Food Regime: From Ketogenic Diet to Yeast Extract

Introduction

After Dr. Elliott Joslin recorded Diabetes in 1893, He had conjured the original concept of sugar intake limitation since then.  Dr. Rollin Woodyatt noted that under conditions of starvation and a low carbohydrate diet, acetone, and beta-hydroxybutyric acid appeared. At the same time, Dr. Russell Wilder dissected that ketonemia could be produced for therapeutic benefit to develop the term “ketogenic diet.” The ketogenic diet (KD) became popular in the treatment of childhood epilepsy. Over the past few decades, many studies have sought to quantify the efficacy of low carbohydrate diets in terms of weight loss and the mechanism has been laboriously explicated.

Brain’s main energy source comes from glucose and ketones that pass through the blood brain barrier to replace the glucose during fasting or energy deprivation.  Ketones have been motivated in the liver by oxidation of free fatty acids in response to low glucose and insulin decreasing during dietary energy or carbohydrate restriction. Therefore ketone bodies like acetoacetate and beta-hydroxybutyrate increase and spare brain glucose to enter the citric acid cycle. In order to reduce cerebral glucose metabolism, a ketogenic diet could be a potential intervention in the high energy-consuming brain activity.  The KD is a high-fat, low-carbohydrate diet that restricts carbohydrates to ≤10% of the energy cost. This nutrient profile promotes a systemic shift from glucose metabolism toward the conversion of fatty acids into ketone bodies as a substrate for energy. Some food products that are known to contain rich ketone body precursors are medium chain triglycerides (MCT) oils.  Dietary MCTs are hydrolyzed rapidly and efficiently by pancreatic lipase into medium chain fatty acids (MCFA).  MCFAs are saturated fatty acids with carbon chain lengths of C6, C8, C10, or C12 that are comprised primarily of octanoic acid (C8), decanoic acid (C10), and small proportions of capric acid (C6) and lauric acid (C12).  Characterized MCFAs are directly absorbed through the gut via the portal vein to the liver, rather than through the thoracic duct lymph system, which is the conventional route for the absorption of triglycerides containing long-chain fatty acids ( LCFA). Within the liver cell mitochondria, MCFAs are rapidly metabolized through beta-oxidation and finally become ketone bodies released into the bloodstream. MCT and MCFA reveal distinct physicochemical and metabolic properties compared to LCFA. As a result, MCT appears as an energy source in the applications that contribute to improving metabolic disorders and brain diseases such as type II diabetes, Alzheimer’s disease (AD), and epilepsies. In recent decades, bioactive compounds from yeast extract synergize the performance by supplying rich amino acids and list of full B-group vitamins, minerals and cell wall polysaccharides ingredients into food recipes.

It is outlined here the application of ketogenic diet in some medical conditions as obesity and diabetes, and the adding of MCT food with rich vitamins, minerals and fibers from yeast extract may aid the individuals who are intolerant of distress for a long term use of a strict ketogenic diet. The new combinations of the dietary recipe will be expected to improve the outcomes.

Conditional Dietary Curriculum

1. Ketogenic Diet

A ketogenic diet (KD) is a high-fat (over 50 % calories as fat), adequate protein (accounts for 30–35% of the daily calories) and low-carbohydrate diet (only 5–10% of total calories per day). The different food supplied has shifted the energy source and driven it to a new metabolism pathways of gluconeogenesis and ketogenesis. Following the nutrient recipe, ketone body level in the plasma  elevates by deprivation of carbohydrate substrate. Mobilization of the lipolysis for energy support for the brain and kidneys will happen, contrary to the effect of an elevation in glucose and insulin levels when fatty acids are driven towards storage rather than consumption.

The KD essentially induces a metabolic program that mimics a physical condition of starvation, that is, during short periods of low carbohydrate intake, carbohydrate glycogen is reconfigured as an energy source. When fasting time is elongated and glycogen reserves are depleted, the gluconeogenesis process will be stimulated in order to supply additional glucose. The synthesis of glucose moves essentially in its core to lactic acid, glycerol and the glucogenic amino acids. Next, ketone bodies are mobilized as a substitute for glucose. The main energy source of dietary fat and the lipid that stored in adipose tissue are mobilized into mitochondria of the liver cell where fatty acids undergo beta-oxidation to produce acetyl-CoA.  After a series of biochemical reactions, the ketone body as acetone, acetoacetate, and beta-hydroxybutyrate has been formed.

KD has been shown to be effective in the short to medium term in helping control lipid profile and as a tool to counteract obesity, leading to a significant decrease in weight, body mass index, and fat mass. It is likely that the weight loss achieved with the KD could lower A1c and benefit some individuals with metabolic ailments such as diabetes mellitus. In addition to its role in determining modifications in metabolic substrates, KD has a role in modulating mitochondrial renewal via mTOR pathways in neurotransmission, oxidative stress, and inflammatory reaction. KD has been detailed to increase plasma fibroblast growth factor 21 (FGF21) levels,  also enhancing the overall efficiency of energy production through respiration. Anti-inflammatory potential may help target the altered energy metabolism of cancer cells. Some studies have demonstrated that KD is associated with a lower risk of cardiovascular mortality, but long-term safety and health have yet to be proven, especially with regard to lipid profile alterations and cardiovascular impact.

KD usually takes at least 2 to 3 weeks and up to 6 to 12 months, for extended periods of time (more than six months) is generally not recommended. Various reports indicate a major adverse effect called “keto flu”, which is a group of transient symptoms reported to commonly happen constipation, headache, bad breath, muscle cramps, diarrhea, vomiting, and general weakness are the main symptoms. To date, the reasons why keto flu occurs has not been fully elucidated. The main hypotheses to its cause are increased urinary sodium and potassium levels, and water loss to dehydrate and acidosis, along with reduced insulin levels and B-group vitamin deficiency. Potential for ketoacidosis and hypoglycemia in some cases has been reported when caloric intake is too low and/or prolonged and repeated fasting. Individual responses may vary and the diet may not be suitable for everyone with elders, pregnant women, adolescence. Close monitoring of blood glucose levels, ketone levels, and potential side effects is necessary. In consideration of its encouraging effects on carbohydrate metabolism and glucose levels, more in-depth investigations are needed to study all the short-term and long-term effects exerted by KDs, in order to determine whether these diets may be safely implemented in different subjects with varied physical status.

2. MCT Food

The KD applying is limited due to the severity of this dietary regime, which requires an almost complete reduction of dietary carbohydrates to enable ketogenesis from the long chain fatty acids (LCFA) that are abundantly distributed in nature. A few alternative strategies have been proposed by adding various ketogenic supplements to KD, including the medium-chain triglycerides (MCTs) which are hydrolyzed to medium-chain fatty acids (MCFAs). As a consumable product, MCFAs are saturated fatty acids with a carbon chain length from 6 to 10 carbon atoms. Most MCTs are produced from coconut and palm kernel oils, also present in milk products.

In contrast to LCFAs which get activated and esterified in intestinal enterocytes to form chylomicron and are transported via lymph transport system,  MCFAs are primarily transported directly to the liver through the portal vein. In liver cells, the MCFAs enter mitochondria where they get activated to undergo beta-oxidation to produce acetyl-CoA. Whereas the activated LCFAs are primarily directed toward triglyceride (TG) storage, phospholipid biosynthesis, and excretion in very low-density lipoprotein (VLDL) particles. The overproduced acetyl-CoA by MCFAs can be redirected to ketogenesis in the mitochondria. The ketone bodies as acetoacetate and beta-hydroxybutyrate, be transported into the bloodstream to other organs like the brain and kidney, where they can be converted back to acetyl-CoA and used in the TCA cycle to produce ATP.Thus MCFAs are used as economic and fast mobilized supply to these energy consuming organs. After combination of MCFAs into the ketogenic diet,  the ketone body contributes to the supply of energy and to fulfill the quick requirements while LCT and LCFA show significantly slow circulation due to their molecular structure and biological properties.  Higher ketone levels may help provide an alternative fuel source for the brain and other organs when carbohydrate intake is restricted, the exogenous ketogenic supplement may help the endogenous lipolysis of the whole body to get weight loss.

It is found that MCT oil improves diabetes risk factors like insulin resistance in participants with type II diabetes following a KD program. This suggests MCTs may help enhance the therapeutic effects of a KD for diabetes management. The search results also clarified that a KD with MCT oil could potentially benefit Alzheimer's disease by promoting ketone metabolism in the brain. This response is directly proportional to their plasma kotone concentrations. Mild to moderate nutritional ketonemia has been shown to be beneficial for the management of severe refractory epilepsy. The ability to rapidly metabolize MCFAs and generate ketone bodies may have evolved as an adaptive mechanism to provide an immediate energy source during periods of starvation or high energy demands. This could be particularly advantageous for brain energy metabolism.

A growing number of studies have demonstrated that MCT supplementation of a regular diet has a positive effect on cognition, both in healthy individuals and those with Alzheimer disease. Although it is generally assumed that the precognitive effects of MCT supplementation are mediated by ketone body, a few animal and in vitro studies have shown that MCFAs may also exert effects in the brain directly, the mechanisms of the beneficial effects on cognition are far from being fully understood.  Moreover, since MCFAs, LCFAs, and glucose participate in mutually intertwined metabolic pathways, some studies have shown odd-chain fatty acid (OCFA) and branch-chain fatty acid (BCFA) also important to affect metabolic health. Many open questions, as MCFAs metabolite-specific mechanisms, and its metabolic consequences, are in potential considerations. However, the amount of MCT oil intake from  the diet should be proper 5ml to 15ml daily. Over the limit of that, most commonly side effects of the oil are gastrointestinal distress, including diarrhea, vomiting, nausea, abdominal cramping, and bloating when consuming large amounts or introducing MCT oil too quickly.

In summary, the rapid conversion of MCTs into ketones, their ability to increase ketone levels, and potential to improve insulin sensitivity make MCT oil and MCT supplementation beneficial adjuncts to a KD for better glycemic control and management of brain function.

3. Yeast Extract Application

Originally, yeast extract is a food ingredient made from bakers' or brewers' yeast (Saccharomyces cerevisiae). In recent decades, it is produced by growing yeast in large fermentation tanks, then breaking down the yeast cells to extract the contents. The extract is full with the proteins, vitamins, minerals, and other compounds, to provide food protein source for essential amino acids, vitamin supply and raw medical material.  A diverse array of bioactive compounds like nucleotides, glycosides, and other secondary metabolites are developing to have new terms in prescriptions, the yeast plays its role from food additive to more therapeutic applications in the health arena.  

Brewer's yeast supplementation has been shown to improve glycemic indices, such as fasting blood sugar and HbA1c, and insulin sensitivity in patients with type 2 diabetes mellitus. The proposed mechanism is that it can enhance insulin receptors and improve glucose metabolism and that have positive impacts on glycemic control, obesity, and related metabolic disorders. Some yeast strains like Saccharomyces cerevisiae may help boost the immune system and reduce inflammation. Likely through a combination of ketogenic diets and MCT intaking regime yeast extract provides essential nutrients that may modulate key metabolic pathways.

Bioactive compounds: Yeast extract contains rich B-group vitamins, such as B1, B2, B3, B6, B7, B9, B12 and folic acid,  that can be used in treatments for vitamin deficiency for malnutrition patients.

Thiamine (B1) serves as a coenzyme that performs various functions,  by aiding in the exchange of aldehyde groups and glycation. These actions are of significant importance and have the potential to influence the onset of diabetes. Niacin ( B3) supplementation improves high-density lipoprotein (HDL) cholesterol while lowering triacylglycerides and low-density lipoprotein (LDL) cholesterol, although the impact of diabetes on these parameters has received less attention. Vitamin B6 is made up of three different molecules, pyridoxal, pyridoxine, and pyridoxamine, along with their phosphorylated derivatives. Like an aminotransferase and as a cofactor for glucose phosphorylase, it plays a crucial role in the metabolism of glucose which is necessary for the utilization of glycogen in the liver and muscles The creation of methionine, pyrimidine, and purine bases all require vitamin B12, which functions as a coenzyme in the metabolic pathways by introducing single-carbon molecules. Type 2 diabetes on metformin has been linked to reduced levels of vitamin B12 in the blood. A deficiency of folic acid that distributes in animal products, leafy greens, legumes, and nuts, has been associated with several health conditions, including megaloblastic anemia, neural tube defects, cardiovascular disease, cancer, and senile dementia. Although vitamin B12 deficiency and the resulting hyperhomocysteinemia are not common, supplementing experiments have been conducted in people with diabetes because of the role folic acid plays in the etiology of the disease. Hyperhomocysteinemia has been linked to inadequate folate and B-12 intakes in individuals with type 2 diabetes, according to a case-control study. Folic acid reverses DNA damage, which can be measured by the appearance of micronuclei. Studies have shown that taking additional folate can help people with type 2 diabetes better control their blood sugar levels by lowering glycosylated hemoglobin, fasting glucose, insulin levels, insulin resistance, and homocysteinemia.

Polysaccharides: Yeast cell wall contains structural polysaccharides like beta-glucans that are composed of D-glucose monomers joined by beta-glycosidic linkages, as linear beta-(1,3) and branched beta-(1,6) arrangement. Beta-glucans are abundancy of hydroxyl groups that form hydrogen bonds with water which gives the molecule capacity in both soluble and insoluble states.

Multiple features of beta-glucan, with anticancer, anti-diabetic, anti-inflammatory,  and a decrease in the glycemic index as well as serum cholesterol and triglyceride, with maintaining the balance of blood glucose and an edifying good for cardiovascular diseases.  Beta-glucans function in the immune system and show antimicrobial properties, which could be the evolutionary legacy remaining from the long ancient days.

Soluble beta-glucan as a ligand binds to its receptor on the surface of cell membrane which belongs to a type II trans-membrane protein receptor Dectin-1 (a C-type lectin receptors, CLRs). It is expressed in macrophage, dendritic, and neutrophil cells, which are responsible for an innate immune response. The binding of Dectin-1 with beta-glucans can start and control the innate immune response, such as phagocytosis, inflammatory cytokines production, ROS production, and pro-inflammatory factors production, leading to the elimination of infectious agents. Additionally, it also promotes Th1 and Th17 responses to arrange immunity to pathogens. Ligand-binding Dectin-1 activates phospholipase to trigger an intracellular Ca2+ flux in dendritic cells. Elevated concentration of Ca2+ is crucial for secreting IL-2, IL-6, IL-10, IL-12, IL-23, and TNF α. Dectin-1 also modulates the expression of cytokines via activating the nuclear factor of activated T cells (NFAT) that regulates IL-2, IL-10, and IL-12 p70 production.

Insuloble beta-glucans remain in the gut to produce short chain fatty acid (SCFA) mainly through saccharolytic cell wall fermentation in the lower part of intestine where beta-glucan escapes digestion. The major products are formate, acetate, propionate and butyrate that can be used by bacteria and absorbed in the intestine. High fiber intake can improve whole-body insulin sensitivity by increasing colonic production of the short-chain fatty acid. Fermentation of the resistant fibers in the colon shows complex dynamic relationships between dietary substrate, microbiota composition and host cells to  form a germ-host ecosystem of mutualism in the human gut. Supplements containing yeast beta-glucan, prebiotics, minerals, and other compounds have been found to improve obesity-related metabolic parameters. Hits from these yeast-based properties can be further validated in more complex functions applied in human health architecture.

However, the nucleic acid level in raw yeast extract is about 15%, 10 times the amount found in human tissues. This is the potential risk associated with gout, a state of hyperuricemia causing urate crystals formation and arthritis in the toe joints. To ensure the safety of yeast-based products as a nutrient source, the nucleic acid content should be reduced to a level allowing a maximum intake of 2g/day and effective techniques are needed to reduce nucleic acid content in preserving the nutritional value.

Perspectives and Conclusions

In the last centennial the environment change and technology progress have dramatically transformed traditional dietary into fast and convenient food.  The food spectrum varies its pattern so speedy more than human genetically and physically could accept. In addition, the modern manufacture pursues higher profit and more efficiency so that fast food overwhelms the national and regional cuisine. The paradox of food production is faced to all of us: the more food genre that is acceptable and the more are probable hazardous factors to human health. The food pattern is of a high carbohydrate, high calories and high flavor, meanwhile, with low fibers, low native and low variety.

Unhealthy food is a widespread problem in the world that greatly affects the quality of life, leading to greater risk for obesity, diabetes, and cardiovascular diseases. Pathologically, diabetes develops progressively as a result of the complex interaction between insulin resistance and beta cells dysfunction. Dietary inputs influence the glucose-insulin homeostasis and thus affect the level of blood sugar, so that the food with low calories and low carbohydrate with low glycemic index significantly decreased the risk of type II diabetes. Besides that, micronutrients such as fibers in the diet also affect the glucose-insulin homeostasis to prevent weight gain and improve markers of insulin sensitivity. Although some food nutrients had a significant benefit for type II diabetes prevention, recent dietary recommendations focus on overall dietary balance rather than single isolated nutrients. Dietary patterns, or combination of regularly consumed foods, can produce synergistic health effects not only by decreasing calories but also through metabolic route toward influencing the insulin response. In this review, we examplified the ketogenic diet, medium chain fatty acid ( combined with a fraction of long chain fatty acid and some odd/branch chain fatty acid ) and yeast extract including B-group vitamin, polysaccharides and so on. More natural food such as vegetables, fruits, legumes, nuts, beans, cereals, whole grains, fish, and unsaturated fats, are also profitable.

With the advances of science and technology, and understanding the essence of individual dietary recipes and medical supervision for genetic propensity, the food industry will produce not only sanitary and agreeable, but also nutritious and healthy food and drink. Although there is no elixir for everybody, edible food supply is the first step to the guidance leading to a healthy journey. With medical intervention, lifestyle correction,  plus appropriate exercise, decreasing the risk of complications, ketogenic diet, M/LCFA,  supplement of yeast extract that contains multiple vitamins and fibers, all contribute to benefit in the general population. But still, there are far and wide terra incognita to be explored in the future.

Written by  Dr. Haining Jin  and  Dr. Bin Xu