Hepatic insulin resistance and Dopaminergic dysfunction in a Ultra High Risk (UHR) population for Schizophrenia

(page 2-4 of the protocol)
The lack of firm knowledge of disease pathology impedes the development of
rational and novel therapeutic strategies in schizophrenia. However, there are
several data indicating that dopaminergic dysfunction in the central nervous
system is involved in the pathogenesis of schizophrenia.
Numerous reports have pointed to a possible relationship between diabetes and
schizophrenia. Since psychotropic medication may affect body composition and
glucose metabolism, direct metabolic squeal of the disease process per se on
whole body glucose and lipid metabolism is difficult to establish in studies
were non drug naïve patients are included. Recently, we have shown that drug
naïve, first episode schizophrenic patients display hepatic insulin resistance
as compared to matched controls. This finding could not be attributed to
differences in intra abdominal fat mass or other known factors associated with
hepatic insulin resistance, suggesting a direct link between schizophrenia and
hepatic insulin resistance.
Intriguing animal studies suggest a key role for pre-autonomic neurons in the
hypothalamus in the regulation of hepatic glucose production and hepatic
insulin sensitivity through sympathetic as well as parasympathetic outflow via
the brain stem nuclei to the liver. This may be an indication of the
hypothalamic involvement of hepatic insulin resistance as found in
schizophrenic patients.
Based on the above we hypothesize that dopaminergic deregulations in
schizophrenia that may be responsible for positive and negative symptoms may
also be responsible for the induction of hepatic insulin resistance.

1)To determine whether subjects at ultra high risk to develop schizophrenia
display hepatic insulin resistance as compared to healthy controls matched for
age, sex, BMI, ethnicity, visceral and subcutaneous fat mass.

2)To determine whether dopaminergic dysregulation is associated with the
occurrence of hepatic insulin resistance.

The hepatic insuline resistance will be analyised in a group of UHR subjects
and healthy controls, by means of a hyperinsulinemic euglycemic clamp. UHR
subjects who develope psychosis and are still antipsychotic naïve will be asked
to participate for a second time.

n.a.

Stabile isotopes are not radioactiev and are therefor harmless.
Patients will be in hospital for about 7 hours.