ANGPTL4 variants E40K and T266M are associated with lower fasting triglyceride levels in Non-Hispanic White Americans from the Look AHEAD Clinical Trial

Background: Elevated triglyceride levels are a risk factor for cardiovascular disease. Angiopoietin-like protein 4 (Angptl4) is a metabolic factor that raises plasma triglyceride levels by inhibiting lipoprotein lipase (LPL). In nondiabetic individuals, the ANGPTL4 coding variant E40K has been associated with lower plasma triglyceride levels while the T266M variant has been associated with more modest effects on triglyceride metabolism. The objective of this study was to determine whether ANGPTL4 E40K and T266M are associated with triglyceride levels in the setting of obesity and T2D, and whether modification of triglyceride levels by these genetic variants is altered by a lifestyle intervention designed to treat T2D. Methods: The association of ANGPTL4 E40K and T266M with fasting triglyceride levels was investigated in 2,601 participants from the Look AHEAD Clinical Trial, all of whom had T2D and were at least overweight. Further, we tested for an interaction between genotype and treatment effects on triglyceride levels. Results: Among non-Hispanic White Look AHEAD participants, ANGPTL4 K40 carriers had mean triglyceride levels of 1.61 +/- 0.62 mmol/L, 0.33 mmol/L lower than E40 homozygotes (p = 0.001). Individuals homozygous for the minor M266 allele (MAF 30%) had triglyceride levels of 1.75 +/- 0.58 mmol/L, 0.24 mmol/L lower than T266 homozygotes (p = 0.002). The association of the M266 with triglycerides remained significant even after removing K40 carriers from the analysis (p = 0.002). There was no interaction between the weight loss intervention and genotype on triglyceride levels. Conclusions: This is the first study to demonstrate that the ANGPTL4 E40K and T266M variants are associated with lower triglyceride levels in the setting of T2D. In addition, our findings demonstrate that ANGPTL4 genotype status does not alter triglyceride response to a lifestyle intervention in the Look AHEAD study

ANGPTL4 variants E40K and T266M are associated with lower fasting triglyceride levels in Non-Hispanic White Americans from the Look AHEAD Clinical Trial

<p>Abstract</p> <p>Background</p> <p>Elevated triglyceride levels are a risk factor for cardiovascular disease. Angiopoietin-like protein 4 (Angptl4) is a metabolic factor that raises plasma triglyceride levels by inhibiting lipoprotein lipase (LPL). In non-diabetic individuals, the <it>ANGPTL4 </it>coding variant E40K has been associated with lower plasma triglyceride levels while the T266M variant has been associated with more modest effects on triglyceride metabolism. The objective of this study was to determine whether ANGPTL4 E40K and T266M are associated with triglyceride levels in the setting of obesity and T2D, and whether modification of triglyceride levels by these genetic variants is altered by a lifestyle intervention designed to treat T2D.</p> <p>Methods</p> <p>The association of <it>ANGPTL4 </it>E40K and T266M with fasting triglyceride levels was investigated in 2,601 participants from the Look AHEAD Clinical Trial, all of whom had T2D and were at least overweight. Further, we tested for an interaction between genotype and treatment effects on triglyceride levels.</p> <p>Results</p> <p>Among non-Hispanic White Look AHEAD participants, <it>ANGPTL4 </it>K40 carriers had mean triglyceride levels of 1.61 ± 0.62 mmol/L, 0.33 mmol/L lower than E40 homozygotes (p = 0.001). Individuals homozygous for the minor M266 allele (MAF 30%) had triglyceride levels of 1.75 ± 0.58 mmol/L, 0.24 mmol/L lower than T266 homozygotes (p = 0.002). The association of the M266 with triglycerides remained significant even after removing K40 carriers from the analysis (p = 0.002). There was no interaction between the weight loss intervention and genotype on triglyceride levels.</p> <p>Conclusions</p> <p>This is the first study to demonstrate that the <it>ANGPTL4 </it>E40K and T266M variants are associated with lower triglyceride levels in the setting of T2D. In addition, our findings demonstrate that <it>ANGPTL4 </it>genotype status does not alter triglyceride response to a lifestyle intervention in the Look AHEAD study.</p

Genetic and environmental determinants of triglyceride levels: ANGPTL4 as a key functional modulator

Background and Aims: The manifestation of chronic diseases such as cardiovascular disease (CVD) is a consequence of a complex interplay of genetic and environmental factors, of which diet plays an important role. The susceptibility to CVD is partly determined by genetic factors, but a “CVD-promoting environment” may also be necessary for its phenotypic expression. Angiopoietin-like 4 (Angptl4) is a dual-function protein: with the N terminus an inhibitor of lipoprotein lipase (LPL), influencing plasma triglycerides, and a C terminus with potential angiogenic properties. Analysis concentrated on the association of two ANGPTL4 coding SNPs with lipid profiles and CVD risk and associated traits in healthy and diseased individuals from 8 separate cohorts. In vitro studies were performed, to further our understanding of the role of this protein in inter-individual variability in triglyceride levels and in the pathogenesis of coronary heart disease. Results: Data has confirmed a strong association of E40K with triglyceride-lowering in over 13,000 individuals from 5 studies. Effects on HDL-raising in those studies with available measures were equally robust and consistent. However, despite these CHD protective effects there is a borderline association of E40K with increased CHD risk, independent of effects on CHD risk. The association of T266M with triglyceride levels, independent of E40K, was only seen under conditions of post-prandial stress and there was no association with CHD risk. In the Look AHEAD cohort of type II diabetes patients, an association of the ANGPTL4 T266M variant with triglyceride levels at baseline, independent of E40K, was reported for the first time. T266M, but not E40K, was independently associated with Angptl4 levels, yet circulating Angptl4 levels showed no correlation with triglyceride levels. Furthermore, T266M was not associated with CHD risk in meta-analysis. The data suggest that circulating Angptl4 does not reflect what is occurring at the cellular level. The in vitro studies confirmed that E40K is unable to inhibit LPL but T266M does not impair this function of the protein. The T266M variant did however effect secretion of the Angptl4 into the media of HEK-293A and Huh7 cells, highlighting the possibility of T266M as a functional variant and providing a biological basis for the association of T266M with circulating Angplt4 levels. Although this may have little importance in circulation, the effect T266M has on protein secretion may be of great importance in a tissue-specific manner when considering the autocrine and paracrine effect of Angptl4. Conclusions: The association studies and in vitro data from this thesis provide new insights into the role of Angptl4 in triglyceride metabolism

Vitamin B12 deficiency induces cholesterol biosynthesis by limiting S-adenosyl methionine and altering the methylation of Srebf1 and Ldlr genes

Maternal vitamin B12 deficiency affecting one-carbonmetabolism influences metabolic status and the degree of insulinresistance of the offspring in adulthood. But its significance andmechanism in the development of adiposity and adipose tissuedysfunction is unknown. To investigate the role of vitamin B12 in the developmentof adipocyte dysfunction. Human pre-adipocytes were differentiatedin customised media with varying concentrations of B12. Adipo-cytes cultured in low B12 (0.15nM) or no B12 conditions hadincreased cholesterol and homocysteine levels and reduced glucoseuptake capacity compared to control (B12 500nM). Global DNAmethylation profiling and bisulphite pyrosequencing showed thatthe promoter regions of sterol regulatory element-binding tran-scription factor 1 (SREBF1) and low density lipoprotein receptor(LDLR) were hypomethylated in B12 deficient conditions, consis-tent with the increased gene expressions. The S-adenosyl methio-nine/S-adenosyl homocysteine ratio was significantly lower in B12deficient conditions. Inhibition of methylation in high B12 condi-tions by 5-aza-2-deoxycytidine led to increased cholesterol accu-mulation but not homocysteine. In two independent clinicalstudies, women at child bearing age (age: 19–39 years) and inearly pregnancy (16–18 weeks), showed that low B12 was asso-ciated with higher total cholesterol, LDL cholesterol and choles-terol to HDL ratio. Regression analysis in the pregnant cohortadjusting for all confounders showed B12 levels to be indepen-dently associated with total cholesterol and triglyceride levels. Vitamin B12 deficiency leads to adipocyte dysfunc-tion by inducing cholesterol biosynthesis and homocysteine.Induction of cholesterol biosynthesis was due to hypomethylationof SREBF1 and LDLR. Clinical observations support that the B12effect is independent and our findings show this link is probably causal

Altered cardiorespiratory and metabolic responses during submaximal exercise in well-controlled males with type 1 diabetes compared to matched non-diabetes controls

Aims: Ketosis-prone Type 2 diabetes (KPDM) describes an unusual form of diabetes: the occurrence of ketosis but negative autoantibodies and the ability to manage without long-term insulin therapy. KPDM is considered primarily a result of acute beta cell failure. We reviewed insulin-dose requirements at hospital discharge as a surrogate measure of acute insulin resistance in newly diagnosed antibody-negative diabetes, in patients with and without significant ketonuria. Methods: Data were collected from patients admitted with ketone-positive symptomatic hyperglycaemia at an urban hospital. All cases were treatment-na€ıve on admission with glucose >12mmol/l and subsequently proved to be negative for GAD and ICA antibody. KPDM had admission pH ≤ 7.30, bicarbonate ≤15mmol/l and urinary ketones ≥80mg/dl. Ketosis-only (KO) had ketones ≥80mg/dl but pH >7.30. Type 2 diabetes had ketones ≤40mg/dl. Data are mean SEM. Results: Over 30 months, 9 KPDM, 19 KO and 10 Type 2 diabetes were studied. There was no difference in age between the KPDM, KO and Type 2 diabetes groups (37.8 4.0, 47.8 2.4, 43.0 3.5 years) and a similar distribution of ethnicity. The admission glucose and HbA1c were no different between groups (glucose 37.2 3.2, 32.0 3.2, 34.9 4.1mmol/l; HbA1c 133 10, 120 7, 114 10mmol/mol). Groups had comparable body weight (87.3 3.7, 92.4 7.3, 100.5 6.7kg). There was a trend to greater total daily dose of insulin at discharge in the KPDM group (72.9 3.2 units/day) than the KO (52.0 6.3 units/day) or Type 2 diabetes (49.4 5.1 units/day) groups, p=0.06. This was significant when normalised per kilogram of body weight (0.85 0.04, 0.56 0.06, 0.51 0.07 units/kg/ day; p=0.01). Conclusion: KPDM appears to exhibit greater insulin resistance than other forms of diabetes at acute presentation. Along with beta cell dysfunction, this may be the precipitant for metabolic destabilisation and ketosis

Methyl donor deficiency due to low vitamin b12 impairs insulin signalling in human adipocytes by down regulating AKT pathway via PTEN and TRB3

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