Acylcarnitine and insulin resistance: does y-butyrobetaine enhance fatty acid oxidation and influence acylcarnitine profiles?

The Western lifestyle and concurrent obesity are the main causes of the
strongly increasing incidence of type 2 Diabetes Mellitus, a condition
characterized mainly by decreased insulin sensitivity of liver and skeletal
muscle. It is suggested that insulin sensitivity is caused by disturbed fatty
acid oxidation (FAO) due to high lipid burden in obese humans, a concept known
as lipotoxicity.
In order to be oxidized, fatty acids need carnitine to pass the mitochondrial
membrane. Together they form acylcarnitines, which are transported from the
cytosol into the mitochondrion for further oxidation. Several relations between
insulin resistance and acylcarnitines are studied and described. For example,
acylcarnitines correlate negatively with insulin sensitivity. It is
hypothesized that relative carnitine deficiency might contribute to
mitochondrial dysfunction and obesity-related impairments in glucose tolerance.
Indeed, insulin dependent type 2 diabetes mellitus patients have lower (~25%)
carnitine concentrations. Although it is currently unclear whether insulin
resistance impairs FAO or impaired FAO contributes to insulin resistance, it is
possible that carnitine supplementation improves insulin sensitivity and
decreases lipid deposition in liver and muscle tissue. Supplementation with
oral carnitine is probably of limited effectiveness, as carnitine uptake in the
liver is low due to the low expression of the carnitine transporter OCTN2 in
liver. In contrast, y-butyrobetaine is taken up very easily in liver and almost
directly converted to carnitine, and administration of y-butyrobetaine
significantly increases tissue carnitine concentrations. We hypothesize that
enhancing the FAO rate by administering the carnitine precursor
y-butyrobetaine, might decrease fat content in liver and subsequently improve
hepatic insulin sensitivity. Additionally this could improve insulin
sensitivity in muscle tissue as well.

Primary: In this pilot study, we want to investigate the effect of
y-butyrobetaine on free carnitine levels and acylcarnitine profiles in lean and
obese subjects after oral administration of y-butyrobetaine.
Secondary: to examine if FAO is enhanced by administration of y-butyrobetaine,
and if this increased FAO rate leads to changes in insulin sensitivity.

STUDYDAY 1
Before y-butyrobetaine administration starts, subjects will be fasted
overnight, an REE will be performed in order to measure the contribution of
fatty acid oxidation to total energy expenditure, and blood will be drawn (to
measure y-butyrobetaine and free carnitine levels, acylcarnitine profiles,
lipid profiles and glucose level). Then subjects will be asked to take
37.5mg/kg y-butyrobetaine.

STUDYDAY 2 to 14
On day 2 to 14, volunteers are asked to take one daily dose of y-butyrobetaine.
On day 2,3 and 8, the volunteers come to the AMC in a sober state for blood
withdrawal.

STUDYDAY 15
On day 14 another overnight fast is performed, followed again by an REE and
blood withdrawal on day 15.

Administration of an oral dose of the nutritional supplement y-butyrobetaine,
for 14 days on a daily basis.

We believe that the risks and burden for the participants of the REE, blood
withdrawal and y-butyrobetaine administration are minimal.