Low-Carbohydrate Nutrition and Metabolism1
Low-Carbohydrate Nutrition and Metabolism1
Low-Carbohydrate Nutrition and Metabolism1
276 Am J Clin Nutr 2007;86:276 – 84. Printed in USA. © 2007 American Society for Nutrition
LOW-CARBOHYDRATE NUTRITION 277
TABLE 1 Glucose-dependent tissues (ie, red blood cells, retina, lens, and
Fuel sources in a low-carbohydrate ketogenic diet renal medulla) receive glucose through gluconeogenesis and gly-
Fatty acids (앒70% of caloric requirements) cogenolysis. (Even if no dietary carbohydrate is consumed, it is
Dietary fat estimated that 200 g glucose/d can be manufactured by the liver
Lipolysis and kidney from dietary protein and fat.) The metabolic state
Adipose stores experienced by a person who is following an LCKD is often
Ketone bodies (앒20% of caloric requirements) compared with the condition of starvation. The main similarities
Dietary fat and protein in metabolism between LCDs and starvation are that there is no
Lipolysis and ketogenesis (or little) intake of exogenous carbohydrate and that there is a
Adipose stores
shift from the use of glucose as fuel toward the use of fatty acids
Glucose (앒10% of caloric requirements)
and ketones as fuel. Under conditions of starvation, endogenous
Gluconeogenesis
Dietary protein and fat (glycerol) sources (eg, muscle protein, glycogen, and fat stores) are used as
Glycogenolysis energy supplies (10). However, under conditions of LCKD in-
take, exogenous sources of protein and fat provide energy, along
with endogenous glycogen and fat stores if caloric expenditure
TABLE 2
Studies of low-carbohydrate ketogenic diet metabolism1
Macronutrients
Study Duration Subjects CHO Pro Fat Energy RQ Insulin Glucagon Glucose Fatty acids -Hydroxybutyrate
with the 5% carbohydrate diet than with the 60% carbohydrate The 2% carbohydrate, 15% protein, and 83% fat weight-
diet. After 1–2 d of the 5% carbohydrate diet and persisting maintenance diet also resulted in lower absorptive and postab-
through the 7-d period, serum -hydroxybutyrate increased from sorptive plasma insulin concentrations than did the 0% fat and
0.1 to 0.4 mmol/L and free fatty acids increased from 0.2 to 41% fat diets (15). Postabsorptive rates of appearance of leucine
0.4 mmol/L. In addition, muscle glycogen (measured by muscle and of leucine oxidation—measures of proteolysis— did not dif-
biopsy) was reduced by 20% after 9 d. fer significantly among the 3 diets. In addition, dietary carbohy-
Glucose kinetics were assessed by stable-isotope techniques drate did not affect the synthesis rates of fibrinogen and albumin.
while resting metabolic rates were calculated from oxygen con- However, this study was limited in that the experimental manip-
sumption (V̇O2) and carbon dioxide production (V̇CO2) was mea- ulation did not provide sufficient potassium or sodium intake, nor
sured by using a metabolic cart. By day 2 of the 5% carbohydrate did it allow time for keto-adaptation to reflect the conditions of
diet, both the glucose rate of appearance and rate of disappear- chronic, very low carbohydrate consumption. Both mineral nu-
ance decreased by 20%, and they remained suppressed on day 7. triture and time for adaptation have been addressed in earlier
In addition, postabsorptive carbohydrate oxidation decreased eucaloric, very-low-carbohydrate feeding studies (20).
Another outpatient feeding study randomly assigned 83 sub-
progressively over the 7-d duration, and this decline was greater
jects to 1 of 3 diets ranging in carbohydrate content from 12% to
TABLE 3
Randomized outpatient trials of a low-carbohydrate ketogenic diet for obesity: estimated dietary intake and effect on weight and fasting serum lipids1
Macronutrients Macronutrients
Reference Duration Subjects CHO Fat Pro Energy Weight LDL TG HDL CHO Fat Pro Energy Weight LDL TG HDL
It is also likely that the regulation of hepatic glucose output is of keto-adaptation, but clinical observation suggests that it prob-
substantially altered after adaptation to an LCKD (keto-adaptation). ably takes from 2 to 4 wk for keto-adaptation to occur.
For example, one study compared a very-low-energy (624 kcal), The second issue has to do with the maintenance of adequate
low-carbohydrate (20% of daily energy intake) diet to a baseline mineral supplementation as long as the ketogenic state is main-
isoenergetic (30 kcal/kg), high-carbohydrate (55%) diet in obese tained. One group of investigators provided supplements con-
subjects with type 2 diabetes (43). After 3 wk of adaptation, the taining 3–5 g sodium/d and 2–3 g potassium/d and found that
very-low-energy, LCD diet resulted in significantly less hepatic circulatory competence during submaximal exercise was sus-
glucose output, and, across all subjects and diets, basal hepatic glu- tained. These supplements also allowed the subjects to achieve
cose output was negatively correlated with plasma ketones (r ҃ nitrogen balance, which had not been achieved in studies that did
Ҁ0.71, P 쏝 0.05). not use supplements (20).
Insulin resistance is reduced with an LCKD, possibly by a The third issue affecting physical performance is adequate
reduction in the availability of dietary glucose, which causes protein intake. It is generally accepted that the preservation of
hyperinsulinemia (44, 45). A consideration of the physiology of LBM and of physical performance during any degree of energy
very-low-carbohydrate dieting leads to a different perspective on restriction occurs when protein is in the range of 1.2 to 1.7 g 䡠 kg
insulin resistance. That is, rather than treating insulin resistance reference body wtҀ1 䡠 dҀ1. The use of the mid-range value of 1.5
by increasing glucose disposal through an increase in nonstorage g 䡠 kgҀ1 䡠 dҀ1 for adults with reference weights ranging from 60
cellular influx (eg, by increasing either the insulin dose or its to 80 kg, this translates into total daily protein intakes of 90 to 120
effect), it could be treated by reducing glucose availability to g/d. When adequate protein intake is expressed in the context of
insulin-resistant tissue (eg, by reducing carbohydrate intake or total daily energy expenditures of 2000 to 3000 kcal/d, 앒15% of
absorption and basal hepatic glucose output), which would re- daily energy expenditure should be provided as protein.
duce the nonstorage cellular influx. Reductions in dietary carbo- Further research on exercising under conditions of LCDs is
hydrate should be used as a strategy to treat insulin resistance. needed. These studies may be optimized by careful attention to
the time needed for keto-adaptation, to mineral supplementation,
Low-carbohydrate diets and exercise and to the daily protein dose. Therapeutic use of ketogenic diets
Over the past several years, 2 reviews focused on LCKD and should not limit most forms of physical activity, with the caveat
exercise have been published. One of these reviews concluded that anaerobic performance (ie, weight lifting or sprinting) may
that submaximal endurance performance can be sustained de- be limited by lower-muscle glycogen concentrations.
spite the virtual exclusion of carbohydrate from the human diet
(46). The other review addressed the intramuscular enzyme ad- Outpatient clinical trials for obesity
aptation that occurs with these diets (47). The efficacy of an LCKD for weight loss has now been estab-
Several important issues arise in the consideration of LCKD lished in 6 outpatient randomized controlled trials (23, 50 –55).
studies in general and of exercise studies in particular: 1) the time All of these trials used the most widely recommended diet at that
allowed for keto-adaptation, 2) the use of electrolyte supplemen- time, a 30%-fat, reduced-calorie diet, as the comparison diet
tation, and 3) the amount of protein intake. To try to examine the (Table 3). There were differences in the intensity of the inter-
first issue, we can consider the multiple studies comparing low- ventions in these outpatient studies. For example, the amount of
carbohydrate with high-carbohydrate diets to test the hypothesis behavioral support ranged from simply providing a popular diet
that “carbohydrate loading” can enhance physical performance. book along with minimal education to providing biweekly group
None of the studies that support this hypothesis maintained the sessions with extensive handouts and close monitoring (51, 55).
LCD for 쏜2 wk (48), and most maintained the LCDs for 울7 d Across these studies, there appeared to be better adherence and
(49). No studies have carefully examined the process or duration greater weight loss as the intensity of the intervention increased.
LOW-CARBOHYDRATE NUTRITION 281
One study (23) used a tapering of carbohydrate, whereas all other diabetes lived for 7 wk as hunter-gatherers. At the end of the
studies used a sudden reduction in carbohydrate. study period, there were significant improvements in weight and
Several of these studies collected detailed outpatient nutri- fasting serum glucose, insulin, and triacylglycerol concentra-
tional intake information (23, 54). Whereas instruction in an tions (77). When the study subjects returned to their previous
LCD does not mention calories, the restriction of dietary carbo- urban lifestyle, the weight and diabetes returned. In another
hydrate leads to a reduction in caloric intake from baseline. The study, 25 Canadian Cree subjects who lived a traditional lifestyle
ad libitum intake can vary from person to person, but, in many for 3 mo in the bush were compared with 26 control subjects who
cases, the protein and fat intakes, in absolute terms, are not much stayed in the community. However, the subjects who lived in the
higher than those of a typical American diet, because the total bush were able to obtain store-bought food, and thus the effects
caloric intake is lower. As such, the LCD is not necessarily a on diabetes indexes were limited (78). If the traditional nutri-
high-protein diet or a high-fat diet. In addition, whereas the diet tional intake is healthier, as these studies suggest, then further
typically contains high amounts of saturated fat, it also contains
research could be directed toward developing sustainable mod-
high amounts of monounsaturated and polyunsaturated fats.
ern lifestyles that use these principles.
Cardiovascular disease risk factors
Potential adverse effects fat causes heart disease. Because of their glucose- and insulin-
As with any large change in nutrient intake, the change to an lowering effects, LCDs should be evaluated as possible treatments
LCD in patients taking medications for diabetes or hypertension for conditions related to hyperglycemia, hyperinsulinemia, and in-
should be made under supervision by clinicians familiar with the sulin resistance.
effects of the diet. Frequently, a reduction in medication will be We emphasize that strategies based on carbohydrate restric-
required to avoid hypoglycemia and hypotension due to over- tion have continued to fulfill their promise in relation to weight
medication. In addition, most clinical studies to date have in- loss and that, contrary to early concerns, they have a generally
cluded a daily multivitamin and mineral supplement along with beneficial effect on most markers of CVD, even in the absence of
the diet. As mentioned previously, sodium and potassium sup- weight loss. In combination with the intuitive and established
plements have also been used. efficacy in relation to glycemic control in diabetics, some form of
Only one of the clinical trials has assessed symptomatic side LCD may be the preferred choice for weight reduction as well as
effects of an LCKD (55). In that study, subjects following an for general health.
LCKD were more likely to experience constipation, headache, The authors’ responsibilities were as follows—ECW: primarily respon-
muscle cramps, diarrhea, weakness, and skin rash than were sible for drafting the original manuscript; all authors: literature search and
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