice, which were then immediately anaesthetized using ketamine/xylazine, and a second blood sample was collected by CP. The CP glucose concentration was significantly higher than TT glucose by a positive bias averaging +80% (P < 0.01), irrespective of the age of the mice. Conversely, the concentrations of the CP lipids, including total cholesterol, high-density lipoprotein cholesterol and triglyceride were lower than TT lipids by a negative bias averaging -25% (P < 0.05). These observations highlight the difficulty in measuring and comparing metabolic parameters such as glucose and lipid between one blood compartment and another. They illustrate the need to standardize sampling sites, especially when repeated blood sampling is required.