From “Sugar, Uric Acid, and the Etiology of Diabetes and Obesity”: Fig. 3, Uric acid: potential mechanisms for insulin resistance and diabetes.
Richard Johnson et al. review multiple mechanisms by which fructose may uniquely drive progression of diabetes and obesity; that is, several reasons sugar consumption may lead to metabolic damage rather than merely providing “empty calories.” Many of these effects are tied to the fact that fructose (unlike glucose) is directly metabolized in the liver, both increasing liver fat and driving production of uric acid.
The potential mechanisms include: (1) Fructose, through its effects on the liver, may suppress appetite less than other carbohydrates or even stimulate it; (2) Fructose leads to insulin resistance by driving liver fat accumulation and mitochondrial oxidative stress; (3) Fructose inhibits nitric oxide release through its effects on uric acid, preventing glucose uptake by skeletal muscle and so dampening insulin’s ability to moderate blood sugar.
Clinical studies have shown fructose intake leads to features of metabolic syndrome including hypertriglyceridemia, decreased insulin sensitivity, and liver fat accumulation. Uric acid plays a role in at least some of these mechanisms and so could be an intermediary in the harmful effects of fructose on metabolism.
The authors summarize contrary evidence, noting in particular that studies testing pure fructose are clinically irrelevant (as we rarely eat fructose without glucose), and that the negative impact of fructose may not be visible in short-term studies. They nonetheless conclude there is growing evidence for fructose playing a role in the development of metabolic syndrome, as well as fatty liver disease, diabetes, high blood pressure, and obesity.
References
1. Johnson RJ, Nakagawa T, Sanchez-Lozada LG et al. Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes 62(10): 3307-3315, 2013.
Comments on Sugar, Uric Acid, and the Etiology of Diabetes and Obesity
Additional reading on fructose and uric acid from the late physician and friend of CrossFit, Dr. Chris King, whose research focused on Maori and Pacific rates of diseases such as type 2 diabetes and obesity (as related to the rise of fructose in native diets due to European/Western influence):
https://drive.google.com/file/d/1iC_Qtiy3B-SlRT3L6VWBcBh59ZQrLYqX
More on King’s research:
https://www.radionz.co.nz/national/programmes/nz-society/audio/201806481/pacific-kryptonite
To look a bit further into a couple of King’s citations…
Uric Acid Induces Hepatic Steatosis by Generation of Mitochondrial Oxidative Stress
https://www.ncbi.nlm.nih.gov/pubmed/23035112
A key metabolic consequence of fructose is its unique ability to stimulate triglyceride production - more technically, to induce de novo lipogenesis (DNL), or fatty acid synthesis within the liver. DNL is important because increased DNL can lead to increased fat storage in the liver, and a fatty liver is both associated with metabolic syndrome and likely plays a causal role in its progression. In this mechanistic trial, researchers found triglyceride production within liver cells was correlated with uric acid exposure, and that uric acid exposure induced mitochondrial oxidative stress. Taken together, these are provided as evidence that uric acid mediates the effect of fructose on triglyceride accumulation, and thus that fructose induces triglyceride production and accumulation by two pathways - directly via fructose-1-phosphate and indirectly via uric acid.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504786/bin/zbc0501230910009.jpg
As a mechanistic study, these results can only be extrapolated to any real-world phenomena with great caution. However, the possible existence of multiple mechanisms by which fructose can induce triglyceride production lends support to other forms of data (including observational evidence) suggesting fructose and/or fructose-containing sugars may drive fatty liver disease and the other metabolic conditions that follow from it.
Uric Acid - Key Ingredient in the Recipe for Cardiorenal Metabolic Syndrome
https://www.ncbi.nlm.nih.gov/pubmed/24454316
This paper summarizes the theoretical role of uric acid in cardiorenal metabolic syndrome (defined here as “a constellation of interactive cardiovascular disease and chronic kidney disease risk factors comprising obesity, insulin resistance, metabolic dyslipidemia, hypertension, cardiac diastolic dysfunction and renal abnormalities” - and so, the role fructose may play in the same by elevating serum uric acid levels. Elevated uric acid levels, they argue, are at least associated with and may directly cause adipose tissue dysfunction, endothelial dysfunction including vascular stiffness, oxidative stress, inflammation, and damage to the heart and kidneys.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3884201/figure/F1/?report=objectonly
Thanks for the additional material
Sugar, Uric Acid, and the Etiology of Diabetes and Obesity
3