This study demonstrates that under hypocaloric conditions, a low-carbohydrate diet (60% fat, 20% carbohydrate) and a low-fat diet (60% carbohydrate, 20% fat) were equally effective in producing weight loss in overweight/obese adults. The observed weight loss (>7%) with both hypocaloric diets is comparable to that achieved in both the Diabetes Prevention Program and the Finnish Diabetes Prevention Trial (8
). In these trials, relatively modest weight loss (5–7% of initial body weight) and moderate physical activity resulted in a 58% reduction in the 4-year incidence of type 2 diabetes (in high-risk individuals with impaired glucose tolerance). The current study demonstrated no difference between a low-fat and a low-carbohydrate weight reduction diet in the effect on insulin sensitivity, which suggests a comparable effect on prevention of diabetes, independent of dietary macronutrient composition. However, it should be noted that subjects enrolled in the current study had mean fasting plasma glucose at the upper end of the normal range (consistent with pre-diabetes and hence increased risk for development of diabetes), a distinction from the diabetes prevention trials that enrolled subjects with impaired glucose tolerance.
Previous studies (25
) have demonstrated more rapid weight loss with low-carbohydrate diets. In this study, we did not restrict carbohydrate sufficiently to induce ketogenesis, and carbohydrate intake was maintained constant throughout the study, rather than the gradual increase in carbohydrate intake advocated by the Atkins diet. Furthermore, the caloric deficit was the same for both diets, and this may explain the comparable weight loss profiles.
A strength of the present study is the randomized controlled design and rigorous dietetic supervision. Menu plans were individually formulated to each volunteer's like/dislikes, and all meals were provided, ensuring that the intended composition was supplied to all volunteers. Although it is impossible to measure compliance with the diets under study, volunteers were reviewed every 2–3 days throughout the study and questioned regarding palatability and compliance with food provided. The intended weight loss was achieved, and this is further evidence of careful nutritional supervision and planning.
The primary outcome measure of insulin sensitivity was assessed using the gold standard hyperinsulinemic-euglycemic clamp combined with isotope dilution techniques. The high-dose insulin infusion used during the euglycemic clamp results in maximally stimulated glucose uptake and reflects skeletal muscle or peripheral insulin sensitivity. In our study group as a whole (n = 24), peripheral insulin sensitivity significantly improved (P = 0.03), but the change was only significant within the low-carbohydrate diet (P = 0.02), and there was no significant difference between groups (P = 0.28). The study was powered to exclude a 10% difference in insulin action, which is a level assumed to have a clinically relevant impact.
There was also no significant effect of altering macronutrient content on either fasting hepatic glucose production or its suppression during the clamp studies, which are both measures of hepatic insulin resistance, which is recognized as an early abnormality in type 2 diabetes (20
). Furthermore, we found no difference in either fasting levels of nonesterified fatty acid concentrations or their suppression during hyperinsulinemia, indicating no differential effect on adipose tissue insulin action and suppression of lipolysis.
Previous studies suggest that improvement in insulin sensitivity after consumption of a low-carbohydrate diet is similar to that seen on a low-fat diet (when associated with weight loss) (25
). However, this is based on suboptimal methods such as the quantitative insulin sensitivity check index (QUICKI). Diets high in total fat and saturated fat (relative to monounsaturated fat) have been shown to impair insulin sensitivity (15
). The mechanism of this effect is not clearly understood, although it is possible that dietary modification modulates changes in the fatty acid composition of cell membranes, thus influencing insulin receptor binding/activity as well as ion permeability and cell signaling (28
). However, no appreciable differences were found between diet groups in the current study using the reference standard technique to assess insulin sensitivity. It is possible that the effects of weight loss overcame any lesser effect of dietary macronutrient intake.
Abnormalities of insulin secretion may also contribute to the development of diabetes (29
). We demonstrated a comparable effect of the two diets on both fasting and meal tolerance–related insulin secretion. Given the similar effects on insulin resistance, we conclude that both diets exert equivalent effects on prevention of diabetes, primarily related to the degree of weight reduction. The comparable reduction in BMI was largely attributable to a decrease in fat mass, mainly from the central body area, as demonstrated by both DEXA scanning and a reduction in waist circumference. Increased central body fat is associated with insulin resistance and the metabolic syndrome, and the reduction in central adiposity was related to the improvement in insulin sensitivity, which in turn might be expected to reduce the risk of type 2 diabetes and also cardiovascular risk (30
As expected, the low-fat diet decreased both LDL and HDL cholesterol. Although the low-carbohydrate diet did not decrease LDL cholesterol, it was not associated with a significant decline in HDL cholesterol. Given the established evidence that LDL lowering reduces the risk of coronary heart disease, the lack of a decrease may be of concern. In contrast to the lack of a change in LDL and HDL in response to the low-carbohydrate diet, there was a significant reduction in triglycerides within this group compared with no significant change within the low-fat group. This response has been consistently reported in other studies comparing a low-carbohydrate and low-fat weight reduction diet (12
). It has been speculated that this result is due to a combination of a decrease in the VLDL production rate and an increase in triglyceride removal from the blood (31
). Previous studies (32
) indicate that increased triglycerides are an independent risk factor for cardiovascular disease, although it is impossible to predict the overall effect of the lipid changes with the low-carbohydrate diet. Further examination of the lipid subfraction profile may help elucidate the effects of the dietary regimens on lipid metabolism. Indeed, previous studies have suggested that low-carbohydrate diets increase LDL particle size and decrease small dense LDL particles (34
A major concern associated with low-carbohydrate diets is that the reciprocal increase in dietary fat intake, particularly if this includes saturated and trans
fat, may have detrimental effects on cardiovascular risk. In addition to examining cardiovascular risk factors, we also assessed arterial stiffness, which is increasingly recognized as an important determinant of cardiovascular risk (35
). Stiffening of the arterial tree increases the velocity and amplitude of the reflected pulse waves from the periphery, with the result that larger waves return to the aorta earlier. This augments central systolic pressure, which increases left ventricular workload and myocardial oxygen demand. In the present study, the change in AIx
(a measure of overall systemic stiffness) was significantly more favorable with the low-fat diet, with a significant and favorable reduction in AIx
compared with a nonsignificant increase in the low-carbohydrate diet group. A post hoc power analysis revealed that the study had 90% power to detect a between-diet difference of 9% for augmentation index. Although an isolated finding in the present study, this is consistent with a recent report that demonstrated a reduction in flow-mediated dilation following a low-carbohydrate diet compared with an increase after a low-fat diet (36
). It is possible that the high fat content of a low-carbohydrate diet exerts detrimental effects on endothelial function, which raises concerns regarding the long-term safety and efficacy of low-carbohydrate diets.
Changes in leptin levels were comparable in both diets and related to weight loss rather than any specific effect of dietary macronutrient composition (37
). Recently, RBP4 has been proposed as an adipocyte-derived factor that may regulate insulin sensitivity (7
). Diet-induced changes in RBP4 were not responsible for the change in insulin sensitivity in the current study, as neither the low-fat nor the low-carbohydrate weight loss regimen had any significant effect on circulating concentrations. This is in keeping with one previous study (38
), but in another study (7
) changes in RBP4 were associated with an improvement in insulin sensitivity. Differences in study design may explain these conflicting findings (e.g., the latter study utilized an exercise intervention and examined both normal subjects and those with type 2 diabetes).
One limitation of this study is that the subjects were of white Western European origin and did not have significant baseline abnormalities. These factors can alter baseline insulin sensitivity and may influence interventional responses. In addition, to allow conclusions to be drawn about varying the carbohydrate and fat content of hypocaloric diets, overall calorie intake was controlled rather than allowing ad libitum consumption, thus allowing protein intake and fiber to be accurately matched in both diets. Furthermore, the type of fat in a low-carbohydrate diet (i.e., saturated/trans
fat versus mono/polyunsaturated fat) may be important (39
). The conclusions from these data must therefore be limited to the described overweight/obese group consuming a weight loss diet in a carefully controlled situation.
In conclusion, under the conditions of this study, a low-carbohydrate hypocaloric diet was as effective as a low-fat hypocaloric diet in achieving significant weight loss during an 8-week period. The 7% weight loss with both diets is comparable with the magnitude seen in diabetes prevention studies and is significant in terms of disease prevention (9
). Both diets promoted weight loss from the central body region and were associated with comparable effects on insulin sensitivity. There was, however, a significant difference in AIx
, a measure of vascular compliance, between the two diets that was not explained by changes in conventional vascular risk factors. This observation is of concern and, if confirmed, would suggest a potentially negative effect of a low-carbohydrate diet on long-term vascular health. Currently, supported by evidence from long-term trials, we believe that a low-fat diet should remain the preferred diet for diabetes prevention.