Low-carbohydrate diet plans have been a subject of vigorous debate. The subject is surprisingly polarizing. ABC News recently reported that a prime-time special on low-carbohydrate diets generated more mail than any program in its history. One physician-researcher reported that his presentation on the Atkins Diet at a conference generated genuine anger among the academicians in the audience (reported in Ref. 15). A little controversy can create a memorable class experience, however, and can heighten interest for learning.
One source of controversy relates to the role of ketosis. Some researchers claim that the greater short-term success of very low-carbohydrate diets is not due to ketosis, but is primarily due to voluntary caloric restriction. A study comparing nonisoenergetic diets revealed that individuals on low-carbohydrate diets tended to consume one-third fewer calories than individuals on typical low-calorie diets did . Some individuals report decreased appetite when protein is abundant in the diet , and ketosis is known to suppress appetite. In fact, ketones are being studied as oral medicines to increase weight loss. Therefore, it may be true that the dramatic effects of low-carbohydrate diets are attributable to fewer calories consumed. Alternatively, a primary mechanism for both ketogenic and nonketogenic (but reduced carbohydrate) diets may simply be the elimination of insulin-mediated swings in blood glucose levels that stimulate hunger . Certainly all these factors, including ketosis, may contribute to the weight loss associated with low-carbohydrate regimens.
While professors without medical credentials should avoid giving medical advice, we should feel free to use the literature to inform. One response to the controversy is to send the students to the literature themselves. An article by Spieth et al.  is recommended for its depth and balance, as are an article by Bachman  and a review from Westman and coworkers . Simple internet searches can yield interesting results, although the information is often too general for a student of biochemistry. Moreover, students are likely to find alarmist treatises from organizations that promote alternate eating plans for moral or philosophical reasons. The range and fervor of opinions is rather fascinating, as some websites endorse low-carbohydrate eating as the cure to countless maladies, while others warn of its perniciousness.
1. Do Low-carbohydrate Diets Harm the Kidneys?
This is a common fear. Many people associate low-carbohydrate diets with the 400 cal/day high-protein liquid diets that caused some deaths in the 1980s, and the kidney damage observed in body builders who consumed high-protein diets over long periods while simultaneously practicing fluid restriction. Certainly the kidneys work harder and excrete more nitrogen when protein is elevated in the diet; however, the only changes researchers have observed associated with low-carbohydrate diets have been limited to increased glomerular filtration (considered benign) and lower calcium levels . These observations were made in epileptic children who had been on an extreme form of the diet for up to 2 years. (The anti-epileptic form of the diet is higher in fat than that typically used for weight loss and maintains ketosis for a much greater time period). In studies of dieters, researchers have been unable to find evidence of kidney damage in individuals dieting over a period of 6 months or less, whether or not the diets were ketogenic [10, 45]. Increased glomerular filtration rate, increased kidney volume, and increased creatine clearance have been reported, but these changes are not indicative of decreased kidney capacity . Such studies have only involved persons with healthy kidneys, however. It is unknown what effects would be observed in people with compromised kidney function.
2. How Do Low-carbohydrate Diets Compare with the Success of Conventional Low-calorie or Low-fat Regimens?
Dozens of clinical studies have investigated the success of low-carbohydrate and ketogenic eating plans, although most involve a relatively short time period (up to 6 months, which is thought to represent the maximum time most individuals will remain on a diet). Studies have included various genders, races, ages, differing levels of obesity, hyperlipidemic and normal-lipidmic patients, diabetics, and nondiabetics. They largely focus on the initially ketogenic (very low-carbohydrate) plans, and most are conducted on an outpatient basis, relying on individual honesty to document food intake. Some of these results are summarized in Table III. The overriding conclusion is that participants on Atkins-type ketogenic diets experienced substantial weight loss of 2.8–12.0 kg typically (or 6.1–26.4 lbs). Weight loss occurred whether or not the diet was accompanied by increased protein or fat. By comparison, traditional high-carbohydrate, low-fat regimens showed significant weight loss as well. Both methods are clearly effective, but most studies showed greater weight loss in the low-carbohydrate groups (Ref. 43 and references therein). When isocaloric diets are compared, the majority of studies still show greater weight loss in the low-carbohydrate dieters [12, 13, 51, 52]. Nonetheless, while most studies of low-carbohydrate diets showed more rapid rate loss at first, two studies found that the difference after 6 months was not substantial. A study by Lean et al. showed an average weight loss of 6.8 kg (or 15.0 lbs) after 6 months of an initially ketogenic Atkins-type low-carbohydrate diet, but this result was not substantially different from the 5.6 kg (or 12.3 pounds) observed after 6 months of a low-fat diet . Another study by Foster et al. showed that weight loss was greater after 6 months on an Atkins-type plan as compared with a low-fat plan, but after a year, the first group had only lost 4.4 kg, which was not substantially different from the low-fat group's average loss of 2.5 kg .
3. Are Low-carbohydrate Diets Bad for the Heart?
The Atkins Diet, especially in its early form, encourages participants to eat fat, including foods high in saturated fat, such as cream and butter, and foods high in cholesterol, such as eggs. The South Beach Diet and the Zone Diet call for limiting fats to the unsaturated variety as much as possible. The idea that bacon, sausage, eggs, and cheese are permitted on the Atkins and similar plans surprises many individuals who have come to associate fats with heart disease. Interestingly, many of the popular low-carbohydrate diet books were authored by cardiologists, and they claim that these eating plans can improve cardiac health. Well-known risk factors for heart disease include high serum triglyceride levels, high total cholesterol and low-density lipoprotein (LDL) cholesterol, and low high-density lipoprotein (HDL) levels. Lesser known risk factors include elevated levels of proteins associated with inflammation such as the high-sensitivity C-reactive protein.
Cardiac disease is multi-factorial, and, with many lifestyle factors other than diet involved, the issue is a complicated one. Results of clinical studies should be interpreted with this fact in mind. A nearly universal result from studies of both ketogenic diets and nonketogenic low-carbohydrate diets is that of lowered plasma triglyceride levels [51, 52, 54]. One study of 41 moderately obese adults following an Atkins-type plan for 6 months reported a mean decrease of as much as 40% in serum triglycerides . However, the role of diet composition in improved triglyceride levels is debatable. Low-fat diets show a similar decrease. Some researchers have reported that nearly any weight loss greater than 5–10% of body mass will result in a decrease in triglyceride levels [56, 57].
Results with LDL-cholesterol levels are more mixed. LDL is the major carrier of cholesterol in the plasma and it has long been known to be atherogenic (associated with plaque development in arteries). At least one study showed unfavorable increases in LDL-cholesterol  after an initially ketogenic low-carbohydrate diet after six months, but the majority of studies reported desirable decreases in LDL levels [51, 52] or no change .
There is a biochemical justification for the claim that a low-carbohydrate diet will lower total cholesterol, including LDL-cholesterol. Insulin acts on a cAMP-dependent cascade that promotes the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), the enzyme that catalyzes a rate-limiting step in cholesterol synthesis (see Fig. 3). Reduced insulin levels would be expected to result in less activity of this enzyme and reduced synthesis of cholesterol.
HDL-cholesterol, in contrast to LDL-cholesterol, is not atherogenic. HDLs are the lipoprotein particles that enable cholesterol to be eliminated from blood vessels and broken down by the liver. Higher HDL levels have been found via both clinical and epidemiological studies to be cardioprotective. The literature has reported for years that low-fat, high-carbohydrate diets are associated with unfavorable decreases in HDL levels (for a representative review, see Ref. 60). In general, however, this risk factor is not well-understood. Tests of low-carbohydrate diets over a 6-month period again showed very mixed results in HDL levels. Several studies reported a decrease in HDLs , while others showed a desirable increase . (For reviews, see Refs. 45, 57, and 61).
Other risk factors have been investigated as well. In one study, an initially ketogenic Atkins-type low-carbohydrate diet was compared with a low-fat diet in healthy, nonobese, normal-lipidmic women for a 6-month period. There were no significant changes in markers of inflammation such as the C-reactive protein, interleukin-6, or tumor necrosis factor α, nor were there significant changes in the size of the LDL particles . In another study, the high-sensitivity C-reactive protein was measured in women whose diets varied in their glycemic load. A strong positive correlation was found between glycemic load and plasma concentrations of this proinflammatory protein .
It is clear that some individuals on low-carbohydrate diets have improved at least some of their cardiac risk factors. While triacylglyceride levels in the plasma are nearly always improved, however, these results do not appear to be dependent on the composition of the diet. Low-fat and low-calorie diets show similar effects. Changes in HDL and LDL levels have thus far been more variable. Although several studies have shown improvement in cardiac profiles, the results have not been universal.
4. Is the Weight Loss Associated with Low-carbohydrate Diets Simply Due to Loss of Water?
The greater initial weight loss seen with low-carbohydrate diets is partly due to water. Breakdown of liver and muscle glycogen results in diuresis (depletion of water). In a typical 70-kg adult, muscle typically stores 400 g of glycogen and the liver typically stores 100 g. Complete mobilization of these stores (representing about 1,600 kcal of energy) can result in a loss of over 2 lbs (about 1 kg). For each gram of glycogen used as energy, twice this mass is lost in water . Ketosis also causes water loss. The kidney filters ketones as anions, increasing distal sodium delivery to the lumen and causing diuresis .
The role of water in overall weight loss is controversial. A study compared individuals fed an 800 cal/day ketogenic low-carbohydrate diet with those on an isocaloric mixed diet. Using nitrogen balance calculations, researchers found that while the low-carbohydrate group showed increased weight loss, the difference was entirely due to water. However, both groups lost an average of 6 lbs (2.8 kg) that were not water , so both approaches appeared to be effective. One problem with this study, however, is that ketosis was not monitored. The 800 cal/day mixed diet may have induced a certain degree of ketosis in participants. While the initial dramatic decrease in water seen with the low-carbohydrate approach raises the risk of dehydration, the rapid weight loss can also be motivating for a dieter. On the other hand, a drawback is that “cheating” can cause a spike in insulin that can reverse the water loss and cause weight gain .