Research Articles

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Systematic review of randomized controlled trials of low‐carbohydrate vs. low‐fat/low‐calorie diets in the management of obesity and its comorbidities


Journal: Obesity Reviews

Publication Date: 12/2008

Summary: There are few studies comparing the effects of low‐carbohydrate/high‐protein diets with low‐fat/high‐carbohydrate diets for obesity and cardiovascular disease risk. This systematic review focuses on randomized controlled trials of low‐carbohydrate diets compared with low‐fat/low‐calorie diets. Studies conducted in adult populations with mean or median body mass index of ≥28 kg m−2 were included. Thirteen electronic databases were searched and randomized controlled trials from January 2000 to March 2007 were evaluated. Trials were included if they lasted at least 6 months and assessed the weight‐loss effects of low‐carbohydrate diets against low‐fat/low‐calorie diets. For each study, data were abstracted and checked by two researchers prior to electronic data entry. The computer program Review Manager 4.2.2 was used for the data analysis. Thirteen articles met the inclusion criteria. There were significant differences between the groups for weight, high‐density lipoprotein cholesterol, triacylglycerols and systolic blood pressure, favouring the low‐carbohydrate diet. There was a higher attrition rate in the low‐fat compared with the low‐carbohydrate groups suggesting a patient preference for a low‐carbohydrate/high‐protein approach as opposed to the Public Health preference of a low‐fat/high‐carbohydrate diet. Evidence from this systematic review demonstrates that low‐carbohydrate/high‐protein diets are more effective at 6 months and are as effective, if not more, as low‐fat diets in reducing weight and cardiovascular disease risk up to 1 year. More evidence and longer‐term studies are needed to assess the long‐term cardiovascular benefits from the weight loss achieved using these diets.


Nutrition and Alzheimer’s disease: The detrimental role of a high carbohydrate diet


Journal: European Journal of Internal Medicine

Publication Date: 04/2011

Summary: Alzheimer’s disease is a devastating disease whose recent increase in incidence rates has broad implications for rising health care costs. Huge amounts of research money are currently being invested in seeking the underlying cause, with corresponding progress in understanding the disease progression. In this paper, we highlight how an excess of dietary carbohydrates, particularly fructose, alongside a relative deficiency in dietary fats and cholesterol, may lead to the development of Alzheimer’s disease. A first step in the pathophysiology of the disease is represented by advanced glycation end-products in crucial plasma proteins concerned with fat, cholesterol, and oxygen transport. This leads to cholesterol deficiency in neurons, which significantly impairs their ability to function. Over time, a cascade response leads to impaired glutamate signaling, increased oxidative damage, mitochondrial and lysosomal dysfunction, increased risk to microbial infection, and, ultimately, apoptosis. Other neurodegenerative diseases share many properties with Alzheimer’s disease, and may also be due in large part to this same underlying cause.

A carbohydrate-restricted diet during resistance training promotes more favorable changes in body composition and markers of health in obese women with and without insulin resistance


Journal: The Physician and Sports Medicine

Publication Date: 05/2011

Summary: To determine whether sedentary obese women with elevated levels of homeostatic model assessment (HOMA) insulin resistance (ie, > 3.5) experience greater benefits from an exercise + higher-carbohydrate (HC) or carbohydrate-restricted weight loss program than women with lower HOMA levels. 221 women (age, 46.5 ± 12 years; body weight, 90.3 ± 16 kg; body mass index, 33.8 ± 5 kg/m(2)) participated in a 10-week supervised exercise and weight loss program. The fitness program involved 30 minutes of circuit-style resistance training 3 days per week. Subjects were prescribed low-fat (30%) isoenergetic diets that consisted of 1200 kcals per day for 1 week (phase 1) and 1600 kcals per day for 9 weeks (phase 2) with HC or higher protein (HP). Fasting blood samples, body composition, anthropometry, resting energy expenditure, and fitness measurements were obtained at 0 and 10 weeks. Subjects were retrospectively stratified into lower (LH) or higher (HH) than 3.5 HOMA groups. Data were analyzed by multivariate analysis of variance with repeated measures and are presented as mean ± standard deviation changes from baseline. Baseline HOMA levels in the LH group were significantly lower than those in the HH group (LH, 0.6 ± 0.7; HH, 6.3 ± 3.4; P = 0.001). Diet and training significantly decreased body weight (-3.5 ± 3 kg), fat mass (-2.7 ± 3 kg), blood glucose (-3%), total cholesterol (-4.5%), low-density lipoproteins (-5%), triglycerides (-5.9%), systolic blood pressure (-2.6%), and waist circumference (-3.7%), while increasing peak aerobic capacity (7.3%). Subjects in the HP group experienced greater weight loss (-4.4 ± 3.6 kg vs -2.6 ± 2.9 kg), fat loss (-3.4 ± 2.7 kg vs -1.7 ± 2.0 kg), reductions in serum glucose (3% vs 2%), and decreases in serum leptin levels (-30.8% vs -10.8%) than those in the HC group. Participants in the HH (-14.1%) and HP-HH (-21.6%) groups observed the greatest reduction in serum blood glucose. A carbohydrate-restricted diet promoted more favorable changes in weight loss, fat loss, and markers of health in obese women who initiated an exercise program compared with a diet higher in carbohydrate. Additionally, obese women who initiated training and dieting with higher HOMA levels experienced greater reductions in blood glucose following an HP diet.

Short-term weight loss and hepatic triglyceride reduction: evidence of a metabolic advantage with dietary carbohydrate restriction


Journal: American Journal of Clinical Nutrition

Publication Date: 05/2011

Summary: Individuals with nonalcoholic fatty liver disease (NAFLD) have excess intrahepatic triglycerides. This is due, in part, to increased hepatic synthesis of fat from carbohydrates via lipogenesis. Although weight loss is currently recommended to treat NAFLD, little attention has been given to dietary carbohydrate restriction. The aim of this study was to determine the effectiveness of 2 wk of dietary carbohydrate and calorie restriction at reducing hepatic triglycerides in subjects with NAFLD. Eighteen NAFLD subjects (n = 5 men and 13 women) with a mean (±SD) age of 45 ± 12 y and a body mass index (in kg/m2) of 35 ± 7 consumed a carbohydrate-restricted (<20 g/d) or calorie-restricted (1200–1500 kcal/d) diet for 2 wk. Hepatic triglycerides were measured before and after intervention by magnetic resonance spectroscopy.  Mean (±SD) weight loss was similar between the groups (−4.0 ± 1.5 kg in the calorie-restricted group and −4.6 ± 1.5 kg in the carbohydrate-restricted group; P = 0.363). Liver triglycerides decreased significantly with weight loss (P < 0.001) but decreased significantly more (P = 0.008) in carbohydrate-restricted subjects (−55 ± 14%) than in calorie-restricted subjects (−28 ± 23%). Dietary fat (r = 0.643, P = 0.004), carbohydrate (r = −0.606, P = 0.008), posttreatment plasma ketones (r = 0.755, P = 0.006), and respiratory quotient (r = −0.797, P < 0.001) were related to a reduction in liver triglycerides. Plasma aspartate, but not alanine, aminotransferase decreased significantly with weight loss (P < 0.001). Two weeks of dietary intervention (≈4.3% weight loss) reduced hepatic triglycerides by ≈42% in subjects with NAFLD; however, reductions were significantly greater with dietary carbohydrate restriction than with calorie restriction. This may have been due, in part, to enhanced hepatic and whole-body oxidation.

Effects of Dietary Composition During Weight Loss Maintenance: A Controlled Feeding Study


Journal: JAMA

Publication Date: 06/2012

Summary: Reduced energy expenditure following weight loss is thought to contribute to weight gain. However, the effect of dietary composition on energy expenditure during weight-loss maintenance has not been studied. To examine the effects of 3 diets differing widely in macronutrient composition and glycemic load on energy expenditure following weight loss. A controlled 3-way crossover design involving 21 overweight and obese young adults conducted at Children’s Hospital Boston and Brigham and Women’s Hospital, Boston, Massachusetts, between June 16, 2006, and June 21, 2010, with recruitment by newspaper advertisements and postings. After achieving 10% to 15% weight loss while consuming a run-in diet, participants consumed an isocaloric low-fat diet (60% of energy from carbohydrate, 20% from fat, 20% from protein; high glycemic load), low-glycemic index diet (40% from carbohydrate, 40% from fat, and 20% from protein; moderate glycemic load), and very low-carbohydrate diet (10% from carbohydrate, 60% from fat, and 30% from protein; low glycemic load) in random order, each for 4 weeks. Primary outcome was resting energy expenditure (REE), with secondary outcomes of total energy expenditure (TEE), hormone levels, and metabolic syndrome components. Compared with the pre-weight-loss baseline, the decrease in REE was greatest with the low-fat diet (mean [95% CI], -205 [-265 to -144] kcal/d), intermediate with the low-glycemic index diet (-166 [-227 to -106] kcal/d), and least with the very low-carbohydrate diet (-138 [-198 to -77] kcal/d; overall P = .03; P for trend by glycemic load = .009). The decrease in TEE showed a similar pattern (mean [95% CI], -423 [-606 to -239] kcal/d; -297 [-479 to -115] kcal/d; and -97 [-281 to 86] kcal/d, respectively; overall P = .003; P for trend by glycemic load < .001). Hormone levels and metabolic syndrome components also varied during weight maintenance by diet (leptin, P < .001; 24-hour urinary cortisol, P = .005; indexes of peripheral [P = .02] and hepatic [P = .03] insulin sensitivity; high-density lipoprotein [HDL] cholesterol, P < .001; non-HDL cholesterol, P < .001; triglycerides, P < .001; plasminogen activator inhibitor 1, P for trend = .04; and C-reactive protein, P for trend = .05), but no consistent favorable pattern emerged. Among overweight and obese young adults compared with pre-weight-loss energy expenditure, isocaloric feeding following 10% to 15% weight loss resulted in decreases in REE and TEE that were greatest with the low-fat diet, intermediate with the low-glycemic index diet, and least with the very low-carbohydrate diet.

The ketogenic diet as a treatment paradigm for diverse neurological disorders


Journal: Frontiers in Pharmacology

Publication Date: 04/2012

Summary: Dietary and metabolic therapies have been attempted in a wide variety of neurological diseases, including epilepsy, headache, neurotrauma, Alzheimer disease, Parkinson disease, sleep disorders, brain cancer, autism, pain, and multiple sclerosis. The impetus for using various diets to treat – or at least ameliorate symptoms of – these disorders stems from both a lack of effectiveness of pharmacological therapies, and also the intrinsic appeal of implementing a more “natural” treatment. The enormous spectrum of pathophysiological mechanisms underlying the aforementioned diseases would suggest a degree of complexity that cannot be impacted universally by any single dietary treatment. Yet, it is conceivable that alterations in certain dietary constituents could affect the course and impact the outcome of these brain disorders. Further, it is possible that a final common neurometabolic pathway might be influenced by a variety of dietary interventions. The most notable example of a dietary treatment with proven efficacy against a neurological condition is the high-fat, low-carbohydrate ketogenic diet (KD) used in patients with medically intractable epilepsy. While the mechanisms through which the KD works remain unclear, there is now compelling evidence that its efficacy is likely related to the normalization of aberrant energy metabolism. The concept that many neurological conditions are linked pathophysiologically to energy dysregulation could well provide a common research and experimental therapeutics platform, from which the course of several neurological diseases could be favorably influenced by dietary means. Here we provide an overview of studies using the KD in a wide panoply of neurologic disorders in which neuroprotection is an essential component.

Is the restricted ketogenic diet a viable alternative to the standard of care for managing malignant brain cancer?


Journal: Epilepsy Research

Publication Date: 07/2012

Summary: Malignant brain cancer persists as a major disease of morbidity and mortality. The failure to recognize brain cancer as a disease of energy metabolism has contributed in large part to the failure in management. As long as brain tumor cells have access to glucose and glutamine, the disease will progress. The current standard of care provides brain tumors with access to glucose and glutamine. The high fat low carbohydrate ketogenic diet (KD) will target glucose availability and possibly that of glutamine when administered in carefully restricted amounts to reduce total caloric intake and circulating levels of glucose. The restricted KD (RKD) targets major signaling pathways associated with glucose and glutamine metabolism including the IGF-1/PI3K/Akt/Hif pathway. The RKD is anti-angiogenic, anti-invasive, anti-inflammatory, and pro-apoptotic when evaluated in mice with malignant brain cancer. The therapeutic efficacy of the restricted KD can be enhanced when combined with drugs that also target glucose and glutamine. Therapeutic efficacy of the RKD was also seen against malignant gliomas in human case reports. Hence, the RKD can be an effective non-toxic therapeutic option to the current standard of care for inhibiting the growth and invasive properties of malignant brain cancer.

Effect of low-calorie versus low-carbohydrate ketogenic diet in type 2 diabetes


Journal: Nutrition

Publication Date: 10/2012

Summary: Effective diabetic management requires reasonable weight control. Previous studies from our laboratory have shown the beneficial effects of a low-carbohydrate ketogenic diet (LCKD) in patients with type 2 diabetes after its long term administration. Furthermore, it favorably alters the cardiac risk factors even in hyperlipidemic obese subjects. These studies have indicated that, in addition to decreasing body weight and improving glycemia, LCKD can be effective in decreasing antidiabetic medication dosage. Similar to the LCKD, the conventional low-calorie, high nutritional value diet is also used for weight loss. The purpose of this study was to understand the beneficial effects of LCKD compared with the low-calorie diet (LCD) in improving glycemia. Three hundred and sixty-three overweight and obese participants were recruited from the Al-Shaab Clinic for a 24-wk diet intervention trial; 102 of them had type 2 diabetes. The participants were advised to choose LCD or LDKD, depending on their preference. Body weight, body mass index, changes in waist circumference, blood glucose level, changes in hemoglobin and glycosylated hemoglobin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, uric acid, urea and creatinine were determined before and at 4, 8, 12, 16, 20, and 24 wk after the administration of the LCD or LCKD. The initial dose of some antidiabetic medications was decreased to half and some were discontinued at the beginning of the dietary program in the LCKD group. Dietary counseling and further medication adjustment were done on a biweekly basis. The LCD and LCKD had beneficial effects on all the parameters examined. Interestingly, these changes were more significant in subjects who were on the LCKD as compared with those on the LCD. Changes in the level of creatinine were not statistically significant. This study shows the beneficial effects of a ketogenic diet over the conventional LCD in obese diabetic subjects. The ketogenic diet appears to improve glycemic control. Therefore, diabetic patients on a ketogenic diet should be under strict medical supervision because the LCKD can significantly lower blood glucose levels.

Low-carbohydrate ketogenic diets, glucose homeostasis, and nonalcoholic fatty liver disease


Journal: Current Opinions in Clinical Nutrition and Metabolic Care

Publication Date: 07/2012

Summary: Obesity-associated nonalcoholic fatty liver disease (NAFLD) is highly prevalent, for which weight loss is the generally recommended clinical management. Low-carbohydrate ketogenic diets have been successful in promoting weight loss, but variations in the range of metabolic responses to these diets indicate that the effects of altering macronutrient content are not completely understood. This review focuses on the most recent findings that reveal the relationship between low-carbohydrate diets and NAFLD in rodent models and humans. Low-carbohydrate diets have been shown to promote weight loss, decrease intrahepatic triglyceride content, and improve metabolic parameters of patients with obesity. These ketogenic diets also provoke weight loss in rodents. However, long-term maintenance on a ketogenic diet stimulates the development of NAFLD and systemic glucose intolerance in mice. The relationship between ketogenic diets and systemic insulin resistance in both humans and rodents remains to be elucidated. Because low-carbohydrate ketogenic diets are increasingly employed for treatment of obesity, NAFLD, and neurological diseases such as epilepsy, understanding the long-term systemic effects of low-carbohydrate diets is crucial to the development of efficacious and safe dietary interventions.

Dietary ketosis enhances memory in mild cognitive impairment


Journal: Nuerobiology of Aging

Publication Date: 02/2012

Summary: We randomly assigned 23 older adults with Mild Cognitive Impairment to either a high carbohydrate or very low carbohydrate diet. Following the six-week intervention period, we observed improved verbal memory performance for the low carbohydrate subjects (p = 0.01) as well as reductions in weight (p < 0.0001), waist circumference (p < 0.0001), fasting glucose (p = 0.009), and fasting insulin (p = 0.005). Level of depressive symptoms was not affected. Change in calorie intake, insulin level, and weight were not correlated with memory performance for the entire sample, although a trend toward a moderate relationship between insulin and memory was observed within the low carbohydrate group. Ketone levels were positively correlated with memory performance (p = 0.04). These findings indicate that very low carbohydrate consumption, even in the short-term, can improve memory function in older adults with increased risk for Alzheimer’s disease. While this effect may be attributable in part to correction of hyperinsulinemia, other mechanisms associated with ketosis such as reduced inflammation and enhanced energy metabolism also may have contributed to improved neurocognitive function. Further investigation of this intervention is warranted to evaluate its preventive potential and mechanisms of action in the context of early neurodegeneration.


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