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Background/objective: Treatment of subjects with non-alcoholic fatty liver disease (NAFLD) with omega-3 polyunsaturated fatty acids (FAs) suggests high levels of docosahexaenoic acid (DHA) tissue enrichment decrease liver fat content. We assessed whether changes in erythrocyte DHA enrichment (as a surrogate marker of changes in tissue enrichment) were associated with alterations in hepatic de novo lipogenesis (DNL), postprandial FA partitioning and hepatic and peripheral insulin sensitivity in a sub-study of the WELCOME trial (Wessex Evaluation of fatty Liver and Cardiovascular markers in NAFLD (non-alcoholic fatty liver disease) with OMacor thErapy)., Subjects/methods: Sixteen participants were randomised to 4 g/day EPA+DHA (n=8) or placebo (n=8) for 15-18 months and underwent pre- and post-intervention measurements. Fasting and postprandial hepatic FA metabolism was assessed using metabolic substrates labelled with stable-isotope tracers ( 2 H 2 O and [U 13 C]palmitate). Insulin sensitivity was measured by a stepped hyperinsulinaemic-euglycaemic clamp using deuterated glucose. Participants were stratified according to change in DHA erythrocyte enrichment (< or ⩾2% post intervention)., Results: Nine participants were stratified to DHA⩾2% (eight randomised to EPA+DHA and one to placebo) and seven to the DHA<2% group (all placebo). Compared with individuals with erythrocyte <2% change in DHA abundance, those with ⩾2% enrichment had significant improvements in hepatic insulin sensitivity, reduced fasting and postprandial plasma triglyceride concentrations, decreased fasting hepatic DNL, as well as greater appearance of 13 C from dietary fat into plasma 3-hydroxybutyrate (all P<0.05)., Conclusions: The findings from our pilot study indicate that individuals who achieved a change in erythrocyte DHA enrichment ⩾2% show favourable changes in hepatic FA metabolism and insulin sensitivity, which may contribute to decreasing hepatic fat content.

The MAP kinase-interacting kinases (MNK1 and MNK2) are non-essential enzymes which are activated by MAP kinases. They are implicated in controlling protein synthesis. Here we show that mice in which the expression of either MNK1 or MNK2 has been knocked out (KO) are protected against adverse effects of high-fat feeding, and in distinct ways. High-fat diet (HFD)-fed MNK2-KO show less weight gain than wild-type animals, and improved glucose tolerance, better insulin sensitivity and markedly diminished adipose tissue inflammation. This suggests MNK2 plays a role in adipogenesis and/or lipogenesis and in macrophage biology. MNK1-KO/HFD mice show better glucose tolerance and insulin sensitivity, but gain weight and show similar adipose inflammation to WT animals. These data suggest MNK1 participates in mediating HFD-induced insulin resistance. Our findings reveal distinct roles for the MNKs in a novel area of disease biology, metabolic dysfunction, and suggests they are potential new targets for managing metabolic disease.

Non-alcoholic fatty liver disease is now recognized as the hepatic component of the metabolic syndrome. Non-alcoholic fatty liver disease is a spectrum of fat-associated liver conditions that can result in end-stage liver disease and the need for liver transplantation. Simple steatosis, or fatty liver, occurs early in non-alcoholic fatty liver disease and may progress to non-alcoholic steatohepatitis, fibrosis and cirrhosis with increased risk of hepatocellular carcinoma. Prevalence estimates for non-alcoholic fatty liver disease range from 17 to 33% in the general populations and it has been estimated that non-alcoholic fatty liver disease exists in up to 70% of people with Type 2 diabetes. Non-alcoholic fatty liver disease increases risk of Type 2 diabetes and cardiovascular disease. In people with Type 2 diabetes, non-alcoholic fatty liver disease is the most frequent cause (∼80%) of fatty liver diagnosed by ultrasound. As non-alcoholic fatty liver disease is strongly associated with insulin resistance, the presence of non-alcoholic fatty liver disease with diabetes often contributes to poor glycaemic control. Consequently, strategies that decrease liver fat and improve whole-body insulin sensitivity may both contribute to prevention of Type 2 diabetes and to better glycaemic control in people who already have developed diabetes. This review summarizes the Dorothy Hodgkin lecture given by the author at the 2012 Diabetes UK annual scientific conference, proposing that fatty acid fluxes through the liver are crucial for the pathogenesis of non-alcoholic fatty liver disease and for increasing insulin resistance., (© 2012 The Author. Diabetic Medicine © 2012 Diabetes UK.)

Non-alcoholic fatty liver disease (NAFLD) is usually a silent disease that occurs in a very high proportion of people with features of the metabolic syndrome, including overweight, insulin resistance and type 2 diabetes. Because obesity and type 2 diabetes are now extremely common in Westernised societies, it is likely that the prevalence of NAFLD increases markedly in the future. Although previously it was thought that NAFLD was harmless, it is now recognised that NAFLD can be a progressive liver condition that increases risk of cirrhosis, end-stage liver disease and hepatocellular carcinoma. Additionally, liver fat accumulation causes insulin resistance and increases risk of type 2 diabetes. Increasing evidence now shows NAFLD is a risk factor for cardiovascular disease (CVD). The purpose of this review is to briefly discuss the pathogenesis of NAFLD, to describe the relationship between NAFLD and CVD and the mechanisms linking both conditions and to discuss some of the treatment options (including lifestyle, nutrition and drugs) that may influence both NAFLD and risk of CVD.

Aims/hypothesis: The relative contributions of fitness (maximal oxygen uptake), physical activity energy expenditure (PAEE) and fatness to whole-body, liver and fat insulin sensitivity is uncertain. The aim of this study was to determine whether fitness and PAEE are associated with whole-body, liver and fat insulin sensitivity independently of body fat., Materials and Methods: We recruited 25 men (mean [SD] age 53 [6] years). Whole-body (M value) and liver (percentage suppression of endogenous glucose output) insulin sensitivity were estimated using a hyperinsulinaemic-euglycaemic clamp. Insulin sensitivity in fat (insulin sensitivity index for NEFA) was estimated during an OGTT. Total and truncal fat were measured by dual-energy X-ray absorptiometry, fitness by treadmill, and PAEE (n = 21) by 3 day heart rate monitoring and Baecke questionnaire., Results: In univariate analyses, fatness was strongly associated with insulin sensitivity (whole-body, liver and fat). Fitness was associated with whole-body (r = 0.53, p < 0.007) and liver (0.42, p = 0.04) insulin sensitivity, while PAEE was associated with liver insulin sensitivity (r = 0.55, p = 0.01). Regression models were established to describe associations between fatness, fitness and physical activity and measures of insulin sensitivity (whole-body, fat and liver) as outcomes. Only fatness was independently associated with whole-body insulin sensitivity (B coefficient -0.01, p = 0.001). Fitness was not associated with any outcome. Only PAEE was independently associated with liver insulin sensitivity (B coefficient 13.5, p = 0.02)., Conclusions/interpretation: Fatness explains most of the variance in whole-body insulin sensitivity. In contrast, PAEE explains most of the variance in liver insulin sensitivity.

Objective: To examine whether fasting insulin concentrations and markers of first-phase insulin secretion are associated with weight gain and changes in distribution of adiposity over 4.4y., Design: Longitudinal prospective population-based cohort study of middle-aged Caucasians., Subjects: 767 subjects (40-65y at baseline) were followed up for a mean of 4.4y., Measurements: 75 g oral glucose tolerance test performed at baseline and follow-up. Insulin was measured at fasting, and 30 and 120 min post-glucose load using a highly specific assay., Results: Fasting insulin levels were correlated with baseline weight (r = 0.32, P<0.001), as was the 30 min insulin incremental response (r = 0.17, P<0.001). Mean weight gain over the 4.4y of follow-up was 2.17 kg (range: -6.17-10.5 kg) for men and 2.49 kg (range: -7.41-12.39 kg) for women. In women, the 30 min insulin incremental response was negatively associated with percentage weight gain (P<0.001), but there was no relationship between fasting insulin levels and weight gain. The baseline fasting insulin was positively correlated with percentage increase in waist- hip ratio (r = 0.12, P = 0.01). In stratified analysis, this relationship was confined to women over the age of 50 y. However, in men, none of these relationships were demonstrable., Conclusion: In middle-aged women reduced first-phase insulin secretion was associated with an increased risk of future weight gain, whereas fasting hyperinsulinaemia was associated with an increase in waist-hip ratio over time.

To investigate whether individual component features of the insulin resistance syndrome were associated with the postprandial triglyceride response, 57 healthy Caucasian men between 57 and 70 years of age underwent a fat tolerance test lasting 8 h. Fasting triglyceride concentrations were associated with the total unfractionated postprandial triglyceride response (r(s) = 0.54, p < 0.001) and the triglyceride-rich lipoprotein (TGRLP) fraction (d < 1.006) at 8 h was associated with the maximum non-esterified fatty acid concentration (NEFA) (r(s) = 0.33, p = 0.01). Measures of obesity (BMI and WHR) were not associated with the postprandial triglyceride response but were inversely related to NEFA suppression (NEFA nadir and BMI, r(s) = 0.31, p = 0.02; and NEFA nadir and WHR, r(s) = 0.36, p = 0.006). Other component features of the IRS, including glucose tolerance and two proxy measures of insulin resistance (fasting insulin concentration and HOMA measurement) were not associated with the postprandial triglyceride response despite being strongly associated with fasting triglyceride concentration. Current smoking habit, chronic alcohol consumption and birth weight were also not associated with an altered postprandial triglyceride response. In conclusion these results show that although component features of the IRS were associated with increased fasting triglyceride concentrations many of these features, including two proxy measures of insulin sensitivity were not associated with an exaggerated postprandial triglyceride response.

Previous reports of a relationship between cigarette smoking and hyperinsulinemia and insulin resistance provide an important possible mechanism by which smoking could be associated with the metabolic cardiovascular syndrome and hence with ischemic heart disease. However, few previous studies have been able to adjust for all the possible confounding factors related both to smoking and to insulin resistance. Therefore, we examined this association in a population-based cohort study of 1,122 individuals aged 40 to 65 years who underwent a 75-g oral glucose tolerance test with specific measurement of insulin, 32,33-split proinsulin, and intact proinsulin concentrations. Physical activity was quantified using the Paffenbarger questionnaire, and smoking status and alcohol consumption were determined using the Health and Lifestyle Survey questionnaire; 17.4% of the population were current smokers and 32.4% were ex-smokers. Current smoking was associated with reduced overall obesity as indicated by the body mass index (BMI) but an increase in central adiposity as measured by the waist to hip ratio (WHR). There were also significant associations between cigarette smoking and the pattern of alcohol intake and physical inactivity. In unadjusted analyses, current smoking was associated with lower fasting and 120-minute insulin and also 120-minute glucose compared with levels in nonsmokers. Adjustment for confounding by age and BMI reduced these differences, but they were increased by adjustment for central obesity. We conclude from this study that a causal relationship between cigarette smoking and insulin resistance is unlikely.

To investigate causes of increased triglyceride concentrations in subjects with normal glucose tolerance (determined by oral glucose tolerance testing using World Health Organization criteria) 883 healthy subjects (389 men and 494 women) between 40 and 65 years of age were studied. Subjects were divided by gender into four groups according to 120-min glucose concentrations. Individuals in the highest quartile of glucose concentration had the highest mean triglyceride concentrations (p < 0.0001) and highest mean non-esterified fatty acid (NEFA) concentrations (p < 0.0001). There was also a clustering of cardiovacular risk factors normally associated with the insulin resistance syndrome in subjects in this group. Regression analysis showed that the most important determinants of triglyceride levels were smoking (men p = 0.001, women p = 0.005), waist:hip ratio (men p = 0.01, women p < 0.001) and NEFA suppression (men p = 0.02, women p = 0.005). NEFAs suppressed 16.7% in women compared to 2.4% in men during the first 30 min of the oral glucose tolerance test (p < 0.001). These results show that a clustering of cardiovascular risk factors associated with decreased NEFA suppression occurs in a sub-group of subjects with normal glucose tolerance and that the pattern of NEFA suppression differs between men and women.

Although plasma insulin and triglyceride concentrations are positively correlated in many studies, the relationships between insulin resistance, insulin secretion and hypertriglyceridaemia remain unclear. To study these associations, subjects between the ages of 40 and 64 were randomly selected from a general practice register and invited to attend for a standard oral glucose tolerance test for measurement of insulin, triglyceride and non-esterified fatty acid concentrations. The study comprised 1122 subjects who were not previously known to have diabetes and who completed the test. Using the World Health Organisation criteria, 51 subjects were classified to have non-insulin-dependent diabetes mellitus, 188 had impaired glucose tolerance and 883 subjects had normal glucose tolerance. Triglyceride concentrations in subjects with glucose intolerance were elevated compared to those in control subjects, even after adjustment for age, obesity and gender (p < 0.001 for subjects with diabetes and p < 0.01 for those with impaired glucose tolerance compared to normal subjects). In separate multiple regression analyses for males and females, the most important determinants of the plasma triglyceride concentration were the area under the non-esterified fatty acid suppression curve (p < 0.001 in both genders) and the waist-hip ratio (p < 0.001 for men and < 0.01 for women). The fasting insulin concentration was independently associated with triglyceride concentration in women only (p < 0.01). The most important determinant of the area under the non-esterified fatty acid suppression curve in men was the 30-min insulin increment, a measure of insulin secretion, (p < 0.001) whereas for women age (p < 0.001) and the body mass index (p < 0.01) were the most important.

Ezetimibe is a relatively new drug that inhibits the absorption of dietary cholesterol in the small intestine. It is a low density lipoprotein-cholesterol (LDL-C) lowering medication that acts directly on the intestine by inhibiting Niemann-Pick C1 Like1 (NPC1L1). Recently, results of the ARBITER 6-HALTS trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies) and the ENHANCE trial (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) showed that ezetimibe had no effect on atherosclerosis despite producing a marked decrease in LDL-C. Recent studies show a potential benefit of ezetimibe in treating insulin resistance, non-alcoholic fatty liver disease (NAFLD), gallstones and dyslipidaemia associated with chronic renal failure and organ transplantation. All of these conditions are known to be associated with an increase in risk of cardiovascular disease (CVD) and further studies are needed to assess the potential benefits of ezetimibe in these therapeutics areas. [ABSTRACT FROM AUTHOR]

The epidemic of obesity is largely responsible for the high prevalence of metabolic syndrome in the developed world. Since 2001 with the development of the NCEP metabolic syndrome classification, simple pragmatic criteria have been available that can be applied in primary care across all continents to diagnose the syndrome. Although there is an ongoing debate about the level of thresholds that should be applied to individual features of the syndrome, it is likely that with further research a consensus will be reached in the near future. It is now clear that metabolic syndrome represents a condition of insulin resistance and ectopic fat accumulation associated with a proinflammatory and procoagulant phenotype. The syndrome is sometimes associated with other conditions such as nonalcoholic fatty liver disease (NAFLD), polycystic ovary syndrome, type 2 diabetes and cardiovascular disease. The purpose of this review is to discuss the clinical and laboratory diagnosis of the metabolic syndrome. The review discusses the various approaches to the investigation of people with the metabolic syndrome. Simple tools for clinical and laboratory diagnosis of metabolic syndrome are described. Some of the more complex biochemical tests that are now being applied in research to the diagnosis of associated conditions, such as NAFLD, are also described. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: We investigated the prognostic implication of metabolic syndrome according to modified National Cholesterol Education Program criteria and the implication of individual features of metabolic syndrome on cardiovascular disease (CVD) and CHD in a 5-year community-based study of people with newly diagnosed type 2 diabetes. Methods: We entered 562 participants, aged 30–74 years, into a cross-sectional analysis and 428 participants (comprising those who were CVD-free at study entry) into a prospective analysis. In both analyses, the association of metabolic syndrome features with CVD/CHD was studied. Binary logistic regression, a Cox regression model and Fisher's exact test were used for statistical analyses. Results: At diagnosis of type 2 diabetes, metabolic syndrome was independently associated with CVD(odds ratio [OR] 2.54; p=0.006) and CHD (OR 4.06; p=0.002). In the 5-year follow-up, metabolic syndrome at baseline was an independent predictor of incident CVD (hazard ratio [HR] 2.05; p=0.019). An increase in the number of individual features of the metabolic syndrome present at the time of diagnosis of type 2 diabetes was associated with a linear increase in incident CVD risk (trend p=0.044) with an almost five-fold increase when all five features were present, compared with hyperglycaemia alone (HR 4.76; p=0.042). Increasing age (HR 1.07; p<0.001), female sex (HR 0.62; p=0.032), total cholesterol (HR 1.43; p=0.01) and lipid-lowering therapy (HR 0.32; p<0.001) were also independent predictors of risk. Conclusions/interpretation: Metabolic syndrome at baseline is associated with an increased risk of incident CVD in the 5 years following diagnosis of type 2 diabetes. CVD-free survival rates declined incrementally as the presence of metabolic syndrome features increased. Thus, identifying the features of metabolic syndrome at diagnosis of type 2 diabetes is potentially a useful prognostic tool for identifying individuals at increased risk of CVD. [ABSTRACT FROM AUTHOR]

The prevalence of diabetes is increased in patients with schizophrenia. Although many reasons, including hereditary and lifestyle factors, contribute to this association, recently there has been heightened interest in the subject because of the link between the use of the newer atypical anti-psychotic drugs and the development of diabetes. These drugs cause significant weight gain and this may be one of the mechanisms by which they increase incident diabetes. The increased prevalence of diabetes among people with schizophrenia has implications for the delivery of care by psychiatrists, diabetologists and primary care. Diabet. Med. 21, 515–523 (2004) [ABSTRACT FROM AUTHOR]

Summary Aims Cross-sectional studies have demonstrated an association between high non-esterified fatty acid (NEFA) concentrations and glucose intolerance. However, the direction of causality in these studies is uncertain. The aim of this study was to examine whether NEFA levels predicted the development of glucose intolerance in a prospective population-based cohort study. Methods Four hundred and eighty-one women and 345 men participated in a prospective cohort study in which NEFA concentrations and glucose tolerance were measured at baseline and then repeated at follow-up 4.5 years later. Results The data do not show longitudinal relationships between baseline NEFA levels and either glucose intolerance or other features of the metabolic syndrome at follow-up. In contrast, strong cross-sectional associations were observed between NEFA measures and glucose intolerance (and other features of the metabolic syndrome) in both baseline and follow-up studies. At follow-up, fasting NEFA levels and two measures of NEFA suppression were markedly different in subjects with features of the metabolic syndrome, compared to subjects with normal glucose tolerance (NGT) (NGT vs. metabolic syndrome for each NEFA value, P < 0.001). Conclusions These results support the hypothesis that plasma NEFA levels change as a consequence of the metabolic syndrome and do not support the notion that increased NEFA levels cause either the metabolic syndrome or diabetes. [ABSTRACT FROM AUTHOR]