Nonalcoholic fatty liver disease (NAFLD) is characterized by low-circulating concentration of high-density lipoprotein cholesterol (HDL-C) and raised triacylglycerol (TAG). Exercise reduces hepatic fat content, improves insulin resistance and increases clearance of very-low-density lipoprotein-1 (VLDL1). However, the effect of exercise on TAG and HDL-C metabolism is unknown. We randomized male participants to 16 wk of supervised, moderate-intensity aerobic exercise ( n = 15), or conventional lifestyle advice ( n = 12). Apolipoprotein A-I (apoA-I) and VLDL-TAG and apolipoprotein B (apoB) kinetics were investigated using stable isotopes (1-[13C]-leucine and 1,1,2,3,3-2H5 glycerol) pre- and postintervention. Participants underwent MRI/spectroscopy to assess changes in visceral fat. Results are means ± SD. At baseline, there were no differences between exercise and control groups for age (52.4 ± 7.5 vs. 52.8 ± 10.3 yr), body mass index (BMI: 31.6 ± 3.2 vs. 31.7 ± 3.6 kg/m2), and waist circumference (109.3 ± 7.5 vs. 110.0 ± 13.6 cm). Percentage of liver fat was 23.8 (interquartile range 9.8–32.5%). Exercise reduced body weight (101.3 ± 10.2 to 97.9 ± 12.2 kg; P < 0.001) and hepatic fat content [from 19.6%, interquartile range (IQR) 14.6–36.1% to 8.9% (4.4–17.8%); P = 0.001] and increased the fraction HDL-C concentration (measured following ultracentrifugation) and apoA-I pool size with no change in the control group. However, plasma and VLDL1-TAG concentrations and HDL-apoA-I fractional catabolic rate (FCR) and production rate (PR) did not change significantly with exercise. Both at baseline (all participants) and after exercise there was an inverse correlation between apoA-I pool size and VLDL-TAG and -apoB pool size. The modest effect of exercise on HDL metabolism may be explained by the lack of effect on plasma and VLDL1-TAG.

Dietary sugars are linked to the development of non-alcoholic fatty liver disease (NAFLD) and dyslipidaemia, but it is unknown if NAFLD itself influences the effects of sugars on plasma lipoproteins. To study this further, men with NAFLD (n = 11) and low liver fat ‘controls’ (n = 14) were fed two iso-energetic diets, high or low in sugars (26% or 6% total energy) for 12 weeks, in a randomised, cross-over design. Fasting plasma lipid and lipoprotein kinetics were measured after each diet by stable isotope trace-labelling. There were significant differences in the production and catabolic rates of VLDL subclasses between men with NAFLD and controls, in response to the high and low sugar diets. Men with NAFLD had higher plasma concentrations of VLDL1-triacylglycerol (TAG) after the high (P<0.02) and low sugar (P<0.0002) diets, a lower VLDL1-TAG fractional catabolic rate after the high sugar diet (P<0.01), and a higher VLDL1-TAG production rate after the low sugar diet (P<0.01), relative to controls. An effect of the high sugar diet, was to channel hepatic TAG into a higher production of VLDL1-TAG (P<0.02) in the controls, but in contrast, a higher production of VLDL2-TAG (P<0.05) in NAFLD. These dietary effects on VLDL subclass kinetics could be explained, in part, by differences in the contribution of fatty acids from intra-hepatic stores, and de novo lipogenesis. The present study provides new evidence that liver fat accumulation leads to a differential partitioning of hepatic TAG into large and small VLDL subclasses, in response to high and low intakes of sugars.

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Abstract Aberrant microbiota composition and function have been linked to several pathologies, including type 2 diabetes. In animal models, prebiotics induce favourable changes in the intestinal microbiota, intestinal permeability (IP) and endotoxaemia, which are linked to concurrent improvement in glucose tolerance. This is the first study to investigate the link between IP, glucose tolerance and intestinal bacteria in human type 2 diabetes. In all, twenty-nine men with well-controlled type 2 diabetes were randomised to a prebiotic (galacto-oligosaccharide mixture) or placebo (maltodextrin) supplement (5·5 g/d for 12 weeks). Intestinal microbial community structure, IP, endotoxaemia, inflammatory markers and glucose tolerance were assessed at baseline and post intervention. IP was estimated by the urinary recovery of oral 51Cr-EDTA and glucose tolerance by insulin-modified intravenous glucose tolerance test. Intestinal microbial community analysis was performed by high-throughput next-generation sequencing of 16S rRNA amplicons and quantitative PCR. Prebiotic fibre supplementation had no significant effects on clinical outcomes or bacterial abundances compared with placebo; however, changes in the bacterial family Veillonellaceae correlated inversely with changes in glucose response and IL-6 levels (r −0·90, P=0·042 for both) following prebiotic intake. The absence of significant changes to the microbial community structure at a prebiotic dosage/length of supplementation shown to be effective in healthy individuals is an important finding. We propose that concurrent metformin treatment and the high heterogeneity of human type 2 diabetes may have played a significant role. The current study does not provide evidence for the role of prebiotics in the treatment of type 2 diabetes.

We aimed to test the hypothesis that the effects of dietary sugar on lipoprotein metabolism are influenced by non-alcoholic fatty liver disease (NAFLD). The effect of two 12 week, iso-energetic diets, high and low in non-milk extrinsic sugars (26% and 6% total energy), matched for macronutrient content, was examined in a randomised, cross-over study in men with NAFLD (n=11) and controls (n= 14). Lipoprotein kinetics and the sources of fatty acids for triacylglycerol (TAG) production were measured using stable isotope tracers. Liver fat was higher after the high versus low-sugar diet in both groups (p<0.02), but men with NAFLD showed a relatively greater response than controls (p<0.05). After the high versus low-sugar diet, VLDL1-TAG production rate was higher in the controls (p <0.002) due to a greater contribution from splanchnic fatty acids (p<0.02) and de novo lipogenesis (p <0.002), whereas in NAFLD, VLDL2-TAG production rate was higher (p <0.05), due to a greater contribution from splanchnic fatty acids (p<0.02). There was no difference in the contribution of systemic NEFA to VLDL1 and VLDL2-TAG production rate between diets in either group. Intermediate density lipoprotein (IDL), LDL2 and LDL3-apolipoprotein B production rates and post-heparin hepatic lipase activity were all higher (p<0.05) on the high-sugar diet in NAFLD. A high sugar intake promoted a greater accumulation of liver fat in NAFLD than controls and increased VLDL-TAG production in both groups, due mainly to an increased contribution of fatty acids from splanchnic sources, which includes hepatic TAG storage …

A 26-year-old nulliparous white woman presented to the emergency department in May, 2009, with pelvic pain, abdominal distension, and vomiting. Pelvic ultrasonography showed enlarged ovaries containing multiple cysts. She was diagnosed with ovarian hyperstimulation syndrome and recovered quickly with rehydration, antiemetics, and analgesia. Because she was not taking fertility treatment or other drugs that might have caused the ovarian hyperstimulation she was referred to the endocrinology clinic. She reported a 1 year history of episodes of pelvic pain, flushing, and vomiting, and amenorrhoea after stopping the oral contraceptive 1 year before. She had no medical history and family history was incomplete because she had been adopted. Examination was normal. Investigations showed a consistently raised plasma follicle stimulating hormone (FSH) (checked three times: 32 IU/L, 26 IU/L, and 32 IU/L; follicular phase normal range 2·5–10·2 IU/L), oestradiol (>3000 pmol/L; follicular phase normal range 72–530 pmol/L), and suppressed luteinising hormone (LH) (<1 IU/L; follicular phase normal range 1·9–12·5 IU/L). The other pituitary axes were intact and urine 5-hydroxyindoleacetic acid concentration was within the normal range. Neither FSH nor LH rose in response to LH-releasing hormone stimulation. We suspected an FSH-secreting pituitary adenoma and pituitary MRI showed a 0·5 cm adenoma (appendix) so she was referred for transsphenoidal surgery, which she underwent uneventfully.

Iodine is a key component of the thyroid hormones which are crucial for brain development. Adequate intake of iodine in pregnancy is important as in utero deficiency may have lifelong consequences for the offspring. Data on the iodine status of UK pregnant women are sparse, and there are no such data for pregnant women in the South East of the UK. A total of 100 pregnant women were recruited to a cross-sectional study carried out at the Royal Surrey County Hospital, Guildford, at their first-trimester visit for an ultrasound scan. The participants provided a spot-urine sample (for the measurement of urinary iodine concentration (UIC) and creatinine concentration) and 24 h iodine excretion was estimated from the urinary iodine:creatinine ratio. Women completed a general questionnaire and a FFQ. The median UIC (85·3 μg/l) indicated that the group was iodine deficient by World Health Organisation criteria. The median values of the iodine:creatinine ratio (122·9 μg/g) and of the estimated 24 h iodine excretion (151·2 μg/d) were also suggestive of iodine deficiency. UIC was significantly higher in women taking an iodine-containing prenatal supplement (n 42) than in those not taking such a supplement (P< 0·001). In the adjusted analyses, milk intake, maternal age and iodine-containing prenatal supplement use were positively associated with the estimated 24 h urinary iodine excretion. Our finding of iodine deficiency in these women gives cause for concern. We suggest that women of childbearing age and pregnant women should be given advice on how to improve their iodine status through dietary means. A national survey of iodine status in UK pregnant women is required.

Previous work has shown increased insulin sensitivity, increased hepatic insulin clearance and lower postprandial insulin responses following treatment with resistant starch, a type of dietary fibre. The objective of this study was to further explore the effects of resistant starch on insulin secretion. Twelve overweight (BMI 28.2±0.4 kg/m(2)) individuals participated in this randomized, subject-blind crossover study. Participants consumed either 40 g type 2 resistant starch or the energy and carbohydrate-matched placebo daily for four weeks. Assessment of the effect on insulin secretion was made at the end of each intervention using an insulin-modified frequently sampled intravenous glucose tolerance test (FSIVGTT). Insulin and C-peptide concentrations were significantly higher during the FSIVGTT following the resistant starch compared with the placebo. Modelling of the data showed significantly improved first-phase insulin secretion with resistant starch. These effects were observed without any changes to either body weight or habitual food intake. This study showed that just four weeks of resistant starch intake significantly increased the first-phase insulin secretion in individuals at risk of developing type 2 diabetes. Further studies exploring this effect in individuals with type 2 diabetes are required.

CONTEXTHigh plasma triglycerides (TG) have been shown to be independent and better predictors of cardiovascular disease than low-density lipoprotein (LDL) cholesterol in women. This may be due to gender differences in very-low-density lipoprotein 1 (VLDL(1))- and VLDL(2)-TG and fatty acid kinetics.OBJECTIVEOur objective was to investigate whether there are differences in VLDL(1)- and VLDL(2)-TG and fatty acid kinetics in obese men and postmenopausal women, a high risk group for cardiovascular disease.RESEARCH DESIGN AND METHODSStable isotopes techniques were used to measure fasting palmitate rate of appearance, metabolic clearance rate, oxidation rate, and nonoxidative disposal rate, VLDL(1)-TG and VLDL(2)-TG fractional catabolic rate (FCR) and production rate (PR). Whole-body fat distribution was measured by magnetic resonance imaging.PARTICIPANTSParticipants included 10 postmenopausal obese women and eight obese men matched for age, body mass index, and fasting plasma TG.RESULTSThe women had lower visceral fat and higher sc fat than the men (P < 0.001 and P < 0.002). Palmitate rate of appearance, metabolic clearance rate, nonoxidative disposal rate, and oxidation rate corrected for resting energy expenditure were greater in the women than the men (all P < 0.03). VLDL(2)-TG PR corrected for fat-free mass was higher in the women (P < 0.001). VLDL(2)-TG and VLDL(2)-cholesterol pools were higher in the women (P < 0.001 and P < 0.008). VLDL(1)-TG FCR and PR and VLDL(2)-TG FCR were not different between genders.CONCLUSIONFatty acid and VLDL(2)-TG flux is higher in postmenopausal obese women than in obese men matched for fasting plasma TG levels.

This study aimed to determine in obese women if endocannabinoid receptor antagonism has effects on fatty acid and triglyceride metabolism and insulin sensitivity which are independent from the metabolic effects of weight loss. Fourteen obese (BMI=33.0±0.5 kg/m2) (mean±SEM) Caucasian post-menopausal women, aged 57.8±4.7 years were studied. The women were randomised to 2 groups, one group received the endocannabinoid receptor antagonist rimonabant (20 mg/d) for 12 weeks. A control group achieved the same weight loss by a hypocaloric dietary intervention over 12 weeks. Palmitate production rate (Ra), a measure of lipolysis, and palmitate oxidation rate, and VLDL1 and VLDL2 triglyceride (TG) kinetics, were measured using isotopic tracers before and after the intervention. Weight loss was not different in the 2 groups; 2.6±0.5 kg with rimonabant and 3.1±1.0 kg in the control group. Palmitate Ra increased with rimonabant with no change in the control group (p=0.03 between groups). Palmitate oxidation rate increased with rimonabant but decreased in the control group (p=0.005 between groups). VLDL1 TG secretion rate decreased in the control group and increased in the rimonabant group (p=0.008 between groups). There was no significant effect on insulin sensitivity. This study suggests that endocannabinoid receptor antagonism for 12 weeks in obese women increased lipolysis and fatty acid oxidation. The increase in VLDL1 TG secretion rate may be due to the increase in lipolysis which exceeded the increase in fatty acid oxidation.

CONTEXT Dietary fibers have been associated with a reduced incidence of type 2 diabetes mellitus in epidemiological studies; however, the precise mechanisms are unknown. OBJECTIVE The objective of the study was to evaluate the efficacy and site of action of an insoluble dietary fiber derived from maize (HAM-RS2) in improving insulin resistance in subjects at increased risk of type 2 diabetes mellitus. DESIGN This study was a randomized, controlled crossover, dietary intervention study. SETTING The study was conducted at the Centre for Diabetes, Endocrinology, and Research, Royal Surrey County Hospital, Guildford, United Kingdom. PARTICIPANTS Fifteen men and women with insulin resistance participated in the study. INTERVENTION The intervention included 40 g/d HAM-RS2 compared with a matched placebo for 8 wk. MAIN OUTCOME MEASURES After each supplement, participants underwent a two-step hyperinsulinemic-euglycemic clamp study with the addition of glucose tracers; a meal tolerance test; arteriovenous sampling across forearm muscle tissue; and a sc adipose tissue biopsy for assessment of gene expression. RESULTS There was enhanced uptake of glucose into the forearm muscle measured by arteriovenous sampling (65 ± 15% increase after resistant starch; P < 0.001). Adipose tissue function was also affected, with enhanced fatty acid suppression after HAM-RS2 treatment and an increase in gene expression for hormone sensitive lipase (P = 0.005), perilipin (P = 0.011), lipoprotein lipase (P = 0.014), and adipose triglyceride lipase (P = 0.03) in biopsy samples. There was no effect on the insulin sensitivity of hepatic glucose production or plasma lipids after HAM-RS2. CONCLUSION HAM-RS2 improved peripheral but not hepatic insulin resistance and requires further study as an intervention in patients with or at risk for type 2 diabetes.

Genetic variants of Period 2 (PER2), a circadian clock gene, have been linked to metabolic syndrome (MetS). However, it is still unknown whether these genetic variants interact with the various types of plasma fatty acids. This study investigated whether common single nucleotide polymorphisms (SNPs) in the PER2 locus (rs934945 and rs2304672) interact with various classes of plasma fatty acids to modulate plasma lipid metabolism in 381 participants with MetS in the European LIPGENE study. Interestingly, the rs2304672 SNP interacted with plasma total SFA concentrations to affect fasting plasma TG, TG-rich lipoprotein (TRL-TG), total cholesterol, apoC-II, apoB, and apoB-48 concentrations (P-interaction < 0.001-0.046). Carriers of the minor allele (GC+GG) with the highest SFA concentration (>median) had a higher plasma TG concentration (P = 0.001) and higher TRL-TG (P < 0.001) than the CC genotype. In addition, participants carrying the minor G allele for rs2304672 SNP and with a higher SFA concentration (>median) had higher plasma concentrations of apo C-II (P < 0.001), apo C-III (P = 0.009), and apoB-48 (P = 0.028) compared with the homozygotes for the major allele (CC). In summary, the rs2304672 polymorphism in the PER2 gene locus may influence lipid metabolism by interacting with the plasma total SFA concentration in participants with MetS. The understanding of these gene-nutrient interactions could help to provide a better knowledge of the pathogenesis in MetS.

OBJECTIVE Previous animal studies suggest a functional relationship between metabolism, type 2 diabetes, and the amplitude of daily rhythms in white adipose tissue (WAT). However, data interpretation is confounded by differences in genetic background and diet or limited sampling points. We have taken the novel approach of analyzing serial human WAT biopsies across a 24-h cycle in controlled laboratory conditions. RESEARCH DESIGN AND METHODS Lean (n = 8), overweight/obese (n = 11), or overweight/obese type 2 diabetic (n = 8) volunteers followed a strict sleep–wake and dietary regimen for 1 week prior to the laboratory study. They were then maintained in controlled light–dark conditions in a semirecumbent posture and fed hourly during wake periods. Subcutaneous WAT biopsies were collected every 6 h over 24 h, and gene expression was measured by quantitative PCR. RESULTS Lean individuals exhibited significant (P < 0.05) temporal changes of core clock (PER1, PER2, PER3, CRY2, BMAL1, and DBP) and metabolic (REVERBα, RIP140, and PGC1α) genes. The BMAL1 rhythm was in approximate antiphase with the other clock genes. It is noteworthy that there was no significant effect (P > 0.05) of increased body weight or type 2 diabetes on rhythmic gene expression. CONCLUSIONS The robust nature of these rhythms and their relative phasing indicate that WAT now can be considered as a peripheral tissue suitable for the study of in vivo human rhythms. Comparison of data between subject groups clearly indicates that obesity and type 2 diabetes are not related to the amplitude of rhythmic WAT gene expression in humans maintained under controlled conditions.

An incremental intravenous low-dose insulin infusion has been used to examine differences in insulin sensitivity between normal young men and women. Fasting blood glucose concentration did not differ significantly at the start of the infusion but women had significantly higher plasma insulin and C-peptide concentrations. Similar changes in blood glucose occurred during insulin infusion but insulin concentrations were higher in women. Blood total ketone bodies and alanine were lower in women over the four hours of infusion. Significant differences were found between normal men and women for the effect of insulin upon blood glucose concentration.

Euglycaemic-hyperinsulinaemic clamp: Insulin infusion was started at a rate of 35 mU insulin/m2 min-1 and the glucose concentration of whole blood was measured every 5 min by use of a glucose analyzer. The infusion of 20% glucose was adjusted as needed to "clamp" blood glucose concentrations at 5 mM for a period of 2 hours and the glucose utilisation rate was derived during the last 30 minutes (steady state) of the clamp.