The effect of lipid lowering by Acipimox on cardiac and skeletal muscle mitochondrial function.

Accumulation of lipid in skeletal and cardiac muscle has been associated with
insulin resistance and cardiomyopathy. In skeletal muscle lipotoxicity has been
suggested to lead to mitochondrial dysfunction. It remains unknown whether
lipotoxicity leads to cardiac mitochondrial dysfunction and due to this also
leads to cardiomyopathy. Although it has been shown that antilipolytic agents
can improve insulin sensitivity, the effect of lowering free fatty acids on
cardiac and skeletal muscle mitochondrial function remains unknown.

The major research objective is to investigate 1) whether lowering cardiac and
muscular lipid content will improve mitochondrial and cellular function in type
2 diabetic patients, and 2) whether this lipid lowering effect also improves
uncoupling in these subjects and leads to a lowering of ROS production.

Type 2 diabetic patients and their BMI-matched controls will be included in a
randomised and blinded cross-over design. Both groups will perform basaline
measurements to compare characteristics. Afterwards, only the type 2 diabetic
patients will will receive a lipid lowering agent (Acipimox) or placebo for 2
weeks in random order. During these treatments, diabetes medication will be
stopped. Baseline measurements will be performed prior to the study and after
each treatment to asses cardiac and muscular lipid accumulation, cardiac
function, mitochondrial function and insulin sensitivity.

Diabetic ubjects will receive Acipimox or a placebo in random order. Acipimox
is a commercially available and registrated drug, that lowers free fatty acids
by inhibiting hormone sensitive lipase in the peripheral adipose tissue. No
serious side-effects are known other than rare anaphylactic reactions.

Before the start of the study subjects will be screened to access eligibility
(visit duration: 30 min). Subsequently both groups will receive their baseline
measurements, for which they have to visit the University twice. Then the
diabetic subjects will receive randomized treatments and will receive the
baseline measurements twice more. The diabetic subjects will eventually visit
the department 7 times (screening and day -2/-1/14/15/56/57) during the 9-weeks
study period. The control subjects only visit the University 3 times
(screening/-2/-1) in a 2 week period. During these visits three
hyperinsulinemic-euglycemic clamps, including 1 muscle biopsy during each
clamp, will be performed and 6 MRS-sessions will take place.