Clinical trial NCT03157960: Effect of Acute Fructose Load in Human
Official title: The Effect of Acute Fructose Load in Patients With Chronic Kidney Disease and Patients With Type 2 Diabetes Compared to Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Chronic Kidney Diseases
Diabetes Mellitus, Type 2
Keywords: Fructose
Uric acid
Oxidised LDL
Interleukin 6
Lead sponsor: Karolinska University Hospital
Sponsor class: OTHER
First posted: 2017-05-17
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Interventional study. Participant will on sex different occasions receive drinks containing fructose (fructose drink, coca-cola or blueberry drink) with and without the addition of a high-fat meal
Primary purpose: BASIC_SCIENCE

Brief summary: The metabolism of the monosaccharide fructose is less controlled than the metabolism of glucose, which will result in the metabolic product uric acid. Elevated serum uric acid levels are associated with increased risk, or worsening, of chronic kidney disease. The mechanisms by which uric acid have detrimental effects are not well defined, but may include an increase in reactive oxygen species and subsequent inflammatory activity. The aim of this study is to investigate the effects of uric acid, markers of oxidative stress and markers of inflammation following a low fructose load reflecting normal conditions. This is an interventional study. On six different occasions patients with chronic kidney disease, patients with type 2 diabetes and healthy controls will receive Blueberry drink, Coca-Cola or pure Fructose drink with similar amount of carbohydrates (140 kcal) with and without a high fat meal represented by a pizza (425 kcal).Serum samples and urinary samples will be collected.

Detailed description: 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.

It is estimated that 7.3 % of the adult population in Sweden is affected by diabetes and that the majority, 85 -90 %, constitutes of type 2 diabetes (T2D). T2D is considered to be one of the most common chronic diseases and the prevalence is expected to rise, and with that an increasing health and economic burden. Worldwide patterns indicate a growing burden as well, particularly in developing countries. T2D is a disease with multifactorial etiology and with complications such as cardiovascular and renal disease, blindness and amputation. Not only does diabetes affect quality of life, it also leads to premature death as life expectancy is reduced with as much as 15 years.

Diabetic nephropathy (DN) has become the most common cause of end-stage renal disease and the earliest sign of DN is presence of microalbuminuria. Further development of macroalbuminuria and a decline in glomerular filtration rate may follow. Among type 2 diabetics in Sweden it was observed that 20% developed albuminuria over the course of 5 years, and 11% developed renal impairment glomerular filtration rate (eGFR of \< 60 mL/min/1.73m2, MDRD formula). Studies indicate that increased oxidative stress through different pathways may play a central role in the development of DN, and chronic hyperglycemia is the primary cause. But there are also other factors that increase oxidative stress and have an impact on development of renal disease, as for example free fatty acids and inflammation. The oxidative stress may cause damage to the renal milieu, as dysfunction of the endothelial cells within glomeruli and tissue injury of the tubule.

Factors related to disease management, as glycemic-, blood pressure- and lipid-control are important in protecting the kidney. Further, smoking cessation, energy balance for a healthy bodyweight and a healthy eating pattern are of importance. In regards of dietary composition, hyperglycemia and dyslipidemia is determined by the amount and quality of ingested carbohydrates and dietary fats. It has been suggested that postprandial hyperglycemia and hypertriglyceridemia triggers oxidative stress and causes inflammation, metabolic alterations associated with endothelial dysfunction. A prospective cohort conducted in 10 European countries, including Sweden (Malmö and Umeå) showed a protective effect of intake of vegetables, fruit and legumes against all-cause and cardiovascular mortality among those with diabetes. Possible mechanism is hypothesized to be attributed to the antioxidative properties. The anti-antioxidant and anti-inflammatory capacities of fruit and vegetables are mentioned as possible mechanisms.

Current Swedish dietary recommendation for diabetic's state that different diets as the Mediterranean and low carbohydrate diet etc. may be beneficial, while the scientific evidence for extremely low carbohydrate diet is yet too weak. They further state that single foods as fruit lower all-cause mortality and vegetables lowers the risk of cardiovascular mortality. Fructose is not discussed in the Swedish dietary recommendations. The American Diabetes Associations dietary recommendations do, however, state that fructose-containing beverages should be avoided due to its impact on metabolic profile.

The scientific evidence for the significance of diet on microvascular complications as kidney disease is scarce and there is a lack of studies on the effect of fruit and vegetables on diabetic nephropathy. This was also stated by Swedish Council on Health Technology Assessment (SBU) in a report published in 2010. SBU further emphasized the lack of dietary studies applicable to conditions in Sweden. Thus, considering the burden of type 2 diabetes and its related complications, the need for proposed studies is substantiate.

The overall aim of this study is to investigate the acute postprandial responses in uric acid, markers of oxidative stress and marker of inflammation after low fructose load with and without a high fat meal among patients with chronic kidney disease (CKD) and patients with type 2 diabetes (T2DM) with and without CKD compared to healthy controls (HC).

Patients with type 2 diabetes, patients with chronic kidney disease (CKD) and GFR \<30 ml/min or dialysis, patients with type 2 diabetes and CKD and control subjects (n= 30 in each group) will be included. Participant will on sex different occasions receive drinks containing fructose with and without the addition of a high-fat meal. After including 8 patients with CKD, 8 patients with T2DM and 8 controls, the preliminary results will be presented.

Eligibility criteria: Inclusion Criteria:

* GFR \<30 ml/min or \>3 months of dialysis for patients with CKD
* Patients with type 2 diabetes with and without CKD
* Controls without diabetes type 2 or CKD

Exclusion Criteria:

* HbA1c \> 100 mmol/mol.
* Signs of fluid overload
* Inability to understand the information provided for the study.
* Ongoing inflammatory disease or infection,
* Treatment with allopurinol or other uric acid lowering agents a

Primary outcomes:
measure: Changes in uric acid (µmol/L)
timeFrame: 2 hours for only drink and 4 hours for drink and a high fat meal
Secondary outcomes:
Other outcomes:
Locations:
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
Study officials:
affiliation: Karolinska University Hospital
name: Peter Stenvinkel, professor
role: STUDY_DIRECTOR
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