The Effect of Acute Fructose Load in Patients With Chronic Kidney Disease and Patients With Type 2 Diabetes Compared to Healthy Subjects

Fructose is a monosaccharide present naturally in foods as fruit, vegetables and honey. In fruit, vegetables and table sugar it is also present as a disaccharide (sucrose), where it is joined with glucose. The intake of fructose has increased dramatically in the last decades. The increase is attributed to the use of free fructose as a sweetener at higher concentrations than naturally occurring in food, where beverages as soft-drinks seem to be the largest contributor to present consumption. Fructose has a low glycemic index and thus helps maintain glycemic control, a property that led to the belief that it was beneficial as a sweetener for those with diabetes.

The body's capacity of absorbing fructose is limited and varies depending on age, health and co-ingested foods. Glucose is the dietary factor that has largest impact on fructose absorption, but animal studies also indicate that saturated fat increase absorption. It has been observed that the maximum fructose absorbing capacity varies between 5 and 50 g when consumed as a single dose. Individuals with type 2 diabetes seems to have a larger capacity to absorb fructose and they have higher levels of fructose in serum and urine when compared to those without diabetes.

Fructose is absorbed in the small intestine by the fructose specific transporter GLUT5. It is further transported to the liver through the portal vein, where it is absorbed and metabolized by liver cells. The metabolism of fructose is independent of insulin. Although some fructose is metabolized by the enterocytes in the small intestine, the liver metabolize the majority of ingested fructose, in comparison to about 15-30% of ingested glucose. The metabolism of fructose differs from glucose in the sense that it is less controlled. While glucose metabolism is regulated by the energy status of the cell and portal glucose concentrations, fructose metabolism lacks control mechanisms leading to different metabolic products and effects.

In the metabolic pathway fructose can be oxidized, converted to glucose or lactic acid, or enter de novo lipogenesis. In the first hepatic metabolic step fructose is phosphorylated by fructokinase, a fructose specific enzyme with high activity, to fructose-1-phosphate. Fructokinase is not regulated by the energy status (ATP) of the cell, and fructose will therefore be metabolized in an unlimited way. This is in contrast to steps in the glycolysis where phosphofructokinase is regulated by ATP. Due to the rapid phosphorylation of fructose, levels of ATP will be depleted followed by an increase in uric acid. An increase in reactive oxygen species will follow the formation of uric acid which may lead to inflammation in the endothelium and inflammatory activity in adipocytes. Animal models show that uric acid may also act directly on tubular cells in the kidney where it causes inflammation. Serum uric acid levels are moreover positively associated with renin activity and hypertension. Further, as fructose is metabolized in a less controlled way than glucose, a larger proportion of fructose is available for de novo lipogenesis (DNL). This may be due to that the capacity of the mitochondria is exceeded and acetyl-Coenzyme A will enter DNL instead of the citric acid cycle. This metabolic effect of glucose is considered as "particularly harmful". Whether glucose is co-ingested with fructose or not may have an impact on the metabolic effects as there will be an effect of secreted insulin. Insulin decreases production of glucose from fructose and stimulates the de novo lipogenesis pathway.

The increase in fructose consumption correlates closely with the rise in obesity, metabolic syndrome and diabetes. Long term consumption of fructose has been shown to cause increased uric acid in the body. Elevated serum uric acid levels are associated with risk of chronic kidney disease both among healthy subject and among those with diabetes. Among those with type 2 diabetes it has also been associated with progression of already established nephropathy.