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Evidence for a common, saturable, triglyceride removal mechanism for chylomicrons and very low density lipoproteins in man.

Hypertriglyceridemic subjects were fed diets in which dietary fat calories were held constant, but carbohydrate calories were varied. Three subjects with fasting chylomicronemia (Type V) were given less carbohydrate and four subjects without fasting chylomicronemia (Type IV) were fed diets with more calories as carbohydrate. The restricted carbohydrate intake led to disappearance of chylomicronemia in those subjects who had chylomicronemia on a normal diet (Type V to IV). In those subjects without chylomicronemia, chylomicronemia appeared in response to increased carbohydrate intake (Type IV to V). Thus chylomicron concentrations in plasma were altered even though fat intake and presumably chylomicron input into plasma was kept constant. These findings provide evidence for saturation of chylomicron removal mechanisms by alteration of endogenous triglyceride-rich lipoprotein concentrations. They suggest that chylomicrons compete with very low density lipoproteins for similar removal mechanisms. The relationship between endogenous triglyceride concentration and the lipolytic activity in plasma following heparin was then evaluated with the use of long-term heparin infusions to release and maintain lipolytic activity in the circulation. 10 subjects were placed on fatfree diets to remove circulating dietary fat. The plasma lipolytic rate during the heparin infusion was measured consecutively on different days in individuals whose triglyceride concentrations were varied by either increasing or decreasing calories. The lipolytic rate was curvilinearly related to the plasma triglyceride concentrations. This curvilinear relationship followed Michaelis-Menton saturation kinetics over a wide range of triglyceride concentrations on fat-free, high-carbohydrate diets, in multiple studies in a group of individuals. These studies suggest that endogenous and exogenous triglyceride compete for a common, saturable, plasma triglyceride removal system related to lipoprotein lipase.

Adult↗

Hypertriglyceridemic very low density lipoproteins induce triglyceride synthesis and accumulation in mouse peritoneal macrophages.

Triglyceride-rich lipoproteins may be responsible for the lipid accumulation in macrophages that can occur in hypertriglyceridemia. Chylomicrons and very low density lipoproteins (VLDL, total and with flotation constant [S(f)] 100-400) from fasting hypertriglyceridemic subjects induced a massive accumulation of oil red O-positive inclusions in unstimulated peritoneal macrophages. Cell viability was not affected. The predominant lipid that accumulated in cells exposed to hypertriglyceridemic VLDL was triglyceride. Hypertriglyceridemic VLDL stimulated the incorporation of [(14)C]oleate into cellular triglyceride up to ninefold in 16 h, but not into cholesteryl esters. Mass increase in cellular triglyceride was 38-fold. The stimulation of cellular triglyceride formation was dependent on time, temperature, and concentration of hypertriglyceridemic VLDL. By contrast, VLDL, low density, and high density lipoproteins from fasting normolipemic subjects had no significant effect on oleate incorporation into neutral lipids or on visible lipid accumulation.(125)I-Hypertriglyceridemic VLDL (S(f) 100-400) were degraded by macrophages in a dose-dependent manner, with 50 and 100% saturation observed at 3 and 24 mug protein/ml (2.5 and 20 nM), respectively. Hypertriglyceridemic VLDL inhibited the internalization and degradation of (125)I-hypertriglyceridemic VLDL (4 nM) by 50% at 3 nM. Cholesteryl ester-rich VLDL from cholesterol-fed rabbits gave 50% inhibition at 5 nM. Low density lipoproteins (LDL) inhibited by 10% at 5 nM and 40% at 47 nM. Acetyl LDL at 130 nM had no effect. We conclude that the massive triglyceride accumulation produced in macrophages by hypertriglyceridemic VLDL is a direct consequence of uptake via specific receptors that also recognize cholesteryl ester-rich VLDL and LDL but are distinct from the acetyl LDL receptor. Uptake of these triglyceride-rich lipoproteins by monocyte-macrophages in vivo may play a significant role in the pathophysiology of atherosclerosis.

Adult↗

Lipoprotein metabolism during acute inhibition of hepatic triglyceride lipase in the cynomolgus monkey.

The role of the enzyme hepatic triglyceride lipase was investigated in a primate model, the cynomolgus monkey. Antisera produced against human postheparin hepatic lipase fully inhibited cynomolgus monkey posttheparin plasma hepatic triglyceride lipase activity. Lipoprotein lipase activity was not inhibited by this antisera. Hepatic triglyceride lipase activity in liver biopsies was decreased by 65-90% after intravenous infusion of this antisera into the cynomolgus monkey. After a 3-h infusion of the antisera, analytic ultracentrifugation revealed an increase in mass of very low density lipoproteins (S(f) 20-400). Very low density lipoprotein triglyceride isolated by isopycnic ultracentrifugation increased by 60-300%. Analytic ultracentrifugation revealed an increase in mass of lipoproteins with flotation greater than S(f) 9 (n = 4). The total mass of intermediate density lipoproteins (S(f) 12-20) approximately doubled during the 3 h of in vivo enzyme inhibition. While more rapidly floating low density lipoproteins (S(f) 9-12) increased, the total mass of low density lipoproteins decreased after infusion of the antibodies. The changes in high density lipoproteins did not differ from those in control experiments. In order to determine whether the increases of plasma concentrations of very low density lipoproteins were due to an increase in the rate of synthesis or a decrease in the rate of clearance of these particles, the metabolism of radiolabeled homologous very low density lipoproteins was studied during intravenous infusion of immunoglobulin G prepared from the antisera against hepatic triglyceride lipase (n = 3) or preimmune goat sera (n = 3). Studies performed in the same animals during saline infusion were used as controls for each immunoglobulin infusion. There was a twofold increase in the apparent half-life of the very low density lipoprotein apolipoprotein-B tracer in animals receiving the antibody, consistent with a decreased catabolism of very low density lipoproteins. Concomitantly, the rise in low density lipoprotein apoprotein-B specific activity was markedly delayed. None of these changes were observed during infusion of preimmune immunoglobulin G.Hepatic triglyceride lipase participates with lipoprotein lipase in the hydrolysis of the lipid in very low density lipoproteins, intermediate density lipoproteins, and the larger low density lipoproteins (S(f) 9-12). Thus, hepatic triglyceride lipase appears to function in a parallel role with lipoprotein lipase in the conversion of very low density and intermediate density lipoproteins to low density lipoproteins (S(f) 0-9).

Animals↗

Structured triglyceride emulsions in parenteral nutrition.

Over the past 3 decades, various concepts for IV fat emulsions (IVFE) have been developed. A randomized, structured-lipid emulsion based on an old technology has recently become available. This structured-lipid emulsion is produced by mixing medium-chain triglycerides and long-chain triglycerides, then allowing hydrolysis to form free fatty acids, followed by random transesterification of the fatty acids into mixed triglyceride molecules. Studies in animals have shown an improvement in nitrogen balance with the use of these lipid emulsions. Only 8 human clinical studies with these products have been performed. The results of these human clinical studies have been less promising than the animal studies; however, an improvement in nitrogen balance and lipid metabolism exceeds results associated with infusion of long-chain triglycerides (LCT) or a physical mixture of long-chain triglycerides and medium-chain triglycerides (LCT-MCT). Structured-lipid emulsion seems to induce less elevation in serum liver function values compared with standard IVFEs. In addition, structured-lipid emulsions have no detrimental effect on the reticuloendothelial system. Further studies are necessary in order to recommend the use of structured-lipid emulsions. The clinical community hopes that chemically defined structured triglycerides will make it possible to determine the distribution of specific fatty acids on a specific position on the glycerol core and therefore obtain specific activity for a specific clinical situation.

Animals↗

Effect of high percentage medium-chain triglyceride diet on mucosal adaptation following massive bowel resection in rats.

Patients undergoing massive small bowel resection for a variety of conditions develop severe nutrient malabsorption which gradually improves through mucosal hyperplasia in the remaining small intestine. Following massive small bowel resection, patients are generally fed elemental diets, often containing high concentrations of medium-chain triglycerides. We evaluated the effect of high percentage medium-chain triglyceride feeding on mucosal adaptation following massive small bowel resection in rats. Twenty 150-g Sprague-Dawley rats were subjected to 60% jejunoileal resection. Another 20 animals received sham operations. One-half of each group were fed a diet containing 83% of the fat as medium-chain triglycerides, the remainder were fed a diet containing 40% medium-chain triglycerides. Animals were pair-fed for 2 wk and subsequently killed. The remaining bowel was removed and unidirectional glucose and leucine uptake were measured using isolated sacs. Mucosal wet weight, protein, and sucrase content were determined. Animals fed medium-chain triglycerides demonstrated decreased mucosal weight in the proximal bowel, decreased mucosal sucrase activity in the proximal bowel, and decreased mucosal leucine uptake in the distal bowel. While medium-chain triglycerides offer an advantage to patients with short bowel syndrome because they are easily absorbed, they may not stimulate the same degree of mucosal adaptation following resection as long-chain triglyceride feedings.

Adaptation, Physiological↗

Structured versus long-chain triglycerides: a safety, tolerance, and efficacy randomized study in colorectal surgical patients.

BACKGROUND: After trauma or surgery, researchers have suggested that medium-chain triglycerides have metabolic advantages, although they are toxic in large doses. To try to reduce this potential toxicity, structured lipids, which provide a higher oxidation rate, faster clearance from blood, improved nitrogen balance, and less accumulation in the reticuloendothelial system, could be used. Therefore, we evaluated, through a blind randomized study, the safety, tolerance, and efficacy of structured triglycerides, compared with long-chain triglycerides (LCT), in patients undergoing colorectal surgery. METHODS: Nineteen patients were randomized to receive long-chain or structured triglycerides as a lipid source. They received the same amount of calories (27.2/kg/d), glucose (4 g/kg/d), protein (0.2 g/kg/d), and lipids (11.2 kcal/kg/d). Patients were evaluated during and after the treatment for clinical and laboratory variables, daily and cumulative nitrogen balance, urinary excretion of 3-methyl-histidine, and urinary 3-methylhistidine/creatinine ratio. RESULTS: No adverse effect that required the interruption of the treatment was observed. Triglyceride levels and clinical and laboratory variables were similar in the two groups. A predominantly positive nitrogen balance was observed from day 2 until day 5 in the LCT group and from day 1 until day 4 in the structured triglycerides group. The cumulative nitrogen balance (in grams) for days 1 to 3 was 9.7+/-5.2 in the experimental group and 4.4+/-11.8 in the control group (p = .2). For days 1 to 5 it was 10.7+/-10.5 and 6.5+/-17.9 (p = .05), respectively. The excretion of 3-methylhistidine was higher in the control group but decreased in the following days and was similar to the experimental group on day 5. CONCLUSIONS: This study represents the first report in which structured triglycerides are administered in postoperative patients to evaluate safety, tolerance, and efficacy. It suggests that Fe73403 is safe, well tolerated, and efficacious in terms of nitrogen balance when compared with LCT emulsion.

Colitis, Ulcerative↗

Association of SNP3 polymorphism in the apolipoprotein A-V gene with plasma triglyceride level in Tunisian type 2 diabetes.

BACKGROUND: Apolipoprotein A-V (Apo A-V) gene has recently been identified as a new apolipoprotein involved in triglyceride metabolism. A single nucleotide polymorphism (SNP3) located in the gene promoter (-1131) was associated with triglyceride variation in healthy subjects. In type 2 diabetes the triglyceride level increased compared to healthy subjects. Hypertriglyceridemia is a risk factor for coronary artery disease. We aimed to examine the interaction between SNP3 and lipid profile and coronary artery disease (CAD) in Tunisian type 2 diabetic patients. RESULTS: The genotype frequencies of T/T, T/C and C/C were 0.74, 0.23 and 0.03 respectively in non diabetic subjects, 0.71, 0.25 and 0.04 respectively in type 2 diabetic patients. Triglyceride level was higher in heterozygous genotype (-1131 T/C) of apo A-V (p = 0.024). Heterozygous genotype is more frequent in high triglyceride group (40.9%) than in low triglyceride group (18.8%); p = 0.011. Despite the relation between CAD and hypertriglyceridemia the SNP 3 was not associated with CAD. CONCLUSION: In type 2 diabetic patients SNP3 is associated with triglyceride level, however there was no association between SNP3 and coronary artery disease.

Aged↗

Triglyceride-rich lipoproteins are associated with hypertension in preeclampsia.

Disorders of the lipoprotein metabolism are a major cause of endothelial dysfunction that may result in hypertension and proteinuria, clinical hallmarks of preeclampsia (PE). Lipoproteins and low-density lipoprotein (LDL) subfractions were investigated in 15 women with severe PE and compared with 23 women with a normal course of pregnancy. Compared with normal pregnancy, in PE apolipoprotein (apo)B in very low-density lipoprotein was increased by 76% (P = 0.008), and the triglyceride content of intermediate dense lipoproteins (IDL) was increased by 51% (P < 0.001); cholesterol and apoB in LDL were decreased by 26% (P = 0.005) and 23% (P = 0.016), respectively. Although not significant, the LDL profile was dominated by the most buoyant LDL-1. ApoB in the most dense LDL (dLDL), namely LDL-5 and LDL-6, was significantly decreased by 49% (P < 0.001) and 55% (P < 0.001), respectively. Diastolic blood pressure was positively correlated with the triglyceride content of IDL (r = 6.31; P < 0.001 and r = 0.352; P = 0.033 by partial correlation controlling for the presence or absence of PE) and negatively correlated with the concentration of apoB in dLDL (r = -0.500; P = 0.002). In addition, IDL triglycerides correlated negatively with infant birth weight percentile (r = -0.373; P = 0.027) and positively with proteinuria (r = 0.430; P = 0.014). Low birth weight was associated with high IDL triglycerides and low rather than high concentrations of dLDL. Triglyceride-rich remnants are known to cause endothelial dysfunction. Because the triglyceride content of IDL was positively correlated with elevated blood pressure and proteinuria, triglyceride-rich remnant lipoproteins might contribute to the pathophysiology of PE.

Adult↗

Plasma lipoproteins, lipolytic enzymes, and very low density lipoprotein triglyceride turnover in Cushing's syndrome.

Plasma lipoproteins, triglyceride turnover, and lipolytic enzymes were measured in 11 women with Cushing's syndrome. The studies were repeated 3 and 12 months after surgical treatment. Eleven healthy women of similar age and relative body weight served as controls. Before treatment the mean values of total cholesterol and triglyceride, of very low-density lipoprotein (VLDL) triglyceride and cholesterol, low density lipoprotein triglyceride and cholesterol, and high density lipoprotein cholesterol were all significantly increased in the patients with Cushing's syndrome. The triglyceride levels were only moderately elevated, the highest values being found in patients with adrenocortical adenoma. The production rate of VLDL triglyceride was higher in patients (13.2 mg/h . kg) than in controls (9.5 mg/h . kg, P less than 0.05), whereas the fractional catabolic rate of VLDL triglyceride was not significantly different. Consistent with the latter finding, the lipoprotein lipase activities of adipose tissue, skeletal muscle, and postheparin plasma were similar in patients and controls. The postheparin plasma hepatic lipase activity of the patients was at the lower end of the normal range. All lipid and lipoprotein abnormalities were completely abolished after successful surgery. It is concluded that endogenous hypercortisolism stimulates the hepatic production of VLDL particles. The effect is probably based on multifactorial mechanisms. In the presence of unchanged removal this leads to elevated levels of VLDL, low density lipoprotein, and high density lipoprotein.

Adult↗

Assimilation and mobilization of triglycerides in subcutaneous abdominal and femoral adipose tissue in vivo in men: effects of androgens.

Studies on regional differences of adipose tissue metabolism have mainly been performed in vitro. To allow measurements of lipid uptake in vivo in man, radioactive label from [9,10-3H]oleic acid in 80 g orally administered milk fat was measured after 4 h in abdominal and femoral sc adipose tissues in 28 middle-aged, abdominally obese men. Radioactivity was measured in adipose tissue triglycerides extracted from needle biopsies. Lipoprotein lipase (LPL) activity was also measured. Uptake of label in triglycerides and LPL activity were higher (20% and 15%, respectively; P < 0.05) in the abdominal compared to the femoral adipose tissue region. The men were then randomly assigned to three groups, receiving testosterone (T), dihydrotestosterone, or placebo, for 9 months. After 2 months of treatment, the procedure of administration of label was repeated, this time using [U-14C]oleic acid as a marker. Measurements of radioactive label was then performed after 4 h and monthly up to 7 months. Supplementation with T was followed by an inhibited uptake of label in triglycerides (34%; P < 0.05), lower LPL activity (48%; P < 0.05), and a shorter t1/2 (30%; P < 0.05) in the abdominal adipose tissue region compared with the dihydrotestosterone and placebo groups. No significant effect of T on triglyceride uptake, LPL activity, or t1/2 was found in sc femoral adipose tissue. It was concluded that the turnover rate of depot triglycerides is more rapid in abdominal compared to femoral sc adipose tissue in men. Furthermore, T supplementation inhibits triglyceride uptake and LPL activity and causes a more rapid turnover of triglycerides only in the sc abdominal adipose tissue region. These results demonstrate the marked effects of T on adipose tissue metabolism in vivo and suggest that T is an important regulator of the proportion of depot fat mass in central and peripheral adipose tissue in men.

Abdomen↗

Hypopituitarsim is associated with triglyceride enrichment of very low-density lipoprotein.

The dyslipidemia associated with hypopituitarism may contribute to increased vascular mortality. The atherogenic potential of lipoproteins is determined not only by concentration but also by their composition. We therefore studied very low-density lipoprotein composition and apolipoprotein B kinetics in 16 hypopituitary subjects and 16 controls. Hypopituitarism was associated with reduced high-density lipoprotein cholesterol (0.98[0.82-1.18] vs. 1.35[1.15-1.41] mmol/liter, P < 0.001) and increased triglyceride concentrations (1.64[1.09-2.77] vs. 1.12[0.66-1.67] mmol/liter, P = 0.01). Total (P = 0.76) and low-density lipoprotein cholesterol (P = 0.56) concentrations were similar. Very low-density lipoprotein- triglyceride was significantly increased (1.48[1.02-2.55] vs. 0.9[0.31-2.30] mmol/liter, P = 0.004), but very low-density lipoprotein cholesterol levels were similar (P = 0.93). The molar ratios of very low-density lipoprotein-triglyceride:apolipoprotein B (6193[4283-9566] vs. 3599[3188-6854], P = 0.005) and very low-density lipoprotein-triglyceride:cholesterol (2.8[1.98-3.78] vs. 1.6[1.44-2.80], P < 0.003) were significantly increased; very low-density lipoprotein-cholesterol:apolipoprotein B molar ratios (P = 0.93) were similar. Very low-density lipoprotein apolipoprotein B fractional synthetic rate (a measure of apolipoprotein B catabolism, P = 0.42) and pool size (P = 0.63) were similar. The very low-density lipoprotein apolipoprotein B absolute synthetic rate (a measure of apolipoprotein B synthesis) tended to be higher in hypopituitarism (17.7[2.91-19.50] vs. 26.6[19.64-28.05] mg/kg per day, P = 0.24) but failed to reach statistical significance. The absolute synthetic rate, and hence very low-density lipoprotein production, correlated with very low-density lipoprotein triglyceride:apolipoprotein B ratio (P = 0.02, Rs = 0.63), suggesting that triglyceride enrichment of very low-density lipoprotein is important in the mechanism underlying very low-density lipoprotein overproduction in hypopituitarism. Because triglyceride-enriched lipoproteins are proatherogenic, this may contribute to the vascular mortality observed in hypopituitarism. The reasons for these observations are unknown; GH deficiency or routine endocrine replacement may be important.

Adenoma↗

Association between small dense low-density lipoprotein and postprandial accumulation of triglyceride-rich remnant-like particles in normotriglyceridemic patients with myocardial infarction.

BACKGROUND: Although the small dense low-density lipoprotein (sd-LDL) is associated with hypertriglyceridemia, more than 60% of myocardial infarction (MI) patients are normotriglyceridemic in the fasting state. This study was aimed to investigate the relationship between the low-density lipoprotein (LDL) phenotype and postprandial hyperlipemia (PPL) in MI patients. METHODS AND RESULTS: Oral fat tolerance tests were performed in 71 patients with acute MI and fasting triglyceride concentrations below 200 mg/dl. Postprandial changes in the LDL particle diameter (LDL-PD) and lipids over a 6-h period after a meal were compared among 4 groups of patients classified according to fasting triglyceride levels (A, B as <150, and C, D as > or =150) and postprandial triglyceride levels (A, C as <230 and B, D as > or =230). Although fasting concentrations of triglyceride and remnant-like particle (RLP)-triglyceride were significantly higher in group C than in group B, the areas under the curves of the RLPs were significantly higher in group B. The triglyceride-to-cholesterol ratio in the RLPs was significantly higher in the PPL group than in the nonPPL group postprandially. The prevalence of sd-LDL (LDL-PD < or =25.5 nm) was significantly higher in group D but similar between groups B and C (23%, 42%, 50% and 83% in groups A, B, C and D, respectively). CONCLUSION: These results suggest that postprandial accumulation of triglyceride-rich lipoproteins is strongly associated with sd-LDL in MI patients without hypertriglyceridemia.

Aged↗

Tumor necrosis factor-increased hepatic very-low-density lipoprotein production and increased serum triglyceride levels in diabetic rats.

Previous studies demonstrated that administration of tumor necrosis factor (TNF) to diabetic rats rapidly increases serum triglyceride levels and stimulates hepatic lipogenesis without affecting the activity of adipose tissue lipoprotein lipase or serum insulin levels. The purpose of this study was to determine the mechanism by which TNF increases serum triglyceride levels and stimulates hepatic fatty acid synthesis in diabetic animals. The maximal increase (approximately 2-fold) in serum triglyceride levels in diabetic rats is seen with a dose of 10 micrograms TNF/200 g body wt, and the half-maximal effect is observed with 5 micrograms TNF/200 g body wt. The clearance of labeled triglyceride-rich lipoproteins from the circulation is not affected by TNF administration (triglyceride t 1/2; diabetic vs. TNF-administered diabetic, 3.5 +/- 0.7 vs. 4.0 +/- 0.6 min, respectively; NS). The production of triglyceride, measured by the Triton WR-1339 technique, is increased twofold in diabetic animals after TNF administration. These results indicate that the rapid increase in serum triglyceride levels after TNF treatment is accounted for by increased hepatic lipoprotein secretion. TNF administration did not alter either the amount or activation state of hepatic acetyl-CoA carboxylase, a key regulatory enzyme in fatty acid synthesis. There was also no change in the hepatic levels of fatty acyl-CoA, an allosteric inhibitor of acetyl-CoA carboxylase. However, there was a 71% increase in hepatic citrate concentrations. Citrate is an allosteric activator of acetyl-CoA carboxylase, and changes in hepatic citrate concentrations have been shown to mediate changes in the rates of fatty acid synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗

CD36 in myocytes channels fatty acids to a lipase-accessible triglyceride pool that is related to cell lipid and insulin responsiveness.

High levels of intramyocellular triglycerides are linked to insulin resistance and reflect conditions in which fatty acid uptake exceeds the myocyte oxidative capacity. CD36 facilitates fatty acid uptake by myocytes, and its level is increased in diabetic muscle. We examined whether high CD36 levels would increase lipid content and susceptibility of myocytes to fatty acid-induced insulin resistance. C2C12 myoblasts with stable fivefold overexpression of CD36 (+CD36) were generated and differentiated into myotubes. CD36 expression increased palmitate uptake, oxidation, and lipid incorporation but had no effect on cell triglyceride content. Importantly, glycerol release increased fourfold, indicating enhanced triglyceride turnover and suggesting that CD36 promotes futile cycling of fatty acids into triglyceride. When +CD36 myotubes were incubated with excess palmitate, CD36 enhancement of glycerol release was blunted, triglyceride content increased above wild-type cells, and insulin resistance of glucose metabolism was observed. In contrast to palmitate, oleate-treated +CD36 cells exhibited enhanced glycerol release and no alteration in triglyceride content or insulin responsiveness. Furthermore, increased expression of hormone-sensitive lipase was measured with CD36 expression and with oleate treatment. In conclusion, high futile cycling of fatty acids is important for maintaining low triglyceride content and insulin responsiveness of myocytes. The findings provide a new perspective related to the etiology of lipid accumulation and insulin resistance in myocytes.

Animals↗

Altering triglyceride concentrations changes insulin-glucose relationships in hypertriglyceridemic patients. Double-blind study with gemfibrozil with implications for atherosclerosis.

OBJECTIVE: To determine whether reducing triglyceride concentrations in humans reduces serum insulin levels and consider the implications of this for the insulin resistance of hypertriglyceridemia. RESEARCH DESIGN AND METHODS: Insulin and glucose levels were determined during an oral glucose tolerance test (OGTT) in 14 volunteers who had a range of basal triglyceride levels. A double-blind crossover design was used to study active and placebo gemfibrozil and relate triglyceride changes to insulin and glucose levels. Diet and weight were kept constant. RESULTS: Glucose concentrations during OGTT were the same in both treatment periods. Insulin concentrations were reduced in proportion to reductions in triglyceride. CONCLUSIONS: Triglyceride reduction in hypertriglyceridemic patients is associated with a decrease in serum insulin. This does not appear to be a direct effect of gemfibrozil, because it does not occur without a sufficient fall in triglyceride levels. Because glucose concentration remains the same despite the reduced insulin, the triglyceride reduction may result in greater sensitivity to insulin. Treatment of hypertriglyceridemia may break a vicious and potentially atherogenic cycle of hypertriglyceridemia and hyperinsulinemia.

Arteriosclerosis↗

Preoperative triglycerides predict post-coronary artery bypass graft survival in diabetic patients: a sex analysis.

OBJECTIVE: Hypertriglyceridemia is commonly observed in association with diabetes. Despite cross-sectional studies and isolated longitudinal analyses in patients without coronary artery disease, the suggestion that triglyceride levels are relevant to subsequent cardiovascular events in the setting of diabetes remains controversial. This study evaluates the predictive value of serum triglyceride levels on mortality in post-coronary artery bypass graft (CABG) diabetic patients with subsequent analysis by sex. RESEARCH DESIGN AND METHODS: This longitudinal observational study involving a large metropolitan hospital consists of 1,172 diabetic post-CABG patients (792 men and 380 women) with lipid data collected between the years 1982 and 1992. Cox proportional hazards regression models were used to estimate the risk of mortality and cardiac events associated with triglyceride levels in the highest quartile (> 2.90 mmol/l for men and > 3.12 mmol/l for women). RESULTS: Elevated preoperative serum triglyceride values in post-CABG subjects with diabetes were correlated with increased overall mortality (hazard ratio [HR] 1.26, 95% CI 1.00-1.59). The greatest influence of triglyceride levels was observed on overall (1.89, 1.30-2.73) and event-free survival (1.49, 1.06-2.08) in women. High triglyceride values were also modestly related to risk of cardiac events in diabetic men (1.28, 0.99-1.66). CONCLUSIONS: These data suggest that increased preoperative triglyceride levels predict increased late mortality and cardiac event risk in diabetic post-CABG patients, more strongly in women than in men.

Cholesterol↗

Remnant-like particle cholesterol, triglycerides, and insulin resistance in nonobese Japanese type 2 diabetic patients.

OBJECTIVE: The aim of the study was to investigate the relationships between remnant-like particle (RLP) cholesterol, triglycerides, and insulin resistance in nonobese Japanese type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A total of 86 nonobese Japanese type 2 diabetic patients (72 men and 14 women, aged 40-83 years, BMI 20.1-26.6 kg/m2) were studied. BMI, HbA1c levels, and fasting concentrations of plasma glucose, serum lipids (RLP cholesterol, total cholesterol, HDL cholesterol, and triglycerides), and serum insulin were measured. Insulin resistance was estimated by the homeostasis model assessment (HOMA-IR). The subjects were divided into two groups according to the value of HOMA-IR. Values >2.5 were indicative of the insulin-resistant state, and values <2.5 were indicative of the insulin-sensitive state. RESULTS: The insulin-resistant group had significantly higher RLP cholesterol and triglyceride levels and lower HDL cholesterol levels compared with the insulin-sensitive group. Univariate regression analysis showed that insulin resistance was positively correlated with BMI (r = 0.254, P = 0.019), HbA1c levels (r = 0.278, P = 0.011), RLP cholesterol levels (r = 0.315, P = 0.004), and triglyceride levels (r = 0.332, P = 0.002) and was negatively correlated with HDL cholesterol levels (r = -0.301, P = 0.006) in our diabetic patients. Multiple regression analysis showed that insulin resistance was independently associated with serum triglyceride levels, which explained 13.5% of the variability of insulin resistance in our nonobese Japanese type 2 diabetic patients. CONCLUSIONS: These results indicate that 1) nonobese Japanese type 2 diabetic patients with insulin resistance are characterized by high RLP cholesterol and triglyceride levels, and low HDL cholesterol levels; and 2) the level of serum triglycerides is an independent predictor of insulin resistance in these patients.

Apolipoproteins↗

Stable isotope methods for the in vivo measurement of lipogenesis and triglyceride metabolism.

Synthesis of fatty acids (via de novo lipogenesis) and triglycerides are important factors in fat accumulation and the efficiency of animal production. Recently, new stable isotope methods using heavy water (2H2O) have made possible the safe, and relatively easy, measurement of both of these processes in vivo in animals and humans over prolonged periods. These methods also provide information on the relative contribution of glycolysis and glyceroneogenesis to triglyceride synthesis under different physiological settings. The data suggest that numerous dietary factors, including nutrient composition and caloric content, may affect de novo lipogenesis. Significant differences in de novo lipogenesis have also been seen across species and in different tissues. The rates of triglyceride synthesis have been shown to be affected by diet and to differ significantly between different adipose depots, with metabolically active depots (e.g., visceral fat) having much more rapid triglyceride turnover than subcutaneous depots. Dietary fat and the peroxisome proliferator-activated-gamma agonist rosiglitazone have both been shown to influence triglyceride synthesis rates and to increase glyceroneogenesis. A significant portion of triglyceride synthesis is not related to triglyceride accumulation but rather is secondary to active lipolysis and reesterification. The application of these new techniques to animals other than rodents will undoubtedly enhance our understanding of adipose tissue biology and could lead to new methods for improving animal production.

Animals↗