Sugar, Uric Acid, and the Etiology of Diabetes and Obesity

Richard J. Johnson; Takahiko Nakagawa; L. Gabriela Sanchez-Lozada; Mohamed Shafiu; Shikha Sundaram; Myphuong Le; Takuji Ishimoto; Yuri Y. Sautin; Miguel A. Lanaspa


Diabetes. 2013;62(10):3307-3315. 

In This Article

Evidence That Fructose Mediates Fatty Liver and Insulin Resistance in Humans

The major source of fructose in the Western diet is from soft drinks and fruit drinks, and this accounts for approximately 7% of caloric intake in the adult, and upward to 15% of total caloric intake in adolescents. Intake of sugar and soft drinks are higher in populations at increased risk for insulin resistance and diabetes, including the African Americans, Hispanics, Native Americans, and subjects with lower income. A meta-analysis concluded that the intake of sugary soft drinks is an independent predictor for the development of metabolic syndrome and/or diabetes.[55] Genetic factors enhance the risk for developing diabetes from soft drinks.[56]

Clinical studies have documented the metabolic effects of fructose. Studies from the 1960s through the 1980s showed that sucrose, or fructose, can worsen hypertriglyceridemia and insulin resistance, especially if subjects were hyperinsulinemic.[57,58] More recently Stanhope et al.[59] fed 25% of diet as fructose or glucose to overweight individuals for 10 weeks. Although some features of metabolic syndrome were induced with glucose, the fructose-fed subjects showed worse postprandial hypertriglyceridemia, increased hepatic de novo synthesis of fatty acids, a decrease in insulin sensitivity (noted by elevations in fasting glucose and insulin levels), increased total and visceral fat (among men), higher 24-h uric acid levels, increased systemic inflammatory mediators (MCP-1), and lower resting energy expenditure.[12,59,60] In another study, Maersk et al.[61] randomized overweight adults to drink 1 L of a sugary soft drink daily for 6 months, with control subjects receiving equivalent amount of diet soft drink, milk, or water. At the end of 6 months, the subjects receiving the sugary soft drinks displayed more visceral, skeletal muscle, and liver fat and higher serum triglycerides and cholesterol compared with the group drinking milk, with a trend toward significance in the other two groups. Tappy and colleagues[62] have also shown the ability of fructose to induce insulin resistance, hepatic lipid accumulation, and hypertriglyceridemia. Similarly, our group administered 200 g fructose to overweight men for 2 weeks and documented higher blood pressure, higher triglycerides, and lower HDL cholesterol compared with baseline, with 25% of the subjects developing de novo metabolic syndrome at 2 weeks.[63] Another study showed that the administration of one 8-oz soft drink per day to adolescents results in increased body weight at 18 months compared with subjects given diet soft drinks.[64]

Intervention studies have also been performed to evaluate the effect of reducing sugar intake on metabolic syndrome. For example, the Atkins diet and other low carbohydrate diets tend to improve features of the metabolic syndrome more than typical low fat diets.[65] A randomized study in school children reported that reducing soft drink intake, resulting in a difference of 175 mL/day between treatment and control subjects, led to a reduction in overweight or obesity by 0.2% in the treated group compared with a 7.5% increase in the control subjects at 12 months.[66] A study in California showed that the banning of soft drinks in schools resulted in a reduction in overall soft drink intake with a decrease in obesity in children 6 to 11 years of age.[67] Less effect was observed in older children, possibly because the overall reduction in soft drink intake in this latter group was less effective.[67] Soft drink intake in the U.S. has decreased since peaking in 1999, and this is also associated with a leveling of the rates of obesity.