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Obesity prevalence continues to rise throughout the developed world, as a result of positive energy balance and reduced physical activity. At present, there is still a perception within the general community, and amongst some nutritionists, that eating multiple small meals spaced throughout the day is beneficial for weight control and metabolic health. However, intervention trials do not generally support the epidemiological evidence, and data is emerging to suggest that increasing the fasting period between meals may beneficially impact body weight and metabolic health. To date, this evidence is of short term duration, and it is becoming increasingly apparent that meal timing must also be considered if we are to ensure optimal health benefits in response to this dietary pattern. The purpose of this review is to summate the existing human literature on modifying meal frequency and timing on body weight control, appetite regulation, energy expenditure, and metabolic health under conditions of energy balance, restriction and surplus. [ABSTRACT FROM AUTHOR]

High saturated fat (HF-S) diets increase intramyocellular lipid, an effect ameliorated by omega-3 fatty acids in vitro and in vivo, though little is known about sex- and muscle fiber type-specific effects. We compared effects of standard chow, HF-S, and 7.5% HF-S replaced with fish oil (HF-FO) diets on the metabolic profile and lipid metabolism gene and protein content in red (soleus) and white (extensor digitorum longus) muscles of male and female C57BL/6 mice (n = 9-12/group). Weight gain was similar in HF-S- and HF-FO-fed groups. HF-S feeding increased mesenteric fat mass and lipid marker, Oil Red O, in red and mixed muscle; HF-FO increased interscapular brown fat mass. Compared to chow, HF-S and HF-FO increased expression of genes regulating triacylglycerol synthesis and fatty acid transport, HF-S suppressed genes and proteins regulating fatty acid oxidation, whereas HF-FO increased oxidative genes, proteins and enzymes and lipolytic gene content, whilst suppressing lipogenic genes. In comparison to HF-S, HF-FO further increased fat transporters, markers of fatty acid oxidation and mitochondrial content, and reduced lipogenic genes. No diet-by-sex interactions were observed. Neither diet influenced fiber type composition. However, some interactions between muscle type and diet were observed. HF-S induced changes in triacylglycerol synthesis and lipogenic genes in red, but not white, muscle, and mitochondrial biogenesis and oxidative genes were suppressed by HF-S and increased by HF-FO in red muscle only. In conclusion, HF-S feeding promotes lipid storage in red muscle, an effect abrogated by the fish oil, which increases mediators of lipolysis, oxidation and thermogenesis while inhibiting lipogenic genes. Greater storage and synthesis, and lower oxidative genes in red, but not white, muscle likely contribute to lipid accretion encountered in red muscle. Despite several gender-dimorphic genes, both sexes exhibited a similar HF-S-induced metabolic and gene expression profile; likewise fish oil was similarly protective in both sexes. [ABSTRACT FROM AUTHOR]

In diet induced and genetically obese rodent models, adipose tissue is associated with macrophage infiltration, which promotes a low grade inflammatory state and the development of insulin resistance. In humans, obesity is also closely linked with macrophage infiltration in adipose tissue, a pro-inflammatory phenotype and insulin resistance. However, whether macrophage infiltration is a direct contributor to the development of insulin resistance that occurs in response to weight gain, or is a later consequence of the obese state is unclear. There are a number of concomitant changes that occur during adipose tissue expansion, including the number and size of adipocytes, the vasculature and the extracellular matrix. In this review, we will examine evidence for and against the role of macrophage recruitment into adipose tissue in promoting the development of insulin resistance in rodents and humans, as well as discuss the emerging role of macrophages in mediating healthy adipose tissue expansion during periods of caloric excess. [ABSTRACT FROM AUTHOR]

The aim of this study was to characterize expression profiles of visceral and subcutaneous adipose tissue in children. Adipose tissue samples were collected from children having elective surgery ( n = 71, [54 boys], 6.0 ± 4.3 years). Affymetrix microarrays ( n = 20) were performed to characterize the functional profile and identify genes of interest in adipose tissue. Visceral adipose tissue had an overrepresentation of Gene Ontology themes related to immune and inflammatory responses and subcutaneous adipose tissue had an overrepresentation of themes related to adipocyte growth and development. Likewise, qPCR performed in the whole cohort showed a 30-fold increase in haptoglobin ( P = 0.005), 7-fold increase in IL-10 ( P < 0.001), 8-fold decrease in VEGF ( P = 0.01) and a 28-fold decrease in TBOX15 ( P < 0.001) in visceral compared to subcutaneous adipose tissue. The inflammatory pattern in visceral adipose tissue may represent an early stage of the adverse effects of this depot, and combined with chronic obesity, may contribute to increased metabolic and cardiovascular risk. [ABSTRACT FROM AUTHOR]

OBJECTIVE--To characterize the relationships among long-term improvements in peripheral insulin sensitivity (glucose disposal rate [GDR]), fasting glucose, and free fatty acids (FFAs) and concomitant changes in weight and adipose tissue mass and distribution induced by lifestyle intervention in obese individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS--We measured GDR, fasting glucose, and FFAs during a euglycemic clamp and adipose tissue mass and distribution, organ fat, and adipocyte size by dual-energy X-ray absorptiometry, CT scan, and adipose tissue biopsy in 26 men and 32 women in the Look-AHEAD trial before and after 1 year of diet and exercise aimed at weight loss. RESULTS--Weight and fasting glucose decreased significantly (P < 0.0001) and significantly more in men than in women (-12 vs. -8% and -16 vs. -7%, respectively; P < 0.05), while FFAs during hyperinsulinemia decreased and GDR increased significantly (P < 0.00001) and similarly in both sexes (-53 vs. -41% had 63 vs. 43%; P = NS). Men achieved a more favorable fat distribution by losing more from upper compared with lower and from deeper compared with superficial adipose tissue depots (P < 0.01). Decreases in weight and adipose tissue mass predicted improvements in GDR but not in fasting glucose or fasting FFAs; however, decreases in FFAs during hyperinsulinemia significantly determined GDR improvements. Hepatic fat was the only regional fat measure whose change contributed independently to changes in metabolic variables. CONCLUSIONS--Patients with type 2 diabetes undergoing a 1-year lifestyle intervention had significant improvements in GDR, fasting glucose, FFAs and adipose tissue distribution. However, changes in overall weight (adipose tissue mass) and hepatic fat were the most important determinants of metabolic improvements. Diabetes 59:627-633, 2010 [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) are postulated to be a common trigger of insulin resistance. For example, treatment of adipocytes with either tumor-necrosis factor-α or dexamethasone increases ROS before impairing glucose uptake. Similarly, treatment with mitochondria-specific antioxidants preserves insulin sensitivity in animal models of insulin resistance. However, it remains unclear whether ROS contribute to insulin resistance in humans. First-degree relatives (FDRs) of type 2 diabetes subjects are at increased risk of developing insulin resistance and type 2 diabetes. Here we review the documented metabolic impairments in FDRs that could contribute to insulin resistance via increased oxidative stress. We propose that lipotoxic intermediates and lipid peroxides in skeletal muscle interfere with insulin signaling and might cause insulin resistance in these ‘at risk’ individuals. [Copyright &y& Elsevier]

Background: Metabolic and behavioral adaptations to caloric restriction (CR) in free-living conditions have not yet been objectively measured. Methodology and Principal Findings: Forty-eight (36.861.0 y), overweight (BMI 27.860.7 kg/m2) participants were randomized to four groups for 6-months; Control: energy intake at 100% of energy requirements; CR: 25% calorie restriction; CR+EX: 12.5% CR plus 12.5% increase in energy expenditure by structured exercise; LCD: low calorie diet (890 kcal/d) until 15% weight reduction followed by weight maintenance. Body composition (DXA) and total daily energy expenditure (TDEE) over 14-days by doubly labeled water (DLW) and activity related energy activity (AREE) were measured after 3 (M3) and 6 (M6) months of intervention. Weight changes at M6 were 21.061.1% (Control), 210.460.9% (CR), 210.060.8% (CR+EX) and 213.960.8% (LCD). At M3, absolute TDEE was significantly reduced in CR (2454676 kcal/d) and LCD (2633666 kcal/d) but not in CR+EX or controls. At M6 the reduction in TDEE remained lower than baseline in CR (23166118 kcal/d) and LCD (23896124 kcal/d) but reached significance only when CR and LCD were combined (2351683 kcal/d). In response to caloric restriction (CR/LCD combined), TDEE adjusted for body composition, was significantly lower by 2431651 and 2240683 kcal/d at M3 and M6, respectively, indicating a metabolic adaptation. Likewise, physical activity (TDEE adjusted for sleeping metabolic rate) was significantly reduced from baseline at both time points. For control and CR+EX, adjusted TDEE (body composition or sleeping metabolic rate) was not changed at either M3 or M6. Conclusions: For the first time we show that in free-living conditions, CR results in a metabolic adaptation and a behavioral adaptation with decreased physical activity levels. These data also suggest potential mechanisms by which CR causes large inter-individual variability in the rates of weight loss and how exercise may influence weight loss and weight loss maintenance. [ABSTRACT FROM AUTHOR]

Insulin resistance is a key defect associated with obesity and type-2 diabetes. The precise factors that lead to insulin resistance have not been elucidated fully, but there is a strong association between insulin resistance and inappropriate lipid accumulation in insulin-target tissues. Over the past decade, several studies have reported changes in markers of mitochondrial metabolism in insulin-resistant individuals. These observations have led to the theory that compromised mitochondrial oxidative function, particularly in skeletal muscle, causes excess lipid deposition and the development of insulin resistance. Here, we review the latest findings regarding the link between mitochondrial metabolism and insulin action and, in particular, highlight several recent studies that call into question the cause-and-effect relationship between mitochondrial dysfunction and insulin resistance. [Copyright &y& Elsevier]

Moderate calorie restriction (CR) has long been recognized to reduce the risk of chronic diseases that are associated with obesity and aging. Intermittent fasting (IF) has recently emerged as a viable alternative to daily CR to reduce risk markers of chronic diseases, such as type 2 diabetes and cardiovascular diseases. The majority of trials have shown that IF provides similar metabolic and weight benefits to CR, although a few suggest that IF maybe superior to CR. The type of fasting protocol that is employed varies widely and could underpin the divergence in study outcomes. This review will discuss the findings of currently available IF versus CR trials, the protocol differences that exist between studies, as well as the gaps that still exist in the field, and finally will highlight upcoming studies that will further our understanding of the metabolic effectiveness of IF diets for metabolic health. [ABSTRACT FROM AUTHOR]

Calorie restriction (CR) produces several health benefits and increases lifespan in many species. Studies suggest that alternate-day fasting (ADF) and exercise can also provide these benefits. Whether CR results in lifespan extension in humans is not known and a direct investigation is not feasible. However, phenotypes observed in CR animals when compared to ad libitum fed (AL) animals, including increased stress resistance and changes in protein expression, can be simulated in cells cultured with media supplemented with blood serum from CR and AL animals. Two pilot studies were undertaken to examine the effects of ADF and CR on indicators of health and longevity in humans. In this study, we used sera collected from those studies to culture human hepatoma cells and assessed the effects on growth, stress resistance and gene expression. Cells cultured in serum collected at the end of the dieting period were compared to cells cultured in serum collected at baseline (before the dieting period). Cells cultured in serum from ADF participants, showed a 20% increase in Sirt1 protein which correlated with reduced triglyceride levels. ADF serum also induced a 9% decrease in proliferation and a 25% increase in heat resistance. Cells cultured in serum from CR participants induced an increase in Sirt1 protein levels by 17% and a 30% increase in PGC-1α mRNA levels. This first in vitro study utilizing human serum to examine effects on markers of health and longevity in cultured cells resulted in increased stress resistance and an up-regulation of genes proposed to be indicators of increased longevity. The use of this in vitro technique may be helpful for predicting the potential of CR, ADF and other dietary manipulations to affect markers of longevity in humans. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Compared with nondiabetic subjects, type 2 diabetic subjects are metabolically inflexible with impaired fasting fat oxidation and impaired carbohydrate oxidation during a hyperinsulinemic clamp. We hypothesized that impaired insulin-stimulated glucose oxidation is a consequence of the lower cellular glucose uptake rate in type 2 diabetes. Therefore, we compared metabolic flexibility to glucose adjusted for glucose disposal rate in nondiabetic versus type 2 diabetic subjects and in the latter group after 1 year of lifestyle intervention (the Look AHEAD [Action For Health in Diabetes] trial). RESEARCH DESIGN AND METHODS--Macronutrient oxidation rates under fasting and hyperinsulinemic conditions (clamp at 80 mU/m² per min), body composition (dual-energy X-ray absorptiometry), and relevant hormonal/metabolic blood variables were assessed in 59 type 2 diabetic and 42 nondiabetic individuals matched for obesity, sex, and race. Measures were repeated in diabetic participants after weight loss. RESULTS--Metabolic flexibility to glucose (change in respiratory quotient [RQ]) was mainly related to insulin-stimulated glucose disposal rate (R² = 0.46, P < 0.0001) with an additional 3% of variance accounted for by plasma free fatty acid concentration at the end of the clamp (P = 0.03). The impaired metabolic flexibility to glucose observed in type 2 diabetic versus nondiabetic subjects (ΔRQ 0.06 ± 0.01 vs. 0.10 ± 0.01, respectively, P < 0.0001) was no longer observed after adjusting for glucose disposal rate (P = 0.19). Additionally, the increase in metabolic flexibility to glucose after weight loss was accounted for by the concomitant increase in insulin-stimulated glucose disposal rate. CONCLUSIONS--This study suggests that metabolic inflexibility to glucose in type 2 diabetic subjects is mostly related to defective glucose transport. [ABSTRACT FROM AUTHOR]

Individuals with insulin resistance and type 2 diabetes have an impaired ability to switch appropriately between carbohydrate and fatty acid oxidation. However, whether this is a cause or consequence of insulin resistance is unclear, and the mechanism(s) involved in this response is not completely elucidated. Whole-body fat oxidation and transcriptional regulation of genes involved in lipid metabolism in skeletal muscle were measured after a prolonged fast and after consumption of either high-fat (76%) or high-carbohydrate (76%) meals in individuals with no family history of type 2 diabetes (control, n = 8) and in age-and fatness-matched individuals with a strong family history of type 2 diabetes (n = 9). Vastus lateralis muscle biopsies were performed before and 3 h after each meal. Insulin sensitivity and fasting measures of fat oxidation were not different between groups. However, subjects with a family history of type 2 diabetes had an impaired ability to increase fatty acid oxidation in response to the high-fat meal (P < 0.05). This was related to impaired activation of genes involved in lipid metabolism, including those for peroxisome proliferator--activated receptor coactivator-lα (PGC1α) and fatty acid translocase (FAT)/CD36 (P < 0.05). Of interest, adiponectin receptor-1 expression decreased 23% after the high-fat meal in both groups, but it was not changed after the high-carbohydrate meal. In conclusion, an impaired ability to increase fatty acid oxidation precedes the development of insulin resistance in genetically susceptible individuals. PGC1α and FAT/CD36 are likely candidates in mediating this response. Diabetes 56:2046-2053, 2007 [ABSTRACT FROM AUTHOR]

Insulin resistance (IR) is typically more severe in obese individuals with type 2 diabetes (T2DM) than in similarly obese non-diabetics but whether there are group differences in body composition and whether such differences contribute to the more severe IR of T2DM is uncertain. DEXA and regional CT imaging were conducted to assess adipose tissue (AT) distribution and fat content in liver and muscle in 67 participants with T2DM (F39/M28, age 60 ± 7 yr, BMI 34 ± 3 kg/m²) and in 35 similarly obese, non-DM volunteers (F20/M15, age 55 ± 8 yr, BMI 33 ± 2 kg/m²). A biopsy of subcutaneous abdominal AT was done to measure adipocyte size. A glucose clamp was performed at an insulin infusion of 80 mU·min-1m-2. There was more severe IR in T2DM (6.1 ± 2.3 vs. 9.9 ± 3.3 mg·min-1·kg-1 FFM-1; P < 0.01). Group comparisons of body composition parameters was performed after adjusting for the effect of age, gender, race, height and total fat mass (FM). T2DM was associated with less leg FM(-1.2 ± 0.4 kg, P <0.01), more trunk FM (+1.1 ± 0.4 kg, P < 0.05), greater hepatic fat (P < 0.05), and more subfascial adipose tissue around skeletal muscle (P < 0.05). There was a significant group X sex interaction for VAT (P < 0.01), with greater VAT in women with T2DM (P < 0.01). Mean adipocyte size (AS) did not significantly differ across groups, and smaller AS was associated with increased leg FM, whereas larger AS was related to more trunk FM (both P < 0.05). Group differences in IR were less after adjusting for group differences in leg FM, trunk FM, and hepatic fat, but these adjustments only partially accounted for the greater severity of IR in T2DM. In summary, T2DM, compared with similarly obese nondiabetic men and women, is associated with less leg FM and greater trunk FM and hepatic fat. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- The purpose of this article was to determine the relationships among total body fat, visceral adipose tissue (VAT), fat cell size (FCS), ectopic fat deposition in liver (intrahepatic lipid [1HL]) and muscle (intramyocellular lipid [IMCL]), and insulin sensitivity index (Si) in healthy overweight, glucose-tolerant subjects and the effects of calorie restriction by diet alone or in conjunction with exercise on these variables. RESEARCH DESIGN AND METHODS -- Forty-eight overweight volunteers were randomly assigned to four groups: control (100% of energy requirements), 25% calorie restriction (CR), 12.5% calorie restriction +12.5% energy expenditure through structured exercise (CREX), or 15% weight loss by a low-calorie diet followed by weight maintenance for 6 months (LCD). Weight, percent body fat, VAT, IMCL, IHL, FCS, and Si were assessed at baseline and month 6. RESULTS -- At baseline, FCS was related to VAT and IHL (P < 0.05) but not to IMCL. FCS was also the strongest determinant of Si (P < 0.01). Weight loss at month 6 was 1 ± 1% (control, mean ± SE), 10 ± 1% (CR), 10 ± 1% (CREX), and 14 ± 1% (LCD). VAT, FCS, percent body fat, and IHL were reduced in the three intervention groups (P < 0.01), but IMCL was unchanged. Si was increased at month 6 (P = 0.05) in the CREX (37 ± 18%) and LCD (70 ± 34%) groups (P < 0.05) and tended to increase in the CR group (40 ± 20%, P = 0.08). Together the improvements in Si were related to loss in weight, fat mass, and VAT, but not IHL, IMCL, or FCS. CONCLUSIONS -- Large adipocytes lead to lipid deposition in visceral and hepatic tissues, promoting insulin resistance. Calorie restriction by diet alone or with exercise reverses this trend. [ABSTRACT FROM AUTHOR]

Context Prolonged calorie restriction increases life span in rodents. Whether prolonged calorie restriction affects biomarkers of longevity or markers of oxidative stress, or reduces metabolic rate beyond that expected from reduced metabolic mass, has not been investigated in humans. Objective To examine the effects of 6 months of calorie restriction, with or without exercise, in overweight, nonobese (body mass index, 25 to <30) men and women. Design, Setting, and Participants Randomized controlled trial of healthy, sedentary men and women (N = 48) conducted between March 2002 and August 2004 at a research center in Baton Rouge, La. Intervention Participants were randomized to 1 of 4 groups for 6 months: control (weight maintenance diet); calorie restriction (25% calorie restriction of baseline energy requirements); calorie restriction with exercise (12.5% calorie restriction plus 12.5% increase in energy expenditure by structured exercise); very low-calorie diet (890 kcal/d until 15% weight reduction, followed by a weight maintenance diet). Main Outcome Measures Body composition; dehydroepiandrosterone sulfate (DHEAS), glucose, and insulin levels; protein carbonyls; DNA damage; 24-hour energy expenditure; and core body temperature. Results Mean (SEM) weight change at 6 months in the 4 groups was as follows: controls, -1.0% (1.1%); calorie restriction, -10.4% (0.9%); calorie restriction with exercise, -10.0% (0.8%); and very low-calorie diet, -13.9% (0.7%). At 6 months, fasting insulin levels were significantly reduced from baseline in the intervention groups (all P<.01), whereas DHEAS and glucose levels were unchanged. Core body temperature was reduced in the calorie restriction and calorie restriction with exercise groups (both P<.05). After adjustment for changes in body composition, sedentary 24-hour energy expenditure was unchanged in controls, but decreased in the calorie restriction (-135 kcal/d [42 kcal/d]), calorie restriction with exercise (-117 kcal/d [52 kcal/d]), and very low-calorie diet (-125 kcal/d [35 kcal/d]) groups (all P<.008). These "metabolic adaptations" (~ 6% more than expected based on loss of metabolic mass) were statistically different from controls (P<.05). Protein carbonyl concentrations were not changed from baseline to month 6 in any group, whereas DNA damage was also reduced from baseline in all intervention groups (P <.005). Conclusions Our findings suggest that 2 biomarkers of longevity (fasting insulin level and body temperature) are decreased by prolonged calorie restriction in humans and support the theory that metabolic rate is reduced beyond the level expected from reduced metabolic body mass. Studies of longer duration are required to determine if calorie restriction attenuates the aging process in humans. [ABSTRACT FROM AUTHOR]

We investigated whether a polymorphism in the promoter region of the TNFα gene (−308 A/G) is associated with reduced weight loss in obese Australian subjects on an energy restricted diet. 189 healthy subjects and 91 subjects with type II diabetes were genotyped for the −308 Nco I polymorphism using PCR-RFLP techniques. A subset of these subjects (211 females and 45 males), were placed on a 30% energy restricted diet (6200 kJ) for 12 weeks. Subjects were assessed every 2 weeks and changes in body weight, waist circumference and BMI were used as determinants of weight loss. Fasting plasma was analysed for glucose, insulin, lipids and free fatty acids. 64% of subjects were GG homozygotes, 31% were AG heterozygotes and 5% were AA homozygotes. There was no significant difference between the allele frequency in healthy subjects (0.21) and type 2 diabetic patients (0.24). The presence of the −308 A/G polymorphism did not significantly influence initial BMI, the amount of weight lost (GG, 8.1±0.65 kg, AG, 6.9±0.77 kg, AA, 7.6±0.12 kg), waist circumference or any metabolic variable. The AA variant at position −308 in the promoter region of the TNFα gene does not influence the amount of weight lost in overweight and obese men and women on a 30% energy restricted diet. [Copyright &y& Elsevier]

C reactive protein (CRP) values in blood are a good indicator of the likelihood of acute coronary and cerebral events in both healthy subjects and patients with coronary artery disease. This indicates that atherosclerotic lesions rich in inflammatory cells and cytokines are more likely to produce acute events either through vasospasm and/or thrombosis and also can be readily detected through elevations in CRP when measured using a high sensitivity assay (hsCRP). However the arterial wall is only one potential source of cytokines which induce CRP production. Fat cells also produce cytokines, in particular IL-6 which induces the synthesis of CRP by the liver. Obesity, especially abdominal obesity, is associated with elevations of hsCRP. This may be of pathogenic significance as CRP stimulates the uptake of LDL by macrophages, induces complement activation which may cause cellular damage in the artery, and enhances monocyte production of tissue factor, thus enhancing the risk of thrombosis. Caloric restriction and weight loss lowers IL-6 and CRP levels and may beneficially suppress an immune response. Whether particular dietary macronutrients or micronutrients alter IL-6 or CRP is unknown but this issue is clearly becoming more important. [Copyright &y& Elsevier]

Cholesterol ester transfer protein (CETP) facilitates reverse cholesterol transport via HDL-C and this activity may be increased in obese subjects. In normal weight subjects the Taq1B variant of the CETP gene is associated with lower CETP activity and higher HDL-C. The aim of this study was to examine the relationship between the Taq1B polymorphism and HDL-C in obese women before and after weight loss. A total of 245 women (41 with type 2 diabetes) were genotyped for the Taq1B variant. Plasma lipids, insulin, glucose and oral glucose tolerance were also measured before and after weight loss. When all subjects were examined together the Taq1B genotype was not associated with HDL-C. However, when non-diabetic subjects were divided by median fasting insulin, a strong linear association was observed between Taq1B genotype and HDL-C in subjects below median for fasting insulin (B1B1 1.19±0.07 mmol/l, B1B2 1.35±0.06, B2B2 1.71±0.09, P<0.000). This association was not observed in subjects with fasting insulin above median or subjects with type 2 diabetes, either before or after weight loss. Therefore, the B2B2 genotype is associated with elevated HDL-C in obese women with low fasting insulin only. Improved insulin sensitivity during weight loss did not change this relationship in women with high fasting insulin or type 2 diabetes. [Copyright &y& Elsevier]

Aim: This qualitative study aimed to explore the experiences of participants who were enrolled in 6‐month controlled weight loss interventions with 2‐month follow‐up to better understand the process of behaviour change and maintenance. Methods: Fifteen participants who completed or dropped out from either a daily energy restriction or intermittent fasting group were recruited using maximum variation purposive sampling. In‐depth, semi‐structured interviews were conducted at the 2‐month follow‐up phase. All interviews were transcribed and analysed using thematic analysis, guided by behaviour change models including transtheoretical model, social cognitive theory and integrated model of change. Results: Participants following both diets showed similar behaviour change patterns. Their first motivations were mostly external and relied on 'accountability' to adhere to the diet when initiating the dietary changes. Participants highlighted the importance of frequent reviews and monitoring in assisting their adherence. This feedback system promoted the development of self‐efficacy and internalised motivation to encourage an 'ownership'. Participants who transitioned successfully from relying on accountability to take 'ownership' of the intervention were more capable of tackling challenges and tailoring their diet to form a new routine for long‐term maintenance. Conclusion: External motivations were key to initiate while internalised motivations were more important to sustain the behaviour change. Health professionals can assist this process through routine monitoring and feedback processes in clinical practice. [ABSTRACT FROM AUTHOR]

Presents a study which sought to determine the optimal diet for improving glucose and lipid profiles in obese patients with type 2 diabetes during moderate energy restriction. Research design and methods; Experimental results; Conclusions.

Arginine metabolites are associated with cardiovascular and all-cause mortality in several patient groups. We investigated whether arginine metabolites are associated with mortality in patients with critical illness and whether associations are independent of other factors affecting prognosis in an Intensive Care Unit (ICU). 1155 acutely unwell adult patients admitted to a mixed medical-surgical ICU were studied. Arginine, asymmetric dimethyl- l -arginine (ADMA), monomethyl- l -arginine (MMA), symmetric dimethyl- l -arginine (SDMA) and l -homoarginine were measured in a plasma sample collected at admission to ICU by liquid chromatography tandem mass spectrometry. Risk of death score was calculated using data submitted to the Australia and New Zealand Intensive Care Society. In this cohort, 163 patients (14.1%) died. ADMA (odds ratio = 1.159 (1.033–1.300) per 0.1 μmol/L increment, p = 0.012), homoarginine (odds ratio = 0.963 (0.934–0.992), p = 0.013) and risk of death score (odds ratio = 1.045 (1.037–1.053) per 1% increment, p < 0.001) were independently associated with mortality in ICU patients. The area under the receiver operator characteristic curve for risk of death score, ADMA and homoarginine combined for mortality was greater than for risk of death score alone (0.815 (95% CI 0.790–0.837) vs 0.796 (95% CI 0.781–0.820), p = 0.019). Other arginine metabolites were not independently associated with mortality. ADMA is positively and homoarginine negatively associated with mortality in ICU patients, independent of other clinical factors. Measuring ADMA and homoarginine may refine models to predict ICU mortality. Reducing ADMA and increasing homoarginine are potential therapeutic targets to reduce mortality in critically ill patients. • Arginine metabolites are independent predictors of mortality in critical illness. • Asymmetric dimethyl- l -arginine was associated with mortality in critical illness. • Homoarginine was negatively associated with mortality in critical illness. • Arginine was not associated with mortality in critical illness. • Arginine metabolites may improve validated critical care prognostic model. [ABSTRACT FROM AUTHOR]

Comments on the contribution of calorie restriction (CR) to the extension of life span. Factors that contributed to the anti-aging effects of CR; Nutrient composition of calorie restricted diets; Criticism on a study on the life span of fruit flies fed with different diets; Efforts of investigators in Baton Rouge, Boston and Saint Louis, Missouri in collaboration with the National Institute on Aging to undertake studies of prolonged CR in humans.

Background:e-Health refers to any health care service delivered through the internet or related technologies, to improve quality of life. Despite the increasing use of e-health interventions to manage type 2 diabetes (T2D), there is a lack of evidence about the effectiveness on diabetes distress and depression, which are common issues in those living with T2D. Purpose:To synthesize and determine the effects of e-health interventions on diabetes distress and depression among patients with T2D. Methods:We systematically searched PubMed, Scopus, Cochrane CENTRAL, and Web of Science for randomized controlled trials (RCTs), non-RCTs and observational cohort studies for the effects of e-health interventions on diabetes distress and depression in patients with T2D up to September 14, 2022. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 recommendations were followed. The risk of bias was assessed according to the Risk-of-Bias 2 tool (RCTs), the Risk Of Bias In Non-randomised Studies-of Interventions (ROBINS-I) (non-RCTs) and the National Institute of Health tool (observational). The standardized mean difference (SMD) and its related 95% confidence intervals (CIs) were estimated with the DerSimonian–Laird method through random-effect models. A pooled raw mean difference (MD) meta-analysis was conducted for RCTs comparing the effects of e-health versus control on diabetes distress screening to display the clinical impact. Results:A total of 41 studies (24 RCTs, 14 non-RCTs, and 3 observational) involving 8,667 individuals were included. The pooled SMD for the effect of e-health versus the control group on diabetes distress was −0.14 (95% CI = −0.24 to −0.04; I2 = 23.9%; n = 10 studies), being -0.06 (95% CI = −0.15 to 0.02; I2 = 7.8%; n = 16 studies) for depression. The pooled raw MD on diabetes distress screening showed a reduction of −0.54 points (95% CI = −0.81 to −0.27; I2 = 85.1%; n = 7 studies). Conclusion:e-Health interventions are effective in diminishing diabetes distress among adults with T2D, inducing clinically meaningful reductions. [ABSTRACT FROM AUTHOR]

Background: Sustained fuel excess triggers low-grade inflammation that can drive mitochondrial dysfunction, a pivotal defect in the pathogenesis of insulin resistance in skeletal muscle.Objectives: This study aimed to investigate whether inflammation in skeletal muscle can be prevented by EPA, and if this is associated with an improvement in mitochondrial fusion, membrane potential, and insulin signaling.Methods: Human primary myotubes were treated for 24 h with palmitic acid (PA, 500 μM) under hyperglycemic conditions (13 mM glucose), which represents nutrient overload, and in the presence or absence of EPA (100 μM). After the treatments, the expression of peroxisome proliferator-activated receptor γ coactivator 1-α (PPARGC1A) and IL6 was assessed by q-PCR. Western blot was used to measure the abundance of the inhibitor of NF-κB (IKBA), mitofusin-2 (MFN2), mitochondrial electron transport chain complex proteins, and insulin-dependent AKT (Ser473) and AKT substrate 160 (AS 160; Thr642) phosphorylation. Mitochondrial dynamics and membrane potential were evaluated using immunocytochemistry and the JC-1 (tetraethylbenzimidazolylcarbocyanine iodide) dye, respectively. Data were analyzed using 1-factor ANOVA followed by Tukey post hoc test.Results: Nutrient excess activated the proinflammatory NFκB signaling marked by a decrease in IKBA (40%; P < 0.05) and the upregulation of IL6 mRNA (12-fold; P < 0.001). It also promoted mitochondrial fragmentation (53%; P < 0.001). All these effects were counteracted by EPA. Furthermore, nutrient overload-induced drop in mitochondrial membrane potential (6%; P < 0.05) was prevented by EPA. Finally, EPA inhibited fuel surplus-induced impairment in insulin-mediated phosphorylation of AKT (235%; P < 0.01) and AS160 (49%; P < 0.05).Conclusions: EPA inhibited NFκB signaling, which was associated with an attenuation of the deleterious effects of PA and hyperglycemia on both mitochondrial health and insulin signaling in human primary myotubes. Thus, EPA might preserve skeletal muscle metabolic health during sustained fuel excess but this requires confirmation in human clinical trials. [ABSTRACT FROM AUTHOR]

Accumulating evidence supports the benefits of intermittent fasting (IF) as a dietary strategy for cardiometabolic health and weight control. However, little is known about the potential implications of IF on mental disorders. The aim of this review was to synthesize evidence regarding the effects of IF on mental disorders (depression, anxiety, and mood state) in the general population. We conducted a systematic search in five databases from inception to January 2022. Randomized and nonrandomized clinical trials (RCTs/nonRCTs) were included. A random effects method was used to pool standardized mean differences (SMDs) and 95% CIs. A total of 14 studies involving 562 individuals were included, of which 8 were RCTs and 6 were nonRCTs. IF showed a moderate and positive effect on depression scores when compared to control groups (SMD: 0.41; 95%CI: 0.05 to 0.76; I2=45%; n = 4). Conversely, within-group analyses did not show any significant effect of IF on anxiety (SMD: 0.10; 95%CI: −0.09 to 0.30; I2=0%; n = 5) or mood state (SMD: 0.14; 95%CI: −0.09 to 0.37; I2=59%; n = 7). IF modalities did not negatively impact mental disorders in the general population. In fact, IF showed a positive influence on diminishing depression scores, and did not modify anxiety or mood. [ABSTRACT FROM AUTHOR]

Aim: To determine whether a digital nudge soon after dinner reduces after‐dinner snacking events as measured objectively by continuous glucose monitoring (CGM) in patients with type 2 diabetes (T2D). Methods: This is a single‐site micro‐randomized trial (MRT). People with T2D, aged 18‐75 years, managed with diet or a stable dose of oral antidiabetic medications for at least 3 months, and who habitual snack after dinner at least 3 nights per week, will be recruited. Picto‐graphic nudges were designed by mixed research methods. After a 2‐week lead‐in phase to determine eligibility and snacking behaviours by a CGM detection algorithm developed by the investigators, participants will be micro‐randomized daily (1:1) to a second 2‐week period to either a picto‐graphic nudge delivered‐in‐time (Intui Research) or no nudge. During lead‐in and MRT phases, 24‐hour glucose will be measured by CGM, sleep will be tracked by an under‐mattress sleep sensor, and dinner timing will be captured daily by photographing the evening meal. Results: The primary outcome is the difference in the incremental area under the CGM curve between nudging and non‐nudging days during the period from 90 minutes after dinner until 04:00 AM. Secondary outcomes include the effect of baseline characteristics on treatment, and comparisons of glucose peaks and time‐in‐range between nudging and non‐nudging days. The feasibility of 'just‐in‐time' messaging and nudge acceptability will be evaluated, along with the analysis of sleep quality measures and their night‐to‐night variability. Conclusions: This study will provide preliminary evidence of the impact of appropriately timed digital nudges on 24 ‐hour intertitial glucose levels resulting from altered after‐dinner snacking in people with T2D. An exploratory sleep substudy will provide evidence of a bidirectional relationship between after‐dinner snacking behaviour, glycaemia and sleep. Ultimately, this study will allow for the design of a future confirmatory study of the potential for digital nudging to improve health related behaviours and health outcomes. [ABSTRACT FROM AUTHOR]

Aims: Contrasting findings exist regarding the association between circulating sex hormone-binding globulin (SHBG) and testosterone levels and type 2 diabetes (T2D) in men. We examined prospective associations of SHBG and sex steroids with incident T2D in a cohort of community-dwelling men.Methods: Participants were from a cohort study of community-dwelling (n = 2563), middle-aged to elderly men (35-80 years) from Adelaide, Australia (the Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) study). The current study included men who were followed for 5 years and with complete SHBG and sex steroid levels (total testosterone (TT), dihydrotestosterone (DHT) and oestradiol (E2)), but without T2D at baseline (n = 1597). T2D was identified by either self-report, fasting glucose (≥ 7.0 mmol/L), HbA1c (≥ 6.5%/48.0 mmol/mol), and/or prescriptions for diabetes medications. Logistic binomial regression was used to assess associations between SHBG, sex steroids and incident T2D, adjusting for confounders including age, smoking status, physical activity, adiposity, glucose, triglycerides, symptomatic depression, SHBG and sex steroid levels.Results: During an average follow-up of 4.95 years, 14.5% (n = 232) of men developed new T2D. Multi-adjusted models revealed an inverse association between baseline SHBG, TT, and DHT levels, and incident T2D (odds ratio (OR) = 0.77, 95% CI [0.62, 0.95], p = 0.02; OR 0.70 [0.57, 0.85], p < 0.001 and OR 0.78 [0.63, 0.96], p = 0.02), respectively. However, SHBG was no longer associated with incident T2D after additional adjustment for TT (OR 0.92 [0.71, 1.17], p = 0.48; TT in incident T2D: OR 0.73 [0.57, 0.92], p = 0.01) and after separate adjustment for DHT (OR 0.83 [0.64, 1.08], p = 0.16; DHT in incident T2D: OR 0.83 [0.65, 1.05], p = 0.13). There was no observed effect of E2 in all models of incident T2D.Conclusions: In men, low TT, but not SHBG and other sex steroids, best predicts the development of T2D after adjustment for confounders. [ABSTRACT FROM AUTHOR]

Despite its widespread clinical use, there is little data available from population-based studies on the determinants of serum sex hormone binding globulin (SHBG). We aimed to examine multifactorial determinants of circulating SHBG levels in community-dwelling men. Study participants comprised randomly selected 35–80 y.o. men (n = 2563) prospectively-followed for 5 years (n = 2038) in the Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) study. After excluding men with illness or medications known to affect SHBG (n = 172), data from 1786 men were available at baseline, and 1476 at follow-up. The relationship between baseline body composition (DXA), serum glucose, insulin, triglycerides, thyroxine (fT4), sex steroids (total testosterone (TT), oestradiol (E2)), and pro-inflammatory cytokines and serum SHBG level at both baseline & follow-up was determined by linear and penalized logistic regression models adjusting for age, lifestyle & demographic, body composition, metabolic, and hormonal factors. Restricted cubic spline analyses was also conducted to capture possible non-linear relationships. At baseline there were positive cross-sectional associations between age (β = 0.409, p<0.001), TT (β = 0.560, p<0.001), fT4 (β = 0.067, p = 0.019) and SHBG, and negative associations between triglycerides (β = -0.112, p<0.001), abdominal fat mass (β = -0.068, p = 0.032) and E2 (β = -0.058, p = 0.050) and SHBG. In longitudinal analysis the positive determinants of SHBG at 4.9 years were age (β = 0.406, p = <0.001), TT (β = 0.461, p = <0.001), and fT4 (β = 0.040, p = 0.034) and negative determinants were triglycerides (β = -0.065, p = 0.027) and abdominal fat mass (β = -0.078, p = 0.032). Taken together these data suggest low SHBG is a marker of abdominal obesity and increased serum triglycerides, conditions which are known to have been associated with low testosterone and low T4. [ABSTRACT FROM AUTHOR]

Background: Hyperglycemia is associated with increased morbidity and mortality in patients with an acute myocardial infarction (AMI). We evaluated whether complications after AMI are associated with absolute or relative glycemia. Methods: A total of 192 patients with AMI were randomized to intensive or conventional insulin therapy. Absolute glycemia was defined as mean blood glucose level (BGL) during the first 24 h following randomization. Relative glycemia was defined by the stress hyperglycaemia ratio (SHR), calculated as mean BGL divided by average glucose concentration over the prior 3 months estimated from glycosylated haemoglobin. The primary endpoint was a "complicated AMI", defined as an AMI complicated by death, congestive cardiac failure, arrhythmia, cardiac arrest, reinfarction, cardiogenic shock, inotrope use or emergency revascularization. Results: There was not a significant association between mean BGL and complicated AMI (odds ratio (OR) 1.05 per mmol/L glucose increment, 95% confidence intervals (CI) 0.93-1.19). In contrast, SHR was positively associated with a complicated myocardial infarction (OR 1.22 per 0.1 SHR increment, 95% CI 1.06-1.42), and individual complications of death (OR 1.55, 95% CI 1.14-2.11), congestive cardiac failure (OR 1.27, 95% CI 1.05-1.54), arrhythmia (OR 1.31, 95% CI 1.12-1.54) and cardiogenic shock (OR 1.42, 95% CI 1.03-1.97). The relationship between SHR and a complicated AMI was independent of diabetic status, intensive insulin therapy, sex and hypoglycemia. Conclusions: Relative, but not absolute, glycemia during insulin treatment is independently associated with complications after an AMI. Future studies should investigate whether basing therapeutic glycaemic targets on relative glycemia improves patient outcomes. [ABSTRACT FROM AUTHOR]

Context:Circulating levels of metabolically protective and adverse cytokines are altered in obese humans and rodent models. However, it is not clear whether these cytokines are altered rapidly in response to over-nutrition, or as a later consequence of the obese state. Methods:Forty sedentary healthy individuals were examined prior to and at 3 and 28 days of high fat overfeeding (+1250 kCal/day, 45% fat). Insulin sensitivity (hyperinsulinaemic-euglycaemic clamp), adiposity, serum levels of adiponectin and fibroblast growth factor-21 (FGF21), fatty acid binding protein-4 (FABP4), lipocalin-2 and plasminogen activator factor-1 (PAI1) were assessed. Statistics were performed by repeated measures ANOVA. Results:Overfeeding increased weight, body fat and liver fat, fasting glucose, insulin and reduced insulin sensitivity by clamp (all P <0.05). Metabolically protective cytokines, adiponectin and FGF21 were increased at day 3 of overfeeding (P ≤0.001) and adiponectin was also elevated at day 28 (P=0.001). FABP4, lipocalin-2 and PAI-1 were not changed by overfeeding at either time point. Conclusion:Metabolically protective cytokines, adiponectin and FGF-21, were increased by over nutrition and weight gain in healthy humans, despite increases in insulin resistance. We speculate that this was in attempt to maintain glucose homeostasis in a state of nutritional excess. PAI-I, FABP4 and lipocalin 2 were not altered by overfeeding suggesting that changes in these cytokines may be a later consequence of the obese state. Clinical trial registration: www.clinicaltrials.gov (NCT00562393) [ABSTRACT FROM AUTHOR]

Background: Changes in the arginine metabolites asymmetric dimethyl-L-arginine (ADMA) and L-homoarginine and acute blood glucose concentrations have been shown to cause endothelial dysfunction and be independently associated with mortality in Intensive Care Unit (ICU) patients. The aim of this study was to investigate whether hyperglycemia potentially modulates these arginine metabolite concentrations to provide a mechanism that may link hyperglycemia and mortality in this patient group. Methods: A clinical and in vitro study were undertaken. Glucose, glycosylated hemoglobin-A1c (HbA1c) and the stress hyperglycemia ratio (SHR) (to quantify absolute, chronic and relative hyperglycemia respectively) were measured in 1155 acutely unwell adult patients admitted to a mixed medical-surgical ICU. SHR was calculated by dividing the admission glucose by the estimated average glucose over the last 3 months, which was derived from HbA1c. ADMA and l-homoarginine were measured in a plasma sample collected at admission to ICU by liquid chromatography tandem mass spectrometry. The activity of dimethylarginine-dimethylaminohydrolase 1 (DDAH1), the main enzyme regulating ADMA concentrations, was assessed at varying glucose concentrations in vitro by quantifying the conversion of ADMA to citrulline in HEK293 cells that overexpress DDAH1. Results: In the clinical study, plasma ADMA was not significantly associated with any measure of hyperglycemia. L-homoarginine was positively associated with glucose (β = 0.067, p = 0.018) and SHR (β = 0.107, p < 0.001) after correction for glomerular filtration rate. However, as l-homoarginine is a negative predictor of mortality, the direction of these associations are the opposite of those expected if hyperglycemia was affecting mortality via changes in l-homoarginine. In vitro DDAH1 activity was not significantly influenced by glucose concentrations (p = 0.506). Conclusion: In critically ill patients the association between relative hyperglycemia and mortality is not mediated by changes in ADMA or L-homoarginine. Trial registration ANZCTR Trial ID ACTRN12615001164583. [ABSTRACT FROM AUTHOR]

The article discusses a study which aims to determine if an energy deficit that creates equal change in fatness can result to greater cardiometabolic benefits when there is aerobic exercise involved. It states that 36 overweight individuals comprised of 16 males and 20 females have been randomly divided into three groups such as caloric restriction (CR), control (CO) with weight-maintenance diet, and CR with aerobic exercise. It mentions that the changes in blood pressure, visceral fat, and fat mass were examined after the 6-month intervention. Results showed that the inclusion of exercise in CR has greatly increased aerobic fitness and helped improve insulin sensitivity, low-density lipoprotein (LDL) cholesterol, and diastolic blood pressure (BP).

Abstract: Calorie restriction (CR) delays the development of age-associated disease and increases lifespan in rodents, but the effects in humans remain uncertain. Purpose: Determine the effect of 6 months of CR with or without exercise on cardiovascular disease (CVD) risk factors and estimated 10-year CVD risk in healthy non-obese men and women. Methods: Thirty-six individuals were randomized to one of three groups for 6 months: Control, 100% of energy requirements; CR, 25% calorie restriction; CR+EX, 12.5% CR+12.5% increase in energy expenditure via aerobic exercise. CVD risk factors were assessed at baseline, 3 and 6 months. Results: After 6 months, CR and CR+EX lost approximately 10% of body weight. CR significantly reduced triacylglycerol (−31±15mg/dL) and factor VIIc (−10.7±2.3%). Similarly CR+EX reduced triacylglycerol (−22±8mg/dL) and additionally reduced LDL-C (−16.0±5.1mg/dL) and DBP (−4.0±2.1mmHg). In contrast, both triacylglycerol (24±14mg/dL) and factor VIIc (7.9±2.3%) were increased in the Control group. HDL-cholesterol was increased in all groups while hsCRP was lower in the Controls versus CR+EX. Estimated 10-year CVD risk significantly declined from baseline by 29% in CR (P <0.001) and 38% in the CR+EX (P <0.001) while remaining unchanged in the Control group. Conclusions: Based on combined favorable changes in lipid and blood pressure, caloric restriction with or without exercise that induces weight loss favorably reduces risk for CVD even in already healthy non-obese individuals. [Copyright &y& Elsevier]

Abstract: We measured gene expression of paracrine regulators involved in adipocyte differentiation within the stromovascular fraction of abdominal subcutaneous adipose tissue from obese individuals with (n =30) and without (n =18) type 2 diabetes mellitus (T2DM). Despite similar adiposity by design, subjects with T2DM had larger adipocytes (0.92±0.28 vs. 0.75±0.17μl, p <0.05) than controls. Gene expression of the adipogenic marker aP2 was lower (0.35±0.16 vs. 0.58±0.27 arbitrary units, p <0.05) whereas the expression of matricellular peptidase, MMP2 was higher (1.65±0.17 vs. 1.27±0.21, p =0.02) in T2DM vs. controls. The gene expression levels between the aP2 and MMP2 were inversely correlated (r =−0.32, p =0.03). We conclude that early steps of adipogenesis may be impaired in T2DM independently of obesity due, in part, to an upregulation of the MMP2 transcription. [Copyright &y& Elsevier]

Human trials that compare intermittent fasting (IF) to calorie restriction (CR) with psychological, behavioral and cognition outcomes are limited. We hypothesized that there would be no difference between CR and IF on perceived eating behaviors, mood, sleep quality, quality of life (QOL) and cognition in women with overweight and obesity. In this prespecified secondary analysis of an open-label, single center, parallel assignment, randomized controlled trial, healthy women with overweight or obesity (N = 46, mean [SD] age 50 [9] years, BMI 32.9 [4.4] kg/m2), without a diagnosed eating disorder and who were randomized into 2 weight loss groups (prescribed 70% of calculated energy requirements as IF or CR) were included. Measurements were assessed in both IF and CR groups following a 12-hour overnight fast during baseline and week 8 and additionally following a 24-hour fast in the IF group only at week 8. We observed that IF produced greater weight and body fat loss than CR (P <.001). We did not detect any statistical difference between groups for the change in dietary restraint, disinhibition, hunger, mood, sleep quality, and QOL. An increase in cognitive performance was found in both IF (P =.036) and CR (P =.006) groups in one of the cognitive tasks, but there was no statistical difference between groups. Perceived eating behaviors, mood, sleep quality and cognitive performance were not changed by an acute 24-hour fast within the IF group (all P >.05). IF may be a viable alternative to CR for weight loss, in the short-term, without adversely impacting eating behaviors, mood, sleep quality, QOL or cognition in healthy women with overweight or obesity. However, larger and long term trials are required. [ABSTRACT FROM AUTHOR]

Obesity and overweight are contributing factors to chronic disease. Lifestyle management, which incorporates advice on moderate daily caloric restriction (CR) and physical activity to reduce body weight, is the cornerstone treatment in practice. Intermittent fasting (IF) is a popular alternative that cycles fasting with unrestricted eating periods. IF appears to be an equivalent approach to CR to induce weight loss, although as yet there is limited long-term evidence. Some controversy exists as to whether IF yields superior health benefits to CR. Discrepancies between studies may be due to the heterogeneity in the design of IF protocols. There is also still some concerns around the safety and feasibility of IF compared to CR, which has not been well-studied to date. Moreover, the underlying cellular pathways that are differentially activated in IF in comparison to CR requires further investigation in humans. This review summarises trials that have compared IF with CR, and discusses evidence from animal studies to raise questions for future research in humans. [ABSTRACT FROM AUTHOR]

Objectives: To determine whether relative hyperglycemia was associated with in-hospital mortality in critically ill patients independent of other prognostic variables and whether this association is affected by background glycemia.Design: Prospective observational study.Setting: Mixed medical-surgical ICU in a metropolitan teaching hospital.Patients: From 2,617 admissions to ICU between January 27, 2016, and March 30, 2017, 1,262 consecutive patients who met inclusion and exclusion criteria were studied.Interventions: Glycosylated hemoglobin was used to estimate average glucose concentration over the prior 3 months. Glucose concentration on ICU admission was divided by estimated average glucose concentration to calculate the stress hyperglycemia ratio, an index of relative glycemia. Risk of death score was calculated using data submitted to the Australia and New Zealand Intensive Care Society.Measurements and Main Results: In this study, there were 186 deaths (14.7%). Admission glucose was significantly associated with mortality in univariate analysis (odds ratio = 1.08 per mmol/L glucose increment; p < 0.001) but not after adjustment for risk of death score (odds ratio = 1.01; p = 0.338). In contrast, stress hyperglycemia ratio was significantly associated with mortality both in univariate analysis (odds ratio = 1.09 per 0.1 stress hyperglycemia ratio increment; p < 0.001) and after adjustment for risk of death score (odds ratio = 1.03; p = 0.014). Unlike admission glucose concentration, stress hyperglycemia ratio was significantly associated with mortality in patients with glycosylated hemoglobin less than 6.5% (odds ratio = 1.08 per 0.1 stress hyperglycemia ratio increment; p < 0.001) and glycosylated hemoglobin greater than or equal to 6.5% (48 mmol/mol) (odds ratio = 1.08 per 0.1 stress hyperglycemia ratio increment; p = 0.005).Conclusions: Unlike absolute hyperglycemia, relative hyperglycemia, as assessed by the stress hyperglycemia ratio, independently predicts in-hospital mortality in critically ill patients across the glycemic spectrum. Future studies should investigate whether using measures of relative hyperglycemia to determine individualized glycemic treatment targets improves outcomes in ICU. [ABSTRACT FROM AUTHOR]

Conception via assisted reproductive technology (ART) increases the risk of type 2 diabetes and cardiovascular disease in adulthood. Underlying differences between ART-conceived and in-vivo-conceived embryos that contribute to this increased risk are, however, not known. This study examined the developmental characteristics of mouse blastocysts derived from ART- compared with in-vivo-conceived embryos. To determine the effect of ovarian stimulation versus IVF versus in-vitro embryo culture on phenotype, six distinct groups of blastocysts were generated. Female mice were naturally cycling or treated with high or mild doses of gonadotrophin, followed by natural mating or IVF under clinical conditions. Embryo morphokinetics were assessed by continuous time-lapse monitoring. Cell lineage allocation to the inner cell mass (Oct4+) or trophectoderm (Cdx2+) was determined by immunohistochemistry, and mitochondrial DNA (mtDNA) copy number was measured by quantitative PCR. Ovarian stimulation increased embryo number but reduced the percentage of blastocysts. Morphokinetic analysis showed that gonadotrophin treatment led to advanced development (P < 0.05) due to earlier post-pronuclear breakdown. The blastocyst rate was reduced in IVF embryos compared with those fertilized in vivo before culture (P < 0.001). Morphokinetics showed that embryo development was slower in all the IVF groups (P < <0.05), due to a delay from the 3-cell stage. A reduced total and trophectoderm cell number was observed in all groups of cultured blastocysts compared with naturally conceived blastocysts (P < 0.01). Gonadotrophin treatment did not affect the blastocyst mtDNA copy number; however, IVF embryos exhibited reduced mtDNA copy number compared with naturally conceived embryos. Ovarian stimulation, IVF and in-vitro culture differentially impair blastocyst developmental kinetics, differentiation and mtDNA copy number. [ABSTRACT FROM AUTHOR]

Background: Plasma concentrations of branched-chain amino acids (BCAAs) and the sulfur-containing amino acid cysteine are associated with obesity and insulin resistance. BCAAs predict future diabetes.Objective: We investigated amino acid changes during food overconsumption.Methods: Forty healthy men and women with a body mass index (mean ± SEM) of 25.6 ± 0.6 were overfed by 1250 kcal/d for 28 d, increasing consumption of all macronutrients. Insulin sensitivity and body composition were assessed at baseline (day 0) and day 28. Fasting serum amino acids were measured at days 0, 3, and 28. Linear mixed-effects models evaluated the effect of time in the total group and separately in those with low and high body fat gain (below compared with at or above median fat gain, 1.95 kg). At days 0 and 28, insulin-induced suppression of serum amino acids during a hyperinsulinemic-euglycemic clamp test and, in a subset (n = 20), adipose tissue mRNA expression of selected amino acid metabolizing enzymes were assessed.Results: Weight increased by 2.8 kg. High fat gainers gained 2.6 kg fat mass compared with 1.1 kg in low fat gainers. Valine and isoleucine increased at day 3 (+17% and +22%, respectively; P ≤ 0.002) and remained elevated at day 28, despite a decline in valine (P = 0.019) from day 3 values. Methionine, cystathionine, and taurine were unaffected. Serum total cysteine (tCys) transiently increased at day 3 (+11%; P = 0.022) only in high fat gainers (P-interaction = 0.043), in whom the cysteine catabolic enzyme cysteine dioxygenase (CDO1) was induced (+26%; P = 0.025) in adipose tissue (P-interaction = 0.045). Overconsumption did not alter adipose tissue mRNA expression of the BCAA-metabolizing enzymes branched-chain keto acid dehydrogenase E1α polypeptide (BCKDHA) or branched-chain amino transferase 1 (BCAT1). In the total population at day 0, insulin infusion decreased all serum amino acids (-11% to -47%; P < 0.01), except for homocysteine and tCys, which were unchanged, and glutathione, which was increased by 54%. At day 28, insulin increased tCys (+8%), and the insulin-induced suppression of taurine and phenylalanine observed at day 0, but not that of BCAAs, was significantly impaired.Conclusions: These findings highlight the role of nutrient oversupply in increasing fasting BCAA concentrations in healthy adults. The link between cysteine availability, CDO1 expression, and fat gain deserves investigation. This trial was registered at www.clinicaltrials.gov as NCT00562393. [ABSTRACT FROM AUTHOR]

Eating during the night may increase the risk for obesity and type 2 diabetes in shift workers. This study examined the impact of either eating or not eating a meal at night on glucose metabolism. Participants underwent four nights of simulated night work (SW1–4, 16:00–10:00 h, <50 lux) with a daytime sleep opportunity each day (10:00–16:00 h, <3 lux). Healthy males were assigned to an eating at night (NE;n = 4, meals; 07:00, 19:00 and 01:30 h) or not eating at night (NEN;n = 7, meals; 07:00 h, 09:30, 16:10 and 19:00 h) condition. Meal tolerance tests were conducted post breakfast on pre-night shift (PRE), SW4 and following return to day shift (RTDS), and glucose and insulin area under the curve (AUC) were calculated. Mixed-effects ANOVAs were used with fixed effects of condition and day, and their interactions, and a random effect of subject identifier on the intercept. Fasting glucose and insulin were not altered by day or condition. There were significant effects of day and condition × day (bothp < 0.001) for glucose AUC, with increased glucose AUC observed solely in the NE condition from PRE to SW4 (p = 0.05) and PRE to RTDS (p < 0.001). There was also a significant effect of day (p = 0.007) but not condition × day (p = 0.825) for insulin AUC, with increased insulin from PRE to RTDS in both eating at night (p = 0.040) and not eating at night (p = 0.006) conditions. Results in this small, healthy sample suggest that not eating at night may limit the metabolic consequences of simulated night work. Further study is needed to explore whether matching food intake to the biological clock could reduce the burden of type 2 diabetes in shift workers. [ABSTRACT FROM PUBLISHER]

Shiftworkers have impaired performance when driving at night and they also alter their eating patterns during nightshifts. However, it is unknown whether driving at night is influenced by the timing of eating. This study aims to explore the effects of timing of eating on simulated driving performance across four simulated nightshifts. Healthy, non-shiftworking males aged 18–35 years (n= 10) were allocated to either an eating at night (n= 5) or no eating at night (n= 5) condition. During the simulated nightshifts at 1730, 2030 and 0300 h, participants performed a 40-min driving simulation, 3-min Psychomotor Vigilance Task (PVT-B), and recorded their ratings of sleepiness on a subjective scale. Participants had a 6-h sleep opportunity during the day (1000–1600 h). Total 24-h food intake was consistent across groups; however, those in the eating at night condition ate a large meal (30% of 24-h intake) during the nightshift at 0130 h. It was found that participants in both conditions experienced increased sleepiness and PVT-B impairments at 0300 h compared to 1730 and 2030 h (p< 0.001). Further, at 0300 h, those in the eating condition displayed a significant decrease in time spent in the safe zone (p< 0.05; percentage of time within 10 km/h of the speed limit and 0.8 m of the centre of the lane) and significant increases in speed variability (p< 0.001), subjective sleepiness (p< 0.01) and number of crashes (p< 0.01) compared to those in the no eating condition. Results suggest that, for optimal performance, shiftworkers should consider restricting food intake during the night. [ABSTRACT FROM AUTHOR]

Background/Aims: The secretions of liver-derived cytokines angiopoietin-like 6, insulin-like growth factor 1, selenoprotein-P and C-reactive protein and adipokines, adiponectin and monocyte chemoattractant protein-1 are altered in obese individuals, and they directly induce insulin resistance in both cellular and animal models. This study is aimed at examining the effects of acute overnutrition on these cytokines in healthy individuals, and identifying association with markers of insulin resistance. Methods: Thirty-one young healthy individuals (10 men, body mass index (BMI) 22.4 ± 2.7; 21 women, BMI 23.3 ± 4.9) were enrolled for the study. Metabolic assessments were done 3 days after an energy balanced diet (30% fat) and 3 days of a high-fat overfeeding diet (+1,250 kcal/day, 45% fat), and the assessments included thefasting body weight and blood samples to analyze the selected cytokines and evaluate the insulin sensitivity by a hyperinsulinemic euglycemic clamp (80 mU/m²/min). Results: Three days of overfeeding increased the body weight, fasting glucose and insulin, and thus the homeostasis model assessment of insulin resistance. However, there were no changes in peripheral insulin sensitivity, or in the circulating cytokines assessed. Conclusions: The hepatokines and adipokines assessed were not acutely sensitive to overnutrition in healthy individuals, despite increases in markers of hepatic insulin resistance. [ABSTRACT FROM AUTHOR]

Objective Glucocorticoids can cause postprandial hyperglycaemia, but the effects on postprandial energy and fat metabolism are uncertain. We investigated the effects of acute and chronic low-dose prednisolone on fasting and postprandial energy expenditure and substrate metabolism. Design An open interventional and cross-sectional study was undertaken. Patients and measurements Eighteen patients who had not taken oral glucocorticoids for ≥6 months were studied before and after 7 days prednisolone (6 mg/day) to assess the acute effects of prednisolone. Baseline data from patients, not on glucocorticoids, were compared with 18 patients on long-term prednisolone (6·5 ± 1·8 mg/day for >6 months) to assess the chronic effects. Energy expenditure and substrate oxidation were measured using indirect calorimetry before and after a mixed meal. Adipocyte insulin resistance index and insulin-mediated suppression of NEFA were calculated from fasting and postprandial insulin and NEFA concentrations. Results There were no significant differences in resting energy expenditure or diet-induced thermogenesis with prednisolone. Acute (−2·1 ± 6·2 vs −16·3 ± 4·8 mg/min, P = 0·01) and chronic (−1·4 ± 2·8 vs −16·3 ± 4·8 mg/min, P = 0·01) prednisolone attenuated postprandial suppression of fat oxidation. Chronic (31·6 ± 3·8 vs 17·0 ± 3·3, P = 0·007), but not acute, prednisolone increased adipocyte insulin resistance index. However, insulin-mediated suppression of NEFA was not significantly different after acute or chronic prednisolone. Conclusions Prednisolone does not alter energy expenditure. However, even at low doses, prednisolone exerts adverse effects on fat metabolism, which could exacerbate insulin resistance and increase cardiovascular risk. Attenuated postprandial suppression of fat oxidation, but not lipolysis, suggests that prednisolone causes greater insulin resistance in skeletal muscle than in adipocytes. [ABSTRACT FROM AUTHOR]

Objective Postprandial hyperglycaemia is associated with increased arterial stiffness and cardiovascular events. Low-dose prednisolone causes insulin resistance that typically manifests as postprandial hyperglycaemia. We investigated whether prednisolone causes postprandial vascular dysfunction in a cohort of patients with rheumatoid arthritis. Design An open interventional and cross-sectional study was undertaken. Patients and measurements Eighteen subjects with rheumatoid arthritis who had not taken oral glucocorticoids for ≥6 months were studied before and after prednisolone 6 mg/day for 7 days to determine the acute effects of prednisolone. Pre-prednisolone data were compared to 18 subjects with rheumatoid arthritis taking long-term (>6 months) prednisolone (6·5 ± 1·8 mg/day) to assess the chronic effects of prednisolone. Augmentation index (by applanation tonometry) and reactive hyperaemia index (by peripheral artery tonometry) were measured before and after a mixed-meal (10 kcal/kg, 45% carbohydrate, 15% protein, 40% fat). Insulin sensitivity was estimated by the Matsuda index and sympathetic nervous system activity from urinary noradrenaline excretion. Results Matsuda index was lower after acute (2·0 ± 1·0 vs 3·6 ± 1·1, P = 0·01) and chronic (1·9 ± 1·0 vs 3·6 ± 1·1, P = 0·04) prednisolone. Postprandial augmentation index was lower after acute prednisolone (2551 ± 197 vs 2690 ± 272%*min, P ≤ 0·001), but not chronic prednisolone. There were no significant differences in reactive hyperaemia index with acute or chronic prednisolone. Noradrenaline excretion was lower after acute (54 ± 8 vs 93 ± 23 nmol/6 h, P = 0·02), but not chronic, prednisolone. Conclusions Prednisolone-induced insulin resistance is not associated with postprandial vascular dysfunction in patients with rheumatoid arthritis. Reduced sympathetic activity may contribute to the reduction in postprandial arterial stiffness with acute prednisolone. [ABSTRACT FROM AUTHOR]

Individuals conceived by in vitro fertilization (IVF) may be at increased risk of cardio-metabolic disorders. We recently reported that IVF conceived male mice displayed impaired glucose metabolism at normal and high body weights. In this study, we examined glucose metabolism in mature female C57BL/6J mice that were conceived by natural conception (NC), by ovarian stimulation (OS) or by IVF following chow or high-fat diet (HFD) for 8 weeks. By design, litter size was comparable between groups, but interestingly the birth weight of IVF and OS females was lower than NC females (p≤0.001). Mature IVF female mice displayed increased fasting glucose as compared to NC and OS mice, irrespective of diet. Mature IVF and OS mice were also more susceptible to the metabolic consequences of high fat diet as compared with NC females, with impaired glucose tolerance (p≤0.01), whereas peripheral insulin resistance and increased hepatic expression of gluconeogenic genes Ppargc1α, Pck1 and G6pc was observed in IVF mice only (p<0.05). This study suggests that ovarian stimulation alone and IVF program distinct metabolic effects in females, but that high fat diet may be required to unmask these effects. This study adds to the growing body of literature that assisted reproduction procedures may increase the risk of developing type 2 diabetes in an obesity prone environment. [ABSTRACT FROM AUTHOR]