Primary Care Corner with Geoffrey Modest MD: Fructose Restriction and Cardiometabolic and Weight Improvement

By Dr. Geoffrey Modest

There are several epidemiologic studies suggesting that fructose plays a role in the development of metabolic syndrome, as well as non-alcoholic fatty liver disease, type 2 diabetes, and cardiovascular disease. A small study just came out assessing 43 children with obesity and metabolic syndrome who were put on a 9 day fructose-restricted diet and then evaluated several metabolic parameters (see  doi:10.1002/oby.21371). This diet attempted to match each participant’s prior macronutrient intake profile


  • 27 Latino and 16 African-American children with obesity and metabolic syndrome (mean age 13.3, weight 93 kg, BMI 35.6)
  • A child-friendly diet: various no- or lower-sugar added processed foods including turkey hot dogs, pizza, bean burritos, baked potato chips, and popcorn


  • Mean caloric intake was 29 kcal/kg: 51% carbs, 16% protein, 33% fat (16% saturated, 9% polyunsat, 13% monounsat), which represents a change of: carbs decreased 4%, protein increased 2% and no change in fat consumption. Within the carbs ingested: dietary sugar decreased from 27.7 to 10.2% and fructose from 11.7 to 3.8%, with increase in dietary fiber
  • ​Despite efforts to maintain body weight, there was a 0.9 kg loss over the 10 days (33 reported they were unable to consume all the food provided…), with predominant weight loss in first 4 days (?water weight?)
  • Systolic BP did not change, but diastolic decreased 4.9 mmHg
  • ​Uric acid increased by 17.8 mmol/L, or 0.3 mg/dl (??, see below)
  • Fasting glucose decreased by 0.3 mmol/L (5 mg/dL), glucose area-under-the-curve decreased by 7.3%, fasting insulin decreased by 53%, and HOMA-IR, a measure of insulin resistance, decreased by 58%
  • Fasting triglycerides decreased by 46%, LDL by 12.5% and HDL by 20%
  • ALT declined nonsignificantly from 28.9 to 26.7 U/L, though AST significantly decreased from 27.4 to 23.8 U/L
  • Analysis restricted to those who did not lose weight did not materially change the above.

Fructose is a sugar with pretty different metabolism and effects: it is metabolized almost exclusively by the liver; it is a substrate for de novo lipogenesis and increased triglycerides; it leads to nonenzymatic fructation and reactive oxygen species causing cellular dysfunction; it does not suppress the hunger hormone ghrelin leading to excessive consumption, does not stimulate insulin release, unlike other sugars, thereby leading to insufficient plasma leptin levels and also to less satiety,and it stimulates the nucleus accumbens leading to increased reward and continued eating (so, there are several ways that consuming fructose does not decrease hunger, and perhaps this explains why so many of these kids were unable to eat all of their prepared food when on the fructose-restricted diet!!). There are also changes in the gut microbiome from fructose, perhaps related to the fact that it is one of the most poorly absorbed short-chain carbohydrates (for a more detailed assessment of the physiologic effects of fructose, see  Obesity Reviews 2012; 13: 799)

One unusual finding was that the changes from the fructose-restricted diet seemed to increase serum uric acid levels. This is a bit contrary to the typical physiologic finding of increased uric acid levels through up-regulated hepatic signal transduction pathways (see JAMA. 2013; 310(1):33), and to the finding of increased gout in the observational Nurses’ Health Study associated with higher fructose ingestion (see JAMA 2010; 304(20): 2270)

So, pretty impressive results in a short-term study, just by changing carbohydrate composition and without significant weight loss (the weight loss that occurred was likely water weight, given the rapidity of weight loss; and, both mathematical modeling controlling for weight and by looking exclusively at those who did not lose weight did not show significant directional differences in the outcomes measured). In particular, even short-term fructose restriction was associated with very impressive changes in markers of insulin resistance (fasting insulin levels and HOMA-IR). This study therefore adds support to strongly encouraging decreasing fructose consumption, the vast majority of which in Western diets is from high-fructose corn syrup and not free fructose from natural foods.

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