Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: two case reports.

Establish dietary-induced ketosis in pediatric oncology patients to determine if a ketogenic state would decrease glucose availability to certain tumors, thereby potentially impairing tumor metabolism without adversely affecting the patient's overall nutritional status.

Case report.

University Hospitals of Cleveland.

Two female pediatric patients with advanced stage malignant Astrocytoma tumors.

Patients were followed as outpatients for 8 weeks. Ketosis was maintained by consuming a 60% medium chain triglyceride oil-based diet.

Tumor glucose metabolism was assessed by Positron Emission Tomography (PET), comparing [Fluorine-18] 2-deoxy-2-fluoro-D-glucose (FDG) uptake at the tumor site before and following the trial period.

Within 7 days of initiating the ketogenic diet, blood glucose levels declined to low-normal levels and blood ketones were elevated twenty to thirty fold. Results of PET scans indicated a 21.8% average decrease in glucose uptake at the tumor site in both subjects. One patient exhibited significant clinical improvements in mood and new skill development during the study. She continued the ketogenic diet for an additional twelve months, remaining free of disease progression.

While this diet does not replace conventional antineoplastic treatments, these preliminary results suggest a potential for clinical application which merits further research.     

Decline of Lactate in Tumor Tissue After Ketogenic Diet: In Vivo Microdialysis Study in Patients with Head and Neck Cancer

In head and neck squamous cell carcinoma (HNSCC) aerobic glycolysis is the key feature for energy supply of the tumor. Quantitative microdialysis (μD) offers an online method to measure parameters of the carbohydrate metabolism in vivo. The aim was to standardize a quantitative μD-study in patients with HNSCC and to prove if a ketogenic diet would differently influence the carbohydrate metabolism of the tumor tissue. Commercially available 100 kDa-CMA71-μD- catheters were implanted in tumor-free and in tumor tissue in patients with HNSCC for simultaneous measurements up to 5 days. The metabolic pattern and circadian rhythm of urea, glucose, lactate, and pyruvate was monitored during 24 h of western diet and subsequent up to 4 days of ketogenic diet. After 3 days of ketogenic diet the mean lactate concentration declines to a greater extent in the tumor tissue than in the tumor-free mucosa, whereas the mean glucose and pyruvate concentrations rise. The in vivo glucose metabolism of the tumor tissue is clearly influenced by nutrition. The decline of mean lactate concentration in the tumor tissue after ketogenic diet supports the hypothesis that HNSCC tumor cells might use lactate as fuel for oxidative glucose metabolism.     

Cancer cachexia: influence of systemic ketosis on substrate levels and nitrogen metabolism

The aim of this study was to determine whether a ketogenic diet could decrease nitrogen losses in cachectic cancer patients and at the same time reduce the supply of glucose for tumor energy metabolism. Five patients with malignant disease and severe weight loss (mean 32%) were fed via a fine bore nasogastric tube. A normal diet was given for 6 d and this was followed by 7 d of an isonitrogenous, isocaloric, ketogenic diet. Both diets were well tolerated. At 7 d the mean ketone body concentration in the blood of patients fed the ketogenic diet was 1.21 +/- 0.33 mM. This ketosis was associated with a significant reduction of the concentration in blood of glucose, lactate, and pyruvate (p less than 0.05). There was, however, no significant alteration in host N balance or whole-body protein synthesis, degradation, or turnover rates. Whether the change from glucose- to fat-derived energy substrates might reduce tumor growth rates in the long term remains to be determined.     

An observational study of sequential protein-sparing,very low-calorie ketogenic diet (Oloproteic diet) and hypocaloric Mediterranean-like diet for the treatment of obesity

The impact of a rehabilitative multi-step dietary program consisting in different diets has been scantily investigated. In an open-label study, 73 obese patients underwent a two-phase weight loss (WL) program: a 3-week protein-sparing, very low-calorie, ketogenic diet (<500?kcal/day; Oloproteic^® Diet) and a 6-week hypocaloric (25–30?kcal/kg of ideal body weight/day), low glycemic index, Mediterranean-like diet (hypo-MD). Both phases improved visceral adiposity, liver enzymes, GH levels, blood pressure and glucose and lipid metabolism. However, the hypo-MD was responsible for a re-increase in blood lipids and glucose tolerance parameters. Changes in visceral adiposity and glucose control-related variables were more consistent in patients with metabolic syndrome. However, in these patients the hypo-MD did not result in a consistent re-increase in glucose control-related variables. A dietary program consisting in a ketogenic regimen followed by a balanced MD appeared to be feasible and efficacious in reducing cardiovascular risk, particularly in patients with metabolic syndrome.     

Stimulation of mild,sustained ketonemia by medium-chain triacylglycerols in healthy humans: Estimated potential contribution to brain energy metabolism

ObjectiveIn humans consuming a normal diet, we investigated 1) the capacity of a medium-chain triacylglycerol (MCT) supplement to stimulate and sustain ketonemia, 2) ¹³C-β-hydroxybutyrate and ¹³C-trioctanoate metabolism, and 3) the theoretical contribution of the degree of ketonemia achieved to brain energy metabolism.MethodsEight healthy adults (26 ± 1 y old) were given an MCT supplement for 4 wk (4 times/d; total of 20 g/d for 1 wk followed by 30 g/d for 3 wk). Ketones, glucose, triacylglycerols, cholesterol, free fatty acids, and insulin were measured over 8 h during two separate metabolic study days before and after MCT supplementation. Using isotope ratio mass spectroscopy, ¹³C-D-β-hydroxybutyrate and ¹³C-trioctanoate β-oxidation to ¹³CO₂ was measured over 12 h on the pre- and post-MCT metabolic study days.ResultsOn the post-MCT metabolic study day, plasma ketones (β-hydroxybutyrate plus acetoacetate) peaked at 476 μM, with a mean value throughout the study day of 290 μM. Post-MCT, ¹³C-trioctanoate β-oxidation was significantly lower 1 to 8 h later but higher 10 to 12 h later. MCT supplementation did not significantly alter ¹³C-D-β-hydroxybutyrate oxidation.ConclusionsThis MCT supplementation protocol was mildly and safely ketogenic and had no side effects in healthy humans on their regular diet. This degree of ketonemia is estimated to contribute up to 8% to 9% of brain energy metabolism.     

The Ketogenic Diet: A Practical Guide for Caregivers

The ketogenic diet is a high-fat, low-carbohydrate diet that results in ketosis. It has been in use for nearly 70 years. Several modifications of the diet's original form, including the medium-chain triglyceride (MCT) diet, have been made in an attempt to overcome the obstacles of compliance and acceptance, which have been critical factors in determining its success. The practical guide for caregivers that is presented here uses elements of both the original ketogenic diet and the MCT diet, with added ideas. Our modified diet has been in use for more than 3 years at Columbia Presbyterian Medical Center Babies and Children's Hospital of New York. The majority of parents and children find our diet more acceptable and/or more user friendly than other types of ketogenic diets. Thus, compliance is better. The variety of foods offered is greater and provides a more normal diet than the other types of ketogenic diets. In addition, the calculations for nutritionists are easier, and parents are able to adjust the diet without the fear that their child will lose ketones. J Am Diet Assoc. 1998;98:316-321.     

Dietary substitution of medium chain triglycerides in subjects with non-insulin-dependent diabetes mellitus in an ambulatory setting: impact on glycemic control and insulin-mediated glucose metabolism.

We have previously shown in an acute inpatient setting that dietary substitution of 77.5% of fat kcal as medium chain triglycerides (MCT) increased insulin-mediated glucose metabolism in patients with non-insulin-dependent diabetes mellitus (NIDDM), and that this effect appeared to be mediated by increases in insulin-mediated glucose disposal. The purpose of this study was to test the application of dietary substitution of medium chain triglycerides as an adjunctive tool in ambulatory therapy of NIDDM.

Five subjects with NIDDM underwent a baseline 6 hour insulin/glucose euglycemic clamp study, with simultaneous 3H-glucose infusion for calculation of glucose disposal rate and hepatic glucose output. Subjects were then randomized to begin one of two 30-day experimental diets, with long chain (LCT) or medium chain triglycerides (MCT), and subsequent crossover to the other diet. A 6 hour euglycemic clamp was repeated after each diet phase.

Diet records and urinary organic acid excretion indicated a high level of dietary compliance by the study participants. Postprandial blood glucose excursions were less after one month on the diet with MCT than after the LCT diet (p = 0.004). However, fasting serum glucose, serum fructosamine (a measure of glycemia), fasting insulin, hepatic glucose output, and insulin-mediated glucose metabolism were not improved by the dietary substitution of MCT.

These data indicate that supplementation of a tolerable amount of MCT in a conventional diabetic exchange diet has little impact on glycemic control in subjects with NIDDM in an ambulatory setting.     

Dietary Canola Oil Suppressed Growth of Implanted MDA-MB 231 Human Breast Tumors in Nude Mice

Long chain omega 3 (n-3) fatty acids, eicosapentaenoic (EPA) and/or docosahexaenoic acid (DHA), have been shown to suppress growth of most cancer cells. In vivo, alpha linolenic acid (ALA, 18:3n-3) can be converted to EPA or DHA. We hypothesized that substituting canola oil (10% ALA) for the corn oil (1% ALA) in the diet of cancer bearing mice would slow tumor growth by increasing n-3 fatty acids in the diet. Sixty nude mice received MDA-MB 231 human breast cancer cells and were fed a diet containing 8% w/w corn oil until the mean tumor volume was 60 mm ³ . The dietary fat of half of the tumor bearing mice was then changed to 8% w/w canola oil. Compared to mice that consumed the corn oil containing diet, the mice that consumed the canola oil containing diet had significantly more EPA and DHA in both tumors and livers, and the mean tumor growth rate and cell proliferation in the tumor were significantly slower (P < 0.05). About 25 days after diet change, mice that consumed the corn oil diet stopped gaining weight, whereas the mice that consumed the canola oil diet continued normal weight gain. Use of canola oil instead of corn oil in the diet may be a reasonable means to increase consumption of n-3 fatty acids with potential significance for slowing growth of residual cancer cells in cancer survivors.     

The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer

Background

Malignant brain cancer persists as a major disease of morbidity and mortality in adults and is the second leading cause of cancer death in children. Many current therapies for malignant brain tumors fail to provide long-term management because they ineffectively target tumor cells while negatively impacting the health and vitality of normal brain cells. In contrast to brain tumor cells, which lack metabolic flexibility and are largely dependent on glucose for growth and survival, normal brain cells can metabolize both glucose and ketone bodies for energy. This study evaluated the efficacy of KetoCal^®, a new nutritionally balanced high fat/low carbohydrate ketogenic diet for children with epilepsy, on the growth and vascularity of a malignant mouse astrocytoma (CT-2A) and a human malignant glioma (U87-MG).

Methods

Adult mice were implanted orthotopically with the malignant brain tumors and KetoCal^® was administered to the mice in either unrestricted amounts or in restricted amounts to reduce total caloric intake according to the manufacturers recommendation for children with refractory epilepsy. The effects KetoCal^® on tumor growth, vascularity, and mouse survival were compared with that of an unrestricted high carbohydrate standard diet.

Results

KetoCal^® administered in restricted amounts significantly decreased the intracerebral growth of the CT-2A and U87-MG tumors by about 65% and 35%, respectively, and significantly enhanced health and survival relative to that of the control groups receiving the standard low fat/high carbohydrate diet. The restricted KetoCal^® diet reduced plasma glucose levels while elevating plasma ketone body (β-hydroxybutyrate) levels. Tumor microvessel density was less in the calorically restricted KetoCal^® groups than in the calorically unrestricted control groups. Moreover, gene expression for the mitochondrial enzymes, β-hydroxybutyrate dehydrogenase and succinyl-CoA: 3-ketoacid CoA transferase, was lower in the tumors than in the contralateral normal brain suggesting that these brain tumors have reduced ability to metabolize ketone bodies for energy.

Conclusion

The results indicate that KetoCal^® has anti-tumor and anti-angiogenic effects in experimental mouse and human brain tumors when administered in restricted amounts. The therapeutic effect of KetoCal^® for brain cancer management was due largely to the reduction of total caloric content, which reduces circulating glucose required for rapid tumor growth. A dependency on glucose for energy together with defects in ketone body metabolism largely account for why the brain tumors grow minimally on either a ketogenic-restricted diet or on a standard-restricted diet. Genes for ketone body metabolism should be useful for screening brain tumors that could be targeted with calorically restricted high fat/low carbohydrate ketogenic diets. This preclinical study indicates that restricted KetoCal^® is a safe and effective diet therapy and should be considered as an alternative therapeutic option for malignant brain cancer.     

A prospective study: growth and nutritional status of children treated with the ketogenic diet

OBJECTIVE: To assess the nutritional status of children treated with the classic and medium-chain triglyceride (MCT) ketogenic diets. DESIGN: A prospective, nonrandomized study design was used to measure nutrient intakes, growth, and biochemical indexes of children, age 1 to 16 years, with intractable epilepsy before and after 4 months' treatment with the classic and MCT ketogenic diets. None of the children had been on earlier dietary regimens. SUBJECTS: Of 58 children asked to participate in the study between September 1998 and July 2000, consent was obtained for 30 children. Fourteen children on the classic diet and 11 children on the MCT diet completed the study (83% completed). Statistical analysis performed Paired t tests were done on anthropometric and biochemical indexes. Nutrient intakes were compared with Dietary Reference Intakes (DRIs). RESULTS: Both groups had statistically significant height increases of 2 to 3 cm (P<.05), but did not have significant increases in height/age percentiles. Weight percentiles decreased by approximately 10 percentiles for both diets; P=.043 for classic diet and.051 for MCT diet. Nutrient intakes from the diet and vitamin and mineral supplements met the DRIs except for phosphorus (both diets) and folate (classic diet). All biochemical indexes, including albumin, remained within the normal range. For the MCT diet, there was a 0.7 decrease in the ratio of total cholesterol to high-density lipoprotein ratios (P<.0009) at 4 months. APPLICATIONS: When treating children on a ketogenic diet, clinicians should recommend adequate intake of energy and protein, a higher proportion of unsaturated to saturated dietary fats, and consider vitamin and mineral supplements.     

Mild experimental ketosis increases brain uptake of 11C-acetoacetate and 18F-fluorodeoxyglucose: a dual-tracer PET imaging study in rats

Abstract

Brain glucose and ketone uptake was investigated in Fisher rats subjected to mild experimental ketonemia induced by a ketogenic diet (KD) or by 48 hours fasting (F). Two tracers were used, ¹¹C-acetoacetate (¹¹C-AcAc) for ketones and ¹⁸F-fluorodeoxyglucose for glucose, in a dual-tracer format for each animal. Thus, each animal was its own control, starting first on the normal diet, then undergoing 48 hours F, followed by 2 weeks on the KD. In separate rats on the same diet conditions, expression of the transporters of glucose and ketones (glucose transporter 1 (GLUT1) and monocarboxylic acid transporter (MCT1)) was measured in brain microvessel preparations. Compared to controls, uptake of ¹¹C-AcAc increased more than 2-fold while on the KD or after 48 hours F (P < 0.05). Similar trends were observed for ¹⁸FDG uptake with a 1.9–2.6 times increase on the KD and F, respectively (P < 0.05). Compared to controls, MCT1 expression increased 2-fold on the KD (P < 0.05) but did not change during F. No significant difference was observed across groups for GLUT1 expression. Significant differences across the three groups were observed for plasma beta-hydroxybutyrate (beta-HB), AcAc, glucose, triglycerides, glycerol, and cholesterol (P < 0.05), but no significant differences were observed for free fatty acids, insulin, or lactate. Although the mechanism by which mild ketonemia increases brain glucose uptake remains unclear, the KD clearly increased both the blood–brain barrier expression of MCT1 and stimulated brain ¹¹C-AcAc uptake. The present dual-tracer positron emission tomography approach may be particularly interesting in neurodegenerative pathologies such as Alzheimer's disease where brain energy supply appears to decline critically.     

Dietary patterns and the adenomacarcinoma sequence of colorectal cancer

Summary Background Food components of a diet are highly related, so that building up dietary patterns may help understand the relationship between chronic diseases and diet, and identify high risk groups that need preventive advice. Aim The aim of this study was to determine dietary patterns associated with the colorectal adenoma–carcinoma pathway. Methods We performed a two–step analysis using first principal component analysis to select the most appropriate food groups, then a hierarchical agglomerative clustering method, in order to determine dietary patterns in 1372 subjects included in a case–control study. Patients with hyperplastic polyps (n = 103), adenomas < 10mm, (n = 154) or larger adenomas (n = 208) were then compared with polyp–free controls (n = 426), and colorectal cancer cases (n = 171) compared with population controls (n = 309) using unconditional logistic regression adjusted on age and gender. Results Cluster analysis determined five food patterns. Cluster 1 identified a low-energy diet; cluster 2 a high–starch, highfat, and low–fruit diet; cluster 3 a high–processed meat, –energy, –alcohol, and –starchy foods diet; cluster 4 a high–fish, –cereals, –honey, –olive oil, –fruit and –vegetables diet; and cluster 5 a high–flour, –sugar, –chocolate, –animal fats, and –eggs diet. Logistic regression identified cluster 2 as significantly associated with risk of small adenomas (OR = 1.7; 95% confidence interval 1.0–2.7), large adenomas (OR = 1.9; 1.2–3.0) and cancers (OR = 1.7; 1.1–2.8) compared with cluster 1. Cluster 4 diet was inversely associated with risk of small adenomas (OR = 0.4; 0.2–1.0). There was no relationship between patterns and risk of hyperplastic polyps. Multiple adjustment decreased the strength of the relationships with cluster 2, which remained significantly associated with adenomas, but not cancer. Conclusion A lowenergy diet appeared as protective all along the adenoma–carcinoma sequence, contrary to a high–energy, high–processed meat and –animal fat diet.In the html abstract, html-text and pdf of the summary of the article“Rouillier P, et al.(2004) Dietary patterns and the adenomacarcinoma sequence of colorectal cancer. Eur J Nutr (published online 20th August 2004)”The online version of the original article can be found atthe numbering of the different clusters in the sub-section “Results” had been mixed up. Instead of:“...Logistic regression identified cluster 1 as significantly associated with risk of small adenomas (OR=1.7; 95% confidence interval 1.0–2.7), large adenomas (OR=1.9; 1.2–3.0) and cancers (OR=1.7; 1.1–2.8) compared with cluster 2. Cluster 4 diet was inversely associated with risk of small adenomas (OR=0.4; 0.2–1.0). There was no relationship between patterns and risk of hyperplastic polyps. Multiple adjustment decreased the strength of the relationships with cluster 1, which remained significantly associated with adenomas, but not cancer.”there should have been:“Logistic regression identified cluster 2 as significantly associated with risk of small adenomas (OR=1.7; 95% confidence interval 1.0–2.7), large adenomas (OR=1.9; 1.2–3.0) and cancers (OR=1.7; 1.1–2.8) compared with cluster 1. Cluster 4 diet was inversely associated with risk of small adenomas (OR=0.4; 0.2–1.0). There was no relationship between patterns and risk of hyperplastic polyps. Multiple adjustment decreased the strength of the relationships with cluster 2, which remained significantly associated with adenomas, but not cancer.”The publisher apologises for any inconvenience caused by this mistake.     

Nutritional–pharmacological combinations

Summary Background Recent studies have suggested that n–9 fatty acids in olive oil prevent colon carcinogenesis while n–6 PUFA seems to activate this process. Aims To evaluate the effects of nutritional–pharmacological combinations made up of olive or soy oilbased diets and the drug sulindac, on colon cancer incidence in a chemically induced (1,2–dimethylhydrazine, DMH) rat cancer model. Methods Male rats were assigned to two different dietary regimes based on a standard murine defined diet (AIN–76A) containing either a low (4%) or high (15 %) concentration of olive or soy oil. Some groups also received sulindac in their food (80 mg/kg food) starting from the ninth week following the first DMH or vehicle administration. Results Oleic and linoleic acid reached higher levels in plasma and liver lipids when rats were fed high concentrations of olive or soy oil, respectively. Rats fed a low or high soy oil–based diet showed no significant difference in the number of aberrant crypt foci (ACF) in proximal or distal colon specimens. In contrast, rats fed a higher olive oil–based diet developed a significantly lower number of ACF than rats fed a low concentration of olive oil. Addition of sulindac reduced the number of ACF in rats fed the 4%, but not the 15%, soy oil diet. In contrast, the effect of sulindac was significant when combined with both the low and high concentrations of olive oil. High soy oilbased diet or DMH treatment upregulated colon expression of Bcl–2, but not that of cyclooxygenase–2 (COX–2). In contrast, olive oil dose–dependently downregulated the expression of both Bcl–2 and COX–2 in colonic mucosa and also abrogated the upregulation of Bcl–2 by DMH. Olive oil/sulindac combinations were effective in downregulating colonic mucosa Bcl–2 expression (with the 4% oil diet) and COX–2 expression (with the 15% oil diet). These effects were not observed in rats fed the soy oil/sulindac combinations. Caspase–3 activity in colonic mucosa was unaffected by soy oil or soy oil/sulindac combinations. The addition of olive oil, on the other hand, significantly enhanced colonic caspase–3 activity. Conclusions Diets containing high levels of olive oil exert a significant protective effect from tumor development that is additive with the inhibitory effect of sulindac. These inhibitory effects are mediated by regulating the expression and activity of key proteins involved in prostaglandin–biosynthesis and apoptosis–induction pathways. It may be concluded that appropriate dietary–pharmacological combination can improve anti–tumor efficacy over either dietary or pharmacological intervention alone.     

Dietary medium-chain triacylglycerol prevents the postprandial rise of plasma triacylglycerols but induces hypercholesterolemia in primary hypertriglyceridemic subjects

BACKGROUND: Previous studies showed divergent results concerning the influence of medium-chain triacylglycerol (MCT) on lipoprotein metabolism. OBJECTIVE: The objective of this study was to compare the effects of MCT and corn oil on plasma lipids in primary hypertriglyceridemic patients. DESIGN: Ten subjects ate different proportions of corn oil and MCT for 12 wk. The subjects first ate a low-fat diet for 2 wk and during the next 4 wk, corn oil was added as the sole source of fat. Thereafter, for 2-wk periods, the subjects were sequentially fed corn oil and MCT mixed in the following proportions: 3:1, 1:1, and 0:1. Fasting plasma total cholesterol, triacylglycerol, and HDL-cholesterol concentrations were measured at the end of each period. At the end of the 100%-corn oil and of the 100%-MCT periods, subjects were fed a test meal containing the respective oil (40 g fat/m(2) body surface area) and total cholesterol and triacylglycerols were measured at 2-h intervals over 8 h; fasting lipoprotein composition was also measured. RESULTS: Compared with corn oil, MCT was associated with a higher mean (+/-SD) fasting total cholesterol concentration (6.39 +/- 1.14 compared with 5.51 +/- 0.98 mmol/L, respectively; P < 0. 05); non-HDL-cholesterol concentrations were also higher with MCT (5. 36 +/- 1.11 mmol/L) than with corn oil (4.51 +/- 0.92 mmol/L; P < 0. 005). In response to the liquid test meal, plasma total cholesterol did not change with either diet but triacylglycerols increased with the 100%-corn oil diet. CONCLUSIONS: MCT prevents the risk of pancreatitis due to postprandial hypertriglyceridemia but has the inconvenience of raising total cholesterol concentrations in primary hypertriglyceridemic subjects.     

Obesity and Circulating Levels of Vitamin D before and after Weight Loss Induced by a Very Low-Calorie Ketogenic Diet

Background: Vitamin D plays a pivotal role in calcium and phosphorus metabolism, also influencing bone tissue. Several studies have reported that vitamin D blood levels were significantly lower in people with obesity, probably due to its uptake by the adipose tissue. Clinical studies that investigated the changes of circulating levels of vitamin D following weight loss reported controversial data. A very low-calorie ketogenic diet is acknowledged as a reliable treatment to achieve a rapid weight loss. Therefore, we investigated the effect of weight loss, consequent to a very low-calorie ketogenic diet, on vitamin D blood concentrations. Methods: A cohort of 31 people with obesity underwent a very low-calorie ketogenic diet for 10–12 weeks. The serum concentrations of vitamin D, parathormone, calcium and phosphorous were measured before and after weight loss; they were compared to a control group of 20 non-obese, non-diabetic, age- and gender-matched persons. Results: Patients with obesity had a higher habitual intake of vitamin D than the control group (p < 0.05). However, the vitamin D blood levels of the obese group were significantly lower than those of the control group (p < 0.005) and they increased after weight loss (p < 0.001). At baseline, vitamin D blood concentrations of the persons with obesity were significantly correlated with both fat mass–kg (r = −0.40; p < 0.05) and body mass index (r = −0.47; p < 0.01). Following very low-calorie ketogenic diet, the change in vitamin D serum concentrations was correlated only with the change in fat mass–kg (r = −0.43; p < 0.01). Conclusion: This study confirmed that patients with obesity have lower vitamin D levels that normalize after significant weight loss, supporting the hypothesis that vitamin D is stored in the adipose tissue and released following weight loss.     

Ketogenic Diet Decreases Alcohol Intake in Adult Male Mice

The classic ketogenic diet is a diet high in fat, low in carbohydrates, and well-adjusted proteins. The reduction in glucose levels induces changes in the body’s metabolism, since the main energy source happens to be ketone bodies. Recent studies have suggested that nutritional interventions may modulate drug addiction. The present work aimed to study the potential effects of a classic ketogenic diet in modulating alcohol consumption and its rewarding effects. Two groups of adult male mice were employed in this study, one exposed to a standard diet (SD, n = 15) and the other to a ketogenic diet (KD, n = 16). When a ketotic state was stable for 7 days, animals were exposed to the oral self-administration paradigm to evaluate the reinforcing and motivating effects of ethanol. Rt-PCR analyses were performed evaluating dopamine, adenosine, CB1, and Oprm gene expression. Our results showed that animals in a ketotic state displayed an overall decrease in ethanol consumption without changes in their motivation to drink. Gene expression analyses point to several alterations in the dopamine, adenosine, and cannabinoid systems. Our results suggest that nutritional interventions may be a useful complementary tool in treating alcohol-use disorders.     

Mild experimental ketosis increases brain uptake of 11C-acetoacetate and 18F-fluorodeoxyglucose: a dual-tracer PET imaging study in rats

Brain glucose and ketone uptake was investigated in Fisher rats subjected to mild experimental ketonemia induced by a ketogenic diet (KD) or by 48 hours fasting (F). Two tracers were used, (11)C-acetoacetate ((11)C-AcAc) for ketones and (18)F-fluorodeoxyglucose for glucose, in a dual-tracer format for each animal. Thus, each animal was its own control, starting first on the normal diet, then undergoing 48 hours F, followed by 2 weeks on the KD. In separate rats on the same diet conditions, expression of the transporters of glucose and ketones (glucose transporter 1 (GLUT1) and monocarboxylic acid transporter (MCT1)) was measured in brain microvessel preparations. Compared to controls, uptake of (11)C-AcAc increased more than 2-fold while on the KD or after 48 hours F (P < 0.05). Similar trends were observed for (18)FDG uptake with a 1.9-2.6 times increase on the KD and F, respectively (P < 0.05). Compared to controls, MCT1 expression increased 2-fold on the KD (P < 0.05) but did not change during F. No significant difference was observed across groups for GLUT1 expression. Significant differences across the three groups were observed for plasma beta-hydroxybutyrate (beta-HB), AcAc, glucose, triglycerides, glycerol, and cholesterol (P < 0.05), but no significant differences were observed for free fatty acids, insulin, or lactate. Although the mechanism by which mild ketonemia increases brain glucose uptake remains unclear, the KD clearly increased both the blood-brain barrier expression of MCT1 and stimulated brain (11)C-AcAc uptake. The present dual-tracer positron emission tomography approach may be particularly interesting in neurodegenerative pathologies such as Alzheimer's disease where brain energy supply appears to decline critically.     

Effects of a medium-chain triacylglycerol/long-chain triacylglycerol fat emulsion containing a reduced ratio of phospholipid to triacylglycerol in pediatric surgical patients

OBJECTIVE: Medium-chain triacylglycerol (MCT) has been shown to provide better nutritional support than long-chain triacylglycerol (LCT). We compared the efficacy of MCT/LCT fat emulsions containing a usual (0.12) or a decreased (0.06) ratio of phospholipid to triacylglycerol (PL:TG) in pediatric patients under surgical stress. METHODS: Three patient groups (n=10 in each) received equivalent amounts of glucose (12 g.kg(-1).d(-1)) and amino acids (2 g.kg(-1).d(-1)), but group A received a 10% MCT fat emulsion (PL:TG 0.06), group B received a 20% MCT fat emulsion (PL:TG 0.06), and group C received a 10% MCT/LCT fat emulsion (PL:TG 0.12) in amounts of 1.5 g.kg(-1).d(-1) in a randomized study. Total parenteral nutrition was given for 7 d. Blood samples were collected before total parenteral nutrition administration and on days 4 and 7 for determination of various biochemical indexes. RESULTS: Serum phospholipid concentrations were significantly higher in group C than in group A or B on days 4 and 7 (P<0.05). Serum triacylglycerol and cholesterol concentrations and the very-low-density lipoprotein percentage were also significantly higher in group C than in group A or B on days 4 and 7 (P<0.05). The high-density lipoprotein percentage was significantly higher in group B on days 4 and 7 (P<0.05). CONCLUSIONS: In pediatric patients under surgical stress, a total parenteral nutrition regimen containing an MCT/LCT fat emulsion with a decreased PL:TG ratio (0.06) is likely to result in partly better lipid and lipoprotein metabolism than an emulsion containing the usual ratio (0.12).     

Dietary omega-3-polyunsaturated fatty acids prevent the development of metastases of colon carcinoma in rat liver

Background Fish oil consisting of omega-3 polyunsaturated fatty acids (PUFA) seems to reduce the incidence of colon cancer. The effect of PUFAs on metastasis of colon carcinoma is still unclear. Aim The study was designed to examine the effects of a diet rich in omega-3-PUFAs on a model of colorectal metastasis. Methods Thirthy animals (WAG/Rij) were randomly assigned to receive an omega-3 diet or a control diet to evaluate their effect on tumor growth. The target male rats (WAG/Rij) were fed a diet containing 15% omega-3-fatty acids three days before and 28 days after intervention and the control rats received 15% coconut oil at the same time points. CC 531 cells, a moderately differentiated colon adenocarcinoma, were injected into the spleen of each rat. After 28 days of diet, animals were sacrificed. The tumor growth was evaluated macroscopically and microscopically in liver tissue. The tissue was examined after immunostaining and the use of monoclonal antibodies. Results PUFAs decreased the index of tumor load from 1.54 in the controls to 0.79 in the treatment group (P = 0.036). While 69.2% of the control animals were tumor positive, only 21.4% of the target animals showed tumor after omega-3-fatty acid (P < 0.05). Conclusion We could show that omega-3-fatty acids may decrease malignant metastatic tumor growth in the liver.     

Low-carbohydrate diets cause obesity, low-carbohydrate diets reverse obesity: a metabolic mechanism resolving the paradox

High-fat diets produce obesity in part because, per calorie, glucose produces greater post-prandial thermogenesis than lipids, an effect probably mediated by glucose-sensing neurons. A very low-carbohydrate/high-fat/high-protein Atkins-type diet produces obesity but is marginally ketogenic in mice. In contrast, high-sucrose/low-fat diets, and very low-carbohydrate/high-fat/low-protein (anti-epileptic) ketogenic diets reverse diet-induced obesity independent of caloric intake. We propose that a non-ketogenic high-fat diet reduces glucose metabolism and signaling in glucose-sensing neurons, thereby reducing post-prandial thermogenesis, and that a ketogenic high-fat diet does not reduce glucose signaling, thereby preventing and/or reversing obesity.