Clusters of adipose tissue dysfunction in adults with type 2 diabetes identify those with worse lipidomic profile despite similar glycaemic control.

AIMS: To investigate clusters of adipose tissue dysfunction, that is, with adipose tissue insulin resistance (ADIPO-IR) and large waist circumference (WC), identify a worse lipidomic profile characterised by a high proportion of lipids rich in saturated fatty acids (SFA). MATERIALS AND METHODS: Hierarchical clustering based on WC and ADIPO-IR (calculated as fasting plasma non-esterified fatty acids times fasting plasma insulin, FFA×INS), was performed in 192 adults with overweight/obesity and type 2 diabetes (T2D) treated with metformin (HbA1c = 7.8%). Free fatty acid composition and lipidomic profile were measured by mass spectrometry (GC-MS and LC-MSQTOF). Indexes of fatty acid desaturation (stearoyl-coA desaturase-1 activity, SCD116 = palmitoleic acid/palmitic acid and SCD118 = oleic acid/stearic acid) and of insulin resistance (HOMA-IR) were also calculated. RESULTS: Three clusters were identified: CL1 (ADIPO-IR = 4.9 ± 2.4 and WC = 96±7 cm, mean ± SD), CL2 (ADIPO-IR = 6.5 ± 2.5 and WC = 114 ± 7 cm), and CL3 (ADIPO-IR = 15.0 ± 4.7 and WC = 107 ± 8 cm). Insulin concentrations, ADIPO-IR, and HOMA-IR significantly increased from CL1 to CL3 (all p < 0.001), while fasting glucose concentrations, HbA1c, dietary lipids and caloric intake were similar. Moreover, CL3 showed significantly higher concentrations of monounsaturated free fatty acids, oleic and palmitoleic acids, triglycerides (TAG) rich in saturated FA and associated with de novo lipogenesis (i.e., TAG 46-50), higher SCD116, SCD118, ceramide (d18:0/18:0), and phosphatidylcholine aa(36:5) compared with CL1/CL2 (all p < 0.005). CONCLUSIONS: High ADIPO-IR and large WC identify a worse lipid profile in T2D characterised by complex lipids rich in SFA, likely due to de novo synthesis given higher plasma monounsaturated FFA and increased desaturase activity indexes. REGISTRATION NUMBER TRIAL: ID NCT00700856 https://clinicaltrials.gov.

High Amylose Wheat Bread at Breakfast Increases Plasma Propionate Concentrations and Reduces the Postprandial Insulin Response to the Following Meal in Overweight Adults.

BACKGROUND: High amylose starchy foods modulate the postprandial metabolic response in humans. However, the mechanisms of their metabolic benefits and their impact on the subsequent meal have not been fully elucidated. OBJECTIVE: We aimed to evaluate whether glucose and insulin responses to a standard lunch are influenced by the consumption of amylose-rich bread at breakfast in overweight adults and whether changes in plasma short chain fatty acids (SCFAs) concentrations contribute to their metabolic effects. METHODS: Using a randomized crossover design, 11 men and 9 women, BMI 30 ± 3 kg/m2, 48 ± 19 y, consumed at breakfast 2 breads made with high amylose flour (HAF): 85%-HAF (180 g) and 75%-HAF (170 g), and control bread (120 g) containing 100% conventional flour. Plasma samples were collected at fasting, 4 h after breakfast, and 2 h after a standard lunch to measure glucose, insulin, and SCFA concentrations. ANOVA posthoc analyses were used for comparisons. RESULTS: Postprandial plasma glucose responses were 27% and 39% lower after breakfasts with 85%- and 70%-HAF breads than control bread (P = 0.026 and P = 0.003, respectively), with no difference after lunch. Insulin responses were not different between the 3 breakfasts, whereas there was a 28% lower response after the lunch following breakfast with 85%-HAF bread than the control (P = 0.049). Propionate concentrations increased from fasting by 9% and 12% 6 h after breakfasts with 85%- and 70%-HAF breads and decreased by 11% with control bread (P < 0.05). At 6 h after breakfast with 70%-HAF bread, plasma propionate and insulin were inversely correlated (r = -0.566; P = 0.044). CONCLUSIONS: Amylose-rich bread reduces the postprandial glucose response after breakfast and insulin concentrations after the subsequent lunch in overweight adults. This second meal effect may be mediated by the elevation of plasma propionate due to intestinal fermentation of resistant starch. High amylose products could be a promising tool in a dietary prevention strategy for type 2 diabetes. THIS TRIAL WAS REGISTERED AT CLINICAL TRIAL REGISTRY AS: NCT03899974 (https://www. CLINICALTRIALS: gov/ct2/show/NCT03899974).

Consensus document on Lipoprotein(a) from the Italian Society for the Study of Atherosclerosis (SISA).

AIMS: In view of the consolidating evidence on the causal role of Lp(a) in cardiovascular disease, the Italian Society for the Study of Atherosclerosis (SISA) has assembled a consensus on Lp(a) genetics and epidemiology, together with recommendations for its measurement and current and emerging therapeutic approaches to reduce its plasma levels. Data on the Italian population are also provided. DATA SYNTHESIS: Lp(a) is constituted by one apo(a) molecule and a lipoprotein closely resembling to a low-density lipoprotein (LDL). Its similarity with an LDL, together with its ability to carry oxidized phospholipids are considered the two main features making Lp(a) harmful for cardiovascular health. Plasma Lp(a) concentrations vary over about 1000 folds in humans and are genetically determined, thus they are quite stable in any individual. Mendelian Randomization studies have suggested a causal role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis and observational studies indicate a linear direct correlation between cardiovascular disease and Lp(a) plasma levels. Lp(a) measurement is strongly recommended once in a patient's lifetime, particularly in FH subjects, but also as part of the initial lipid screening to assess cardiovascular risk. The apo(a) size polymorphism represents a challenge for Lp(a) measurement in plasma, but new strategies are overcoming these difficulties. A reduction of Lp(a) levels can be currently attained only by plasma apheresis and, moderately, with PCSK9 inhibitor treatment. CONCLUSIONS: Awaiting the approval of selective Lp(a)-lowering drugs, an intensive management of the other risk factors for individuals with elevated Lp(a) levels is strongly recommended.

Dietary determinants of postprandial blood glucose control in adults with type 1 diabetes on a hybrid closed-loop system.

AIMS/HYPOTHESIS: The aim of this work was to assess the relationship between meal nutrients and postprandial blood glucose response (PGR) in individuals with type 1 diabetes on a hybrid closed-loop system (HCLS). METHODS: The dietary composition of 1264 meals (398 breakfasts, 441 lunches and 425 dinners) was assessed by 7-day food records completed by 25 individuals with type 1 diabetes on HCLSs (12 men/13 women, mean ± SD age 40 ± 12 years, mean ± SD HbA1c 51 ± 10 mmol/mol [6.9 ± 0.2%]). For each meal, PGR (continuous glucose monitoring metrics, glucose incremental AUCs) and insulin doses (pre-meal boluses, post-meal microboluses automatically delivered by the pump and adjustment boluses) over 6 h were evaluated. RESULTS: Breakfast, lunch and dinner significantly differed with respect to energy and nutrient intake and insulin doses. The blood glucose postprandial profile showed an earlier peak after breakfast and a slow increase until 4 h after lunch and dinner (p < 0.001). Mean ± SD postprandial time in range (TIR) was better at breakfast (79.3 ± 22.2%) than at lunch (71.3 ± 23.9%) or dinner (70.0 ± 25.9%) (p < 0.001). Significant negative predictors of TIR at breakfast were total energy intake, per cent intake of total protein and monounsaturated fatty acids, glycaemic load and absolute amounts of cholesterol, carbohydrates and simple sugars consumed (p < 0.05 for all). No significant predictors were detected for TIR at lunch. For TIR at dinner, a significant positive predictor was the per cent intake of plant proteins, while negative predictors were glycaemic load and intake amounts of simple sugars and carbohydrate (p < 0.05 for all). CONCLUSIONS/INTERPRETATION: This study shows that nutritional factors other than the amount of carbohydrate significantly influence postprandial blood glucose control. These nutritional determinants vary between breakfast, lunch and dinner, with differing effects on postprandial blood glucose profile and insulin requirements, thus remaining a challenge to HCLSs.

A wheat aleurone-rich diet improves oxidative stress but does not influence glucose metabolism in overweight/obese individuals: Results from a randomized controlled trial.

BACKGROUND AND AIMS: Aleurone is the innermost layer of wheat bran, rich in fiber, minerals, vitamins, phenolic compounds, and betaine. The metabolic effects of aleurone rich foods are still unknown. Our aim was to investigate the effects of consuming a Wheat Aleurone rich diet vs. a Refined Wheat diet for 8 weeks on fasting and postprandial glycemic and lipid metabolism, inflammation, and oxidative stress in overweight/obese individuals. METHODS AND RESULTS: According to a randomized cross-over study design, 23 overweight/obese individuals, age 56 ± 9 years (M±SD), were assigned to two isoenergetic diet - Wheat Aleurone and Refined Wheat diets - for 8 weeks. The diets were similar for macronutrient composition but different for the aleurone content (40-50 g/day in the Wheat Aleurone diet). After each diet, fasting and postprandial plasma metabolic profile, ferulic acid metabolites and 8-isoprostane concentrations in 24-h urine samples were evaluated. Compared with the Refined Wheat Diet, the Wheat Aleurone Diet increased fasting plasma concentrations of betaine by 15% (p = 0.042) and decreased the excretion of 8-isoprostane by 33% (p = 0.035). Conversely, it did not affect the fasting and postprandial glucose, insulin and triglyceride responses, homocysteine, and C-Reactive Protein concentrations, nor excretion of phenolic metabolites. CONCLUSION: An 8-week Wheat Aleurone Diet improves the oxidative stress and increases plasma betaine levels in overweight/obese individuals with an increased cardiometabolic risk. However, further studies with longer duration and larger sample size are needed to evaluate the benefits of aleurone-rich foods on glucose and lipid metabolism in individuals with more severe metabolic abnormalities. CLINICAL TRIAL REGISTRY NUMBER: NCT02150356, (https://clinicaltrials.gov).

The Pro12Ala polymorphism of PPARγ2 modulates beta cell function and failure to oral glucose-lowering drugs in patients with type 2 diabetes.

BACKGROUND: We evaluate whether the Pro12Ala polymorphism of peroxisome proliferator-activated receptor γ2 (PPARγ2) has a role in the progression of diabetes by modulating the occurrence of treatment failure to glucose-lowering drugs. METHODS: We studied 215 patients with type 2 diabetes participating in the Thiazolidinediones Or Sulphonylureas and Cardiovascular Accidents Intervention Trial study. All participants were insufficiently controlled (glycated haemoglobin [HbA1c ] 7.0%-9.0%) with metformin 2 g/day and were randomly allocated to add-on pioglitazone or a sulfonylurea. Treatment failure was defined as HbA1c ≥8% on two consecutive visits, 3 months apart. RESULTS: Carriers or non-carriers of the polymorphism had similar age, body mass index, and diabetes duration. Ala carriers had lower fasting plasma insulin, better insulin sensitivity (Homeostasis Model Assessment [HOMA]2-%S), and worse beta cell secretion (HOMA2-%B) than non-carriers. During 24 months of follow-up, 32.5% among the Ala carriers and 8.6% among non-carriers (P < 0.001) developed treatment failure with a cumulative incidence of 18.6 vs 4.6/100 person-years. Those patients who developed treatment failure were older, had a younger age at diabetes diagnosis (48 ± 10 vs 52 ± 7 years; P = 0.032), higher HbA1c (8.1 ± 0.5 vs 7.7 ± 0.5%; P < 0.001), and lower HOMA2-%B (30 ± 12 vs 46 ± 29; P = 0.015) at study entry, as compared to those who did not develop treatment failure. At multivariate analysis, the Pro12Ala polymorphism was significantly associated with treatment failure (hazard ratio [HR] 4.45; 95% confidence interval [CI] 1.79-11.1; P < 0.001); HbA1c at study entry was the other independent predictor of failure in this study population. CONCLUSION: The Pro12Ala polymorphism is associated with a greater insulin sensitivity, reduced beta cell function and a substantially increased risk of treatment failure.

Putative metabolites involved in the beneficial effects of wholegrain cereal: Nontargeted metabolite profiling approach.

BACKGROUND AND AIMS: Wholegrain cereals have been implicated in the reduction of lifestyle-related chronic diseases risk including cardiovascular diseases and type 2 diabetes. Molecular mechanisms responsible for the beneficial health effects are not entirely understood. The aims of this study were 1) to identify new potential plasma biomarker candidate metabolites of wholegrain cereal foods intake and 2) to examine whether some putative metabolites associated with wholegrain foods intake may play a role in the improvement of cardiometabolic risk factors. METHODS AND RESULTS: Analysis have been conducted in 54 individuals with metabolic syndrome of both genders, age 40-65 years, randomly assigned to 2 dietary interventions lasting 12-week: 1) wholegrain enriched diet (n = 28), and 2) refined-wheat cereals diet (control diet) (n = 26). Nontargeted metabolite profiling analysis was performed on fasting plasma samples collected at baseline and at the end of the experimental diets. Our data show that, at the end of the intervention, a higher intake of wholegrain (tertile 3) was significantly associated with a marked increase in several lipid compounds, as PC (20:4/16:1), LPC (20:4), LPC (22:6), LPC (18:3), LPC (22:5), and a phenolic compound (P < .05 for all). In the wholegrain group, higher concentrations of these metabolites (tertile 3 vs tertile 1 of each metabolite) were significantly associated with lower postprandial insulin and triglyceride responses (P < .05) by 29% and 37%, respectively. CONCLUSION: These observations suggest a possible role of lipid and polyphenol metabolites in the postprandial metabolic benefits of wholegrains in subjects at high risk of cardiovascular disease. In addition, they provide insight into the role of these metabolites as potential candidate biomarkers of wholegrain foods. The study was registered on ClinicalTrials.gov (identifier: NCT00945854).

Dietary inflammatory index score, glucose control and cardiovascular risk factors profile in people with type 2 diabetes.

We examined the relationships between the dietary inflammatory index (DII®), dietary habits and cardiovascular risk factor profiles in people with type 2 diabetes mellitus (T2DM). Energy-adjusted DII (E-DII™) scores were calculated from a Food Frequency Questionnaire in 2568 T2DM patients from different parts of Italy. Analyses were conducted according to quartiles of sex-specific E-DII scores. Higher, more pro-inflammatory, (quartile 4) E-DII scores were associated with overall poor quality of the diet characterised by higher content of refined carbohydrates, added sugars, saturated fat and cholesterol and lower unsaturated fat, fibre and polyphenols compared to quartile 1. Higher E-DII scores also were associated with higher waist circumference (105.4 vs. 103.5 cm; p = 0.002), triglycerides (154.6 vs. 146.1 mg/dL; p = 0.005), diastolic blood pressure (80.05 vs. 78.6 mmHg; p = 0.04) and lower HDL-cholesterol (45.3 vs. 47.4 mg/dL; p = 0.04). In conclusion, E-DII is a potent marker of overall quality of the diet and is associated with an unfavourable cardiovascular risk factor profile.

Long-term body weight trajectories and metabolic control in type 1 diabetes patients on insulin pump or multiple daily injections: A 10-year retrospective controlled study.

BACKGROUND AND AIMS: Overweight/obesity is a clinical concern also in patients with Type 1 diabetes (T1DM). These patients' body weight may vary depending on whether treatment consists in continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDI), as these treatments lead to different blood glucose control, insulin doses, and eating behaviors. We compared long-term body weight trajectories in persons with diabetes on CSII or MDI regimens. METHODS AND RESULTS: Annual changes in body weight, HbA1c, and daily insulin doses over 6-10 years were retrospectively analyzed in T1DM adult patients on CSII (n = 90) or MDI (n = 90), strictly matched for sex, age, BMI, and diabetes duration. Mean follow-up was 9.1 ± 1.4 years. Body weight increased linearly (∼0.5 kg per year) throughout the observation period (p = 0.001, repeated measures ANOVA) with no significant difference between the CSII and MDI cohorts (p = 0.74), in either normal-weight or overweight/obese patients. HbA1c over follow-up was lower with CSII than with MDI (p = 0.037), maintaining the initial reduction after starting pump therapy. Insulin doses over follow-up were stably lower than baseline (∼20%) with CSII, while linearly increasing (∼20% from baseline to the end of observation) with MDI (p = 0.002). Mean annual weight changes correlated directly with total insulin dose changes (r = 0.191; p = 0.011) and baseline HbA1c level (r = 0.267; p = 0.001), and inversely with HbA1c changes (-0.173; p = 0.021) and baseline age (r = -0.254; p = 0.001). CONCLUSION: T1DM patients on CSII or MDI showed comparable body weight gain over a 10-year follow-up, despite improved glycemic control and decreased insulin doses with CSII.

Subjective satiety and plasma PYY concentration after wholemeal pasta.

Dietary fiber and whole grain foods may contribute to the regulation of appetite; however, evidence has produced inconclusive findings. The objective was to evaluate the effects of an experimental wholemeal pasta on appetite ratings, plasma concentrations of gastrointestinal hormones involved in appetite control, and postprandial glucose/insulin responses in healthy adults. Fourteen healthy adults (7M/7F), mean age 30±2 yrs (mean±SEM), participated in a randomized, controlled, crossover trial. Participants consumed on two different days, at one week interval, 117g of wholemeal pasta or 100g of refined wheat pasta (control pasta), similar in energy and macronutrient composition except for fiber amount, which was higher in wholemeal pasta (11 vs 3 g). Appetite ratings, glucose/insulin/lipid and gastrointestinal hormone responses were measured at fasting and for 4-h after the ingestion of the pasta tests, after which self-reported energy intake for 8-h was evaluated. After the wholemeal pasta, the desire to eat and the sensation of hunger were lower (-16%, p=0.04 and -23%, p=0.004, respectively) and satiety was higher (+13%; p=0.08) compared with the control pasta; no effect on self-reported energy intake at subsequent meal was observed. After wholemeal pasta, glucose, triglyceride increased and GLP-1 responses were not different compared to control pasta but insulin response at 30 min (p<0.05) and ghrelin at 60 min (p=0.03) were lower and PYY levels higher (AUC=+44%, p=0.001). The appetite rating changes correlated with PYY plasma levels (p<0.03). In conclusion, consumption of whole grain instead of refined wheat pasta contributed to appetite control but did not seem to influence acute energy balance. Appetite ratings were associated with modifications in PYY hormone concentrations.

Reduction in liver fat by dietary MUFA in type 2 diabetes is helped by enhanced hepatic fat oxidation.

AIMS/HYPOTHESIS: The aim of this work was to investigate hepatic lipid metabolic processes possibly involved in the reduction of liver fat content (LF) observed in patients with type 2 diabetes after an isoenergetic diet enriched in monounsaturated fatty acids (MUFAs). METHODS: This is an ancillary analysis of a published study. In a parallel-group design, 30 men and eight women, aged 35-70 years, with type 2 diabetes and whose blood glucose was controlled satisfactorily (HbA1c < 7.5% [58 mmol/mol]) by diet or diet plus metformin, were randomised by MINIM software to follow either a high-carbohydrate/high-fibre/low-glycaemic index diet (CHO/fibre diet, n = 20) or a high-MUFA diet (MUFA diet, n = 18) for 8 weeks. The assigned diets were known for the participants and blinded for people doing measurements. Before and after intervention, LF was measured by 1H-MRS (primary outcome) and indirect indices of de novo lipogenesis (DNL) (serum triacylglycerol palmitic:linoleic acid ratio), stearoyl-CoA desaturase activity (SCD-1) (serum triacylglycerol palmitoleic:palmitic acid ratio) and hepatic ß-oxidation of fatty acids (ß-hydroxybutyrate plasma concentrations) were measured. RESULTS: LF was reduced by 30% after the MUFA diet, as already reported. Postprandial ß-hydroxybutyrate incremental AUC (iAUC) was significantly less suppressed after the MUFA diet (n = 16) (-2504 ± 4488 µmol/l × 360 min vs baseline -9021 ± 6489 µmol/l × 360 min) while it was unchanged after the CHO/fibre diet (n = 17) (-8168 ± 9827 µmol/l × 360 min vs baseline -7206 ± 10,005 µmol/l × 360 min, p = 0.962) (mean ± SD, p = 0.043). In the participants assigned to the MUFA diet, the change in postprandial ß-hydroxybutyrate iAUC was inversely associated with the change in LF (r = -0.642, p = 0.010). DNL and SCD-1 indirect indices did not change significantly after either of the dietary interventions. CONCLUSIONS/INTERPRETATION: Postprandial hepatic oxidation of fatty acids is a metabolic process possibly involved in the reduction of LF by a MUFA-rich diet in patients with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01025856 FUNDING : The study was funded by Ministero Istruzione Università e Ricerca and Italian Minister of Health.

How Well Can We Control Dyslipidemias Through Lifestyle Modifications?

The role for lifestyle modifications to correct dyslipidemia(s) is reviewed. Dietary composition is crucial. Replacing saturated fat with MUFA or n-6 PUFA lowers plasma low-density lipoproteins (LDL) cholesterol and ameliorates the LDL/HDL ratio. Replacing saturated fat with carbohydrates has diverging effects due to the heterogeneity of carbohydrate foods. Diets rich in refined carbohydrates increase fasting and postprandial triglycerides, whereas the consumption of fiber-rich, low GI foods lowers LDL cholesterol with no detrimental effects on triglycerides. The role of polyphenols is debated: available evidence suggests a lowering effect of polyphenol-rich foods on postprandial triglycerides. As for functional foods, health claims on a cholesterol lowering effect of psyllium, beta-glucans and phytosterols are accepted by regulatory agencies. The importance of alcohol intake, weight reduction, and physical activity is discussed. In conclusion, there is evidence that lifestyle affects plasma lipid. A multifactorial approach including multiple changes with additive effects is the best option. This may also ensure feasibility and durability. The traditional Mediterranean way of life can represent a useful model.

Polyphenol-rich diets improve glucose metabolism in people at high cardiometabolic risk: a controlled randomised intervention trial.

AIM/HYPOTHESIS: Dietary polyphenols and long chain n-3 polyunsaturated fatty acids (LCn3) are associated with lower cardiovascular risk. This may relate to their influence on glucose metabolism and diabetes risk. We evaluated the effects of diets naturally rich in polyphenols and/or LCn3 of marine origin on glucose metabolism in people at high cardiometabolic risk. METHODS: According to a 2 × 2 factorial design, individuals with high waist circumference and at least one more component of the metabolic syndrome were recruited at the obesity outpatient clinic. Eighty-six participants were randomly assigned by MINIM software to an isoenergetic diet: (1) control, low in LCn3 and polyphenol (analysed n = 20); (2) rich in LCn3 (n = 19); (3) rich in polyphenols (n = 19); or (4) rich in LCn3 and polyphenols (n = 19). The assigned diets were known for the participants and blinded for people doing measurements. Before and after the 8 week intervention, participants underwent a 3 h OGTT and a test meal with a similar composition as the assigned diet for the evaluation of plasma glucose, insulin and glucagon-like peptide 1 (GLP-1) concentrations, and indices of insulin sensitivity and beta cell function. RESULTS: During OGTT, polyphenols significantly reduced plasma glucose total AUC (p = 0.038) and increased early insulin secretion (p = 0.048), while LCn3 significantly reduced beta cell function (p = 0.031) (two-factor ANOVA). Moreover, polyphenols improved post-challenge oral glucose insulin sensitivity (OGIS; p = 0.05 vs control diet by post hoc ANOVA). At test meal, LCn3 significantly reduced GLP-1 total postprandial AUC (p < 0.001; two-factor ANOVA). CONCLUSION/INTERPRETATION: Diets naturally rich in polyphenols reduce blood glucose response, likely by increasing early insulin secretion and insulin sensitivity. These effects may favourably influence diabetes and cardiovascular risk. The implications of the decrease in insulin secretion and postprandial GLP-1 observed with diets rich in marine LCn3 need further clarification. TRIAL REGISTRATION: ClinicalTrials.gov NCT01154478. FUNDING: The trial was funded by European Community's Seventh Framework Programme FP7/2009-2012 under grant agreement FP7-KBBE-222639, Etherpaths Project and 'Ministero Istruzione Università e Ricerca' PRIN 2010-2011 - 2010JCWWKM.

Fatty acid composition of cholesterol esters reflects dietary fat intake after dietary interventions in a multinational population.

BACKGROUND: The effects of different dietary fatty acids (FA) on cardiovascular risk still needs clarification. Plasma lipids composition may be a biomarker of FA dietary intake. PURPOSE: To evaluate in a composite population the relationships between changes in dietary fat intake and changes in FA levels in serum cholesterol esters. METHODS: In a multinational, parallel-design, dietary intervention (KANWU study), dietary intakes (3-day food record) and FA composition of serum cholesterol esters (gas-liquid chromatography) were evaluated at baseline and after 3 months in 162 healthy individuals, randomly assigned to a diet containing a high proportion of saturated (SFA) or monounsaturated (MUFA) fat, with a second random assignment to fish oil or placebo supplements. RESULTS: Main differences in serum lipid composition after the two diets included saturated (especially myristic, C14:0, and pentadecanoic, C15:0) and monounsaturated (oleic acid, C18:1 n-9) FA. C14:0 and C15:0 were related to SFA intake, while C18:1 n-9 was associated with MUFA intake. Fish oil supplementation induced a marked increase in eicosapentaenoic (C20:5 n-3) and docosahexaenoic (C22:6 n-3) acids. After the 3-month intervention, Δ-9 desaturase activity, calculated as palmitoleic acid/palmitic acid (C16:1/C16:0) ratio, was more reduced after the MUFA (0.31±0.10 vs 0.25±0.09, p<0.0001) than SFA diet (0.31±0.09 vs 0.29±0.08, p=0.006), with a statistically significant difference between the two groups (p<0.0001). CONCLUSIONS: This study shows that serum cholesterol ester FA composition can be used during randomized controlled trials as an objective indicator of adherence to experimental diets based on saturated and monounsaturated fat modifications, as well as fish oil supplementation.

Predominant role of obesity/insulin resistance in oxidative stress development.

BACKGROUND: Hyperlipidaemia, hyperglycaemia and hyperinsulinaemia, hallmarks of the postprandial state, have been also associated with increased oxidative stress and lipoprotein oxidation contributing to vascular injury and atherosclerosis. However, the specific links among metabolic disorders, postprandial state, insulin resistance and oxidative stress are still to be clarified. This study aimed at investigating the individual role played by obesity, insulin resistance and type 2 diabetes in the occurrence of fasting and postprandial oxidative stress. DESIGN: Biomarkers of oxidative stress [F2-isoprostanes and circulating oxidized low-density lipoproteins (LDL)], LDL oxidability (conjugated diene kinetic, thiobarbituric acid reactive substances (TBARs) formation and electronegativity increase) and antioxidant vitamins (ß-carotene, α-tocopherol and retinol) were evaluated at fasting and 6 h after a standard fat-rich meal in 10 obese diabetic (ObD), 11 obese and 11 normal-weight control men. Insulin sensitivity was evaluated by euglycaemic hyperinsulinaemic clamp. RESULTS: ObD and obese subjects, characterized by a similar level of adiposity and insulin resistance, showed higher urinary F2-isoprostanes and circulating oxidized LDL, an increased susceptibility to oxidation of plasma LDL (lower lag phase, higher TBARs formation, and higher relative electrophoretic mobility), and lower plasma content of ß-carotene and retinol than control subjects, both at fasting and after the test meal. CONCLUSIONS: Obesity and insulin resistance, more than type 2 diabetes, play the most relevant role in oxidative stress development. The correction of obesity and insulin resistance might be a useful strategy in counteracting systemic oxidative stress.

Dietary carbohydrates for diabetics.

The literature on the impact of dietary carbohydrates in the regulation of blood glucose levels and other metabolic abnormalities in diabetic patients over the last 3 years is reviewed. We try to differentiate the metabolic effects due to the amount of carbohydrates from those due to their different types. The review comprises a part dealing with the effects of diets having low or high carbohydrate content on body weight reduction, and a part in which the amount and the quality of carbohydrates are discussed in relation to isoenergetic diets. Overall, the data accumulated in the period considered seem to confirm that the decrease in energy intake is more important than the qualitative composition of the diet to reduce body weight, but that both the amount and the quality of carbohydrates are important in modulating blood glucose levels and other cardiovascular risk factors in both the fasting and the postprandial phases in diabetic individuals.

Effects of baked products enriched with n-3 fatty acids, folates, ß-glucans, and tocopherol in patients with mild mixed hyperlipidemia.

OBJECTIVE: To assess whether a diet containing foods enriched with ß-glucans (3.6 g/d), folic acid (1600 µg/d), long-chain (800 mg/d) and short-chain (400 mg/d) n-3 fatty acids, and tocopherols (120 mg/d) is able to modulate positively the cardiovascular risk profile in people at slightly increased cardiovascular risk. METHODS: Sixteen subjects with mild plasma lipid abnormalities were studied according to a randomized crossover design. After a 2-week run-in period, they followed a diet containing baked products enriched with active nutrients (active diet) or a diet containing the same products but without active nutrients (control diet) for 1 month and then crossed over to the other diet. At the end of each period, a test meal of the same composition as the corresponding diet was administered, and plasma samples were obtained before and for 6 hours after the meal. Hunger and satiety were evaluated by the visual analog scale at fasting and after the meal. RESULTS: Fasting plasma triglycerides were significantly lower after the active versus the control diet (1.56 ± 0.18 vs 1.74 ± 0.16 mmol/l, p < 0.05), as was the postprandial level of chylomicron triglycerides and the insulin peak (p < 0.05). The active diet also reduced fasting homocysteine (8 ± 0.6 vs 10 ± 0.8 µmol/l, p < 0.05) and the feeling of hunger at the fifth and sixth hour (p < 0.05). CONCLUSIONS: Baked functional products enriched with n-3 fatty acids, folates, ß-glucans, and tocopherols within the context of a balanced diet lower fasting and postprandial plasma triglycerides, fasting homocysteinemia, and the postprandial insulin peak. They induce a greater feeling of satiety with possible beneficial implications on energy intake.

An Isoenergetic Multifactorial Diet Reduces Pancreatic Fat and Increases Postprandial Insulin Response in Patients With Type 2 Diabetes: A Randomized Controlled Trial.

OBJECTIVE: To compare the effect of an isocaloric multifactorial diet with a diet rich in monounsaturated fatty acids (MUFA) and similar macronutrient composition on pancreatic fat (PF) and postprandial insulin response in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: According to a randomized controlled parallel-group design, 39 individuals with T2D, 35-75 years old, in satisfactory blood glucose control, were assigned to an 8 week isocaloric intervention with a multifactorial diet rich in MUFA, polyunsaturated fatty acids, fiber, polyphenols, and vitamins (n = 18) or a MUFA-rich diet (n = 21). Before/after the intervention, PF content was measured by the proton-density fat fraction using a three-dimensional mDIXON MRI sequence, and plasma insulin and glucose concentrations were measured over a 4 h test meal with a similar composition as the assigned diet. RESULTS: After 8 weeks, PF significantly decreased after the multifactorial diet (from 15.7 ± 6.5% to 14.1 ± 6.3%; P = 0.024), while it did not change after the MUFA diet (from 17.1 ± 10.1% to 18.6 ± 10.6%; P = 0.139) with a significant difference between diets (P = 0.014). Postprandial glucose response was similar in the two groups. Early postprandial insulin response (incremental postprandial areas under the curve [iAUC0-120]) significantly increased with the multifactorial diet (from 36,340 ± 34,954 to 44,138 ± 31,878 pmol/L/min; P = 0.037), while it did not change significantly in the MUFA diet (from 31,754 ± 18,446 to 26,976 ± 12,265 pmol/L/min; P = 0.178), with a significant difference between diets (P = 0.023). Changes in PF inversely correlated with changes in early postprandial insulin response (r = -0.383; P = 0.023). CONCLUSIONS: In patients with T2D, an isocaloric multifactorial diet, including several beneficial dietary components, markedly reduced PF. This reduction was associated with an improved postprandial insulin response.

Liver fat in obesity: role of type 2 diabetes mellitus and adipose tissue distribution.

BACKGROUND: Fatty liver is commonly associated with insulin-resistant conditions, often related to increased abdominal visceral fat. Our objective was to elucidate the specific roles of obesity, type 2 diabetes mellitus, insulin-resistance and abdominal fat distribution. MATERIALS AND METHODS: The study population comprised 13 diabetic obese (DO), 10 nondiabetic obese (NDO), and nine normal-weight control (C) men aged 28-65 years, with normal plasma triglyceride levels. DO were in good glycaemic control (HbA1c = 6·8 ± 0·8%) (M ± SD) with diet (n = 8) or diet + metformin (n = 5). Liver fat content was measured by (1) H-magnetic resonance spectroscopy, abdominal fat distribution by magnetic resonance imaging and insulin sensitivity by hyperinsulinaemic euglycaemic clamp. RESULTS: DO and NDO subjects had similar whole-body insulin resistance, BMI and waist circumference, higher than those of C subjects (P < 0·001). DO had more liver fat (11·9 ± 7·0%) than NDO (5·2 ± 2·8%, P < 0·05) and C (1·6 ± 1·0%, P < 0·001). Abdominal fat was greater in DO and NDO than in C (visceral: DO 3184 ± 843, NDO 2843 ± 1378 vs. C 1212 ± 587 cm(3), P < 0·001; subcutaneous: DO 4029 ± 362, NDO 5197 ± 1398 vs. C 2312 ± 626 cm(3), P < 0·001), visceral fat being not significantly different between the two obese groups, and subcutaneous fat significantly less in DO than in NDO (P < 0·05). CONCLUSIONS: Type 2 diabetes is associated with increased fat accumulation in the liver, independent of obesity and whole-body insulin resistance. The increased liver fat in DO patients may be part of an altered regional fat distribution that includes an inadequate subcutaneous fat storing capacity, rather than simply being a consequence of increased abdominal visceral content.

Plasma TMAO increase after healthy diets: results from 2 randomized controlled trials with dietary fish, polyphenols, and whole-grain cereals.

BACKGROUND: Plasma trimethylamine N-oxide (TMAO) has drawn much attention as a marker of several chronic diseases. Data on the relation between diet and TMAO are discordant and few human intervention studies have assessed causality for this association. OBJECTIVES: We aimed to evaluate the effects on plasma TMAO of diets based on foods rich in polyphenols (PP) and/or long-chain n-3 fatty acids (LCn3) or whole-grain cereals (WGCs), in individuals at high cardiometabolic risk. METHODS: An ancillary study was performed within 2 randomized controlled trials, aimed at evaluating the medium-term effects on cardiometabolic risk factors of diets naturally rich in PP and/or LCn3 (Etherpaths Project) or WGCs (HealthGrain Project). RESULTS: In the Etherpaths study (n = 78), the changes in TMAO (8-wk minus baseline) were statistically significant for the diets rich in LCn3 (+1.15 ± 11.58 µmol/L) (P = 0.007), whereas they were not for the diets rich in PP (-0.14 ± 9.66 µmol/L) (P = 0.905) or their interaction (P = 0.655) (2-factor ANOVA). In the HealthGrain Study (n = 48), the TMAO change (12-wk minus baseline) in the WGC group (+0.94 ± 3.58 µmol/L) was significantly different from that in the Refined Cereal group (-1.29 ± 3.09 µmol/L) (P = 0.037). Considering the pooled baseline data of the participants in the 2 studies, TMAO concentrations directly correlated with LCn3, EPA (20:5n-3), and protein intake, but not SFAs, fiber, MUFAs, and PP intake. Among food groups, TMAO directly correlated with the intake of fish, vegetables, and whole-grain products, but not meat, processed meat, and dairy products. CONCLUSIONS: Diets rich in LCn3 of marine origin or WGCs significantly increased plasma TMAO concentration. These changes mirrored the direct associations between TMAO concentrations and intakes of fish and WGCs, suggesting that TMAO reflects intakes of these healthy foods and, therefore, it is not a universally valid biomarker of cardiometabolic risk independent of the background diet.These trials were registered at clinicaltrials.gov as NCT01154478 and NCT00945854.