Therapeutic roles of ketogenic diets
There is no doubt that there is strong supportive evidence that the use of ketogenic diets in weight-loss therapy is effective; however, there are contrasting theories regarding the mechanisms through which they work. Some researchers suggest that there are not in fact any metabolic advantages in low-carbohydrate diets and that weight loss results simply from reduced caloric intake, probably due to the increased satiety effect of protein.12 Others instead promote the hypothesis that there is indeed a distinct metabolic advantage, which has recently been explored in more detail, raising interest in the role of VLCKD in weight loss and effects on metabolism in general.13 The first law of thermodynamics, also known as the law of conservation of energy, has in effect controlled the concepts for the basis of weight loss for over a century—resulting in a difficulty in accepting other ways of thinking. Adhering to these traditional concepts the US Department of Agriculture has concluded that diets, which reduce calories, will result in effective weight loss independent of the macronutrient composition, which is considered less important, even irrelevant.14 In contrast with these views, the majority of ad-libitum studies demonstrate that subjects who follow a low-carbohydrate diet lose more weight during the first 3–6 months compared with those who follow balanced diets.15, 16, 17 One hypothesis is that the use of energy from proteins in VLCKD is an ‘expensive’ process for the body and so can lead to a ‘waste of calories’, and therefore increased weight loss compared with other ‘less-expensive’ diets.13, 18, 19 The average human body requires 60–65 g of glucose per day, and during the first phase of a diet very low in carbohydrates this is partially (16%) obtained from glycerol, with the major part derived via gluconeogenesis from proteins of either dietary or tissue origin.12 The energy cost of gluconeogenesis has been confirmed in several studies7 and it has been calculated at ∼400–600 Kcal/day (due to both endogenous and food source proteins.18 Despite this, there is no direct experimental evidence to support this intriguing hypothesis; on the contrary, a recent study reported that there were no changes in resting energy expenditure after a VLCKD.20 A simpler, perhaps more likely, explanation for improved weight loss is a possible appetite-suppressant action of ketosis. The mechanism for this is not established but evidence supports direct action of KBs together with modifications in levels of hormones, which influence appetite, such as ghrelin and leptin.21 Here we can summarize (listed in order of importance and available evidence) that the weight-loss effect of VLCKD seems to be caused by several factors:
Several lines of evidence point to beneficial effects of VLCKD on cardiovascular risk factors. In the past Keto Pills , there have been doubts expressed about their long-term safety and increased effectiveness compared with ‘balanced’ diets,25 and clearly negative opinions regarding possible deleterious effects on triglycerides and cholesterol levels in the blood.26 However, the majority of recent studies seem instead to amply demonstrate that the reduction of carbohydrates to levels that induce physiological ketosis (see above ‘What is ketosis?’ section) can actually lead to significant benefits in blood lipid profiles.15, 17, 27 The VLCKD effect seems to be particularly marked on the level of blood triglycerides,24, 28 but there are also significant positive effects on total cholesterol reduction and increases in high-density lipoprotein.24, 28, 29 Furthermore, VLCKD have been reported to increase the size and volume of low-density lipoprotein–cholesterol particles,29 which is considered to reduce cardiovascular disease risk, as smaller low-density lipoprotein particles have a higher atherogenicity. There are also direct diet-related effects on overall endogenous cholesterol synthesis. A key enzyme in cholesterol biosynthesis is 3-hydroxy-3-methylglutaryl–CoA reductase (the target for statins), which is activated by insulin, which means that an increase in blood glucose and consequently of insulin levels will lead to increased endogenous cholesterol synthesis. A reduction in dietary carbohydrate will have the opposite effect and this, coupled with the additional inhibition by dietary cholesterol and fats on endogenous synthesis, is likely to be the mechanism via which physiological ketosis can improve lipid profiles. Hence, there are strong doubts about the negative effects of dietary fats when they are consumed as part of a VLCKD, on cholesterol and triglycerides blood levels, whereas there are strong pointers to the beneficial effects of VLCKD on these cardiovascular risk parameters.27, 28
Insulin resistance is the primary feature underlying type 2 diabetes (T2D) but it also exists across a continuum in the general population, and to varying extents it disrupts insulin action in cells, which can cause a wide spectrum of signs and symptoms. A primary feature of insulin resistance is an impaired ability of muscle cells to take up circulating glucose. A person with insulin resistance will divert a greater proportion of dietary carbohydrate to the liver where much of it is converted to fat (that is, de novo lipogenesis), as opposed to being oxidized for energy in skeletal muscle.30 Although Hellerstein31 has recently reported that de novo lipogenesis contributes only ∼20% of new triglycerides, this greater conversion of dietary carbohydrate into fat, much of it entering the circulation as saturated fat, is a metabolic abnormality that significantly increases risk for diabetes and heart disease. Thus, insulin resistance functionally manifests itself as ‘carbohydrate intolerance’. When dietary carbohydrate is restricted to a level below which it is not significantly converted to fat (a threshold that varies from person to person), signs and symptoms of insulin resistance improve or often disappear completely.
In studies that have evaluated well-formulated very-low-carbohydrate diets and documented high rates of compliance in individuals with T2D, results have been nothing short of remarkable. Bistrian et al.32 reported withdrawal of insulin and major weight loss in a matter of weeks in T2D individuals who were fed a very-low-calorie and -carbohydrate diet. Gumbiner et al.33 fed obese T2D individuals two types of hypocaloric (650 kcal) diets for 3 weeks, they were matched for protein but one was much lower in carbohydrate content (24 vs 94 g/day). As expected, the lower-carbohydrate diet resulted in significantly greater levels of circulating ketones (∼3 mmol/l), which was strongly associated with a lower hepatic glucose output. Interestingly, there was a strong inverse correlation between circulating ketones and hepatic glucose output, suggesting that higher levels of ketones are associated with more favourable effects on glycaemic control in diabetics. More recently, Boden et al.34 performed an in-patient study in obese T2D individuals who were fed a low-carbohydrate (<20 g/day) diet for 2 weeks. Plasma glucose fell from 7.5 to 6.3 mmol/l, haemoglobin A1c decreased from 7.3 to 6.8% and there were dramatic improvements (75%) in insulin sensitivity.
In a longer study35 obese T2D individuals were prescribed a well-formulated ketogenic diet for 56 weeks, and significant improvements in both weight loss and metabolic parameters were seen at 12 weeks and continued throughout the 56 weeks as evidenced by improvements in fasting circulating levels of glucose (−51%), total cholesterol (−29%), high-density lipoprotein–cholesterol (63%), low-density lipoprotein–cholesterol (−33%) and triglycerides (−41%). It is of interest to note that in a recent study in overweight non/diabetic subjects, it was reported that during ketosis fasting glucose was not affected, but there was an elevation in post-prandial blood glucose concentration. This data suggests a different effect of ketosis on glucose homeostasis in diabetic and non-diabetic individuals.21 Other studies support the long-term efficacy of ketogenic diets in managing complications of T2D.36, 37 Although significant reductions in fat mass often results when individuals restrict carbohydrate, the improvements in glycaemic control, haemoglobin A1c and lipid markers, as well as reduced use or withdrawal of insulin and other medications in many cases, occurs before significant weight loss occurs. Moreover, in isocaloric experiments individuals with insulin resistance showed dramatically improved markers of metabolic syndrome than diets lower in fat.27 It is interesting in this respect that a recent extremely large epidemiological study reported that diabetes risk is directly correlated, in an apparently causative manner, with sugar intake alone, independently of weight or sedentary lifestyle.38