High-fat Low-carbohydrate Diets Research Articles

A very-low carbohydrate content in a high-fat diet modifies the plasma metabolome and impacts systemic inflammation and experimental atherosclerosis

Ketogenic diets (KDs) are very high-fat low-carbohydrate diets that promote nutritional ketosis and are widely used for weight loss, although concerns about potential adverse cardiovascular effects remain. We investigated a very high-fat KD's vascular impact and plasma metabolic signature compared to a non-ketogenic high-fat diet (HFD). Apolipoprotein E deficient (ApoE −/−) mice were fed a KD (%kcal:81:1:18, fat/carbohydrate/protein), a non-ketogenic high-fat diet with half of the fat content (HFD) (%kcal:40:42:18, fat/carbohydrate/protein) for 12 weeks. Plasma samples were used to quantify the major ketone body beta−hydroxybutyrate (BHB) and several pro-inflammatory cytokines (IL-6, MCP-1, MIP-1alpha, and TNF alpha), and to targeted metabolomic profiling by mass spectrometry. In addition, aortic atherosclerotic lesions were quantified ex-vivo by magnetic resonance imaging (MRI) on a 14-tesla system. KD was atherogenic when compared to the control diet, but KD mice, when compared to the HFD group (1) had markedly higher levels of BHB and lower levels of cytokines, confirming the presence of ketosis that alleviated the well-established fat-induced systemic inflammation; (2) displayed significant changes in the plasma metabolome that included a decrease in lipophilic metabolites and an increase in hydrophilic metabolites; (3) had significantly lower levels of several atherogenic lipid metabolites, including phosphatidylcholines, cholesterol esters, sphingomyelins, and ceramides; and (4) presented significantly lower aortic plaque burden. KD was atherogenic and was associated with specific metabolic changes but alleviated the fat-induced inflammation and lessened the progression of atherosclerosis when compared to the HFD.

Effect of High-fat Low-carbohydrate Diet on the Structure of Intestinal Flora in T2DM Patients: A Narrative Review

High-fat low-carbohydrate diets are currently popular as one of the methods of weight loss, and the influence of this diet on the structure of intestinal flora in T2DM is a topical issue in the field of research. Despite the controversial result of the studies published so far in patients with type 2 diabetes. As one of the important microbial symbiotic systems in the human body, the intestinal flora is considered to be closely related to the development of type 2 diabetes. The intestinal flora structure abundance of type 2 diabetes patients is different from that of the general healthy population, and alterations in the structure of the intestinal flora can affect intestinal hormone secretion, which in turn affects the blood glucose level in type 2 diabetic patients. It is feasible to treat type 2 diabetes by altering the intestinal flora. Therefore, this narrative review proposes that the possible reason for the treatment of T2DM by high-fat low-carbohydrate diet is that the method of high-fat low-carbohydrate diet alters the intestinal flora structure of patients with T2DM, and treats patients with T2DM by altering their intestinal flora structure, which provides some new ideas and methods for the treatment and prevention of T2DM.

LIVER METABOLIC EFFECTS OF A HIGH-FAT LOW- CARBOHYDRATE DIET IN RATS: A STUDY UNDER DIFFERENT ENERGY CONDITIONS

The beneficial effects of high-fat, low-carbohydrate (HFLC) diets on glucose metabolismhave been questioned and its effects on liver metabolism are not totally clear. This workaimed to evaluate the HFLC diet effects under different energy conditions on glucosehomeostasis, fatty liver development and hepatic gluconeogenesis using the isolated perfusedrat liver. HFLC diet (79% fat, 19% protein, and 2% carbohydrates in Kcal%) wasadministered to rats over four weeks under three conditions: hypercaloric; isocaloric andhypocaloric (energy reduction of 20%). Fasting blood glucose levels and total fat in the liverwere higher in all HFLC diet rats. Oral glucose tolerance was impaired in isocaloric andhypercaloric groups, although insulin sensitivity wasn´t altered. HFLC diet also causedmarked liver metabolic alterations: higher gluconeogenesis rate from lactate and a reducedcapacity to catabolize alanine, the latter effect more intense in the hypocaloric condition. Weconcluded that, even when HFLC diets are used for weight loss, our data imply that they canpotentially cause harmful consequences for the liver.

Individual Postprandial Glycemic Responses to Diet in N-of-1 Trials: Westlake N-of-1 Trials for Macronutrient Intake (WE-MACNUTR)

ObjectivesWe aimed to use a novel ‘N-of-1’ study design to investigate the individual variability in postprandial glycemic response when eating diets with different macronutrient distributions among healthy adults. MethodsThirty apparently healthy young Chinese adults aged between 22 and 34 years were enrolled. Each participant was provided with high-fat, low-carbohydrate (HF-LC) and low-fat, high-carbohydrate (LF-HC) diets for six days wearing the continuous glucose monitor systems, respectively, in a randomized sequence, interspersed by a six-day wash-out period. Three cycles were conducted. The primary outcomes were the differences of maximum postprandial glucose (MPG), mean amplitude of glycemic excursions (MAGE), and area under the curve (AUC24) between intervention periods of LF-HC and HF-LC diets. A Bayesian model was used to determine responders with the posterior probability of any one of the three outcomes reaching a clinically meaningful difference. ResultsTwo participants abandoned at an early stage of the intervention, and the remaining 28 participants were included in the analysis set. The LF-HC diet, compared with the HF-LC diet, induced a higher MPG (n = 7) or MAGE (n = 5, with 3 overlapping with MPG) response among 9 individuals, who were identified as high-carb responders. On the other hand, the HF-LC diet, compared with the LF-HC diet, induced a higher MPG (n = 3) or MAGE (n = 4, with 1 overlapping with MPG) response among 6 individuals, who were identified as high-fat responders. ConclusionsThe present study supports N-of-1 trials’ feasibility for defining personalized nutritional advice modulating postprandial hyperglycemia and potentially preventing cardiometabolic diseases. Funding SourcesNational Natural Science Foundation of China.

The impact on metabolic and reproductive diseases of low-carbohydrate and ketogenic diets

With low carbohydrate diets glucose becomes unavailable as a source of energy for our body, leading to the production of ketones from fatty acids in the liver. The increase in plasma ketones is known as nutritional ketosis. The available evidence from basic and clinical studies indicates that both low carbohydrate and high fat low carbohydrate diets are effective for weight loss and are better than non-intervention. However, low carbohydrate diet and ketogenic diets induce unique metabolic changes and consistently improve some markers of cardiovascular risk, lowering elevated blood glucose, insulin, triglycerides, ApoB and saturated fat concentrations, reducing small dense LDL particle numbers, glycated hemoglobin levels, blood pressure and body weight while increasing HDL-cholesterol concentrations and reversing non-alcoholic fatty liver disease. Low carbohydrate diets are an efficient strategy for the management of obesity and metabolic syndrome. They may also benefit patients with polycystic ovary syndrome. They must be prescribed by trained professionals to balance the risks and benefits for each individual patient. Future research is required to improve the knowledge about individual responses to dietary interventions, their safety, tolerance, efficacy and long-term effects.

Ketogenic diets, not for everyone

The adoption of low-carbohydrate diets can lead to weight loss in many patients. However, these now widespread diets also have the potential to exacerbate hypercholesterolemia. The objective of this study is to display the potentially harmful effects of the ketogenic diet on cholesterol levels in patients with or without underlying hyperlipidemia. We describe 5 patients who developed marked increases in plasma cholesterol on ketogenic diets and assessed whether they had a well-described underlying genetic hyperlipidemia. Three out of 5 patients had extraordinary increases of blood cholesterol levels to over 500mg/dL. The other 2 patients more than doubled their low-density lipoprotein cholesterol levels on a ketogenic diet. One patient had an APOE E2/E2 genotype. A higher burden of common genetic polymorphisms was found in 2 patients, with no major mutations found. No potential genetic cause was seen in a fourth patient, and the fifth patient had no genetic testing. Three patients, including the one who was most hypercholesterolemic, had a marked reduction in cholesterol after reverting to a more liberal diet. One refused to change his diet but had a satisfactory low-density lipoprotein cholesterol reduction on ezetimibe. These cases should serve as a caution that high-fat low-carbohydrate diets have the potential to exacerbate or cause hypercholesterolemia in patients with or without underlying genetic hyperlipidemia.

Effects Of High-fat Diet And Exercise On Total Plasma Macronutrient Contents By Fourier-transform Infrared Spectroscopy

High fat-low carbohydrate (HFLC) diets are increasingly considered by endurance athletes to enhance their performances and overall health. Total macronutrient contents in plasma may be affected by diets and exercise. PURPOSE: To examine the effects of HFLC diet and an acute bout of exercise on total plasma macronutrient contents in trained males. METHODS: Eight trained distance runners (age = 39.5±9.9 years and VO2max = 47.9±7.6 mL/kg/min) that were on high-carbohydrate (HC) diets adopted the HFLC diet for 3 weeks, which consisted of 70% of overall caloric intake from fats and no more than 50g of carbohydrates. At the end of each diet trial, participants performed an indoor treadmill exercise for 50 minutes at varying race paces followed by an outdoor 5-km time trial. Overnight fasting blood samples were collected at pre- (baseline) and post-exercise (24-hours) to analyze changes in total plasma lipids, proteins, and carbohydrates using attenuated total reflectance Fourier-transform infrared spectroscopy (ATR FT-IR). The O-H stretch vibrational band of water was used to normalize the IR spectra and the protein content was quantified by measuring the amide I peak intensity at 1600 - 1700 cm-1. To quantify the lipids and carbohydrates, the samples were lyophilized and measured by the intensities at 2800 - 3000 cm-1 and 800 - 1200 cm-1, respectively. RESULTS: The ATR FT-IR analysis showed that total plasma proteins remained unchanged (HC baseline = 135.20±4.20 and HFLC baseline = 135.24±3.91AU). However, the HC diet at baseline showed a significant accumulation of lipids (30.06±7.75 AU, 95% CI = 6.93) and carbohydrates (42.92±11.62 AU, 95% CI = 10.39). Additionally, total lipids in the HC diet significantly decreased at 24-hours post-exercise (from 30.06±7.75 to 28.51±7.91 AU, p=0.016). CONCLUSION: A short-term high-fat diet does not significantly alter any macronutrient contents in plasma, whereas a high-carbohydrate diet increases an accumulation of lipids and carbohydrates. Elevated plasma lipids and carbohydrates with a high-carbohydrate diet may be due to decreased insulin sensitivity, which consequently led to increased plasma lipid contents. Notably, decreased total plasma lipid content following an acute bout of exercise suggests that lipids were the primary energy substrate.

High-fat, low-carbohydrate diet promotes arrhythmic death and increases myocardial ischemia-reperfusion injury in rats.

High-fat, low-carbohydrate diets (HFLCD) are often eaten by humans for a variety of reasons, but the effects of such diets on the heart are incompletely understood. We evaluated the impact of HFLCD on myocardial ischemia/reperfusion (I/R) using an in vivo model of left anterior descending coronary artery ligation. Sprague-Dawley rats (300 g) were fed HFLCD (60% calories fat, 30% protein, 10% carbohydrate) or control (CONT; 16% fat, 19% protein, 65% carbohydrate) diet for 2 wk and then underwent open chest I/R. At baseline (preischemia), diet did not affect left ventricular (LV) systolic and diastolic function. Oil red O staining revealed presence of lipid in the heart with HFLCD but not in CONT. Following I/R, recovery of LV function was decreased in HFLCD. HFLCD hearts exhibited decreased ATP synthase and increased uncoupling protein-3 gene and protein expression. HFLCD downregulated mitochondrial fusion proteins and upregulated fission proteins and store-operated Ca(2+) channel proteins. HFLCD led to increased death during I/R; 6 of 22 CONT rats and 16 of 26 HFLCD rats died due to ventricular arrhythmias and hemodynamic shock. In surviving rats, HFLCD led to larger infarct size. We concluded that in vivo HFLCD does not affect nonischemic LV function but leads to greater myocardial injury during I/R, with increased risk of death by pump failure and ventricular arrhythmias, which might be associated with altered cardiac energetics, mitochondrial fission/fusion dynamics, and store-operated Ca(2+) channel expression.

Genetic Variation in the Glucose-Dependent Insulinotropic Polypeptide Receptor Modifies the Association between Carbohydrate and Fat Intake and Risk of Type 2 Diabetes in the Malmö Diet and Cancer Cohort

A common genetic variant (rs10423928, A-allele) in the glucose-dependent insulinotropic polypeptide receptor gene (GIPR) is associated with decreased insulin secretion. Glucose-dependent insulinotropic polypeptide is secreted after food consumption and gipr knockout mice fed a high-fat diet are protected against obesity and disturbances in glucose homeostasis. Our objective was to examine the interactions between rs10423928 and macronutrients and fiber intakes on body mass index and type 2 diabetes risk. Among nondiabetic subjects in the Swedish population-based Malmö Diet and Cancer cohort (n = 24,840; 45-74 yr), 1541 diabetes cases were identified during 12 yr of follow-up. Dietary intakes were assessed using a diet history method. Incident type 2 diabetes was identified through registers. There was no indication that dietary intakes significantly modify the association between GIPR genotype and body mass index (P interaction >0.08). We observed significant interactions between GIPR genotype and quintiles of carbohydrate (P = 0.0005) and fat intake (P = 0.0006) on incident type 2 diabetes. The TT-genotype carriers within the highest compared with the lowest carbohydrate quintile were at 23% (95% confidence interval = 5-39%) decreased type 2 diabetes risk. In contrast, AA-genotype carriers in the highest compared with the lowest fat quintile were at 69% (95% confidence interval = 29-86%) decreased risk. Our prospective, observational study indicates that the type 2 diabetes risk by dietary intake of carbohydrate and fat may be dependent on GIPR genotype. In line with results in gipr knockout mice, AA-genotype carriers consuming high-fat low-carbohydrate diets had reduced type 2 diabetes risk, whereas high-carbohydrate low-fat diets benefitted the two thirds of population homozygous for the T-allele.

IMPACT OF HIGH-FAT, LOW-CARBOHYDRATE DIET ON MYOCARDIAL ISCHEMIA / INFARCTION: AN IN VIVO STUDY

High-Fat, Low-Carbohydrate diets (HFLCD) are popular but the effect on myocardial ischemia is not known. We examined the impact of HFLCD using an in vivo model of ligation of the left anterior descending coronary artery (LAD). 300 gram Sprague Dawley rats were fed HFLCD (60p cal fat, 30&

IMPACT OF HIGH-FAT, LOW-CARBOHYDRATE DIET ON INSULIN SENSITIVITY AND TCA CYCLE SUBSTRATE ENTRY DURING ISCHEMIA-REPERFUSION

High-Fat, Low-Carbohydrate diets (HFLCD) are often used for weight loss, but the impact of these diets on myocardial metabolism is unknown. We investigated the effect of HFLCD on myocardial insulin sensitivity and TCA cycle substrate entry at baseline and with ischemia-reperfusion (I/R). 250g male

Dietary Macronutrient Content Alters Cortisol Metabolism Independently of Body Weight Changes in Obese Men

Dietary macronutrient composition influences cardiometabolic health independently of obesity. Both dietary fat and insulin alter glucocorticoid metabolism in rodents and, acutely, in humans. However, whether longer-term differences in dietary macronutrients affect cortisol metabolism in humans and contribute to the tissue-specific dysregulation of cortisol metabolism in obesity is unknown. The objective of the study was to test the effects of dietary macronutrients on cortisol metabolism in obese men. The study consisted of two randomized, crossover studies. The study was conducted at a human nutrition unit. Participants included healthy obese men. INTERVENTIONS, OUTCOME MEASURES, AND RESULTS: Seventeen obese men received 4 wk ad libitum high fat-low carbohydrate (HF-LC) (66% fat, 4% carbohydrate) vs. moderate fat-moderate carbohydrate (MF-MC) diets (35% fat, 35% carbohydrate). Six obese men participated in a similar study with isocaloric feeding. Both HF-LC and MF-MC diets induced weight loss. During 9,11,12,12-[(2)H](4)-cortisol infusion, HF-LC but not MF-MC increased 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity (rates of appearance of cortisol and 9,12,12-[(2)H](3)-cortisol) and reduced urinary excretion of 5alpha- and 5beta-reduced [(2)H](4)-cortisol metabolites and [(2)H](4)-cortisol clearance. HF-LC also reduced 24-h urinary 5alpha- and 5beta-reduced endogenous cortisol metabolites but did not alter plasma cortisol or diurnal salivary cortisol rhythm. In sc abdominal adipose tissue, 11beta-HSD1 mRNA and activity were unaffected by diet. A low-carbohydrate diet alters cortisol metabolism independently of weight loss. In obese men, this enhances cortisol regeneration by 11beta-HSD1 and reduces cortisol inactivation by A-ring reductases in liver without affecting sc adipose 11beta-HSD1. Alterations in cortisol metabolism may be a consequence of macronutrient dietary content and may mediate effects of diet on metabolic health.

Effect of Source of Carbohydrate as Influenced by Dietary Fat: Carbohydrate ratio and forced exercise in rats

The effects were studied of changing the carbohydrate source in diets high or low in fat and fed to sedentary or force-exercised rats. Eighty mature, male rats were either force-exercised by treadmill-running every day or allowed voluntary activity in an activity cage. The 40 animals receiving each exercise treatment were then fed ad libitum either a high fat-low carbohydrate diet or a diet low in fat and high in carbohydrate. Equicaloric intakes of the 2 diets provided equal intakes of protein, vitamins and minerals. The 20 animals receiving each diet at each exercise level were divided into 4 groups of 5 animals each to receive their dietary carbohydrate as: 1) cornstarch, 2) lactose, 3) sucrose, or 4) a mixture approximating the carbohydrate composition of an average U. S. “market basket” diet. The animals fed lactose as the only carbohydrate in a low fat-high carbohydrate diet had diarrhea and weighed less than all other animals, even when diets were corrected to equicaloric intakes by analysis of covariance. Metabolism of 1-14C- and 6-14C-glucose to 14CO2 and U-14C-glucose to citrate-14C indicated greater activity of the HMP shunt pathway in animals fed lactose. The moderate level of forced exercise used in this study significantly lowered the ingesta-free body weights of animals fed equicaloric amounts of the high fat-low carbohydrate diets, but had no effect on the body weights of animals fed equicaloric amounts of the high carbohydrate-low fat diets. This appeared to indicate a greater muscular efficiency in rats fed the high carbohydrate-low fat diets than in those fed the high fat-low carbohydrate diets. Body composition was altered by all three of the main experimental variables. Animals fed the high fat-low carbohydrate diet had more body fat than animals of the same weight fed the high carbohydrate-low fat diet. Force-exercised animals had less body fat than animals of the same weight allowed voluntary activity only. Among rats of the same weight, those fed starch as the only source of carbohydrate had more body fat than those fed the other carbohydrate sources. However, rats fed starch had a lower carcass concentration of cholesterol than rats fed the other carbohydrate sources. Rats fed the mixture of carbohydrates at either a high or a low level in the diet increased in body cholesterol more rapidly as they gained weight than rats fed the single carbohydrate sources. Weight control was of primary value in limiting the cholesterol content of the animals fed the carbohydrate mixture, regardless of fat:carbohydrate ratio of the diet.

Effect of Diet on Insulin Response in Normal and Hypophy-sectomized Dogs

In another paper1 are described the effects of high fat-low carbohydrate and low fat-high carbohydrate diets on the glucose tolerance in normal and hypophysectomized dogs. We report here the effect of similar diets on the insulin response of such animals.Ten normal dogs were fed from one to 3 weeks on a diet consisting of 100 gm. of fat and 350 gm. raw lean meat daily. The animals were then given 0.5 units of insulin per kilo of body weight intravenously and their response to insulin determined by blood sugar determinations made at the intervals indicated in the table. The same animals were then given a low fat-high carbohydrate diet consisting of 100 gm. cane sugar, one liter of skimmed milk and 300 gm. of whole wheat bread daily for a similar time period. Their insulin response was again determined.The results are presented in Table I. Their analysis shows no consistent effect of change in diet on insulin response.Six hypophysectomized dogs within 2 months following the operation were given the above di...