Low-carbohydrate Ketogenic Diet Research Articles

Efficacy of Low-Carbohydrate Diets Versus Low-Fat Diets in Glycemic Control Among Patients With Type 2 Diabetes: A Systematic Review.

This systematic review evaluates the comparative efficacy of low-carbohydrate diets (LCDs) versus low-fat diets (LFDs) in improving glycemic control, weight management, and lipid profiles in individuals with type 2 diabetes mellitus (T2DM) or prediabetes. Seven randomized controlled trials involving diverse populations were included, with dietary interventions ranging from very low-carbohydrate ketogenic (LCK) diets (typically <10% of total caloric intake from carbohydrates, with higher fat and moderate protein) to moderate carbohydrate regimens (30-45% of total calories). LFDs, in contrast, prioritized carbohydrate intake (50-60% of total calories), with reduced fat (<20-30%) and moderate protein (15-20%). Across studies, LCDs consistently demonstrated greater reductions in HbA1c, fasting glucose, and triglycerides, alongside superior weight loss and increased high-density lipoprotein cholesterol compared to LFDs. Additionally, LCDs were associated with significant reductions in diabetes medication use, highlighting their potential to decrease pharmacological dependency and improve metabolic outcomes, including enhanced insulin sensitivity and reduced inflammation. Despite variability in long-term outcomes and adherence, LCDs emerged as a promising alternative to traditional dietary approaches for managing T2DM. Further research is warranted to explore strategies to improve dietary adherence, such as behavioral interventions and technological support, and to evaluate long-term sustainability, including their effects on cardiovascular health and quality of life. These findings underscore the transformative potential of LCDs in diabetes management and highlight the need for personalized dietary approaches.

Nutritional assessment and medical dietary therapy for management of obesity in patients with non-dialysis chronic kidney disease: a practical guide for endocrinologist, nutritionists and nephrologists. A consensus statement from the Italian society of endocrinology (SIE), working group of the club nutrition-hormones and metabolism; the Italian society of nutraceuticals (SINut), club ketodiets and nutraceuticals "KetoNut-SINut"; and the Italian society of nephrology

Chronic kidney disease (CKD) is a serious health concern with an estimated prevalence of about 13.4% worldwide. It is cause and consequence of various comorbidities, including cardiovascular diseases. In parallel, common pathological conditions closely related to ageing and unhealthy dietary habits increase the risk of CKD development and progression, including type 2 diabetes and obesity. Among these, obesity is either independent risk factor for new onset kidney disease or accelerates the rate of decline of kidney function by multiple mechanisms. Therefore, the role of diets aimed at attaining weight loss in patients with obesity is clearly essential to prevent CKD as to slow disease progression. Various dietary approaches have been licensed for the medical dietary therapy in CKD, including low-protein diet and Mediterranean diet. Interestingly, emerging evidence also support the use of low-carbohydrate/ketogenic diet (LCD/KD) in these patients. More specifically, LCD/KDs may efficiently promote weight loss, improve metabolic parameters, and reduce inflammation and oxidative stress, resulting in a dietary strategy that act globally in managing collateral conditions that are directly and indirectly related to the kidney function. This consensus statement from the Italian Society of Endocrinology (SIE), working group of the Club Nutrition - Hormones and Metabolism; the Italian Society of Nutraceuticals (SINut), Club Ketodiets and Nutraceuticals "KetoNut-SINut"; and the Italian Society of Nephrology (SIN) is intended to be a guide for Endocrinologist, Nutritionists and Nephrologist who deal with the management of patients with obesity with non-dialysis CKD providing a practical guidance on assessing nutritional status and prescribing the optimal diet in order to best manage obesity to prevent CKD and its progression to dialysis.

CTNI-64. TRIAL IN PROGRESS: DIET2TREAT -- A RANDOMIZED MULTICENTER PHASE 2 TRIAL OF A KETOGENIC DIET VS STANDARD DIETARY GUIDANCE IN COMBINATION WITH STANDARD-OF-CARE TREATMENT FOR PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA

Abstract BACKGROUND Many glioblastoma (GBM) patients inquire about the potential therapeutic benefits of a high fat / low carbohydrate ketogenic diet (KD). Preclinical models and early-phase trials have shown encouraging results, but definitive evidence of clinical efficacy is lacking. METHODS We are conducting a multicenter randomized controlled phase 2 clinical trial (NCT05708352) of KD vs standard dietary guidance (SD) for patients with newly diagnosed GBM. All patients receive standard-of-care chemoradiation. Inclusion criteria: newly diagnosed GBM, age ≥ 18 years, Karnofsky Performance Status ≥ 70. Exclusion criteria: inability to wean steroids below 8 mg dexamethasone/day, Body Mass Index &amp;lt; 21 kg/m2, food preferences incompatible with KD. Patients are randomized 1:1 to implement either KD or SD for a study period of 18 weeks, starting alongside chemoradiation. The primary outcome is overall survival for patients randomized to the KD arm compared to those randomized to the SD arm. Secondary outcomes include progression-free survival, health-related quality-of-life (FACT-BR, FACIT-F), cognitive performance (HVLT-R, Trail-Making Test A/B), and physical activity (modified Godin leisure questionnaire, continuous activity monitoring (Fitbit)). Patients randomized to the KD arm will be provided a fingerstick monitor to check blood ketone and glucose levels twice daily. Glucose and ketone levels are also periodically monitored for patients on the SD arm. Blood, tumor, and stool samples are being collected for high throughput profiling to assess the effects of KD on metabolic markers and immune response. Target accrual is 170 patients over 5 years. Enrollment began in July 2023 and is ongoing. As of May 2024, the trial is open for enrollment at Cedars-Sinai and UCSF, and will be opening soon at Duke, St. John’s Cancer Institute, and the Medical College of Wisconsin. 13 patients have been randomized to date. Funding provided by NIH R01CA276919 and the Foundation for Metabolic Cancer Therapies.

Effect of weight-maintaining ketogenic diet on glycemic control and insulin sensitivity in obese T2D subjects

IntroductionLow carbohydrate ketogenic diets have received renewed interest for the treatment of obesity and type 2 diabetes. These diets promote weight loss, improve glycemic control, and reduce insulin resistance. However,...

Comparative Efficacy of Low-Carbohydrate and Ketogenic Diets on Diabetic Retinopathy and Oxidative Stress in High-Fat Diet-Induced Diabetic Rats.

This study examined the effect of a low-carbohydrate diet (LCD) and a low-carbohydrate ketogenic diet (LCKD) on diabetic retinopathy in high-fat diet-induced diabetes mellitus in rats and studied the mechanisms of action. Rats were divided into four groups: the Control group, which was fed a normal diet for 16 weeks; the HFD group, which was fed a high-fat diet (HFD) for the first 8 weeks and then switched to a normal diet for 8 weeks; the HFD+LCD group, fed a HFD for 8 weeks followed by an LCD for 8 weeks, and the HFD+LCKD group, which was fed a HFD for 8 weeks followed by an LCKD for 8 more weeks. Both the LCD and the LCKD effectively reduced the final body and total fat weights and decreased fasting serum levels of glucose, insulin, hemoglobin A1 (HbA1C), triglycerides, cholesterol, and LDL-c. They also reduced the levels of malondialdehyde (MDA), tumor necrosis factor-α, vascular endothelial factor, caspapse-3, and bax. In the HFD rats, we found increased serum levels of β-Hydroxybutyrate and upregulated expression of Bcl2, glutathione, superoxide dismutase, and hemeoxygenase-1. Moreover, the LCD and LCKD significantly reduced mRNA levels of Kelch-like ECH-associated protein 1 (Keap1) and enhanced mRNA and nuclear concentrations of nuclear factor erythroid factor 2 (Nrf2). All these effects were associated with improved layers of the retina in the HFD - LCD and HFD + LCKD rats but not in HFD animals. The impact of the LCKD was always more profound on all measured parameters and on improving the structure of the retina compared to the LCD. In conclusion, the LCKD is superior to the LCD in preventing diabetic retinopathy in HFD-fed rats. Mechanistically, our results suggest that the hypoglycemic and hypolipidemic conditions and the Nrf2-dependent antioxidant and anti-inflammatory effects may be involved in the preventative effects of the LCD and LCKD.

Impact of very low carbohydrate ketogenic diets on cardiovascular risk factors among patients with type 2 diabetes; GRADE-assessed systematic review and meta-analysis of clinical trials

ObjectiveThis study was designed to evaluate the impact of VLCKD on cardiovascular risk factors in patients with T2DM.MethodsUntil March 2024, extensive searches were conducted on PubMed, Scopus, Web of Science, Embase, and other relevant databases. The purpose was to identify clinical trials examining the impact of VLCKD on glycemic control, lipid profile, and blood pressure. The GRADE (Grading of Recommendations Assessment, Development, and Evaluation) method was used to assess the evidence’s degree of certainty.ResultsOur initial search found a total of 2568 records and finally 29 trials were included in final analysis. Our results showed that adherence from VLCKD led to significant reduction in fasting blood sugar (WMD= -11.68 mg/dl; 95% CI: -18.79, -4.56; P = 0.001), HbA1c (WMD= -0.29; 95% CI: -0.44, -0.14; P < 0.001), HOMA-IR(WMD= -0.71; 95% CI: -1.14, -0.29; P = 0.001), insulin (WMD= -1.45; 95% CI: -2.54, -0.36; P = 0.009), triglyceride (WMD= -17.95; 95% CI: -26.82, -9.07; P < 0.001), systolic blood pressure (WMD= -2.85, 95% CI: -4.99, -0.71; P = 0.009) and diastolic blood pressure (WMD= -1.40; 95% CI: -2.66, -0.13; P = 0.03). We also found a significant increase in high-density lipoprotein (HDL) level after adherence from VLCKD diet (WMD = 3.93, 95% CI: 2.03, 5.84; P = 0.000). We couldn’t find any significant differences between groups in term of LDL and total cholesterol levels.ConclusionPeople following a VLCKD experience a more significant improvement in cardiovascular risk factors when compared to individuals on control diets.

Ketogenic diet-induced bile acids protect against obesity through reduced calorie absorption.

The low-carbohydrate ketogenic diet (KD) has long been practiced for weight loss, but the underlying mechanisms remain elusive. Gut microbiota and metabolites have been suggested to mediate the metabolic changes caused by KD consumption, although the particular gut microbes or metabolites involved are unclear. Here, we show that KD consumption enhances serum levels of taurodeoxycholic acid (TDCA) and tauroursodeoxycholic acid (TUDCA) in mice to decrease body weight and fasting glucose levels. Mechanistically, KD feeding decreases the abundance of a bile salt hydrolase (BSH)-coding gut bacterium, Lactobacillus murinus ASF361. The reduction of L. murinus ASF361 or inhibition of BSH activity increases the circulating levels of TDCA and TUDCA, thereby reducing energy absorption by inhibiting intestinal carbonic anhydrase 1 expression, which leads to weight loss. TDCA and TUDCA treatments have been found to protect against obesity and its complications in multiple mouse models. Additionally, the associations among the abovementioned bile acids, microbial BSH and metabolic traits were consistently observed both in an observational study of healthy human participants (n = 416) and in a low-carbohydrate KD interventional study of participants who were either overweight or with obesity (n = 25). In summary, we uncover a unique host-gut microbiota metabolic interaction mechanism for KD consumption to decrease body weight and fasting glucose levels. Our findings support TDCA and TUDCA as two promising drug candidates for obesity and its complications in addition to a KD.

Adult Inception of Ketogenic Diet Therapy Increases Sleep during the Dark Cycle in C57BL/6J Wild Type and Fragile X Mice.

Sleep problems are a significant phenotype in children with fragile X syndrome. Our prior work assessed sleep-wake cycles in Fmr1KO male mice and wild type (WT) littermate controls in response to ketogenic diet therapy where mice were treated from weaning (postnatal day 18) through study completion (5-6 months of age). A potentially confounding issue with commencing treatment during an active period of growth is the significant reduction in weight gain in response to the ketogenic diet. The aim here was to employ sleep electroencephalography (EEG) to assess sleep-wake cycles in mice in response to the Fmr1 genotype and a ketogenic diet, with treatment starting at postnatal day 95. EEG results were compared with prior sleep outcomes to determine if the later intervention was efficacious, as well as with published rest-activity patterns to determine if actigraphy is a viable surrogate for sleep EEG. The data replicated findings that Fmr1KO mice exhibit sleep-wake patterns similar to wild type littermates during the dark cycle when maintained on a control purified-ingredient diet but revealed a genotype-specific difference during hours 4-6 of the light cycle of the increased wake (decreased sleep and NREM) state in Fmr1KO mice. Treatment with a high-fat, low-carbohydrate ketogenic diet increased the percentage of NREM sleep in both wild type and Fmr1KO mice during the dark cycle. Differences in sleep microstructure (length of wake bouts) supported the altered sleep states in response to ketogenic diet. Commencing ketogenic diet treatment in adulthood resulted in a 15% (WT) and 8.6% (Fmr1KO) decrease in body weight after 28 days of treatment, but not the severe reduction in body weight associated with starting treatment at weaning. We conclude that the lack of evidence for improved sleep during the light cycle (mouse sleep time) in Fmr1KO mice in response to ketogenic diet therapy in two studies suggests that ketogenic diet may not be beneficial in treating sleep problems associated with fragile X and that actigraphy is not a reliable surrogate for sleep EEG in mice.

Abstract PO3-02-03: Ketogenic diet and letrozole to inhibit PI3K signaling in ER+ breast cancer

Abstract Obesity is associated with an increased risk of breast cancer recurrence, similar in magnitude to the reduction in risk seen with the use of adjuvant chemotherapy. However, whether and how obesity causes that increased risk of recurrence remains unknown. Plausible mechanisms include obesity-mediated increases in estrogen signaling, inflammatory conditions resulting from obesity, or effects on insulin or other growth factor signaling pathways resulting from the insulin-resistant state that often accompanies obesity. While phosphatidyl inositol 3-kinase (PI3K) signaling is the normal, biological effector of insulin signaling, abnormal activation of PI3K is of particular concern in breast cancer, where it is associated with resistance to endocrine therapies and HER2-targeted therapies. We hypothesize that at least part of the adverse outcome associated with obesity results from aberrant activation of PI3K signaling in tumors. This may confer resistance to established therapies, or directly stimulate tumor growth (particularly in tumors with existing PI3K pathway mutations), or both. We tested a dietary intervention designed to alter insulin resistance pathophysiology coupled with endocrine therapy in the well-established neoadjuvant treatment paradigm in breast cancer. This will allow us to study the effects of the dietary intervention directly on tumor biology. The primary objective of this neoadjuvant study was to assess feasibility and tolerability of 2 weeks of a very low-carbohydrate ketogenic diet in combination with letrozole for patients with early stage operable ER+ disease. Up to 36 patients will be enrolled for this pilot and feasibility study (24 in the treatment group and 12 controls). Baseline metabolic parameters will be measured and the treatment group will begin a dietitian-supervised 2-week diet to induce a ketogenic state, along with letrozole 2.5 mg daily. The control group will receive only letrozole. At the end of 2 weeks, patients will proceed with surgical treatment of their breast cancer. We will report the primary outcome measure of feasibility, assessed by determining 1) the proportion of patients in the diet group achieving ketosis, 2) adherence to the diet and 3) participant-reported measures of stress, fatigue, and emotional health. For both groups, cell proliferation will be measured in a tumor biopsy obtained from the surgical specimen and compared with the pre-treatment diagnostic biopsy. Correlative studies will evaluate tumor markers of insulin/PI3K signaling before and after the intervention and between diet and control. Citation Format: Brent Rexer, Vandana Abramson, Sara Nunnery, Sonya Reid, Laura Kennedy, Melinda Sanders, Jessica Bennett, Paula Gonzalez-Ericsson, Violeta Sanchez. Ketogenic diet and letrozole to inhibit PI3K signaling in ER+ breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-02-03.

A ketogenic diet enhances fluconazole efficacy in murine models of systemic fungal infection.

Invasive fungal infections are a significant public health concern, with mortality rates ranging from 20% to 85% despite current treatments. Therefore, we examined whether a ketogenic diet could serve as a successful treatment intervention in murine models of Cryptococcus neoformans and Candida albicans infection in combination with fluconazole-a low-cost, readily available antifungal therapy. The ketogenic diet is a high-fat, low-carbohydrate diet that promotes fatty acid oxidation as an alternative to glycolysis through the production of ketone bodies. In this series of experiments, mice fed a ketogenic diet prior to infection with C. neoformans and treated with fluconazole had a significant decrease in fungal burden in both the brain (mean 2.66 ± 0.289 log10 reduction) and lung (mean 1.72 ± 0.399 log10 reduction) compared to fluconazole treatment on a conventional diet. During C. albicans infection, kidney fungal burden of mice in the keto-fluconazole combination group was significantly decreased compared to fluconazole alone (2.37 ± 0.770 log10-reduction). Along with higher concentrations of fluconazole in the plasma and brain tissue, fluconazole efficacy was maximized at a significantly lower concentration on a keto diet compared to a conventional diet, indicating a dramatic effect on fluconazole pharmacodynamics. Our findings indicate that a ketogenic diet potentiates the effect of fluconazole at multiple body sites during both C. neoformans and C. albicans infection and could have practical and promising treatment implications.IMPORTANCEInvasive fungal infections cause over 2.5 million deaths per year around the world. Treatments for fungal infections are limited, and there is a significant need to develop strategies to enhance antifungal efficacy, combat antifungal resistance, and mitigate treatment side effects. We determined that a high-fat, low-carbohydrate ketogenic diet significantly potentiated the therapeutic effect of fluconazole, which resulted in a substantial decrease in tissue fungal burden of both C. neoformans and C. albicans in experimental animal models. We believe this work is the first of its kind to demonstrate that diet can dramatically influence the treatment of fungal infections. These results highlight a novel strategy of antifungal drug enhancement and emphasize the need for future investigation into dietary effects on antifungal drug activity.

The Significant Impact of High-Fat, Low-Carbohydrate Ketogenic Diet on Serum Lipid Profile and Atherosclerotic Cardiovascular Disease Risk in Overweight and Obese Adults.

Background and objectives Overweight and obesity are becoming more commonplace globally. The ketogenic diet (KD), also known as the high-fat, low-carbohydrate diet, has become increasingly popular in recent years as a means to lose weight quickly. This present study aims to examine the clinical effects of ketogenic diets in individuals who are obese or overweight by evaluating or assessing variations in metabolic parameters associated with lipid control, the risk of atherosclerotic cardiovascular disease, and other kidney risk indicators. Methods and subjects This observational case-control research involved 250 individuals in total and was conducted from May 2023 to January 2024. Of these, 158 were on a ketogenic diet, and 92 adults not following any type of diet were chosen to serve as controls. The biochemistry parameters of the kidney function test and lipid profile were measured for the two comparing groups. Data were analyzed for statistical significance using the Student t-test, Mann-Whitney U test, and one-way analysis of variance (ANOVA), followed by a post hoc test (least significant difference (LSD)). Chi-square tests were employed in the analysis to compare proportions. Results Out of 250 participants, there was a 20-80 age range, with their median age being 40 years old. The two comparing groups' lipid profiles were very different from one another; the cardiovascular risk (triglyceride (TG)/high-density lipoprotein (HDL)), total cholesterol, low-density lipoprotein (LDL), and triglyceride levels were all greater in the KD group when compared to the non-KD group. The mean LDL cholesterol (LDL-C) of the normal-weight participants was 56 mg/dL (p=0.079). Thereafter, it experienced a significant rise to 97.58 mg/dL and 108.2 mg/dL in thoseindividuals who were overweight and obese, respectively (p<0.020). Conclusions As obesity rates in the populace keep rising, dietary fads such as the ketogenic diet are gaining traction. Although they could help with weight loss, this study had a notable observation of severe hypercholesterolemia and increased risk of atherosclerotic cardiovascular disease among the ketogenic diet participants. Additional research is necessary to ascertain if a ketogenic diet can be sustained over the long term and how it affects endpoints that are more clinically significant, such as morbidity and mortality due to obesity.

Effects of ketogenic diet on weight loss parameters among obese or overweight patients with polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trails.

To evaluate how effective a low carbohydrate ketogenic diet (KD) is for changing key physical measurements such as weight, waist circumference (WC), body mass index (BMI), and fat mass (FM) in women with polycystic ovary syndrome (PCOS) who were obese or overweight. Several online databases, including PubMed, Scopus, EMBASE, Cochrane Library, and Web of Science (WOS), were searched systematically to find relevant randomized controlled trials (RCTs) up until June 2023. The Q-test and I2 statistics were used to assess the level of heterogeneity among the included studies. The data were then combined using either a fixed or random effects model and presented as a weighted mean difference (WMD) along with a 95% confidence interval (CI). Of the 682 citations, 11 RCTs were included. The pooled results showed a significant decrease in the WMD of weight levels [WMD = -9.13 kg; 95% CI, -11.88, -6.39, P < 0.001; I2 = 87.23%] following KD. Moreover, KD significantly reduced BMI levels [WMD = -2.93 kg/m2; 95% CI, -3.65, -2.21, P < 0.001; I2 = 78.81%] compared to the controls. Patients with PCOS received KD demonstrated significant decrease in WC [WMD = -7.62 cm; 95% CI, -10.73, -4.50, P < 0.001; I2 = 89.17%] and FM [WMD = -5.32 kg; 95% CI, -7.29, -3.36, P < 0.001; I2 = 83.97%]. KD was associated with lower weight loss (WL) parameters, including weight, BMI, WC, and FM, in obese or overweight women with PCOS, highlighting the significance of physicians and nurses in taking care of the nutritional needs of overweight/obese patients with PCOS.

Dietary and Metabolic Approaches for Treating Autism Spectrum Disorders, Affective Disorders and Cognitive Impairment Comorbid with Epilepsy: A Review of Clinical and Preclinical Evidence.

Epilepsy often occurs with other neurological disorders, such as autism, affective disorders, and cognitive impairment. Research indicates that many neurological disorders share a common pathophysiology of dysfunctional energy metabolism, neuroinflammation, oxidative stress, and gut dysbiosis. The past decade has witnessed a growing interest in the use of metabolic therapies for these disorders with or without the context of epilepsy. Over one hundred years ago, the high-fat, low-carbohydrate ketogenic diet (KD) was formulated as a treatment for epilepsy. For those who cannot tolerate the KD, other diets have been developed to provide similar seizure control, presumably through similar mechanisms. These include, but are not limited to, the medium-chain triglyceride diet, low glycemic index diet, and calorie restriction. In addition, dietary supplementation with ketone bodies, polyunsaturated fatty acids, or triheptanoin may also be beneficial. The proposed mechanisms through which these diets and supplements work to reduce neuronal hyperexcitability involve normalization of aberrant energy metabolism, dampening of inflammation, promotion of endogenous antioxidants, and reduction of gut dysbiosis. This raises the possibility that these dietary and metabolic therapies may not only exert anti-seizure effects, but also reduce comorbid disorders in people with epilepsy. Here, we explore this possibility and review the clinical and preclinical evidence where available.

Abstract C052: Ketogenic diet enhanced nutrient metabolic pathways but did not inhibit tumor growth in an obesity-associated PDAC mouse model

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal 5-year survival rate due to ineffective treatments. Obesity is a recognized risk factor for PDAC. Thus, developing effective weight management strategies is essential to decrease obesity, and potentially mitigate PDAC risk. The high-fat, low-carbohydrate ketogenic diet (KD) promotes weight loss and is a promising therapeutic strategy in some cancer preclinical models by altering tumor metabolism. Purpose: The KD will disrupt cancer metabolism, promote weight loss, and delay tumor growth in obesity-associated PDAC. Methods: C57BL/6 mice were fed an obesogenic high-fat diet (HFD) for 15 weeks to induce obesity, after which were randomized to a control diet (CD), a KD, or continued in the HFD for 7 weeks. After, mice were orthotopically injected with mouse KRas G12D/Trp53−/−/PDX-1-CRE (mKPC) cells containing the firefly luciferase gene. Tumor growth was monitored using luminescence through an In Vivo Imaging System. Body weight, glucose tolerance tests, and ketone measurements were performed before, during, and at the study end. Tumors metabolomics were analyzed by Liquid Chromatography Mass Spectrometry. Results: Mice gained weight after 15 weeks of an obesogenic diet. Mice that were switched to a KD or CD lost weight compared to mice that remained on the HFD following diet intervention. Mice fed a KD maintained increased ketone concentrations and increased glucose tolerance after tumors. However, none of the dietary interventions decreased tumor growth. Tumors in mice fed a KD showed significant enrichment in metabolic processes, such as, vitamin B6 and vitamin B5 metabolism, the citrate cycle, and arginine biosynthesis compared to mice that remained on a HFD. Conclusions: Although the KD induced weight loss and altered tumor metabolism, it was insufficient to decrease tumor growth in an obesogenic PDAC mouse model. Our data identified vitamin B6 and vitamin B5 metabolism, the citrate cycle, and arginine biosynthesis as important compensatory metabolic processes induced by the KD. Understanding the availability and functions of these metabolic processes could identify mechanisms of diet interventions for obesity-associated PDAC to decrease obesity, and potentially mitigate PDAC growth. Citation Format: Ericka Velez-Bonet, Kristyn Gumpper-Fedus, Fouad Choueiry, Zhu Jiangjiang, Zobeida Cruz-Monserrate. Ketogenic diet enhanced nutrient metabolic pathways but did not inhibit tumor growth in an obesity-associated PDAC mouse model [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C052.

Ketogenic diet for epilepsy and obesity: Is it the same?

The term “ketogenic diet” (KD) is used for a wide variety of diets with diverse indications ranging from obesity to neurological diseases, as if it was the same diet. This terminology is confusing for patients and the medical and scientific community. The term “ketogenic” diet implies a dietary regimen characterized by increased levels of circulating ketone bodies that should be measured in blood (beta-hydroxybutyrate), urine (acetoacetate) or breath (acetone) to verify the “ketogenic metabolic condition”. Our viewpoint highlights that KDs used for epilepsy and obesity are not the same; the protocols aimed at weight loss characterized by low-fat, low-CHO and moderate/high protein content are not ketogenic by themselves but may become mildly ketogenic when high calorie restriction is applied. In contrast, there are standardized protocols for neurological diseases treatment for which ketosis has been established to be part of the mechanism of action. Therefore, in our opinion, the term ketogenic dietary therapy (KDT) should be reserved to the protocols considered for epilepsy and other neurological diseases, as suggested by the International Study Group in 2018. We propose to adjust the abbreviations in VLCHKD for Very Low CarboHydrate Ketogenic Diet and VLEKD for Very Low Energy Ketogenic Diet, to clarify the differences in dietary composition. We recommend that investigators describe the researchers describing efficacy or side effects of KDs, to clearly specify the dietary protocol used with its unique acronym and level of ketosis, when ketosis is considered as a component of the diet's mechanism of action.

Ketogenic strategies for Alzheimer’s disease and other memory impairments: History, rationale, and 288 caregiver case reports

Glucose hypometabolism predates Alzheimer’s disease symptoms by at least one to two decades. Ketones are an alternative fuel to glucose and are taken up normally in affected regions of the Alzheimer’s brain and could address certain pathologies that are common in the aging brain and exaggerated in Alzheimer’s disease including insulin resistance, a brain-energy deficit, mitochondrial dysfunction, oxidative stress, and neuroinflammation. Ketones have also been shown to reduce formation of beta-amyloid plaques and neurofibrillary tangles in animal models. Experts have estimated that at least 30 percent of Alzheimer’s and other dementias could be avoided by adopting a healthy diet, increasing physical activity, and correcting other modifiable lifestyle risk factors. Mild to moderate ketosis can be achieved through consumption of a healthy whole food low-carbohydrate ketogenic diet, ketogenic oils containing medium-chain triglycerides, or exogenous ketone supplements as well as intermittent or overnight fasting, and moderately vigorous aerobic exercise. An analysis was performed of 288 anecdotal reports about people with Alzheimer’s, other dementias, Parkinson’s disease with dementia, mild cognitive impairment, and other diagnosed or subjective memory impairments consuming coconut oil and/or medium-chain triglyceride oil. Improvement was reported by 89.2 percent, no improvement by 7.3 percent, and no improvement but stabilization for at least 3 months by 2.4 percent. One or more improvements were reported in the areas of memory/cognition (65.3%), social/behavior/ mood/personality (32.6%), speech/language/conversation (33%), resumption of self-care/other activities (24.7%), physical symptoms (18.4%), sleep (3.5%), appetite (2.4%), vision (1.4%), and improvement that was otherwise unspecified (8%). Certain fatty acids found in medium-chain triglyceride oil and coconut oil are ketogenic but also have other important biological effects which, along with polyphenols and other bioactive substances in virgin coconut oil, could explain these results. Adopting a personalized ketogenic lifestyle plan using one or more ketogenic strategies could address certain pathological processes that occur in the aging brain while potentially improving symptoms in people with Alzheimer’s disease. In addition, this approach could possibly prevent or delay the onset of cognitive impairment during aging, though larger long-term studies would be needed to confirm this.

Nutritional Intervention in Cushing's Disease: The Ketogenic Diet's Effects on Metabolic Comorbidities and Adrenal Steroids.

a very low-calorie ketogenic diet (VLCKD) is associated with improvement of metabolic and cardiovascular disorders. We aimed to evaluate the effects of a VLCKD in patients with Cushing's disease (CD) as adjunctive therapy to treatment for the primary disease. we evaluated clinical, hormonal and metabolic parameters in 15 patients with CD and 15 controls at baseline after 1 week and 3 weeks of VLCKD and, further, after 2 weeks of a low-carbohydrate ketogenic diet (LCKD). after 5 weeks of diet, a significant decrease in BMI (p = 0.002), waist circumference (WC) (p = 0.024), systolic blood pressure (p = 0.015), diastolic blood pressure (p = 0.005), ACTH (p = 0.026), cortisone (p = 0.025), total cholesterol (p = 0.006), LDL cholesterol (p = 0.017), triglycerides (p = 0.016) and alkaline phosphatase (p = 0.008) and a significant increase in HDL cholesterol (p = 0.017), vitamin D (p = 0.015) and oral disposition index (oDI) (p = 0.004) was observed in the CD patients. A significant decrease in BMI (p = 0.003), WC (p = 0.002), systolic blood pressure (p = 0.025), diastolic (p = 0.007) blood pressure and total cholesterol (p = 0.026) and an increase in HDL cholesterol (p = 0.001) and oDI (p < 0.001) was observed in controls. the current study confirms that a ketogenic diet is effective in improving metabolic disorders in CD and shows that a nutritional approach may be combined with conventional CD therapy in order to improve metabolic and cardiovascular comorbidities.

Glucose restriction induces AMPK-SIRT1-mediated circadian clock gene Per expression and delays NSCLC progression

The rhythmic expression of the circadian clock is intimately linked to the health status of the body. Disturbed circadian clock rhythms might lead to a wide range of metabolic diseases and even cancers. Our previous study showed that glucose restriction was able to inhibit non-small cell lung cancer (NSCLC). In the current study, we found that glucose restriction enhanced apoptosis and cell growth delay in NSCLC cells. In addition, we used GEPIA database analysis to derive different effects of each circadian clock gene on lung cancer tissue. Among these circadian clock genes, Per (Period) is lowly expressed in cancer tissues and highly expressed in normal tissues. Moreover, the higher expression of Per in cancer patients has a better prognostic significance. Furthermore, we revealed that glucose restriction induced the expression of the circadian clock gene Per in NSCLC cells by upregulating SIRT1 (Sirtuin1) via activation of the energy response factor AMPK (AMP-activated protein kinase). Changes in Per expression following upregulation or downregulation of AMPK were consistent with AMPK expression. Additionally, a low-carbohydrate ketogenic diet significantly delayed tumor progression in a xenograft tumor model of severe combined immunodeficiency (SCID) mice. Meanwhile, the ketogenic diet increased the expression of AMPK, SIRT1 and Per in vivo. Besides, the ketogenic diet was found to restore the normal rhythmic level of Per by Zeitgeber Time (ZT) experiments. Taken these together, these results indicated a novel mechanism that glucose restriction induces AMPK-SIRT1 mediated circadian clock gene Per expression and delays NSCLC progression, which provided more evidence for glucose restriction as an adjuvant clinical therapeutic strategy in NSCLC.

Ketogenic Diet Affects Sleep Architecture in C57BL/6J Wild Type and Fragile X Mice.

Nearly half of children with fragile X syndrome experience sleep problems including trouble falling asleep and frequent nighttime awakenings. The goals here were to assess sleep-wake cycles in mice in response to Fmr1 genotype and a dietary intervention that reduces hyperactivity. Electroencephalography (EEG) results were compared with published rest-activity patterns to determine if actigraphy is a viable surrogate for sleep EEG. Specifically, sleep-wake patterns in adult wild type and Fmr1KO littermate mice were recorded after EEG electrode implantation and the recordings manually scored for vigilance states. The data indicated that Fmr1KO mice exhibited sleep-wake patterns similar to wild type littermates when maintained on a control purified ingredient diet. Treatment with a high-fat, low-carbohydrate ketogenic diet increased the percentage of non-rapid eye movement (NREM) sleep in both wild type and Fmr1KO mice during the dark cycle, which corresponded to decreased activity levels. Treatment with a ketogenic diet flattened diurnal sleep periodicity in both wild type and Fmr1KO mice. Differences in several sleep microstructure outcomes (number and length of sleep and wake bouts) supported the altered sleep states in response to a ketogenic diet and were correlated with altered rest-activity cycles. While actigraphy may be a less expensive, reduced labor surrogate for sleep EEG during the dark cycle, daytime resting in mice did not correlate with EEG sleep states.

What We Have Learned About Combining a Ketogenic Diet and Chemoimmunotherapy: a Case Report and Review of Literature.

A high-fat, moderate-protein, low-carbohydrate ketogenic diet has been reported in the literature as a treatment option for patients with cancer. A 69-year-old veteran was initially diagnosed with stage III colorectal cancer and progressed to having liver, pancreatic, and omental lymph node involvement despite completing adjuvant FOLFOX (fluorouracil, leucovorin calcium, and oxaliplatin) after surgery. The patient was treated with FOLFIRI (fluorouracil, leucovorin calcium, and irinotecan hydrochloride) and bevacizumab, followed by encorafenib and cetuximab on progression. Subsequently, he received pembrolizumab but continued to progress. The patient was later placed on trifluridine/tipiracil and bevacizumab concurrent with a ketogenic diet. Positron emission tomography and carcinoembryonic antigen levels indicated disease stabilization for 10 months. On progression, the patient was transitioned to ipilumimab and nivolumab and continued to adhere to the ketogenic diet. The patient's disease has continued to remain stable for the past 1 year. His degree of ketosis was determined using the glucose ketone index. The patient continues to have a good quality of life during concurrent ketogenic diet and therapy. This case supports the tolerability of the ketogenic diet along with chemotherapy and immunotherapy and should be considered as an adjunct to standard cancer treatment. In this report, we reviewed the latest literature about cellular mechanism of the ketogenic diet and the efficacy and relationship with chemotherapy and immunotherapy. We are about to open a ketogenic diet protocol at the Veterans Affairs Central California Health Care System in Fresno.