Effect of Acute Fructose Load in Human
Condition: Chronic Kidney Diseases; Diabetes Mellitus, Type 2
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Diabetes Mellitus, Type 2
Study type: Interventional

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.
    

Intervention name(s): Blueberry drink; Blueberry and pizza; Soft beverage; Soft beverage and pizza; Fructose; Fructose and pizza
Intervention type(s): Other; Other; Other; Other; Other; Other
Intervention description(s): Participant receive blueberry drink; Participant receive blueberry drink and a slice of pizza; Participant receive a soft beverage drink; Participant receive a soft beverage drink and a slice of pizza; Participant receive a drink containing fructose; Participant receive a fructose drink and a slice of pizza
Allocation: Randomized
Intervention model: Crossover Assignment
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
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Fructose; Uric acid; Oxidised LDL; Interleukin 6