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The recognition that the increase of plasma triglyceride rich lipoproteins (TRLs) is associated with multiple alterations of other lipoproteins species that are potentially atherogenic has expanded the picture of diabetic dyslipidaemia. The discovery of heterogeneity within major lipoprotein classes VLDL, LDL and HDL opened new avenues to reveal the specific pertubations of diabetic dyslipidaemia. The increase of large VLDL 1 particles in Type 2 diabetes initiates a sequence of events that generates atherogenic remnants, small dense LDL and small dense HDL particles. Together these components comprise the atherogenic lipid triad. Notably the malignant nature of diabetic dyslipidaemia is not completely shown by the lipid measures used in clinical practice. The key question is what are the mechanisms behind the increase of VLDL 1 particles in diabetic dyslipidaemia? Despite the advances of recent years, our understanding of VLDL assembly and secretion is still surprisingly incomplete. To date it is still unclear how the liver is able to regulate the amount of triglycerides incorporated into VLDL particles to produce either VLDL 1 or VLDL 2 particles. The current evidence suggests that the machinery driving VLDL assembly in the liver includes (i) low insulin signalling via PI-3 kinase pathway that enhances lipid accumulation into \"nascent \" VLDL particles (ii) up-regulation of SREBP-1C that stimulates de novo lipogenesis and (iii) excess availability of \"polar molecules\" in hepatocytes that stabilizes apo B 100. Recent data suggest that all these steps could be fundamentally altered in Type 2 diabetes explaining the overproduction of VLDL apo B as well as the ability of insulin to suppress VLDL 1 apo B production in Type 2 diabetes. Recent discoveries have established the transcription factors including PPARs, SREBP-1 and LXRs as the key regulators of lipid assembly in the liver. These observations suggest these factors as a new target to tailor more efficient drugs to treat diabetic dyslipidaemia.

We assessed the effects of vildagliptin, a novel dipeptidyl peptidase IV inhibitor, on postprandial lipid and lipoprotein metabolism in patients with type 2 diabetes. This was a single-centre, randomised, double-blind study in drug-naive patients with type 2 diabetes. Patients received vildagliptin (50 mg twice daily, n=15) or placebo (n=16) for 4 weeks. Triglyceride, cholesterol, lipoprotein, glucose, insulin, glucagon and glucagon-like peptide-1 (GLP-1) responses to a fat-rich mixed meal were determined for 8 h postprandially before and after 4 weeks of treatment. Relative to placebo, 4 weeks of treatment with vildagliptin decreased the AUC(0-8h) for total trigyceride by 22+/-11% (p=0.037), the incremental AUC(0-8h) (IAUC(0-8h)) for total triglyceride by 85+/-47% (p=0.065), the AUC(0-8h) for chylomicron triglyceride by 65+/-19% (p=0.001) and the IAUC(0-8h) for chylomicron triglyceride by 91+/-28% (p=0.002). This was associated with a decrease in chylomicron apolipoprotein B-48 (AUC(0-8h), -1.0+/-0.5 mg l(-1) h, p=0.037) and chylomicron cholesterol (AUC(0-8h), -0.14+/-0.07 mmol l(-1) h, p=0.046). Consistent with previous studies, 4 weeks of treatment with vildagliptin also increased intact GLP-1, suppressed inappropriate glucagon secretion, decreased fasting and postprandial glucose, and decreased HbA(1c) from a baseline of 6.7% (change, -0.4+/-0.1%, p<0.001), all relative to placebo. Treatment with vildagliptin for 4 weeks improves postprandial plasma triglyceride and apolipoprotein B-48-containing triglyceride-rich lipoprotein particle metabolism after a fat-rich meal. The mechanisms underlying the effects of this dipeptidyl peptidase IV inhibitor on postprandial lipid metabolism remain to be explored.

Aims/hypothesis To study the heritability and familiality of type 2 diabetes and related quantitative traits in families from the Botnia Study in Finland. Methods Heritability estimates for type 2 diabetes adjusted for sex, age and BMI are provided for different age groups of type 2 diabetes and for 34 clinical and metabolic traits in 5,810 individuals from 942 families using a variance component model (SOLAR). In addition, family means of these traits and their distribution across families are calculated. Results The strongest heritability for type 2 diabetes was seen in patients with age at onset 35–60 years ( h 2  = 0.69). However, including patients with onset up to 75 years dropped the h 2 estimates to 0.31. Among quantitative traits, the highest h 2 estimates in all individuals and in non-diabetic individuals were seen for lean body mass ( h 2  = 0.53–0.65), HDL-cholesterol (0.52–0.61) and suppression of NEFA during OGTT (0.63–0.76) followed by measures of insulin secretion (insulinogenic index [IG 30 ] = 0.41–0.50) and insulin action (insulin sensitivity index [ISI] = 0.37–0.40). In contrast, physical activity showed rather low heritability (0.16–0.18), whereas smoking showed strong heritability (0.57–0.59). Family means of these traits differed two- to fivefold between families belonging to the lowest and highest quartile of the trait ( p  < 0.00001). Conclusions/interpretation To detect stronger genetic effects in type 2 diabetes, it seems reasonable to restrict inclusion of patients to those with age at onset 35–60 years. Sequencing of families with extreme quantitative traits could be an important next step in the dissection of the genetics of type 2 diabetes.

Aims/hypothesis We determined whether hepatic fat content and plasma adiponectin concentration regulate VLDL₁ production. Methods A multicompartment model was used to simultaneously determine the kinetic parameters of triglycerides (TGs) and apolipoprotein B (ApoB) in VLDL₁ and VLDL₂ after a bolus of [²H₃]leucine and [²H₅]glycerol in ten men with type 2 diabetes and in 18 non-diabetic men. Liver fat content was determined by proton spectroscopy and intra-abdominal fat content by MRI. Results Univariate regression analysis showed that liver fat content, intra-abdominal fat volume, plasma glucose, insulin and HOMA-IR (homeostasis model assessment of insulin resistance) correlated with VLDL₁ TG and ApoB production. However, only liver fat and plasma glucose were significant in multiple regression models, emphasising the critical role of substrate fluxes and lipid availability in the liver as the driving force for overproduction of VLDL₁ in subjects with type 2 diabetes. Despite negative correlations with fasting TG levels, liver fat content, and VLDL₁ TG and ApoB pool sizes, adiponectin was not linked to VLDL₁ TG or ApoB production and thus was not a predictor of VLDL₁ production. However, adiponectin correlated negatively with the removal rates of VLDL₁ TG and ApoB. Conclusions/interpretation We propose that the metabolic effect of insulin resistance, partly mediated by depressed plasma adiponectin levels, increases fatty acid flux from adipose tissue to the liver and induces the accumulation of fat in the liver. Elevated plasma glucose can further increase hepatic fat content through multiple pathways, resulting in overproduction of VLDL₁ particles and leading to the characteristic dyslipidaemia associated with type 2 diabetes.

Laser treatment for diabetic retinopathy is often associated with visual field reduction and other ocular side-effects. Our aim was to assess whether long-term lipid-lowering therapy with fenofibrate could reduce the progression of retinopathy and the need for laser treatment in patients with type 2 diabetes mellitus. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a multinational randomised trial of 9795 patients aged 50–75 years with type 2 diabetes mellitus. Eligible patients were randomly assigned to receive fenofibrate 200 mg/day (n=4895) or matching placebo (n=4900). At each clinic visit, information concerning laser treatment for diabetic retinopathy—a prespecified tertiary endpoint of the main study—was gathered. Adjudication by ophthalmologists masked to treatment allocation defined instances of laser treatment for macular oedema, proliferative retinopathy, or other eye conditions. In a substudy of 1012 patients, standardised retinal photography was done and photographs graded with Early Treatment Diabetic Retinopathy Study (ETDRS) criteria to determine the cumulative incidence of diabetic retinopathy and its component lesions. Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN64783481. Laser treatment was needed more frequently in participants with poorer glycaemic or blood pressure control than in those with good control of these factors, and in those with a greater burden of clinical microvascular disease, but the need for such treatment was not affected by plasma lipid concentrations. The requirement for first laser treatment for all retinopathy was significantly lower in the fenofibrate group than in the placebo group (164 [3·4%] patients on fenofibrate vs 238 [4·9%] on placebo; hazard ratio [HR] 0·69, 95% CI 0·56–0·84; p=0·0002; absolute risk reduction 1·5% [0·7–2·3]). In the ophthalmology substudy, the primary endpoint of 2-step progression of retinopathy grade did not differ significantly between the two groups overall (46 [9·6%] patients on fenofibrate vs 57 [12·3%] on placebo; p=0·19) or in the subset of patients without pre-existing retinopathy (43 [11·4%] vs 43 [11·7%]; p=0·87). By contrast, in patients with pre-existing retinopathy, significantly fewer patients on fenofibrate had a 2-step progression than did those on placebo (three [3·1%] patients vs 14 [14·6%]; p=0·004). An exploratory composite endpoint of 2-step progression of retinopathy grade, macular oedema, or laser treatments was significantly lower in the fenofibrate group than in the placebo group (HR 0·66, 95% CI 0·47–0·94; p=0·022). Treatment with fenofibrate in individuals with type 2 diabetes mellitus reduces the need for laser treatment for diabetic retinopathy, although the mechanism of this effect does not seem to be related to plasma concentrations of lipids.

Aims/hypothesis Pharmacological augmentation of glucagon-like peptide 1 receptor signalling by dipeptidyl peptidase 4 (DPP-4) inhibition reduced intestinal lipoprotein secretion in experimental studies, suggesting that DPP-4 inhibitors may ameliorate dyslipidaemia and thus reduce cardiovascular risk in patients with type 2 diabetes. We assessed the effects of alogliptin (Alo) and Alo co-administered with pioglitazone (Pio) vs placebo (Pbo) on triacylglycerol (TG)-rich lipoproteins in type 2 diabetes before and following a high-fat meal. Methods Seventy-one patients (age 18–70 years), who did not reach HbA 1c 6.5% (48 mmol/mol) with lifestyle and/or metformin, sulfonylurea or glinide therapy, participated in this 16 week, double-centre (university hospitals) Pbo-controlled parallel-group study. All participants, people doing measurements or examinations, and people assessing the outcomes were blinded to group assignment. Fasting TG 1.7–5.0 mmol/l was among the entry criteria. Patients received a high-fat mixed meal before and 4 and 16 weeks after randomisation (allocation by central office) to Alo ( n  = 25), Alo/Pio ( n  = 22) or Pbo ( n  = 24). Blood was sampled at pre-specified intervals, starting at 15 min before and ending 8 h after meal ingestion. Results At week 16, Alo ( n  = 25) and Alo/Pio ( n  = 21) vs Pbo ( n  = 24) produced similar significant reductions in total postprandial TG response (incremental AUC [iAUC]; p  < 0.001), as well as in chylomicron TG ( p  < 0.001) and VLDL1 TG iAUCs ( p  < 0.001 and p  = 0.012, respectively). Postprandial chylomicron apolipoprotein B-48 iAUC showed a significant decrease after Alo treatment ( p  = 0.028), and a non-significant trend towards a decrease with Alo/Pio ( p  = 0.213). The incidence of adverse events was low and consistent with previous studies. Conclusions/interpretation Treatment with Alo and Alo/Pio produced significant reductions in postprandial TG and TG-rich lipoproteins, contributing to an improved overall cardiometabolic risk profile in type 2 diabetes. The data support the concept that incretins not only modulate glucose metabolism but also influence chylomicron metabolism in intestinal cells. Trial registration: ClinicalTrials.gov number NCT00655863. Funding: The study was funded by Takeda Global Research & Development.

Aims/hypothesis The weak relationship between insulin resistance and total serum triacylglycerols (TGs) could be in part due to heterogeneity of TG molecules and their distribution within different lipoproteins. We determined concentrations of individual TGs and the fatty acid composition of serum and major lipoprotein particles and analysed how changes in different TGs and fatty acid composition are related to features of insulin resistance and abdominal obesity. Methods We performed lipidomic analyses of all major lipoprotein fractions using two analytical platforms in 16 individuals, who exhibited a broad range of insulin sensitivity. Results We identified 45 different TGs in serum. Serum TGs containing saturated and monounsaturated fatty acids were positively, while TGs containing essential linoleic acid (18:2 n-6) were negatively correlated with HOMA-IR. Specific serum TGs that correlated positively with HOMA-IR were also significantly positively related to HOMA-IR when measured in very-low-density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs) and LDL, but not in HDL subfraction 2 (HDL₂) or 3 (HDL₃). Analyses of proportions of esterified fatty acids within lipoproteins revealed that palmitic acid (16:0) was positively related to HOMA-IR when measured in VLDL, IDL and LDL, but not in HDL₂ or HDL₃. Monounsaturated palmitoleic (16:1 n-7) and oleic (18:1 n-9) acids were positively related to HOMA-IR when measured in HDL₂ and HDL₃, but not in VLDL, IDL or LDL. Linoleic acid was negatively related to HOMA-IR in all lipoproteins. Conclusions/interpretation Serum concentrations of specific TGs, such as TG(16:0/16:0/18:1) or TG(16:0/18:1/18:0), may be more precise markers of insulin resistance than total serum TG concentrations.

Upper body abdominal subcutaneous adipose tissue (SAT) can be divided into deep SAT (DSAT) and superficial SAT (SSAT) depots. Studies on adipose tissue fatty acid (FA) composition have made no distinction between these two depots. The aim of this study is to determine whether DSAT and SSAT differ in FA composition. We studied the FA composition of DSAT and SSAT in 17 male and 13 female volunteers using non-invasive proton magnetic resonance spectroscopy in vivo . Magnetic resonance imaging was used to differentiate between DSAT and SSAT. Adipose tissue spectra were analysed for lipid unsaturation, or double bond (DB) content, and polyunsaturation (PU), according to previously validated methods. The DSAT depot was more saturated than the SSAT depot, in both men (0.833±0.012 vs 0.846±0.009 DB, P <0.002) and women (0.826±0.018 vs 0.850±0.018 DB, P <0.002). In contrast, PU did not differ between DSAT and SSAT in either men (0.449±0.043 vs 0.461±0.044 PU, P =0.125) or women (0.411±0.070 vs 0.442±0.062 PU, P =0.234) and displayed a close correlation between the depots ( R =0.908, P <0.001, n =30). The higher saturation in DSAT compared with SSAT can be attributed to a higher ratio of saturated to monounsaturated FAs. These results should be taken into account when determining the FA composition of SAT.

Aims/hypothesis The apolipoprotein B (ApoB):apolipoprotein A (ApoA)-I ratio may be a better indicator of cardiovascular disease (CVD) risk in people with type 2 diabetes than traditional lipid risk markers (LDL-cholesterol, HDL-cholesterol and triacylglycerol), but whether the ApoB:ApoA-I ratio should be used to indicate lipid-lowering therapy is still debated. Methods The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study randomised 9,795 patients with type 2 diabetes to fenofibrate (200 mg daily) or placebo and followed them up for a median of 5 years. We compared ApoB, ApoA-I, ApoAII and the ApoB:ApoA-I ratio with traditional lipid variables as predictors of CVD risk. We estimated the HR of the effect of 1 SD difference in baseline concentrations of lipids, apolipoproteins and respective ratios on the risk of CVD events and also used receiver operating characteristic curve analysis. Results In the placebo group, the variables best predicting CVD events were non-HDL-cholesterol:HDL-cholesterol, total cholesterol:HDL-cholesterol (HR 1.21, p < 0.001 for both), ApoB:ApoA-I (HR 1.20, p < 0.001), LDL-cholesterol:HDL-cholesterol (HR 1.17, p < 0.001), HDL-cholesterol (HR 0.84, p < 0.001) and ApoA-I (HR 0.85, p < 0.001). In the fenofibrate group, the first four predictors were very similar (but ApoB:ApoA-I was fourth), followed by non-HDL-cholesterol and ApoB. Lipid ratios and ApoB:ApoA-I performed better than any single lipid or apolipoprotein in predicting CVD risk. Conclusions/interpretation In patients with type 2 diabetes in the FIELD study, traditional lipid ratios were as strong as the ApoB:ApoA-I ratio in predicting CVD risk. The data provide little evidence for replacement of traditional lipids and their ratios with measures of ApoB, ApoA-I and their ratio.

Aims/hypothesis We studied the impact of baseline lipid variables on the progression of renal disease in a large nationwide prospective cohort of patients with type 1 diabetes. Methods A total of 2,304 adult patients with type 1 diabetes and available lipid profiles participating in the Finnish Diabetic Nephropathy Study (FinnDiane) were evaluated. Data on progression of renal disease were verified from medical files and patients were followed for 5.4 ± 2.0 (mean ± SD) years. Results High triacylglycerol, apolipoprotein (Apo) B, ApoA-II and HDL₃-cholesterol concentrations predicted incident microalbuminuria. Progression to macroalbuminuria was predicted by high triacylglycerol and ApoB. When AER was entered into the model, triacylglycerol was no longer an independent predictor, but when patients with normal AER and microalbuminuria at baseline were pooled, triacylglycerol, HbA₁c, male sex and AER were all independent predictors of renal disease. High total cholesterol, LDL-cholesterol, non-HDL-cholesterol and triacylglycerol as well as low HDL-cholesterol, HDL₂-cholesterol, ApoA-I and ApoA-II concentrations were predictive of progression to end-stage renal disease. However, when estimated GFR was entered into the model, only total cholesterol remained an independent predictor of progression. Conclusions/interpretation Lipid abnormalities, particularly high triacylglycerol concentrations, increase the risk of progression of renal disease.