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Genetic Studies of Metabolomics Change After a Liquid Meal Illuminate Novel Pathways for Glucose and Lipid Metabolism.
Li-Gao, R, Hughes, DA, van Klinken, JB, de Mutsert, R, Rosendaal, FR, Mook-Kanamori, DO, Timpson, NJ, Willems van Dijk, K
Diabetes. 2021;(12):2932-2946
Abstract
Humans spend the greater part of the day in a postprandial state. However, the genetic basis of postprandial blood measures is relatively uncharted territory. We examined the genetics of variation in concentrations of postprandial metabolites (t = 150 min) in response to a liquid mixed meal through genome-wide association studies (GWAS) performed in the Netherlands Epidemiology of Obesity (NEO) study (n = 5,705). The metabolite response GWAS identified an association between glucose change and rs10830963:G in the melatonin receptor 1B (β [SE] -0.23 [0.03], P = 2.15 × 10-19). In addition, the ANKRD55 locus led by rs458741:C showed strong associations with extremely large VLDL (XXLVLDL) particle response (XXLVLDL total cholesterol: β [SE] 0.17 [0.03], P = 5.76 × 10-10; XXLVLDL cholesterol ester: β [SE] 0.17 [0.03], P = 9.74 × 10-10), which also revealed strong associations with body composition and diabetes in the UK Biobank (P < 5 × 10-8). Furthermore, the associations between XXLVLDL response and insulinogenic index, HOMA-β, Matsuda insulin sensitivity index, and HbA1c in the NEO study implied the role of chylomicron synthesis in diabetes (with false discovery rate-corrected q <0.05). To conclude, genetic studies of metabolomics change after a liquid meal illuminate novel pathways for glucose and lipid metabolism. Further studies are warranted to corroborate biological pathways of the ANKRD55 locus underlying diabetes.
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Vitamin D receptor gene polymorphisms affecting changes in visceral fat, waist circumference and lipid profile in breast cancer survivors supplemented with vitamin D3.
Kazemian, E, Amouzegar, A, Akbari, ME, Moradi, N, Gharibzadeh, S, Jamshidi-Naeini, Y, Khademolmele, M, As'habi, A, Davoodi, SH
Lipids in health and disease. 2019;(1):161
Abstract
OBJECTIVE We investigated whether vitamin D receptor (VDR) polymorphisms are associated with circulating metabolic biomarkers and anthropometric measures changes in breast cancer survivors supplemented with vitamin D3. METHODS One hundred sixty-eight breast cancer survivors admitted to Shohaday-e-Tajrish hospital received 4000 IU of daily vitamin D3 supplements for 12 weeks. Anthropometric measurements as well dietary, physical activity and plasma metabolic biomarkers assessments were performed before and after intervention. VDR polymorphisms were considered as the main exposures. Multivariate multiple linear regression analyses were used to determine the association between the VDR single-nucleotide polymorphisms (SNPs) and changes in metabolic and anthropometric measures in response to vitamin D3 supplementation. RESULTS One hundred twenty-five (85%) women had insufficient and inadequate levels of plasma 25-hydroxy vitamin D (25(OH)D) at baseline. Compared to the AA genotype of the ApaI, the aa category showed greater increase in muscle mass [71.3(10.7131.9)] and higher decrease in LDL-C [- 17.9(- 33.6, - 2.3)] levels after adjustment for potential confounders. In addition, the heterozygous genotype (Bb) of the BsmI VDR was associated with higher increase in WC following vitamin D3 supplementation, compared to BB [2.7(0.1,5.3)]. Haplotype score analyses indicate a significant association between inferred haplotypes from BsmI, ApaI, TaqI and FokI, BsmI and Cdx2 VDR polymorphisms and on-study visceral fat changes. CONCLUSIONS Findings of this study showed that genetic variation in the VDR gene was associated with changes in cardio-metabolic parameters in breast cancer survivors, supplemented with vitamin D3, results could provide a novel insight into better understanding of which subset of individuals benefit most from normalization of vitamin D status. TRIAL REGISTRATION This trial has been registered on the Iranian Registry of Clinical Trials (IRCT) under the identification code: IRCT2017091736244N1, registration date: 2017-11-10, http://www.irct.ir/trial/27153 and was approved by the ethics committees of the National Nutrition and Food Technology Research Institute (NNFTRI), Shahid Beheshti University of Medical Sciences (SBMU).
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Dissecting the association of autophagy-related genes with cardiovascular diseases and intermediate vascular traits: A population-based approach.
Portilla-Fernandez, E, Ghanbari, M, van Meurs, JBJ, Danser, AHJ, Franco, OH, Muka, T, Roks, A, Dehghan, A
PloS one. 2019;(3):e0214137
Abstract
Autophagy is involved in cellular homeostasis and maintenance and may play a role in cardiometabolic health. We aimed to elucidate the role of autophagy in cardiometabolic traits by investigating genetic variants and DNA methylation in autophagy-related genes in relation to cardiovascular diseases and related traits. To address this research question, we implemented a multidirectional approach using several molecular epidemiology tools, including genetic association analysis with genome wide association studies data and exome sequencing data and differential DNA methylation analysis. We investigated the 21 autophagy-related genes in relation to coronary artery disease and a number of cardiometabolic traits (blood lipids, blood pressure, glycemic traits, type 2 diabetes). We used data from the largest genome wide association studies as well as DNA methylation and exome sequencing data from the Rotterdam Study. Single-nucleotide polymorphism rs110389913 in AMBRA1 (p-value = 4.9×10-18) was associated with blood proinsulin levels, whereas rs6587988 in ATG4C and rs10439163 in ATG4D with lipid traits (ATG4C: p-value = 2.5×10-15 for total cholesterol and p-value = 3.1×10-18 for triglycerides, ATG4D: p-value = 9.9×10-12 for LDL and p-value = 1.3×10-10 for total cholesterol). Moreover, rs7635838 in ATG7 was associated with HDL (p-value = 1.9×10-9). Rs2447607 located in ATG7 showed association with systolic blood pressure and pulse pressure. Rs2424994 in MAP1LC3A was associated with coronary artery disease (p-value = 5.8×10-6). Furthermore, we identified association of an exonic variant located in ATG3 with diastolic blood pressure (p-value = 6.75×10-6). Using DNA methylation data, two CpGs located in ULK1 (p-values = 4.5×10-7 and 1×10-6) and two located in ATG4B (2×10-13 and 1.48×10-7) were significantly associated with both systolic and diastolic blood pressure. In addition one CpG in ATG4D was associated with HDL (p-value = 3.21×10-5). Our findings provide support for the role of autophagy in glucose and lipid metabolism, as well as blood pressure regulation.
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Redundancy in regulation of lipid accumulation in skeletal muscle during prolonged fasting in obese men.
Høgild, ML, Gudiksen, A, Pilegaard, H, Stødkilde-Jørgensen, H, Pedersen, SB, Møller, N, Jørgensen, JOL, Jessen, N
Physiological reports. 2019;(21):e14285
Abstract
Fasting in human subjects shifts skeletal muscle metabolism toward lipid utilization and accumulation, including intramyocellular lipid (IMCL) deposition. Growth hormone (GH) secretion amplifies during fasting and promotes lipolysis and lipid oxidation, but it is unknown to which degree lipid deposition and metabolism in skeletal muscle during fasting depends on GH action. To test this, we studied nine obese but otherwise healthy men thrice: (a) in the postabsorptive state ("CTRL"), (b) during 72-hr fasting ("FAST"), and (c) during 72-hr fasting and treatment with a GH antagonist (GHA) ("FAST + GHA"). IMCL was assessed by magnetic resonance spectroscopy (MRS) and blood samples were drawn for plasma metabolomics assessment while muscle biopsies were obtained for measurements of regulators of substrate metabolism. Prolonged fasting was associated with elevated GH levels and a pronounced GHA-independent increase in circulating medium- and long-chain fatty acids, glycerol, and ketone bodies indicating increased supply of lipid intermediates to skeletal muscle. Additionally, fasting was associated with a release of short-, medium-, and long-chain acylcarnitines to the circulation from an increased β-oxidation. This was consistent with a ≈55%-60% decrease in pyruvate dehydrogenase (PDHa) activity. Opposite, IMCL content increased ≈75% with prolonged fasting without an effect of GHA. We suggest that prolonged fasting increases lipid uptake in skeletal muscle and saturates lipid oxidation, both favoring IMCL deposition. This occurs without a detectable effect of GHA on skeletal muscle lipid metabolism.
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Moderate Renal Impairment Does Not Impact the Ability of CSL112 (Apolipoprotein A-I [Human]) to Enhance Cholesterol Efflux Capacity.
Gille, A, Duffy, D, Tortorici, MA, Wright, SD, Deckelbaum, LI, D'Andrea, DM
Journal of clinical pharmacology. 2019;(3):427-436
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Abstract
CSL112 (apolipoprotein A-I [human]) is a novel intravenous formulation of plasma-derived apolipoprotein A-I (apoA-I) that enhances cholesterol efflux capacity. Renal impairment is a common comorbidity in acute myocardial infarction patients and is associated with impaired lipid metabolism. The aim of this phase 1 study was to assess the impact of moderate renal impairment on the pharmacokinetic and pharmacodynamic profile of CSL112. Sixteen subjects with moderate renal impairment and 16 age-, sex-, and weight-matched subjects with normal renal function participated in the study. Within each renal function cohort, subjects were randomized 3:1 to receive a single intravenous infusion of CSL112 2 g (n = 6) or placebo (n = 2) or CSL112 6 g (n = 6) or placebo (n = 2). At baseline, subjects with moderate renal impairment versus normal renal function had higher total cholesterol efflux, ABCA1-dependent cholesterol efflux capacity, and pre-β1-high-density lipoprotein (HDL) levels. Infusing CSL112 resulted in similar, immediate, robust, dose-dependent elevations in apoA-I and cholesterol efflux capacity in both renal function cohorts and significantly greater elevations in pre-β1-HDL (P < .05) in moderate renal impairment. Lecithin-cholesterol acyltransferase activity, demonstrated by a time-dependent change in the ratio of unesterified to esterified cholesterol, did not differ by renal function. No meaningful changes in proatherogenic lipid levels were observed. Moderate renal impairment did not impact the ability of CSL112 to enhance cholesterol efflux capacity. CSL112 may represent a novel therapy to reduce the risk of early recurrent cardiovascular events following acute myocardial infarction in patients with or without moderate renal impairment.
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Pharmacokinetic and Pharmacodynamic Effects of Oral CXA-10, a Nitro Fatty Acid, After Single and Multiple Ascending Doses in Healthy and Obese Subjects.
Garner, RM, Mould, DR, Chieffo, C, Jorkasky, DK
Clinical and translational science. 2019;(6):667-676
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Abstract
10-nitro-9(E)-octadec-9-enoic acid (CXA-10), a novel nitro fatty acid compound, demonstrates potential as a therapeutic agent in multiple disease indications in which oxidative stress, inflammation, fibrosis, and/or direct tissue toxicity play significant roles. Phase I studies were conducted in healthy and obese subjects to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of oral CXA-10 after single and multiple doses in the fed and fasted states that would confirm the mechanisms of action of CXA-10. After single and multiple ascending doses, CXA-10 demonstrated dose-proportional increases in plasma exposure. CXA-10 decreased levels of biomarkers associated with altered inflammation and metabolic stress observed from nonclinical studies. In CXA-10-202, a consistent decrease from baseline was observed with CXA-10 150 mg dose, but not 25 or 450 mg doses, for biomarkers of altered inflammation and metabolic dysfunction, including leptin, triglycerides, cholesterol, MCP-1, and IL-6. In CXA-10-203, after coadministration with CXA-10, geometric mean peak plasma concentration (Cmax ) and area under the plasma concentration-time curve from time point 0 to the end of the dosing interval (AUC0-t ) decreased 20% and 25% for pravastatin, increased 10% and 25% for simvastatin, and decreased 20% and 5% for ezetimibe. These findings are consistent with the pharmacological effects of CXA-10. Adverse events (AEs) were dose-related, and the most frequently reported AEs (>10% of subjects) were diarrhea, abdominal pain, and nausea. CXA-10 was safe and well-tolerated with no clinically significant abnormalities reported on physical examination, vital signs, clinical laboratory evaluations, or electrocardiographic evaluation. Phase II studies are underway in patients with focal segmental glomerulosclerosis and pulmonary arterial hypertension to investigate the efficacy and tolerability of CXA-10 75-300 mg once daily.
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Effects of Bauhinia forficata Link Tea on Lipid Profile in Diabetic Patients.
Córdova Mariángel, P, Avello Lorca, M, Morales Leon, F, Fernández Rocca, P, Villa Zapata, L, Pastene Navarrete, E
Journal of medicinal food. 2019;(3):321-323
Abstract
Twenty-five type 2 diabetic volunteer patients (mean age 62 years) were recruited in a quasi-experimental study without a control group to evaluate the effects of Bauhinia forficata Link tea on lipid profiles. Participants drank the tea of 0.4% B. forficata in 200 mL of water twice a day for 3 months. The clinical parameters evaluated were cholesterol and triglycerides (mg/dL), total cholesterol (mg/dL), weight (kg), postprandial glycemia (mg/dL), and glycosylated hemoglobin (HbA1c). For the study period, statistically significant decreases in triglycerides and total cholesterol levels of 48 and 17 mg/dL, respectively, were observed. B. forficata tea as a complementary therapy in type 2 diabetic patients may help to reduce the levels of some lipid profile parameters. Further studies are suggested to evaluate the effect of the tea.
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[Effect of specialized product with modified carbohydrate profile on clinical and metabolic parameters in patients with type 2 diabetes].
Sharafetdinov, KK, Plotnikova, OA, Nazarova, AM, Kondratyeva, OV, Frolova, YV, Kochetkova, AA, Vorobyeva, VM
Voprosy pitaniia. 2019;(4):88-94
Abstract
The prevalence of type 2 diabetes mellitus (DM2) determines the need to develop evidence-based methods for preventing this disease, including personalized approaches to the dietary correction of metabolic disorders in DM2, including the use of specialized foods. Aim. To evaluate the effect of a low-calorie diet with the inclusion of a specialized product (SP) with a modified carbohydrate profile (dry instant mixture) on the glycemic and metabolic control indicators in patients with DM2. Material and methods. The study included 30 patients with DM2 with concomitant obesity, grade I-III, who were on oral sugar-lowering therapy. Within 2 weeks, patients of the main group received a low- calorie diet (1550 kcal/day) with the inclusion of SP with a modified carbohydrate profile (based on maltitol and with sweeteners) with strawberry flavor in the form of a drink (30 g dry mix per 150 ml of water) for the second breakfast instead of a carbohydrate-containing dish, which provided the intake of 7.8 g of protein, 6.1 g of fat, 1.8 g of carbohydrates, 5.6 g of maltitol. The comparison group received a low-calorie diet (1550 kcal/day) without the inclusion of SP. In all patients, on the background of complex therapy, anthropometric indices, body composition, parameters of carbohydrate, lipid and protein metabolism, liver function, and lipid peroxidation were assessed. Results and discussion. It was shown that SP inclusion into the hypocaloric diet was accompanied by a significant decrease in the level of basal glycemia by an average of 17.4% from the initial level (p<0.05), serum total cholesterol (TC) and low density lipoproteins cholesterol (LDL-C) on average by 26.9 and 36.2% of baseline, respectively, p<0.05, while in patients of the comparison group, the change in fasting blood glucose was not statistically significant (a decrease of 8.1%), and the decrease in TC and LDL-C was on average 22.1 and 21.0%, respectively (p<0.05). At the same time, against the background of complex therapy, positive dynamic in lipid peroxidation in the main group was observed: the level of blood serum malondialdehyde decreased on average by 25.3% from the baseline values (p<0.05). Conclusion. The inclusion of SP with a modified carbohydrate profile in a low-calorie diet is accompanied by an improvement in glycemic control, lipid metabolism and antioxidant status of patients with DM2, helping to reduce the risk of developing systemic vascular complications in this disease.
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Effects of soybean lipid infusion on triglyceride and unbound free fatty acid levels in preterm infants.
Hegyi, T, Kleinfeld, A, Huber, A, Weinberger, B, Memon, N, Joe Shih, W, Carayannopoulos, M, Oh, W
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 2019;(19):3226-3231
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Objective: To determine the plasma triglyceride (TG) and unbound free fatty acid (FFAu) levels in infants treated with increasing dosages of soybean lipid, intralipid (IL), infusion. Study design: TG and FFAu levels were measured in 78 preterm infants (BW 500-2000 g; GA 23-34 weeks) using the fluorescent probe ADIFAB2 and enzymatic method. Results: The infants' BW was 1266.2 ± 440.7 g and GA 28.8 ± 3.1 weeks. TG levels were 77.4 ± 50 mg/dL, 140.2 ± 188 mg/dL (p < .04 compared to levels during low dose IL infusion) and 135.6 ± 118 mg/dL (p < .004), respectively during increased IL rates. FFAu levels were 17.7 ± 13 nM, 47.3 ± 102.8 nM (p = .07) and 98 ± 234 nM (p = .03). TG levels correlated with IL dose, the rate of IL administration, and FFAu levels. TG and FFAu levels were higher in infants below 28 weeks' gestation Conclusions: Increasing dosage of IL is associated with increasing levels of TG and FFAu, especially in infants below 29 weeks of gestation. The increased level of FFAu suggests inefficient cellular utilization.
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The PNPLA3 I148M variant is associated with transaminase elevations in type 2 diabetes patients treated with basal insulin peglispro.
Pillai, S, Duvvuru, S, Bhatnagar, P, Foster, W, Farmen, M, Shankar, S, Harris, C, Bastyr, E, Hoogwerf, B, Haupt, A
The pharmacogenomics journal. 2018;(3):487-493
Abstract
Basal insulin peglispro (BIL) is a novel insulin with hepato-preferential action. In phase 3 trials, BIL showed significantly improved glycemic control but higher levels of transaminases (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), triglycerides (TGs) and liver fat content (LFC) compared with insulin glargine (GL). As variants in PNPLA3 (I148M) and TM6SF2 (E167K) are associated with nonalcoholic fatty liver disease, we assessed these variants in type 2 diabetes (T2D) patients randomized to receive BIL (n=1822) or GL (n=1270) in three phase 3 trials. Magnetic resonance imaging assessments of LFC were conducted in a subset of patients (n=296). Analyses showed α-corrected significant increases in change from baseline in AST (P=0.0004) and nominal increases in ALT (P=0.019), and LFC (P=0.035) for PNPLA3 (148M/M) genotypes in the BIL arm at 26 weeks but no significant associations in GL. PNPLA3 (148M/M) was also associated with increases in total cholesterol (P=0.014) and low-density lipoprotein cholesterol (P=0.005) but not with hemoglobin A1c or TG. T2D patients with the PNPLA3 (148M/M) genotype treated with BIL may be more susceptible to increased liver fat deposition. The current data provide further insights into the biological role of PNPLA3 in lipid metabolism.