High Glycemic Diets Induce Fatty Liver

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is fast becoming a major public health concern, coincident with the increasing prevalence of obesity. Although lifestyle greatly influences development of NAFLD, the specific dietary causes remain largely unknown. The purpose of this study was to determine whether a diet high in rapidly absorbed carbohydrate (RAC) vs. slowly absorbed carbohydrate (SAC), controlled for confounding dietary factors, causes NAFLD in mice with similar body weight. An animal model was chosen because of logistical and ethical challenges to conducting this study in humans.

RESEARCH METHODS AND PROCEDURES: Male 129SvPas mice were fed diets high in either RAC (amylopectin; high glycemic index) or SAC (amylose; low glycemic index) for 25 weeks. Diets were controlled for macronutrient and micronutrient content, differing only in starch type. Body weight and composition were measured throughout the study. Hepatic and plasma triacylglycerol concentrations were quantified at the end of the study.

RESULTS: Body weight was not significantly different between the two groups. However, total body adiposity increased twice as much, in absolute terms, in the mice fed RAC vs. SAC (12.2 +/- 2.9% vs. 6.1 +/- 4.2%, p < 0.0001). Hepatic triacylglycerol content was 2-fold greater in the RAC group (20.7 +/- 9.4 vs. 9.6 +/- 4.9 mg/g, p = 0.01). In addition, plasma insulin and triacylglycerol concentrations were higher in the RAC group.

DISCUSSION: A diet high in RAC causes accumulation of fat in liver, adipose tissue, and plasma in mice. Therefore, a low glycemic index diet may help prevent or treat NAFLD in humans.

From press release:

Diets rich in rapidly-digested carbohydrates not only expand waistlines, but may also cause fatty liver, a condition that can lead to liver failure and death, finds a new study in mice.

If confirmed in humans, the findings suggest that fatty liver disease -- on the upsurge among Americans as a byproduct of the obesity epidemic -- may be preventable and possibly treatable through dietary changes.

The researchers, led by David Ludwig, MD, PhD, director of the Optimal Weight for Life program at Children's Hospital Boston, fed mice either a high- or a low-glycemic index diet. High-glycemic index foods, including white bread, white rice, most prepared breakfast cereals and concentrated sugar, raise blood sugar quickly. Low-glycemic index foods, like most vegetables, fruits, beans and unprocessed grains, raise blood sugar slowly.

On the high-glycemic index diet, mice ate a type of cornstarch that is digested quickly whereas on the low-glycemic index diet, mice ate a type of cornstarch that is digested slowly. The diets had equal amounts of total calories, fat, protein, and carbohydrate, and the mice were otherwise treated identically.

After six months, the mice weighed the same. However, mice on the low-glycemic index diet were lean, with normal amounts of fat in throughout their bodies. Mice on the high-glycemic index diet had twice the normal amount of fat in their bodies, blood and livers.

When sugar melts out of high-glycemic index food, Ludwig explains, it drives up production of insulin, which tells the body to make and store fat. Nowhere is this message felt more strongly than in the liver, because the pancreas, which makes insulin, dumps the hormone directly into the liver, where concentrations can be many times higher than in the rest of the body. Fat buildup in the liver, or fatty liver, is usually symptomless, but it increases the risk for liver inflammation, which can progress to hepatitis and, in some cases, liver failure.

Fatty liver is becoming more common in Americans, especially in children, says Ludwig. Many cases in adults can be explained by alcoholism, but not the pediatric cases. Where just one case of fatty liver was reported in children in 1980, now between 1 in 4 and 1 in 2 overweight American children are estimated to have the condition. As these millions of children age, some will progress to full-blown liver disease.

"This is a silent but dangerous epidemic," says Ludwig. "Just as type 2 diabetes exploded into our consciousness in the 1990s, so we think fatty liver will in the coming decade."

A previous study found that Italians who ate higher-glycemic index diets had fattier livers, but the study wasn't tightly controlled. The new study makes clear that the type of carbohydrate can cause fatty liver in animals, independent of other elements of diet or lifestyle.

"Our experiment creates a very strong argument that a high-glycemic index diet causes, and a low-glycemic index diet prevents, fatty liver in humans," says Ludwig.

Ludwig and colleagues now hope to confirm this in a just-launched clinical trial -- and to show that a low-glycemic index diet can reverse fatty liver in overweight children. The children, aged 8 to 17, will be randomized to either the low-glycemic diet or a low-fat diet.

Low-fat diets are currently the standard treatment, Ludwig says, but many children with fatty liver don't respond to them. "We think it is a misconception that the fat you're eating goes into the liver," he says.

Ludwig hypothesizes that obesity, sedentary lifestyles and increased consumption of refined carbohydrates are "synergistically" fueling a fatty liver epidemic in children. Ironically, low-fat diets have only made matters worse, replacing fat with sugar or starchy foods that actually increase fat deposition in the body.

"Two low-fat Twinkies, billed as a health food, contain the same amount of sugar as an oral glucose tolerance test -- a test used to determine how much sugar someone can digest," Ludwig says. He notes that the French delicacy pate de fois gras -- the fatty liver of a duck or goose -- is produced by over-feeding the animals with high-glycemic index grains.