Comparing the effect of a high SFA diet and high fructose diet on hepatic insulin sensitivity

The liver is an important organ in our body and, among other things, plays an
important role in fat and sugar metabolism in the body. A disturbance of fat
and sugar metabolism in the liver leads to accumulation of fat in the liver and
lowers insulin sensitivity. The more sensitive the body is to insulin, the
better it can regulate blood sugar. Thus, low insulin sensitivity results in
poorer blood sugar regulation. However, little is known about how accumulation
of fat in the liver contributes to poorer insulin sensitivity in humans.

Previous research conducted by us has shown that specifically the accumulation
of saturated fat in the liver is associated with poorer insulin sensitivity. In
addition, we know that the production of new fats in the liver from sugars
specifically increases saturated fat in the liver. This fat production in the
liver is additionally associated with poorer insulin sensitivity. Until now it
is unknown whether the saturated fat in the liver or specifically the process
of new fat production (de novo lipogenesis) is the main culprit for insulin
sensitivity. We want to investigate this by using two different diets.

Diet can influence the new production of fat from sugars and the amount of
saturated fat in the liver. A diet high in saturated fat can directly increase
the amount of saturated fat in the liver. Examples of products with relatively
high saturated fat are: meatballs, steak, snacks, butter, full-fat cheese,
butter cookies, milk chocolate. A diet high in fructose increases the process
of production of new (saturated) fats in the liver. Thus, this diet may
indirectly increase saturated fat in the liver and decrease insulin
sensitivity. It is possible that there are other negative effects of the
production of newly synthesized fat on insulin sensitivity. Examples of
products relatively high in fructose are: Fruit juices, soft drinks, candy,
jam, syrup, sweetened breakfast cereals.

Primairy objective:
To determine the effect of a 4-week high SFA diet compared to a 4-week high
fructose diet on hepatic insulin sensitivity (determined by insulin-stimulated
suppression of endogenous glucose production).

Secondary objectives:
- To determine the effect of a 4-week high SFA diet compared to a 4-week high
fructose diet on hepatic saturated fatty acid fraction
- To determine the effect of a 4-week high SFA diet compared to a 4-week high
fructose diet on de novo lipogenesis

Exploratory objective:
- To determine the effect of a 4-week high SFA diet compared to a 4-week high
fructose diet on sleeping metabolic rate (SMR) and nocturnal substrate
metabolism (RER, fat and carbohydrate oxidation).

This is a randomized intervention study comparing the effects of a 4-week high
SFA diet compared to a 4-week high fructose diet on hepatic insulin sensitivity
in 14 overweight/obese males and females.
Volunteers who are included will visit the University for 14 visits:
- one general screening visit incl. MRI scan,
- for each of the two study periods four short visits to determine body weight
and discuss dietary compliance.
- For each of the two periods an MRI scan at the beginning and at the end
during which liver fat composition and content are measured.
- For each of the two periods, an overnight visit where de novo lipogenesis and
nocturnal substrate oxidation are measured.
- for each of the two periods a 24-hour visit during which insulin sensitivity
is measured
- one follow-up visit 4 weeks after the end of the last diet.
The 4-week SFA diet and the 4-week fructose diet will be followed randomly,
alternating with (at least) a 6-week wash-out period.

Participants follow a 4-week high SFA diet and a 4-week high fructose diet.
Examples of products included in the high SFA diet include: Red meat, mature
48+ cheese, butter, all-butter biscuits, full-fat dairy products, milk
chocolate. Examples of products included in the high fructose diet include:
Fruit juices, soda drinks, candy, jam, syrup, sweetened cereals, cookies.
The saturated fat diet will be high in fats (40-50 En% vs. 20-30 En% in the
fructose diet) and will consist of about 20En% saturated fat (vs. 5En% in the
fructose diet). The fructose diet will be high in carbohydrates (60-70 En% vs.
35-45 En% in the SFA diet) and will consist of about 20En% fructose (vs. 5En%
in the SFA diet).

The risks of the performed measurements and the physical discomfort are low;
risks related to the measurements are low because of clear exclusion criteria
aimed at reducing risks and the well-experienced researchers performing these
tests and isotopically-labelled water ingestion is entirely safe and non-toxic
with body water enrichment up to 20 mol%. The prescribed diets will consist of
only commercially available food products and the intake of these products is
therefore considered safe. Furthermore, the effects of the diet in humans are
quickly reversible and after the subjects have completed the two diets, they
will receive tips and recipes to return to a healthier diet. After two weeks,
they will be contacted by phone to discuss progress and after 4 weeks, a final
visit will take place to check that blood values are within normal ranges,
weight has not increased and subjects adhere to a healthier diet. In the case
of a persistent unhealthy diet, we will discuss other support options with the
participant