Ketosis during pregnancy has been known for many years. Fetal growth depends on constant energy supply, so physiological mechanisms should have been developed during evolution to assure intra-uterine development under starvation or food scarcity. Most studies focusing on pregnancy and fetal development have been done, for obvious reasons, on animals. It is not possible to extrapolate every detail, but it gives us a great idea and explanation for the metabolic changes observed during pregnancy. Briefly, there are two metabolic periods clearly differentiated during gestation. The first one, corresponding to the first two thirds, is the anabolic phase characterized by hyperphagia and enhanced storage of body fat (we will call it Phase I). During the last third of gestation, the catabolic phase, fetal growth is very rapid, so the energy needs of the fetus are increased (1) (we will call it Phase II). Insulin metabolism, as an acquired evolutionary mechanism, plays a key role during this process. During Phase I, there is a 3.0 to 3.5 fold increase in first-phase and second-phase insulin release in response to glucose, without an alteration in peripheral IS (2). This assures that accumulation of protein, glucose and fat is appropriate for late pregnancy. As pregnancy progresses, this increase in glucose-stimulated insulin secretion is maintained, but IS is reduced in 50-70% (3, 4) during late pregnancy (Phase II). This mechanism serves to redistribute glucose and energy to the rapid growing fetus. In addition to peripheral IR (but not hepatic), gluconeogenesis (GnG) is increased 16 to 30% to supply the placenta and fetus demand. Contrary to the main GnG precursors in non-pregnant adults, glycerol is the main glucose precursor, which represents a mechanism by which in the abscence of food, the mother is capable of producing the necessary glucose from a substrate that is readily available during fasting and not depend on external substrates. This process is accentuated by fasting, commonly known as "accelerated starvation": compared to non-pregnant, women during gestation exhibit a pronounced hypoglycemia and rapid rise in KB. GnG increases parallels the rise in KB (4). Because of its increased utilization, glucose has drawn much attention away from the importance of KB in fetal development. bOHB is utilized in a dose-dependent manner by the rat conceptus (5) and serves to spare glucose and lactate for biosynthetic pathways (6). bOHB seems to be the main oxidative fuel to the human fetal brain, measured by the production of CO2 (7). A classic study done on rat embryos underscore the importance of both glucose and bOHB to a proper development (8). Researchers tested the effect of increasing doses of glucose, KB or both on organ teratogenesis. They first tested glucose alone. According to the authors:(...) we found that isosmotic supplementation of the culture medium with 12 mg/mL D-glucose during the 48-h incubations effected a generalized retardation of rat-embryo growth and lesions such as microencephaly, exencephaly, open neural tube, and pericardial edema (6). We documented specificity by demonstrating that the findings are not replicated with isosmotic equimolar additions of certain other hexoses, such as sorbitol, fructose, inositol, or galactose (6). Teratogenic potentialities of high glucose concentrations have also been demonstrated with cultured mouse embryos. Sadler elicited dysmorphogenic effects with increasing frequency by adding 5mg/mL or 8 mg/mL D-glucose to the suspending rat serum during mouse-embryo culture (33).
So high glucose concentrations are teratogenic for the embryo. They went further and examinated the effect of increasing doses. During the period of these studies in 1980-1981, isosmotic additions of 12 mg/ mL elicited a 49% incidence of minor and a 23% incidence of major lesions. By contrast isosmotic additions of 3 mg/mL D-glucose to the incubation medium did not evoke any discernible lesions during 48 h of culture, 6mg/mL resulted in only a 2.2% incidence of minor and no major lesions, and 9 mg/mL D glucose were required to elicit 5.1% major and 17.8% minor lesions in the cultured intact embryos from our outbred strain of Charles River Sprague-Dawley rats.
They concluded:(...) the dysmorphogenic potentialities of ambient glucose are clearly concentration dependent although the precise relationships may be quantitatively different in various species or in different strains from the same species.
So we know that hyperglicemia is teratogenic. But what about increasing doses of bOHB? Preliminary acute incubations with 14C-labelled 14C-hydroxybutyrate indicated that cultured embryo units can oxidize ketones on day 10.4 as well as 1 1.4 of development (36) so that ketones can subserve nutrient functions in some portions of the conceptus at both times. What about the effects of ketones on embryogenesis during these intervals? As summarized in Figure 3, isosmotic additions of 2 or 4 mM buffered D,L sodium (3-hydroxybutyrate during 48-h culture of rat conceptus from day 9.5 to 1 1 .5 of development did not elicit any discernible dysmorphogenesis.
So physiological concentrations of bOHB, as in a low carbohydrate diet, ARE NOT TERATOGENIC. Problems appear only when going above this threshold, as in DK. However, with 8 mM, 24.5% of the embryos developed minor lesions, and the inclusion of 16 mM D,L /3-hydroxybutyrate was associated with a 71% frequency of minor and 45% incidence of major lesions (36).
See the trend? With 8mM only a quarter developed minor lesions. But when levels went way up (not physiological) lesions are aggraviated.
On the left, added concentrations of glucose and on the right, added concentrations of bOHB. The trend is clear, there is no damage when KB are in the physiological range, but when levels increase to concentrations seen in DK, boom! As always, the problem arises with hyperketonemia, not ketosis. Its easier to develop hyperglycemia than hyperketonemia (except during starvation). Lastly, what happens if we mix the minimally teratogenic amount of glucose (6mg/dL) with the minimally teratogenic amount of bOHB (8mM)? Sinergy! 66% displayed minor lesions and 27.7% major lesions. Some of the effects could not be explained by normal growth retardation. KB are so important to normal growth that there is evidence that fetal ketogenesis occurs (9). To achieve an optimal development, the fetus must not be exposed to increased concentrations of KB nor glucose. Both sources of fuel are necessary but in the right amount. The body adapts to this situation increasing the production of glucose from glycerol, reducing the need for ingesting extra glucose. Increasing calories and carbohydrates during pregnancy predisposes the mother to hyperglycemia, GD and IR, neonatal macrosomy and teratogenesis. Reducing the GL of the diet has shown to offer benefits compared to a low-fat diet (10), even when carbohydrate intake is reduced to 40-45% of total calories (11). Controlled studies adressing the effects of less than 40% of carbohydrates are scarce (evil ketosis!). Nevertheless, going zero carb can be as dangerous as going high carb* (12). But there is no need to go up to 60%. In rats, the requirement for normal growth seems to be around 18-20% (13), comparable amount of carbohydrates eaten by most low carbers and/or paleo, while the human fetus consumes around 20-25g/glucose per day during late gestation (4). Maintaining a proper diet with plenty of saturated fat, low carbohydrate and adequate protein/EPA+DHA is essential for a healthy pregnancy. Quality over quantity. Any experiences to share?*Although this is physiolgically impossible. Only achievable eating zero carb protein drinks and oil.
Traditional ketogenic diets are both low in protein and carbohydrates. The main argument is that because almost 60% of the ingested amino acids are glucogenic, one must also restrict protein intake to achieve ketosis. According to VanItallie and Nufert (see Ketosis Essentials):"This occurs because approximately 48 to 58% of the amino acids in most dietary proteins are glucogenic. For every 2 grams of protein consumed in a carbohydrate-free diet, somewhere between 1.0 and 1.2 grams are potentially convertible to glucose. Therefore, to obtain a degree of hyperketonemia (approximately 2–7 mM/L) believed to be therapeutically effective in certain important medical conditions such as epilepsy, patients must rigorously restrict protein as well as carbohydrate intake and, when possible, increase their level of physical activity. (my emphasis)"
This is why, for example, a typical ketogenic diet to treat epilepsy utilizes a ratio of 4:1 or 3:1 (Fat:Protein+Carbohydrates). So what happens when we eat a high fat/high protein diet? Let's look at Eskimos (1). On average, they consume approximately 280g of protein, 125g of fat and 54g of carbohydrate. This gives us a total of 2461 kcal of which 45.5% is protein, 45.71% is fat, and around 8.77% is carbohydrate. This is both high protein and high fat, and very low carbohydrate. Kind of my ideal diet. When researchers studied their metabolisms, they found that they are not in ketosis during their usual diet. Ketosis is developed during fasting, but to a much lesser degree than other human subjects. The authors concluded:"Eskimos show a remarkable power to oxidize fats completely, as evidenced by the small amount of acetone bodies excreted in the urine in fasting."
Further studies showed the same results. For instance, Steffanson and Andersen, both who lived eating 9 years an Eskimo diet, participated in a controlled study eating only meat for one year (2). Besides health improvements, a very mild ketosis was observed, similar to the Eskimo studies. But these studies are really old (late 20's-early 30's) and the degree of ketosis was measured by urinary ketones. It is known that ketonemia is a better indicator of the degree of ketosis than ketonuria (3, 4, 5). This is very important because measuring ketosis by ketonuria tend to show many false positives (throw away dose damn strips!). During popular weight loss ketogenic diets, ketonuria (6, 7) and ketonemia (8) are observed despite the high percentage of calories derived from dietary protein. Even with a low calorie high protein diet (PSMF) ketonemia appears (9).If KB are excreted by urine, why does ketonuria not always correlate with the degree of ketosis? The answer lies in KB metabolism. During fasting, KB start to rise until a plateau is reached almost at 5 days. This occurs both because of a reduced skeletal muscle clearance and decreased production by a negative feedback loop (10). The effect on KB removal rate is equal on both diabetic and normal subjects, only differing on the production rate of KB (ketogenesis)*. Urinary excretion of KB is always < 10% of total turnover. So the level of KB in plasma is determined by the difference between ketogenesis and clearance by extra hepatic tissues, while ketonuria accounts only for a small part of the equation. Increasing the utilization of ketones by peripheral tissues reduces its excretion, so one active keto-adapted person can be in strong ketosis but show almost no urinary ketones. Although the degree of ketosis is dependent on the amount of dietary fat, there are some tools for increasing it without decreasing protein intake and/or increasing fat intake. Exercise has shown to increase both ketogenesis and metabolic clearance rate (11), but the effect on the latter is abolished at high concentrations (12) and when basal ketone concentrations are high (5.7mM) (13). This is because skeletal muscle adapts to use FFA as energy and spares ketones for non-FFA-using tissues, like the brain. During a LCKD, exercise enhances ketogenesis and the degree of ketonemia, as RQ values during exercise in ketogenic conditions have shown to be as low as 0.7 (14) and even 0.66 (15). In fact, post-exercise ketosis is a well known phenomenon (16). The hormonal environment is another factor that influences ketogenesis and plays a direct role in the enhancing properties of exercise. Insulin is the classic anti-ketogenic hormone, while catecholamines are strong ketogenic activators (17, 18). Exercise increases the body energy needs and catecholamine secretion, while decreasing insulin and glucose levels (16). With some differences, this scenario is similar during fasting. Traditionally, studies on FK and energy metabolism during fasting have been done during starvation, but lately ADF and IF is being studied as a potential therapy to treat and prevent several diseases. For example, ADF increases bOHB levels after 22 days even while eating ad libitum and without carbohydrate restriction (19). Moreover, KB begin to rise after an overnight fast in "normal" people**. This is because during short term fasting the expression of PDK4, LDL, UCP3 and CPTI is increased, showing a "glucose-sparing" mechanism and shifting towards a lipolytic metabolism (20). This changes arent reversed by a LCKD, which has similar effects on gene expression. IF/ADF would potentiate the effects of a LCKD on ketogenesis, lipid metabolism and glucose sparing. Another aspect which influences the degree of ketosis is food. It is well known that coconut oil (and specifically MCTs) increases plasma KB (21, 22). Black tea has also shown some ketogenic properties (23). Adrenergic stimulation by dietary stimulants (such as coffee or green tea) could induce ketogenesis, specially during a fast, where adrenergic sensitivity is increased. Both adrenaline and noradrenaline have ketotic effects (24). Catechin-poylphenols in green tea, for example, have shown to inhibit catechol-O-methyl-transferase and caffeine to inhibit transcellular phosphodiesterases (25). SummaryYou can eat a high protein diet and still induce strong ketosis. A combination of a high fat/high protein diet, resistance exercise and fasting (as per my recommendations in my introduction post) induces a strong metabolic response of adaptation to a ketotic environment, without worrying on specific macros or restricting too much protein intake. Addendum: That certain amino acids are glucogenic means that they can potentially be converted to glucose. In this case, when keto-adapted, glucose needs are reduced, so is GnG. This has been observed in studies in which a severe carbohydrate restriction only increases GnG slightly after a few days (26, 27). Increasing glucogenic precursors per se does not rise BG levels (28)***, which might affect ketosis. Hepatic glucose output is an extremely well regulated process which serves to mantain BG levels in an adequate range and prevent hypoglycemia. As keto-adaptation occurs, glycogenolisis is reduced and GnG increased, in a controlled manner. GnG must not be avoided, its the natural and optimal way to control glycemia****. *The reason why ketoacidosis is not developed under non-diabetic circumstances is because of insulin, which controls the rate of ketogenesis and lipolysis. ** "Normal" as someone who eats SAD or a high carbohydrate diet. *** This is why protein does not rise BG levels. **** In TIIDM subjects, for example, this HGO control is dysregulated so hyperglycemia occurs.
