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Introduction: We have previously shown that hyperbaric oxygen treatment (HBOT) increased insulin sensitivity in men who were obese or overweight, both with and without type 2 diabetes. The aim of this study was to test whether this insulin-sensitising effect is seen in hyperbaric air (HA)., Methods: Men with type 2 diabetes who were obese or overweight were randomised to two groups: HBOT (n = 13) or HA (n = 11). A hyperinsulinaemic euglycaemic glucose clamp (80 mU·m -2 ·min -1 ) was performed at baseline and during hyperbaric intervention. Both groups were compressed to 203 kPa (two atmospheres absolute) for 90 minutes followed by a linear 30-minute decompression. The HBOT group breathed oxygen via a hood while the HA group breathed chamber air. Insulin sensitivity was assessed from the glucose infusion rate (GIR) during the last 30 minutes in the hyperbaric chamber (SS1) and the first 30 minutes after exit (SS2). Data were analysed for within-group effect by paired student t-test and between-group effect by one-way ANOVA., Results: HBOT increased GIR by a mean 26% at SS1 (P = 0.04) and 23% at SS2 (P = 0.018). There was no significant change in GIR during or after HA. A between-group effect was evident for the change in GIR at SS1 in HBOT vs HA (P = 0.036)., Conclusions: The pathway by which insulin sensitivity is increased in men with type 2 diabetes requires the high oxygen partial pressures of HBOT and should be further investigated. Insulin sensitivity was not changed in hyperbaric air., (Copyright: This article is the copyright of the authors who grant Diving and Hyperbaric Medicine a non-exclusive licence to publish the article in electronic and other forms.)

Introduction: Previous studies using a hyperinsulinaemic, euglycaemic glucose clamp have demonstrated an increase in peripheral insulin sensitivity in men with and without Type-2 diabetes mellitus on the third and thirtieth hyperbaric oxygen treatment (HBOT) session. In two studies using different techniques for assessment of insulin sensitivity, we investigated the onset and duration of this insulin-sensitising effect of HBOT., Methods: Men who were obese or overweight but without diabetes were recruited. One study performed a hyperinsulinaemic euglycaemic glucose clamp (80 mU.m -2 .min -1 ) at baseline and during the first HBOT exposure (n = 9) at a pressure of 203 kPa. Data were analysed by paired t-test. The other study assessed insulin sensitivity by a frequently sampled intravenous glucose tolerance test (FSIGT) at three time points: baseline, during the third HBOT and 24-hours post-HBOT (n = 9). Results were analysed by repeated-measures ANOVA., Results: There was a significant 23% increase in insulin sensitivity by clamp measured during the first HBOT exposure. The FSIGT showed no significant changes in insulin sensitivity., Conclusions: The hyperinsulinaemic, euglycaemic glucose clamp demonstrated a significant increase in peripheral insulin sensitivity during a single, 2-hour HBOT session in a group of men who were obese or overweight but without diabetes. As an alternate technique for assessing insulin sensitivity during HBOT, the FSIGT failed to show any changes during the third HBOT and 24-hours later, however modification of the study protocol should be considered., (Copyright: This article is the copyright of the authors who grant Diving and Hyperbaric Medicine a non-exclusive licence to publish the article in electronic and other forms.)

Selenoprotein P (SeP) is secreted primarily by the liver and postulated to cause insulin resistance. The aim of this study was to measure plasma SeP in individuals who are lean (N=29) or overweight/obese (N=34), and examine relationships between circulating SeP, SEPP1 (SeP, plasma 1) expression in subcutaneous adipose tissue, and markers of insulin resistance. SeP was higher in individuals who were overweight/obese (P<0.001), and associated with insulin resistance by HOMA-IR and by clamp, but not independently of BMI. SEPP1 mRNA was correlated negatively with BMI, suggesting there may be tissue specific regulation. This study suggests that obesity, rather than insulin resistance, is central to the increase in SeP., (Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.)

Background & Aim: Western diets rich in animal protein and poor in fruit and vegetables increase the body acid load, a predictor of type 2 diabetes risk. The relationships between dietary acid load, mild metabolic acidosis and insulin resistance remain unclear. The objective of this study was to assess the association between dietary acid load, body acid/base markers and peripheral insulin resistance at baseline and following a short-term overfeeding intervention in healthy individuals., Methods: In a cross-sectional study of 104 men and women, insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp. Plasma lactate, a marker of metabolic acidosis, was assessed and acid load scores (potential renal acid load, PRAL and net endogenous acid production, NEAP) derived from diet diaries. The cohort was grouped into lean and overweight/obese and the latter further classified as insulin-sensitive (Obsen) and insulin-resistant (Obres) based on hyperinsulinemic-euglycemic clamp glucose infusion rate (GIR, top tertile vs. bottom 2 tertiles). A subset of 40 individuals participated in an overfeeding intervention (+1250 kcal/day) for 28 days and studies repeated., Results: Obsen and Obres were matched for adiposity (BMI and fat mass, both P = 1). Fasting plasma lactate was higher in Obres (0.78 [0.63-1.14] mmol/L) compared with both lean (0.71 [0.44-0.90] mmol/L, P = 0.02) and Obsen (0.67 [0.56-0.79] mmol/L, P = 0.04) and not different between lean and Obsen (P = 0.9). Overfeeding was characterized by an increase in dietary acid load scores PRAL (P = 0.003) and NEAP (P = 0.05), a reduction in GIR necessary to maintain euglycemia (P = 0.03) and an increase in fasting plasma lactate (P = 0.02). The change in lactate was inversely associated with the change in GIR (r = -0.36, P = 0.03)., Conclusions: Mild metabolic acidosis, measured by plasma lactate, aligns with insulin resistance independent of obesity and is induced by short-term increases in energy and dietary acid load in healthy humans. Further studies are required to determine whether buffering mild metabolic acidosis improves insulin resistance and reduces diabetes risk., (Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

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., (© 2015 John Wiley & Sons Ltd.)

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 the fasting 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., (© 2016 S. Karger AG, Basel.)

In vitro fertilization (IVF) may influence the metabolic health of children. However, in humans, it is difficult to separate out the relative contributions of genetics, environment, or the process of IVF, which includes ovarian stimulation (OS) and embryo culture. Therefore, we examined glucose metabolism in young adult humans and in adult male C57BL/6J mice conceived by IVF versus natural birth under energy-balanced and high-fat-overfeeding conditions. In humans, peripheral insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamp (80 mU/m(2)/min), was lower in IVF patients (n = 14) versus control subjects (n = 20) after 3 days of an energy-balanced diet (30% fat). In response to 3 days of overfeeding (+1,250 kcal/day, 45% fat), there was a greater increase in systolic blood pressure in IVF versus controls (P = 0.02). Mice conceived after either OS alone or IVF weighed significantly less at birth versus controls (P < 0.01). However, only mice conceived by IVF displayed increased fasting glucose levels, impaired glucose tolerance, and reduced insulin-stimulated Akt phosphorylation in the liver after 8 weeks of consuming either a chow or high-fat diet (60% fat). Thus, OS impaired fetal growth in the mouse, but only embryo culture resulted in changes in glucose metabolism that may increase the risk of the development of metabolic diseases later in life, in both mice and humans., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

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.

Background: Mitochondrial dysfunction and increased oxidative stress are associated with obesity and type 2 diabetes. High fat feeding induces insulin resistance and increases skeletal muscle oxidative stress in rodents, but there is controversy as to whether skeletal muscle mitochondrial biogenesis and function is altered., Methodology and Principal Findings: Forty (37 ± 2 y) non-obese (25.6 ± 0.6 kg/m(2)) sedentary men (n = 20) and women (n = 20) were overfed (+1040 ± 100 kcal/day, 46 ± 1% of energy from fat) for 28 days. Hyperinsulinemic-euglycemic clamps were performed at baseline and day 28 of overfeeding and skeletal muscle biopsies taken at baseline, day 3 and day 28 of overfeeding in a sub cohort of 26 individuals (13 men and 13 women) that consented to having all 3 biopsies performed. Weight increased on average in the whole cohort by 0.6 ± 0.1 and 2.7 ± 0.3 kg at days 3 and 28, respectively (P<0.0001, without a significant difference in the response between men and women (P = 0.4). Glucose infusion rate during the hyperinsulinemic-euglycemic clamp decreased from 54.8 ± 2.8 at baseline to 50.3 ± 2.5 µmol/min/kg FFM at day 28 of overfeeding (P = 0.03) without a significant difference between men and women (P = 0.4). Skeletal muscle protein carbonyls and urinary F2-isoprostanes increased with overfeeding (P<0.05). Protein levels of muscle peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α) and subunits from complex I, II and V of the electron transport chain were increased at day 3 (all P<0.05) and returned to basal levels at day 28. No changes were detected in muscle citrate synthase activity or ex vivo CO(2) production at either time point., Conclusions: Peripheral insulin resistance was induced by overfeeding, without reducing any of the markers of mitochondrial content that were examined. Oxidative stress was however increased, and may have contributed to the reduction in insulin sensitivity observed.

Objective: Chronic low-grade inflammation is a feature of obesity and is postulated to be causal in the development of insulin resistance and type 2 diabetes. The aim of this study was to assess whether overfeeding induces peripheral insulin resistance in lean and overweight humans, and, if so, whether it is associated with increased systemic and adipose tissue inflammation., Research Design and Methods: Thirty-six healthy individuals undertook 28 days of overfeeding by +1,250 kcal/day (45% fat). Weight, body composition, insulin sensitivity (hyperinsulinemic-euglycemic clamp), serum and gene expression of inflammation markers, immune cell activation, fat cell size, macrophage and T-cell numbers in abdominal subcutaneous adipose tissue (flow cytometry and immunohistochemistry) were assessed at baseline and after 28 days., Results: Subjects gained 2.7 +/- 1.6 kg (P < 0.001) and increased fat mass by 1.1 +/- 1.6% (P < 0.001). Insulin sensitivity decreased by 11% from 54.6 +/- 18.7 to 48.9 +/- 15.7 micromol/(kg of FFM)/min (P = 0.01). There was a significant increase in circulating C-reactive protein (P = 0.002) and monocyte chemoattractant protein-1 (P = 0.01), but no change in interleukin-6 and intercellular adhesion molecule-1. There were no changes in fat cell size, the number of adipose tissue macrophages or T-cells, or inflammatory gene expression and no change in circulating immune cell number or expression of their surface activation markers after overfeeding., Conclusions: Weight gain-induced insulin resistance was observed in the absence of a significant inflammatory state, suggesting that inflammation in subcutaneous adipose tissue occurs subsequent to peripheral insulin resistance in humans.

Reactive oxygen species (ROS) are postulated to be a common trigger of insulin resistance. For example, treatment of adipocytes with either tumor-necrosis factor-alpha 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 (c) 2009 Elsevier Ltd. All rights reserved.)

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.

Obesity was first described as a low-grade inflammatory condition more than a decade ago. However, it is only relatively recently that obese individuals have been described with increased macrophage infiltration of adipose tissue, as well as an increase in the number of "M1" or "classically activated" macrophages. Furthermore, macrophages have been identified as the primary source of many of the circulating inflammatory molecules that are detected in the obese state and are postulated to be causal both in the development of insulin resistance and in the progression to type 2 diabetes. There is also novel evidence to suggest that macrophages inhibit adipocyte differentiation, potentially leading to adipocyte hypertrophy, altered secretion of adipokines and ectopic storage of lipid within liver, muscle and other non-adipose tissues. Currently, it is not clear what causes increased macrophage infiltration of adipose tissue in obese individuals. Theories include altered signalling by adipocytes, nutritional induction of metabolic endotoxemia or reduced angiogenesis and local adipose cell hypoxia. Importantly, PPAR-gamma agonists have been shown to alter macrophage phenotype to "M2" or an "alternatively activated" anti-inflammatory phenotype and may induce macrophage specific cell death. Consequently, excitement surrounds the potential for specific inhibition of macrophage infiltration of adipose tissue via pharmacotherapy for obese patients and more particularly as adjunct therapy to improve insulin sensitivity in obese individuals with insulin resistance and overt type 2 diabetes.

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/m(2)) and in 35 similarly obese, non-DM volunteers (F20/M15, age 55 +/- 8 yr, BMI 33 +/- 2 kg/m(2)). A biopsy of subcutaneous abdominal AT was done to measure adipocyte size. A glucose clamp was performed at an insulin infusion of 80 mU x min(-1) x m(-2). There was more severe IR in T2DM (6.1 +/- 2.3 vs. 9.9 +/- 3.3 mg x min(-1) x kg 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.

Background: Impaired mitochondrial function in skeletal muscle is implicated in the development of insulin resistance. However, potential differences in fatness and fitness may influence previous results., Methods: Subjects (n=18) were divided into insulin-sensitive (IS) and insulin-resistant (IR) groups by median glucose infusion rate during a hyperinsulinemic euglycemic clamp. Weight, VO2max (maximal aerobic capacity), and percentage body fat were measured before and after 6 continuous weeks of aerobic exercise training at 55-70% VO2max (40 min/session, 4 d/wk)., Results: Age, percentage fat, and VO2max were not different between IS and IR groups at baseline. Expression of the nuclear encoded PGC1alpha and mitochondrial encoded gene COX1 were significantly lower in the IR group (P<0.05). Citrate synthase activity and protein levels of subunits from complexes I and III of the respiratory chain were also lower in the IR group (P<0.05). Insulin sensitivity and aerobic fitness were increased after exercise training in both groups (P<0.001), and the expression of mitochondrial encoded genes CYTB and COX1 was also increased (P<0.01). However, there was no change in PGC1alpha expression, mitochondrial enzyme activity, or protein levels of complexes of the respiratory chain in response to exercise in either group., Conclusion: This study confirms that IR men have reduced markers of mitochondrial metabolism, independent of fatness and fitness. Moderate exercise training did not alter these markers despite improving fitness and whole body insulin sensitivity. This study suggests that additional mechanisms may be involved in improving insulin resistance after exercise training in obese men.

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]

Objective: This study aimed to compare intermittent fasting (IF) versus continuous energy intakes at 100% or 70% of calculated energy requirements on insulin sensitivity, cardiometabolic risk, body weight, and composition.Methods: Women with overweight (n = 88; 50 ± 1 years, BMI 32.3 ± 0.5 kg/m2 ) were randomized to one of four diets (IF70, IF100, dietary restriction [DR70], or control) in a 2:2:2:1 ratio for 8 weeks. IF groups fasted for 24 hours after breakfast on three nonconsecutive days per week. All foods were provided and diets matched for macronutrient composition (35% fat, 15% protein, 50% carbohydrate). Insulin sensitivity by hyperinsulinemic-euglycemic clamp, weight, body composition, and plasma markers were assessed following a "fed" day (12-hour fast) and a 24-hour fast (IF only).Results: IF70 displayed greater reductions in weight, fat mass, total- and low-density lipoprotein cholesterol, and nonesterified fatty acids compared with DR70 and IF100 (all P ≤ 0.05). IF100 lost more weight and fat than control. However, fasting insulin was increased. There were no group differences in insulin sensitivity by clamp; however, a 24-hour fast transiently reduced insulin sensitivity.Conclusions: When prescribed at matched energy restriction, IF reduced weight and fat mass and improved total and low-density lipoprotein cholesterol more than DR. IF prescribed in energy balance did not improve health compared with other groups, despite modest weight loss. [ABSTRACT FROM AUTHOR]

Background Skeletal muscle extracellular matrix (ECM) remodeling has been proposed as a feature of the pathogenic milieu associated with obesity and metabolic dysfunction. The aim of the current study was to examine the timeline of this response and determine whether 3 and 28 days of overfeeding alters markers of ECM turnover. Methods Forty healthy individuals were overfed by 1250 kcal/day for 28 days. Hyperinsulinemic–euglycemic clamps and abdominal fat distribution were performed at baseline and day 28 of overfeeding and skeletal muscle biopsies taken at baseline, day 3 and day 28. mRNA expression (COL1a1, COL3a1, MMP2, MMP9, TIMP1, CD68, Integrin) was performed in 19 subjects that consented to having all biopsies performed and microarray analysis was performed in 8 participants at baseline and day 28. Results In the whole cohort, body weight increased by 0.6 ± 0.1 and 2.7 ± 0.3 kg at days 3 and 28 (both P < 0.001), respectively. Glucose infusion rate during the hyperinsulinemic–euglycemic clamp decreased from 54.8 ± 2.8 at baseline to 50.3 ± 2.5 μmol/min/kg FFM at day 28 of overfeeding (P = 0.03). Muscle COL1 and COL3 and MMP2 mRNA levels were significantly higher 28 days after overfeeding (all P < 0.05), with no significant changes in MMP9, TIMP1, CD68 and integrin expression. Microarray based gene set tests revealed that pathways related to ECM receptor interaction, focal adhesion and adherens junction were differentially altered. Conclusions Skeletal muscle ECM remodeling occurs early in response to over-nutrition with as little as 3% body weight gain. Our findings contribute to the growing evidence linking muscle ECM remodeling and accumulation as another sequela of obesity-related insulin resistance. [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]

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]

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]

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]

Background: Large cohort longitudinal studies have almost unanimously concluded that metabolic health in obesity is a transient phenomenon, diminishing in older age. We aimed to assess the fate of insulin sensitivity per se over time in overweight and obese individuals. Methods: Individuals studied using the hyperinsulinaemic-euglycaemic clamp at the Garvan Institute of Medical Research from 2008 to 2010 (n = 99) were retrospectively grouped into Lean (body mass index (BMI) < 25 kg/m2) or overweight/obese (BMI ≥ 25 kg/m2), with the latter further divided into insulin-sensitive (ObSen) or insulin-resistant (ObRes), based on median clamp M-value (M/I, separate cut-offs for men and women). Fifty-seven individuals participated in a follow-up study after 5.4 ± 0.1 years. Hyperinsulinaemic-euglycaemic clamp, dual-energy X-ray absorptiometry and circulating cardiovascular markers were measured again at follow-up, using the same protocols used at baseline. Liver fat was measured using computed tomography at baseline and proton magnetic resonance spectroscopy at follow-up with established cut-offs applied for defining fatty liver. Results: In the whole cohort, M/I did not change over time (p = 0.40); it remained significantly higher at follow-up in ObSen compared with ObRes (p = 0.02), and was not different between ObSen and Lean (p = 0.41). While BMI did not change over time (p = 0.24), android and visceral fat increased significantly in this cohort (ptime ≤ 0.0013), driven by ObRes (p = 0.0087 and p = 0.0001, respectively). Similarly, systolic blood pressure increased significantly over time (ptime = 0.0003) driven by ObRes (p = 0.0039). The best correlate of follow-up M/I was baseline M/I (Spearman's r = 0.76, p = 1.1 × 10−7). Conclusions: The similarity in insulin sensitivity between the ObSen and the Lean groups at baseline persisted over time. Insulin resistance in overweight and obese individuals predisposed to further metabolic deterioration over time. [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]