Carbohydrate-induced Hypertriglyceridemia Research Articles

Sugar industry sponsorship of germ-free rodent studies linking sucrose to hyperlipidemia and cancer: An historical analysis of internal documents.

In 1965, the Sugar Research Foundation (SRF) secretly funded a review in the New England Journal of Medicine that discounted evidence linking sucrose consumption to blood lipid levels and hence coronary heart disease (CHD). SRF subsequently funded animal research to evaluate sucrose’s CHD risks. The objective of this study was to examine the planning, funding, and internal evaluation of an SRF-funded research project titled “Project 259: Dietary Carbohydrate and Blood Lipids in Germ-Free Rats,” led by Dr. W.F.R. Pover at the University of Birmingham, Birmingham, United Kingdom, between 1967 and 1971. A narrative case study method was used to assess SRF Project 259 from 1967 to 1971 based on sugar industry internal documents. Project 259 found a statistically significant decrease in serum triglycerides in germ-free rats fed a high sugar diet compared to conventional rats fed a basic PRM diet (a pelleted diet containing cereal meals, soybean meals, whitefish meal, and dried yeast, fortified with a balanced vitamin supplement and trace element mixture). The results suggested to SRF that gut microbiota have a causal role in carbohydrate-induced hypertriglyceridemia. A study comparing conventional rats fed a high-sugar diet to those fed a high-starch diet suggested that sucrose consumption might be associated with elevated levels of beta-glucuronidase, an enzyme previously associated with bladder cancer in humans. SRF terminated Project 259 without publishing the results. The sugar industry did not disclose evidence of harm from animal studies that would have (1) strengthened the case that the CHD risk of sucrose is greater than starch and (2) caused sucrose to be scrutinized as a potential carcinogen. The influence of the gut microbiota in the differential effects of sucrose and starch on blood lipids, as well as the influence of carbohydrate quality on beta-glucuronidase and cancer activity, deserve further scrutiny.

The Scap/SREBP Pathway Is Essential for Developing Diabetic Fatty Liver and Carbohydrate-Induced Hypertriglyceridemia in Animals

Insulin resistance leads to hypertriglyceridemia and hepatic steatosis and is associated with increased SREBP-1c, a transcription factor that activates fatty acid synthesis. Here, we show that steatosis in insulin-resistant ob/ob mice was abolished by deletion of Scap, an escort protein necessary for generating nuclear isoforms of all three SREBPs. Scap deletion reduced lipid synthesis and prevented fatty livers despite persistent obesity, hyperinsulinemia, and hyperglycemia. Scap deficiency also prevented steatosis in mice fed high-fat diets. Steatosis was also prevented when siRNAs were used to silence Scap in livers of sucrose-fed hamsters, a model of diet-induced steatosis and hypertriglyceridemia. This silencing reduced all three nuclear SREBPs, decreasing lipid biosynthesis and abolishing sucrose-induced hypertriglyceridemia. These results demonstrate that SREBP activation is essential fordevelopment of diabetic hepatic steatosis and carbohydrate-induced hypertriglyceridemia, but not insulin resistance. Inhibition of SREBP activation has therapeutic potential for treatment of hypertriglyceridemia and fatty liver disease.

Carbohydrate-induced hypertriglyceridemia: modifying factors and implications for cardiovascular risk.

High-carbohydrate/low-fat, isocaloric diets have repeatedly been shown to increase plasma triglyceride concentrations. The present review addresses recent developments relevant to several important unresolved issues. These include the type of dietary carbohydrate that is most likely to induce hypertriglyceridemia, predictors of individual susceptibility, modifiable physiologic factors that may mitigate the plasma triglyceride response, underlying metabolic mechanisms that are responsible for increased plasma triglycerides, and implications of altered serum lipid profiles for atherogenic risk. Although some progress has been made in this field, the central public health issue - the net effect on cardiovascular risk - remains unresolved.

Effect of Dietary Carbohydrate on Triglyceride Metabolism in Humans

When the content of dietary carbohydrate is elevated above the level typically consumed (>55% of energy), blood concentrations of triglycerides rise. This phenomenon, known as carbohydrate-induced hypertriglyceridemia, is paradoxical because the increase in dietary carbohydrate usually comes at the expense of dietary fat. Thus, when the content of the carbohydrate in the diet is increased, fat in the diet is reduced, but the content of fat (triglycerides) in the blood rises. The present article will review studies of carbohydrate-induced hypertriglyceridemia, highlighting data obtained in fasted subjects habituated to high carbohydrate diets, data obtained from subjects in the fed state, and metabolic studies investigating fatty acid and triglyceride synthesis in subjects consuming diets of different carbohydrate content. The available data have been recently expanded by new methodologies, such as the use of stable isotopes, to investigate the metabolism of sugars in humans in vivo. Given the significant increase in body weight observed in the American population over the past decade and the changing availability of carbohydrate in the food supply, future studies of carbohydrate-induced hypertriglyceridemia promise to provide important information of how the macronutrient composition of the diet can influence health.

Dietary fiber prevents carbohydrate-induced hypertriglyceridemia.

Plant foods rich in carbohydrate and dietary fiber have many health benefits. One concern often expressed about higher carbohydrate, lower fat diets is that they may increase fasting serum triglycerides. Recently the importance of hypertriglyceridemia as an independent risk factor for coronary heart disease has been reaffirmed. For 40 years, clinicians have noted "carbohydrate-induced hypertriglyceridemia" when persons were fed high-carbohydrate, low-fiber diets. The role of fiber in protecting from carbohydrate-induced hypertriglyceridemia has not been discussed by many reviewers. Systematic review of the literature documents that high fiber intakes clearly protect from carbohydrate-induced hypertriglyceridemia. These are reviewed. Thus, recent and earlier research indicates that use of a higher carbohydrate, higher fiber diet compared with a lower carbohydrate, higher fat diet is associated with a small reduction in fasting serum triglyceride values.

Carbohydrate-Induced Hypertriglyceridemia: An Insight into the Link between Plasma Insulin and Triglyceride Concentrations

Carbohydrate-Induced Hypertriglyceridemia: An Insight into the Link between Plasma Insulin and Triglyceride Concentrations

Effects of dietary fat restriction on particle size of plasma lipoproteins in postmenopausal women

Hypertriglyceridemia is an independent risk factor for coronary artery disease (CAD) and is also commonly associated with other coronary risk factors, ie, small, dense low-density lipoprotein (LDL) particles and low plasma levels of high-density lipoprotein cholesterol (HDL-C). Dietary fat restriction is recommended for the prevention of nutrition-related cancers. Low-fat, high-carbohydrate intake can increase plasma triglyceride (TG) and decrease HDL-C. In general, plasma TG levels are inversely related to the particle size of LDL. We investigated the effects of dietary fat restriction on the concentration and particle size of plasma lipoproteins in 14 healthy postmenopausal women (aged 61 ± 11 years). During a 4-month period of eucaloric controlled feeding, dietary fat was reduced stepwise from a habitual intake of 33% ± 8% to 23% and then to 14% of daily energy. Changes in the plasma lipid level and particle size of very—low-density lipoprotein (VLDL), LDL, and HDL were determined at the end of each dietary phase. Increasing carbohydrate intake without weight loss was associated with an increase in plasma TG (1.86 ± 0.30 v 2.47 ± 0.37 mmol/L) and decreases in total cholesterol (5.82 ± 0.25 v 5.40 ± 0.21 mmol/L), LDL-C (3.07 ± 0.18 v 2.61 ± 0.21 mmol/L), HDL-C (1.42 ± 0.1 v 1.24 ± 0.1 mmol/L), and apolipoprotein (apo) A1 (5.14 ± 0.25 v 4.61 ± 0.36 mmol/L), whereas plasma apo B did not change. The particle size of VLDL increased (42.7 ± 1.4 v 47.0 ± 0.9 nm). However, there was no change in either LDL (25.1 ± 0.2 v 25.3 ± 0.2 nm) or HDL particle size. Although at each level of dietary fat intake LDL particle size correlated inversely with plasma TG and apo B, there was no relationship between the increase in plasma TG and LDL particle size. These results show that hypertriglyceridemia caused by a eucaloric high-carbohydrate intake is not associated with a decrease in LDL particle size. Therefore, carbohydrate-induced hypertriglyceridemia may not have the same atherogenic potential as genetic hypertriglyceridemias.

Pathogenesis of carbohydrate-induced hypertriglyceridemia using HepG2 cells as a model system.

This study compares the effects of glucose and fatty acid on hepatic lipid synthesis and apolipoprotein (apo) B secretion. To do so, varying concentrations of either glucose or oleic acid were added to the medium in which HepG2 cells were being incubated. Intracellular triacylglycerol and cholesteryl ester synthesis and secretion were measured by addition of radioisotopic tracers and by determination of mass, whereas apo B concentration in the medium was measured by a specific enzyme-linked immunosorbent assay. The data indicate that increasing concentrations of glucose in the medium resulted in increased synthesis of triacylglycerol within the cell and increased secretion of triacylglycerol into the medium. Apo B secretion into the medium, however, did not change, and intracellular synthesis and secretion of cholesteryl ester did not change as well. By contrast, addition of oleic acid to the medium resulted in increased synthesis and secretion of both cholesteryl ester and triacylglycerol, and this was associated with increased secretion of apo B into the medium. Thus, a carbohydrate load resulted in secretion of normal numbers of triacylglycerol-enriched apo B particles by this hepatocyte cell line, whereas a fatty acid load led to the secretion of increased numbers of apo B particles, which were essentially normal in composition.

Will a high-carbohydrate, low-fat diet lower plasma lipids and lipoproteins without producing hypertriglyceridemia?

A sudden increase in dietary carbohydrate invariably increases the plasma levels of very low density lipoprotein (VLDL) and triglyceride. The present studies were designed to test the hypothesis that dietary carbohydrate-induced hypertriglyceridemia need not occur. In the first study we fed gradually increasing amounts of carbohydrate and gradually decreasing amounts of fat to eight subjects. The usual American diet (40% fat, 45% carbohydrate, and 15% protein) was followed in sequence by four diets in a phased regimen, the carbohydrate increasing by 5% of total calories and the fat content decreasing by 5% for each dietary period. In the last dietary period (phase 4), 20% of the energy was in the form of fat and 65% in the form of carbohydrates; the cholesterol content was 100 mg/day. Throughout the study, plasma triglyceride and VLDL triglyceride levels did not change significantly. The plasma total and low density lipoprotein (LDL) cholesterol levels were greatly reduced, by 15% and 22%, respectively (p = 0.004). Plasma high density lipoprotein (HDL) cholesterol levels decreased concomitantly. In the second study, after a washout period six of the subjects were initially fed the phase 4 high-carbohydrate diet for a 10-day period. The plasma triglyceride concentration increased over baseline levels by 47%, and VLDL triglyceride levels increased by 73%. We conclude that although a sudden increase in dietary carbohydrate increases the plasma triglyceride level, patients gradually introduced to a high-carbohydrate, low-fat diet may achieve a significant reduction of plasma total and LDL cholesterol without developing carbohydrate-induced hypertriglyceridemia.

Persistence of Hypertriglyceridemic Effect of Low-Fat High-Carbohydrate Diets in NIDDM Patients

Although low-fat high-carbohydrate diets are recommended for patients with non-insulin-dependent diabetes mellitus (NIDDM) in an effort to reduce the risk of coronary artery disease (CAD), the results of short-term studies have shown that these diets can lead to changes in carbohydrate and lipid metabolism associated with an increased risk of CAD. This study has extended these earlier observations by determining the metabolic effects of such diets over a longer period in these patients. The comparison diets contained either 40 or 60% of the total calories as carbohydrates, with reciprocal changes in fat content from 40 to 20% consumed in random order for 6 wk in a crossover experimental design. The ratio of polyunsaturated to saturated fat and the total cholesterol intake were held constant in the two diets. Plasma glucose and insulin concentrations were significantly (P less than .001) elevated throughout the day when patients consumed the 60% carbohydrate diet, and 24-h urinary glucose excretion more than doubled (0.8 vs. 1.8 mol/24 h). Fasting plasma total and very-low-density lipoprotein (VLDL) triglyceride (TG) concentrations increased by 30% (P less than .001) after 1 wk on the 60% carbohydrate diet, and the magnitude of carbohydrate-induced hypertriglyceridemia persisted unchanged throughout the 6-wk study period. Total plasma cholesterol concentrations were similar after both diets. However, VLDL cholesterol (VLDL-chol) was significantly increased, whereas both low-density lipoprotein (LDL-) and high-density lipoprotein (HDL-) chol concentrations were significantly decreased after consumption of the 60% carbohydrate diet. Consequently, neither total-chol-to-HDL-chol nor LDL-chol-to-HDL-chol ratios changed.(ABSTRACT TRUNCATED AT 250 WORDS)

Health implications of wheat fiber

Various aspects of the benefits of dietary fiber are reviewed and discussed. The reported effects of wheat fiber intake on bowel function, diabetes, hyperlipidemia, coronary heart disease (CHD), hypertension, and colon cancer prevention are examined. The review concludes that what foods as major sources of dietary fibers offer both well-defined and potential health benefits, but much research to quantify these effects is needed. A number of hypotheses are reviewed. Limited information indicates that wheat foods and wheat fiber have important effects on color function and may reduce serum triglycerides, CHD risk or protect against carbohydrate-induced hypertriglyceridemia and colon cancer, but additional well-designed studies are necessary.(wz)

Inhibition of carbohydrate-induced hypertriglyceridemia by metformin.

The ability of metformin to prevent carbohydrate-induced hypertriglyceridemia was studied in fructose fed rats. The results indicated that plasma triglycerides were approximately 50% reduced in the drug treated rats and the reduction was associated with lowered very low density lipoprotein-triglyceride secretion rates and plasma insulin levels. Since the drug does not affect the fructose intestinal absorption, it did not prevent normal rate of weight gain. These results provide further evidence for the existence of a causal relationship between plasma TG concentration and plasma insulin concentration; metformin is able to modify both these variables likely affecting primarily the ambient insulin level.

Studies of the mechanism of fructose-induced hypertriglyceridemia in the rat

Carbohydrate-induced hypertriglyceridemia is easily produced in the rat, and fructose has been shown to be particularly potent in this regard. In this study we have compared the effects of feeding rats diets high (66% of total calories) in fructose or glucose on various aspects of carbohydrate and lipid metabolism. The results confirmed previous observations that fructose (456 ± 276 mg/dl) was more potent ( p < 0.001) in raising plasma TG concentration than was glucose (242 ± 13 mg/dl), and indicated that the difference in magnitude of hypertriglyceridemia produced by the two carbohydrates was closely related to the ability of the test diets to increase VLDL-TG secretion ( r = 0.85, p < 0.001). Both glucose and fructose feeding led to comparable degrees of hyperinsulinemia, and plasma TG concentrations increased before hyperinsulinemia evolved in fructose-fed rats. Therefore, it was concluded that fructose can act directly on the liver to increase VLDL-TG secretion, and that fructose-induced hypertriglyceridemia can occur in the absence of hyperinsulinemia. On the other hand, the rise in plasma TG concentration produced by fructose was reduced dramatically in exercise-trained rats, and this was associated with a decrease in plasma insulin concentration. Based upon these observations, we suggest that fructose feeding produces hypertriglyceridemia by directly stimulating hepatic VLDL-TG secretion, as well as by producing insulin resistance and hyperinsulinemia, and that it is the combined effect of these two separate actions which accounts for the magnitude of fructose-induced hypertriglyceridemia.

Reduction of carbohydrate-induced hypertriglyceridemia in (fa,fa) “Zucker” rats by the α-glucosidase inhibitor acarbose (BAY g 5421)

Inhibition of carbohydrate digestion by the α-glucosidase inhibitor acarbose (BAY g 5421) reduces carbohydrate-induced postprandial blood glucose increase and insulin secretion. As a consequence, in feeding experiments sucrose-induced hyperinsulinemia and hypertriglyceridemia in genetically obese (fa,fa) “Zucker” rats were dose-dependently reduced by addition of acarbose to the diet (15–80 mg/100 g feed). The body weight gain was dose-dependently reduced. In short-term experiments with a fat-free diet acarbose not only prevented serum triglyceride and free fatty acid increase in spite of lowered insulin concentrations but also decreased their concentrations below the values obtained on standard feed. Under these conditions there were no significant effects on body weight. Hypertriglyceridemia induced by i.v. injection of the lipoprotein lipase inhibitor Triton WR 1339 was reduced without affecting body weight in “Zucker” rats after 3 days on a fat-free diet supplemented with acarbose. The triglyceride increase was even lower than in animals kept on standard feed. The data demonstrate that acarbose reduces sucrose-induced hypertriglyceridemia in (fa,fa) “Zucker” rats by diminishing VLDL production and/or secretion rather than by increasing VLDL removal from the blood.

Ability of exercise to inhibit carbohydrate-induced hypertriglyceridemia in rats

The ability of spontaneous running to prevent carbohydrate-induced hypertriglyceridemia was studied in young, nonobese rats. Exercise-trained and sedentary rats were fed a diet consisting of (as percent total calories) 12% fat, 22% protein, and 66% carbohydrate. The source of the carbohydrate was varied, and experiments were carried out with sucrose and glucose as the sole dietary carbohydrate. Plasma triglyceride (TG) levels rose in response to both forms of dietary carbohydrate in both sedentary and exercise-trained rats, but the magnitude of the elevation was greatly attenuated in the exercise-trained group. Plasma insulin concentrations were also significantly lower in exercise-trained rats. Measurements of hepatic very low density lipoprotein (VLDL)-TG secretion rate and adipose tissue lipoprotein lipase (LPL) activity were made in an effort to determine how exercise-training prevented the development of carbohydrate-induced hypertriglyceridemia. The results of these studies indicated that perfused livers of exercise-trained rats secreted significantly less VLDL-TG, whereas adipose tissue LPL activity of the two groups was similar. On the basis of these results, it is postulated that the ability of exercise-training to inhibit carbohydrate-induced hypertriglyceridemia is due to an increase in insulin sensitivity resulting from chronic exercise. As a result, the postprandial insulin responses to high carbohydrate diets would be relatively reduced in exercise-trained rats, leading to decreased hepatic VLDL-TG secretion, and lower plasma triglyceride concentrations.

Inhibition of carbohydrate-induced hypertriglyceridemia by a disaccharidase inhibitor

The ability of an inhibitor of intestinal alpha-glucosiadase activity to prevent sucrose-induced hypertriglyceridemia was studied in nonobese rats. The results indicated that plasma triglyceride levels were approximately twice as high in untreated rats, and the reduction in plasma triglyceride levels of drug-treated rats was associated with lowered very low density lipoprotein-triglyceride secretion rates and plasma insulin levels. Since these changes could be produced with an amount of glucosidase inhibitor which did not prevent normal rate of weight gain, the possibility arises that this approach may be useful in the treatment of various hypertriglyceridemic states in man. Finally, the observation that the fall in plasma TG concentration was associated with a fall in plasma insulin concentration provides further evidence for the existence of a causal relationship between the two variables.

Lecithin-cholesterol acyltransferase activity in carbohydrate-induced hypertriglyceridemia in mice.

Feeding to mice of both basal as well as high sucrose diet led to increased levels of plasma triglycerides, which was associated with increased lecithin-cholesterol acyltransferase activity. Although males had significantly higher LCAT activity than females in all the dietary groups, sex difference in the plasma triglycerides was observed in high sucrose group only. Increase in plasma triglycerides in experimental groups was associated with an increase in LCAT activity.

Effect of various dietary carbohydrates on supplementary cholesterol

The effect of addition of different carbohydrates (starch, glucose, fructose) to the feed was investigated using the experimental animal. Additionally, the admixture of cholesterol and of cholesterol plus cholic acid was tested. Fructose (70% of the feed) causes a slight increase in serum triglyceride concentration and a very slight increase in triglyceride concentration in the liver. Fructose and to a lesser degree glucose cause an increase in pyruvate kinase activity in the liver. The activity of glucose-6-phosphate dehydrogenase is increased slightly following high-dosed glucose, whereas the increase is very pronounced following fuctose-rich feed. The admixture of cholesterol (with cholic acid) causes a decrease in glucose-6-phosphate dehydrogenase activity up to 70%. The activity of glutamate dehydrogenase is decreased also following cholesterol admixture. A fructose-rich diet causes a slight degree of hyperlipemia with a metabolic situation similar to a latent diabetic state. This effect is greatly intensified by the addition of cholesterol and cholic acid to the diet of the rats. Especially striking was the increase in serum-free-fatty-acid concentrations in all groups of animals. This is speculated to be a sign of insulin deficiency. The so-called "carbohydrate-induced hypertriglyceridemia" is obviously intensified within a short period by the admixture of cholesterol plus cholic acid to the experimental diet.

Diurnal Patterns of Triglycerides, Free Fatty Acids, Blood Sugar, and Insulin during Carbohydrate-Induction in Man and Their Modification by Nocturnal Suppression of Lipolysis

Previous studies have shown that carbohydrate induction of hypertriglyceridemia in normal subjects occurs at night and appears to be related to a rise of free fatty acids after diurnal feeding of high-carbohydrate formula diet. The present investigation was undertaken to observe the effect on 24-h triglyceride, free fatty acid, blood sugar, and plasma insulin profiles of inhibition of nocturnal lipolysis by glucose or nicotinic acid in normal subjects and in patients with type IV hyperlipoproteinemia. In 10 normal subjects and 10 patients with primary type IV hyperlipoproteinemia, plasma triglyceride, free fatty acid, blood sugar, and insulin levels were followed in short intervals for 24 h while a 2,400 cal, 80% carbohydrate, fat-free formula diet was given in six equal portions during the day (control experiments). This procedure was repeated in the same subjects, 10 of whom (5 normal subjects and 5 patients) received additional feedings of glucose between 2000 and 0600 h while the other 10 persons (5 normal subjects and 5 patients) were given nicotinic acid by intravenous infusion during the same time interval. Both procedures resulted in maintained lowering of free fatty acid levels over 24 h. Mitigation of carbohydrate-induced hypertriglyceridemia appeared to result from the additional glucose in normals and in patients. Nicotinic acid abolished the nocturnal rise of plasma triglyceride levels which in the control studies of normal subjects had resulted in approximate doubling of triglyceride levels in 24 h. The effectiveness of nicotinic acid in inhibiting nocturnal lipolysis and preventing carbohydrate-induction of hypertriglyceridemia might have consequences for management of endogenous hypertriglyceridemia.

Effects of insulin on lipoprotein lipase activity in the rat heart and adipose tissue.

Effects of insulin on lipoprotein lipase activity in the rat heart and adipose tissue.